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Kattna A, Singh L. Genistein as a renoprotective agent: mechanistic insights into antioxidant, anti-inflammatory, and fibrosis-regulating pathways. Mol Biol Rep 2025; 52:500. [PMID: 40411620 DOI: 10.1007/s11033-025-10603-2] [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: 03/22/2025] [Accepted: 05/12/2025] [Indexed: 05/26/2025]
Abstract
Kidney diseases refer to a group of disorders that affect the structure and function of the kidneys, impairing their ability to filter waste products, excess fluids, and toxins from the blood. These diseases can be acute and chronic, and if left untreated, can lead to kidney failure. Their progression is closely associated with inflammation and oxidative stress. Key signaling cascades, such as TLR-4/MAPK and TLR-4/NF-κB, are instrumental in fostering renal inflammation. Excessive ROS production worsens kidney damage, whereas activation of the Nrf-2/ARE pathway mitigates this by enhancing antioxidant defense. Moreover, the TGF-β/Smad pathway is heavily implicated in driving renal fibrosis, a major factor in disease progression. Additionally, elevated uric acid levels exacerbate inflammatory signaling, thereby worsening renal injury and dysfunction. Current treatments for kidney diseases have several concerns, including the need for routine monitoring, side effects, and long-term regimens. Several natural compounds have shown promise in supporting kidney health by modulating these key molecular targets. Genistein is a naturally occurring isoflavone predominantly found in soybeans and soy-based products, such as tofu, soy milk, and tempeh. It has demonstrated beneficial effects in various renal disorders, including both acute and chronic conditions, by regulating key molecular mediators involved in tissue injury, fibrosis, and cellular defense mechanisms. These mediators include TLR-4, MAPK, NF-κB, TGF-β, Smads, ACE, angiotensin, SIRT1, Nrf-2, ROS, SERBP, JAK/STAT and cytokines, among others. Considering the potential of genistein in modulating these mediators, the current review investigates the mechanistic interactions among these mediators in mediating its renoprotective effects.
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Affiliation(s)
- Ayush Kattna
- University Institute of Pharma Sciences, Chandigarh University, Mohali, Punjab, India
| | - Lovedeep Singh
- University Institute of Pharma Sciences, Chandigarh University, Mohali, Punjab, India.
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Buonfiglio F, Böhm EW, Tang Q, Daiber A, Gericke A. Revisiting the renin-angiotensin-aldosterone system in the eye: Mechanistic insights and pharmacological targets. Pharmacol Res 2025; 216:107771. [PMID: 40348100 DOI: 10.1016/j.phrs.2025.107771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 04/22/2025] [Accepted: 05/07/2025] [Indexed: 05/14/2025]
Abstract
The renin-angiotensin-aldosterone system (RAAS) plays a fundamental role in regulating blood pressure and fluid homeostasis through key effectors such as angiotensin II and aldosterone. These agents and their receptors have become crucial molecular targets in several cardiovascular and renal diseases. Over the past few decades, a growing body of evidence has revealed the presence of RAAS components in ocular structures, suggesting a tissue-specific RAAS within the eye. Building on this knowledge, studies have indicated that the ocular RAAS plays a significant role in the pathogenesis of various eye diseases. An impaired and overactivated RAAS contributes to the development of severe and widespread disorders affecting both the anterior and posterior segments of the eye. In this context, the current work aims to delve into the pivotal molecular pathways involving the RAAS, with an in-depth exploration of the ocular pathophysiology. It focuses on the relationship between overactivation of the RAAS and oxidative stress, as well as the exacerbation of neovascularization and inflammatory processes. The objective is to provide an updated and comprehensive understanding of the role of the RAAS in ophthalmological diseases, highlighting the therapeutic potential of RAAS modulators and discussing the controversies and challenges in this area of research.
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Affiliation(s)
- Francesco Buonfiglio
- Department of Ophthalmology, University Medical Center of the Johannes Gutenberg, University, Langenbeckstr.1, Mainz 55131, Germany.
| | - Elsa Wilma Böhm
- Department of Ophthalmology, University Medical Center of the Johannes Gutenberg, University, Langenbeckstr.1, Mainz 55131, Germany.
| | - Qi Tang
- Department of Ophthalmology, University Medical Center of the Johannes Gutenberg, University, Langenbeckstr.1, Mainz 55131, Germany.
| | - Andreas Daiber
- Department of Cardiology I, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz 55131, Germany.
| | - Adrian Gericke
- Department of Ophthalmology, University Medical Center of the Johannes Gutenberg, University, Langenbeckstr.1, Mainz 55131, Germany.
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Islam MA, Ford Versypt AN. Mathematical modeling of impacts of patient differences on renin-angiotensin system and applications to COVID-19 lung fibrosis outcomes. Comput Biol Med 2025; 186:109631. [PMID: 39753028 PMCID: PMC11932320 DOI: 10.1016/j.compbiomed.2024.109631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 12/23/2024] [Accepted: 12/24/2024] [Indexed: 02/20/2025]
Abstract
Patient-specific premorbidity, age, and sex are significant heterogeneous factors that influence the severe manifestation of lung diseases, including COVID-19 fibrosis. The renin-angiotensin system (RAS) plays a prominent role in regulating the effects of these factors. Recent evidence shows patient-specific alterations of RAS peptide homeostasis concentrations with premorbidity and the expression level of angiotensin-converting enzyme 2 (ACE2) during COVID-19. However, conflicting evidence suggests decreases, increases, or no changes in RAS peptides after SARS-CoV-2 infection. A multiscale computational model was developed to quantify the systemic contribution of heterogeneous factors of RAS during COVID-19. Three submodels were connected-an agent-based model for in-host COVID-19 response in the lung tissue, a RAS dynamics model, and a fibrosis dynamics model to investigate the effects of patient-group-specific factors in the systemic alteration of RAS and collagen deposition in the lung. The model results indicated cell death due to inflammatory response as a major contributor to the reduction of ACE and ACE2. The model explained possible mechanisms for conflicting evidence of patient-group-specific changes in RAS peptides in previously published studies. RAS peptides decreased for all virtual patient groups with aging in both sexes. In contrast, large variations in the magnitude of reduction were observed between male and female virtual patients in the older and middle-aged groups. The patient-specific variations in homeostasis RAS peptide concentrations of SARS-CoV-2-negative patients affected the dynamics of RAS during infection. This model may find further applications in patient-specific calibrations of tissue models for acute and chronic lung diseases to develop personalized treatments.
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Affiliation(s)
- Mohammad Aminul Islam
- Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA
| | - Ashlee N Ford Versypt
- Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA; Department of Biomedical Engineering, University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA; Institute for Artificial Intelligence and Data Science, University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA; Witebsky Center for Microbial Pathogenesis and Immunology, University at Buffalo, The State University of New York, Buffalo, NY, 14203, USA; Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, 14215, USA.
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Zamani S, Salehi M, Abbaszadeh-Goudarzi G, Cheraghali D, Ehterami A, Esmaili S, Rezaei Kolarijani N. Evaluation effect of alginate hydrogel containing losartan on wound healing and gene expression. J Biomater Appl 2025; 39:762-788. [PMID: 39454093 DOI: 10.1177/08853282241292144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2024]
Abstract
Skin tissue engineering has become an increasingly popular alternative to conventional treatments for skin injuries. Hydrogels, owing to their advantages have become the ideal option for wound dressing, and they are extensively employed in a mixture of different drugs to accelerate wound healing. Sodium alginate is a readily available natural polymer with advantages such as bio-compatibility and a non-toxicological nature that is commonly used in hydrogel form for medical applications such as wound repair and drug delivery in skin regenerative medicine. Losartan is a medicine called angiotensin receptor blocker (ARB) that can prevent fibrosis by inhibiting AT1R (angiotensin II type 1 receptor). In this research, for the first time, three-dimensional scaffolds based on cross-linked alginate hydrogel with CaCl2 containing different concentrations of losartan for slow drug release and exudate absorption were prepared and characterized as wound dressing. Alginate hydrogel was mixed with 10, 1, 0.1, and 0.01 mg/mL of losartan, and their properties such as morphology, chemical structure, water uptake properties, biodegradability, stability assay, rheology, blood compatibility, and cellular response were evaluated. In addition, the therapeutic efficiency of the developed hydrogels was then assessed in an in vitro wound healing model and with a gene expression. The results revealed that the hydrogel produced was very porous (porosity of 47.37 ± 3.76 µm) with interconnected pores and biodegradable (weight loss percentage of 60.93 ± 4.51% over 14 days). All hydrogel formulations have stability under various conditions. The use of CaCl2 as a cross-linker led to an increase in the viscosity of alginate hydrogels. An in vitro cell growth study revealed that no cytotoxicity was observed at the suggested dosage of the hydrogel. Increases in Losartan dosage, however, caused hemolysis. In vivo study in adult male rats with a full-thickness model showed greater than 80% improvement of the primary wound region after 2 weeks of treatment with alginate hydrogel containing 0.1 mg/mL Losartan. RT-PCR and immunohistochemistry analysis showed a decrease in expression level of TGF-β1 and VEGF in treatment groups. Histological analysis demonstrated that the alginate hydrogel containing Losartan can be effective in wound repair by decreasing the size of the scar and tissue remodeling, as evidenced by future in vivo studies.
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Affiliation(s)
- Sepehr Zamani
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Majid Salehi
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
- Tissue Engineering and Stem Cells Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
- Sexual Health and Fertility Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
- Health Technology Incubator Center, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Ghasem Abbaszadeh-Goudarzi
- Department of Medical Biotechnology, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Danial Cheraghali
- Department of Mechanical Engineering, New Jersey Institute of Technology, Newark, NJ, USA
| | - Arian Ehterami
- Institute for Regenerative Medicine (IREM), University of Zurich, Zurich, Switzerland
| | - Samaneh Esmaili
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Nariman Rezaei Kolarijani
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
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He Y, Dai MS, Tao LY, Gu X, Wang H, Liu P. Pericarpium Trichosanthis Inhibits TGF-β1-Smad3 Pathway-Induced Cardiac Fibrosis in Heart Failure Rats via Upregulation of microRNA-29b. J Gene Med 2025; 27:e70003. [PMID: 39800345 DOI: 10.1002/jgm.70003] [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: 05/04/2024] [Revised: 10/25/2024] [Accepted: 11/16/2024] [Indexed: 05/02/2025] Open
Abstract
Cardiac dysfunction and adverse consequences induced by cardiac fibrosis have been well documented. However, the cardiac fibrosis pathway in chronic heart failure (CHF) remains unclear, and it is therefore necessary to conduct further research for the sake of developing more effective therapeutic strategies for CHF. Some recent studies suggest that Pericarpium Trichosanthis (PT) may help improve the progression of fibrotic diseases. To validate this possibility, we conducted an experiment to evaluate the effect of PT on cardiac fibrosis and explore the hidden mechanism. In the experiment, we induced cardiac fibrosis in rats by left anterior descending (LAD) coronary artery ligation. The findings revealed that PT reduced myocardial fibrosis and increased cardiac activity in CHF rats receiving LAD ligation. In addition, the TGF-β1 level was decreased, and the miR-29b expression was increased in CHF rats after PT treatment. Our in vitro experiment also demonstrated that PT treatment suppressed fibroblast activation and collagen synthesis in cardiac fibroblasts stimulated by TGF-β1， and at the same time decreased the TGF-β1 level and increased the miR-29b expression. We further verified that this action was correlated with the TGF-β/Smad3 signaling pathway. We also observe that miR-29b could suppress the TGF-β1 expression, and the suppression of miR-29b weakened the anti-fibrotic effect of PT. This suggests that PT could cure cardiac fibrosis and dysfunction both in vitro and in vivo via the TGF-β/Smad3 signaling pathway, while miR-29b may participate in this action.
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Affiliation(s)
- Yue He
- Shanghai University of Traditional Chinese Medicine, Shanghai Eighth People's Hospital, Shanghai, China
| | - Meng-Shi Dai
- Department of Geriatrics, Huashan Hospital, Fudan University, Shanghai, China
| | - Li-Yu Tao
- Shanghai University of Traditional Chinese Medicine, Shuguang Hospital, Shanghai, China
| | - Xinsheng Gu
- Department of Cardiology, Shanghai Eighth People's Hospital, Shanghai, China
| | - Hao Wang
- Experimental Teaching Center of Basic Medicine, Fudan University, Shanghai, China
| | - Ping Liu
- Shanghai University of Traditional Chinese Medicine, Longhua Hospital, Shanghai, China
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Collet A, Sanges S, Ghulam A, Genin M, Soudan B, Sobanski V, Hachulla E, Dubucquoi S, Djobo B, Espiard S, Douillard C, Launay D. Steroid hormones in systemic sclerosis: associations with disease characteristics and modifications during scleroderma renal crisis. Rheumatology (Oxford) 2025; 64:283-295. [PMID: 38141209 DOI: 10.1093/rheumatology/kead699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 11/16/2023] [Accepted: 12/06/2023] [Indexed: 12/25/2023] Open
Abstract
OBJECTIVE The renin-angiotensin-aldosterone system (RAAS) and glucocorticoids (GCs) are involved in vascular remodeling and fibrosis but have not been extensively studied in systemic sclerosis (SSc). Our aim was to investigate the RAAS and GC hormones in SSc patients. METHODS Serum levels of renin (dosage and activity), aldosterone and its precursors (DOC, B, 18-OH-DOC, 18-OH-B), and GCs (cortisol, cortisone, 11-deoxycortisol, 18-OH-F) were assessed in 122 SSc patients and 52 healthy controls. After applying stringent inclusion criteria aimed at ensuring accurate hormone assessments (exclusion of interfering drugs, strict sampling conditions), we analysed RAAS hormones in 61 patients, and GCs in 96 patients. Hormone levels were compared between patients and controls; and associations with disease characteristics were assessed in patients. RESULTS Regarding RAAS hormones, SSc patients displayed significantly lower aldosterone levels (although within normal range), similar renin levels, and higher B levels than controls. Abnormal RAAS hormone levels were associated with a more severe SSc phenotype (lung and skin fibrosis, heart and pulmonary vascular involvements, inflammation). Regarding GC hormones, SSc patients had higher levels of cortisol, 11-desoxycortisol (precursor) and 18-OH-F (metabolite) but lower levels of cortisone (inactive counterpart) than controls. RAAS hormone levels were assessed in five SSc patients before and during scleroderma renal crisis (SRC): concentrations varied considerably between patients, but consistently included normal/increased aldosterone levels and elevated renin levels. CONCLUSION RAAS and GC hormones are abnormally produced in SSc patients, especially in patients with severe SSc and during SRC. This could suggest a participation of these hormonal systems in SSc pathogenesis.
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Affiliation(s)
- Aurore Collet
- Univ. Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, Lille, France
- INSERM, Lille, France
- Département de Médecine Interne et Immunologie Clinique, CHU Lille, Lille, France
- Centre National de Référence Maladies Auto-immunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), Lille, France
- Health Care Provider of the European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases Network (ReCONNET), Lille, France
- Institut d'Immunologie, Pôle de Biologie Pathologie Génétique, CHU Lille, Lille, France
| | - Sebastien Sanges
- Univ. Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, Lille, France
- INSERM, Lille, France
- Département de Médecine Interne et Immunologie Clinique, CHU Lille, Lille, France
- Centre National de Référence Maladies Auto-immunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), Lille, France
- Health Care Provider of the European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases Network (ReCONNET), Lille, France
| | - Amjad Ghulam
- Service Hormonologie, Métabolisme, Nutrition, Oncologie, Pôle de Biologie Pathologie Génétique, CHU Lille, Lille, France
| | - Michaël Genin
- Univ. Lille, CHU Lille, ULR 2694 - METRICS: Évaluation des Technologies de Santé et des Pratiques Médicales, Lille, France
| | - Benoît Soudan
- Service Hormonologie, Métabolisme, Nutrition, Oncologie, Pôle de Biologie Pathologie Génétique, CHU Lille, Lille, France
| | - Vincent Sobanski
- Univ. Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, Lille, France
- INSERM, Lille, France
- Département de Médecine Interne et Immunologie Clinique, CHU Lille, Lille, France
- Centre National de Référence Maladies Auto-immunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), Lille, France
- Health Care Provider of the European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases Network (ReCONNET), Lille, France
| | - Eric Hachulla
- Univ. Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, Lille, France
- INSERM, Lille, France
- Département de Médecine Interne et Immunologie Clinique, CHU Lille, Lille, France
- Centre National de Référence Maladies Auto-immunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), Lille, France
- Health Care Provider of the European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases Network (ReCONNET), Lille, France
| | - Sylvain Dubucquoi
- Univ. Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, Lille, France
- INSERM, Lille, France
- Institut d'Immunologie, Pôle de Biologie Pathologie Génétique, CHU Lille, Lille, France
| | - Bodale Djobo
- Service Hormonologie, Métabolisme, Nutrition, Oncologie, Pôle de Biologie Pathologie Génétique, CHU Lille, Lille, France
| | - Stéphanie Espiard
- Department of Endocrinology, Diabetology, Metabolism and Nutrition, CHU Lille, Lille, France
| | - Claire Douillard
- Department of Endocrinology, Diabetology, Metabolism and Nutrition, CHU Lille, Lille, France
| | - David Launay
- Univ. Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, Lille, France
- INSERM, Lille, France
- Département de Médecine Interne et Immunologie Clinique, CHU Lille, Lille, France
- Centre National de Référence Maladies Auto-immunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), Lille, France
- Health Care Provider of the European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases Network (ReCONNET), Lille, France
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Ruan Y, Yu Y, Wu M, Jiang Y, Qiu Y, Ruan S. The renin-angiotensin-aldosterone system: An old tree sprouts new shoots. Cell Signal 2024; 124:111426. [PMID: 39306263 DOI: 10.1016/j.cellsig.2024.111426] [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: 06/30/2024] [Revised: 08/25/2024] [Accepted: 09/17/2024] [Indexed: 09/27/2024]
Abstract
The intricate physiological and pathological diversity of the Renin-Angiotensin-Aldosterone System (RAAS) underpins its role in maintaining bodily equilibrium. This paper delves into the classical axis (Renin-ACE-Ang II-AT1R axis), the protective arm (ACE2-Ang (1-7)-MasR axis), the prorenin-PRR-MAP kinases ERK1/2 axis, and the Ang IV-AT4R-IRAP cascade of RAAS, examining their functions in both physiological and pathological states. The dysregulation or hyperactivation of RAAS is intricately linked to numerous diseases, including cardiovascular disease (CVD), renal damage, metabolic disease, eye disease, Gastrointestinal disease, nervous system and reproductive system diseases. This paper explores the pathological mechanisms of RAAS in detail, highlighting its significant role in disease progression. Currently, in addition to traditional drugs like ACEI, ARB, and MRA, several novel therapeutics have emerged, such as angiotensin receptor-enkephalinase inhibitors, nonsteroidal mineralocorticoid receptor antagonists, aldosterone synthase inhibitors, aminopeptidase A inhibitors, and angiotensinogen inhibitors. These have shown potential efficacy and application prospects in various clinical trials for related diseases. Through an in-depth analysis of RAAS, this paper aims to provide crucial insights into its complex physiological and pathological mechanisms and offer valuable guidance for developing new therapeutic approaches. This comprehensive discussion is expected to advance the RAAS research field and provide innovative ideas and directions for future clinical treatment strategies.
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Affiliation(s)
- Yaqing Ruan
- The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou 350004, China; Fujian University of Traditional Chinese Medicine, Fuzhou 350000, China
| | - Yongxin Yu
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Meiqin Wu
- The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou 350004, China; Fujian University of Traditional Chinese Medicine, Fuzhou 350000, China
| | - Yulang Jiang
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yuliang Qiu
- The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou 350004, China; Fujian University of Traditional Chinese Medicine, Fuzhou 350000, China.
| | - Shiwei Ruan
- The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou 350004, China; Fujian University of Traditional Chinese Medicine, Fuzhou 350000, China.
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Saulnier NM, Thorne DM, Bablu FE, Suzuki AM, Khan RL, Oliveira KX, Suzuki YJ. Characterizations of angiotensin-converting enzyme-2 (ACE2) peptidase activity. Arch Biochem Biophys 2024; 761:110167. [PMID: 39349131 PMCID: PMC11560506 DOI: 10.1016/j.abb.2024.110167] [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: 06/09/2024] [Revised: 09/23/2024] [Accepted: 09/27/2024] [Indexed: 10/02/2024]
Abstract
Angiotensin (Ang) II (1-8) is a potent vasoconstrictor known for its role in hypertension. Angiotensin-converting enzyme (ACE2) converts Ang II (1-8) to a vasodilator Ang (1-7) by removing the carboxy-terminal Phe. ACE2 more recently gained attention as the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that caused the coronavirus disease 2019 (COVID-19) pandemic. Given the pathophysiological importance of ACE2, the present study examined the mechanism of ACE2 catalytic activity by comparing the ability of angiotensin molecules of various lengths to compete with the artificial fluorogenic substrate. The Fluorimetric SensoLyte 390 ACE2 Activity Assay uses an Mca/Dnp fluorescence resonance energy transfer peptide as the substrate. Results showed that the natural substrate Ang II (1-8) competed with the fluorogenic substrate, reducing the fluorescence signals. Deletion of C-terminal Phe resulted in the loss of the ability to compete with the artificial substrate, as shown by the actions of Ang (1-7), Ang (2-7), and Ang (5-7). By contrast, the loss of N-terminal Asp potentiated the ability to compete with the substrate as seen by the action of Ang III (2-8). However, the loss of two amino acids (Asp-Arg) from the N-terminus reduced the ability to compete with the substrate as observed by the actions of Ang IV (3-8) and Ang (5-8). Ang I (1-10) and Ang (1-9) did not strongly compete with the substrate. Interestingly, shorter peptides Ang (1-5) and Ang (1-4) potentiated the ACE2 activity. These results suggest that Ang II and Ang III are the best natural substrates for ACE2.
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Affiliation(s)
- Nathalie M Saulnier
- Department of Pharmacology & Physiology, Georgetown University Medical Center, Washington DC 20007, USA
| | - Devyn M Thorne
- Department of Pharmacology & Physiology, Georgetown University Medical Center, Washington DC 20007, USA
| | - Fariha E Bablu
- Department of Pharmacology & Physiology, Georgetown University Medical Center, Washington DC 20007, USA
| | - Alessia M Suzuki
- Department of Pharmacology & Physiology, Georgetown University Medical Center, Washington DC 20007, USA
| | - Rafa L Khan
- Department of Pharmacology & Physiology, Georgetown University Medical Center, Washington DC 20007, USA
| | - Katelin X Oliveira
- Department of Pharmacology & Physiology, Georgetown University Medical Center, Washington DC 20007, USA
| | - Yuichiro J Suzuki
- Department of Pharmacology & Physiology, Georgetown University Medical Center, Washington DC 20007, USA.
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9
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Benken ST, Thomas R, Fraidenburg DR, Benken JJ. Angiotensin II as a Vasopressor for Perioperative Hypotension in Solid Organ Transplant. Biomedicines 2024; 12:1817. [PMID: 39200281 PMCID: PMC11351893 DOI: 10.3390/biomedicines12081817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 07/29/2024] [Accepted: 08/07/2024] [Indexed: 09/02/2024] Open
Abstract
During the perioperative period of transplantation, patients experience hypotension secondary to the side effects of anesthesia, surgical stress, inflammatory triggering, and intraoperative fluid shifts, among others causes. Vasopressor support, in this context, must reverse systemic hypotension, but ideally, the agents used should benefit allograft function and avoid the adverse events commonly seen after transplantation. Traditional therapies to reverse hypotension include catecholamine vasopressors (norepinephrine, epinephrine, dopamine, and phenylephrine), but their utility is limited when considering allograft complications and adverse events such as arrhythmias with agents with beta-adrenergic properties. Synthetic angiotensin II (AT2S-[Giapreza]) is a novel vasopressor indicated for distributive shock with a unique mechanism of action as an angiotensin receptor agonist restoring balance to an often-disrupted renin angiotensin aldosterone system. Additionally, AT2S provides a balanced afferent and efferent arteriole vasoconstriction at the level of the kidney and could avoid the arrhythmic complications of a beta-adrenergic agonist. While the data, to date, are limited, AT2S has demonstrated safety in case reports, pilot studies, and small series in the kidney, liver, heart, and lung transplant populations. There are physiologic and hemodynamic reasons why AT2S could be a more utilized agent in these populations, but further investigation is warranted.
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Affiliation(s)
- Scott T. Benken
- Department of Pharmacy Practice, University of Illinois Chicago College of Pharmacy, Chicago, IL 60612, USA; (R.T.); (J.J.B.)
| | - Riya Thomas
- Department of Pharmacy Practice, University of Illinois Chicago College of Pharmacy, Chicago, IL 60612, USA; (R.T.); (J.J.B.)
| | - Dustin R. Fraidenburg
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep, and Allergy, University of Illinois Chicago College of Medicine, Chicago, IL 60612, USA;
| | - Jamie J. Benken
- Department of Pharmacy Practice, University of Illinois Chicago College of Pharmacy, Chicago, IL 60612, USA; (R.T.); (J.J.B.)
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10
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Samuel CS, Li Y, Wang Y, Widdop RE. Functional crosstalk between angiotensin receptors (types 1 and 2) and relaxin family peptide receptor 1 (RXFP1): Implications for the therapeutic targeting of fibrosis. Br J Pharmacol 2024; 181:2302-2318. [PMID: 36560925 DOI: 10.1111/bph.16019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 12/15/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Class A, rhodopsin-like, G-protein-coupled receptors (GPCRs) are by far the largest class of GPCRs and are integral membrane proteins used by various cells to convert extracellular signals into intracellular responses. Initially, class A GPCRs were believed to function as monomers, but a growing body of evidence has emerged to suggest that these receptors can function as homodimers and heterodimers and can undergo functional crosstalk to influence the actions of agonists or antagonists acting at each receptor. This review will focus on the angiotensin type 1 (AT1) and type 2 (AT2) receptors, as well as the relaxin family peptide receptor 1 (RXFP1), each of which have their unique characteristics but have been demonstrated to undergo some level of interaction when appropriately co-expressed, which influences the function of each receptor. In particular, this receptor functional crosstalk will be discussed in the context of fibrosis, the tissue scarring that results from a failed wound-healing response to injury, and which is a hallmark of chronic disease and related organ dysfunction. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc.
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Affiliation(s)
- Chrishan S Samuel
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia
- Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Yifang Li
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia
| | - Yan Wang
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia
| | - Robert E Widdop
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia
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11
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Harrison JM, Leong EK, Osborne ND, Marshall JS, Bezuhly M. AT2R Activation Improves Wound Healing in a Preclinical Mouse Model. Biomedicines 2024; 12:1238. [PMID: 38927444 PMCID: PMC11200587 DOI: 10.3390/biomedicines12061238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 05/23/2024] [Accepted: 05/28/2024] [Indexed: 06/28/2024] Open
Abstract
Abnormal skin healing resulting in chronic wounds or hypertrophic scarring remains a major healthcare burden. Here, the antifibrotic angiotensin II type 2 receptor (AT2R) signaling pathway was modulated to determine its impact on cutaneous wound healing. Balb/c mice received two splinted full-thickness wounds. Topical treatments with the selective AT2R agonist compound 21 (C21) and/or selective antagonist PD123319 or saline vehicle were administered until sacrifice on post-wounding days 7 or 10. The rate of wound re-epithelialization was accelerated by PD123319 and combination treatments. In vitro, C21 significantly reduced human fibroblast migration. C21 increased both collagen and vascular densities at days 7 and 10 post-wounding and collagen I:III ratio at day 10, while PD123319 and combination treatments decreased them. Genes associated with regeneration and repair were upregulated by C21, while PD123319 treatment increased the expression of genes associated with inflammation and immune cell chemotaxis. C21 treatment reduced wound total leukocyte and neutrophil staining densities, while PD123319 increased these and macrophage densities. Overall, AT2R activation with C21 yields wounds that mature more quickly with structural, cellular, and gene expression profiles more closely approximating unwounded skin. These findings support AT2R signal modulation as a potential therapeutic target to improve skin quality during wound healing.
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Affiliation(s)
- Julia M. Harrison
- Department of Surgery, IWK Health Centre, 5850/5980 University Avenue, Halifax, NS B3K 6R8, Canada;
- Department of Surgery, Dalhousie University, 5850 College St, Halifax, NS B3H 4H7, Canada
| | - Edwin K. Leong
- Department of Pathology, Dalhousie University, 5850 College St, Halifax, NS B3H 4H7, Canada
| | - Natasha D. Osborne
- Department of Microbiology & Immunology, Dalhousie University, 5850 College St, Halifax, NS B3H 4H7, Canada;
| | - Jean S. Marshall
- Department of Pathology, Dalhousie University, 5850 College St, Halifax, NS B3H 4H7, Canada
- Department of Microbiology & Immunology, Dalhousie University, 5850 College St, Halifax, NS B3H 4H7, Canada;
| | - Michael Bezuhly
- Department of Surgery, IWK Health Centre, 5850/5980 University Avenue, Halifax, NS B3K 6R8, Canada;
- Department of Surgery, Dalhousie University, 5850 College St, Halifax, NS B3H 4H7, Canada
- Department of Microbiology & Immunology, Dalhousie University, 5850 College St, Halifax, NS B3H 4H7, Canada;
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12
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Liang L, Chung SI, Guon TE, Park KH, Lee JH, Park JW. Statin administration or blocking PCSK9 alleviates airway hyperresponsiveness and lung fibrosis in high-fat diet-induced obese mice. Respir Res 2024; 25:213. [PMID: 38762465 PMCID: PMC11102611 DOI: 10.1186/s12931-024-02842-x] [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: 03/28/2024] [Accepted: 05/07/2024] [Indexed: 05/20/2024] Open
Abstract
BACKGROUND Obesity is associated with airway hyperresponsiveness and lung fibrosis, which may reduce the effectiveness of standard asthma treatment in individuals suffering from both conditions. Statins and proprotein convertase subtilisin/kexin-9 inhibitors not only reduce serum cholesterol, free fatty acids but also diminish renin-angiotensin system activity and exhibit anti-inflammatory effects. These mechanisms may play a role in mitigating lung pathologies associated with obesity. METHODS Male C57BL/6 mice were induced to develop obesity through high-fat diet for 16 weeks. Conditional TGF-β1 transgenic mice were fed a normal diet. These mice were given either atorvastatin or proprotein convertase subtilisin/kexin-9 inhibitor (alirocumab), and the impact on airway hyperresponsiveness and lung pathologies was assessed. RESULTS High-fat diet-induced obesity enhanced airway hyperresponsiveness, lung fibrosis, macrophages in bronchoalveolar lavage fluid, and pro-inflammatory mediators in the lung. These lipid-lowering agents attenuated airway hyperresponsiveness, macrophages in BALF, lung fibrosis, serum leptin, free fatty acids, TGF-β1, IL-1β, IL-6, and IL-17a in the lung. Furthermore, the increased RAS, NLRP3 inflammasome, and cholecystokinin in lung tissue of obese mice were reduced with statin or alirocumab. These agents also suppressed the pro-inflammatory immune responses and lung fibrosis in TGF-β1 over-expressed transgenic mice with normal diet. CONCLUSIONS Lipid-lowering treatment has the potential to alleviate obesity-induced airway hyperresponsiveness and lung fibrosis by inhibiting the NLRP3 inflammasome, RAS and cholecystokinin activity.
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Affiliation(s)
- Lin Liang
- Graduate School of Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea
| | - Sook In Chung
- Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea
| | - Tae-Eun Guon
- Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea
| | - Kyung Hee Park
- Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea
- Division of Allergy and Immunology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea
| | - Jae-Hyun Lee
- Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea
- Division of Allergy and Immunology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea
| | - Jung-Won Park
- Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea.
- Division of Allergy and Immunology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea.
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13
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Danielpour D. Advances and Challenges in Targeting TGF-β Isoforms for Therapeutic Intervention of Cancer: A Mechanism-Based Perspective. Pharmaceuticals (Basel) 2024; 17:533. [PMID: 38675493 PMCID: PMC11054419 DOI: 10.3390/ph17040533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/11/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
The TGF-β family is a group of 25 kDa secretory cytokines, in mammals consisting of three dimeric isoforms (TGF-βs 1, 2, and 3), each encoded on a separate gene with unique regulatory elements. Each isoform plays unique, diverse, and pivotal roles in cell growth, survival, immune response, and differentiation. However, many researchers in the TGF-β field often mistakenly assume a uniform functionality among all three isoforms. Although TGF-βs are essential for normal development and many cellular and physiological processes, their dysregulated expression contributes significantly to various diseases. Notably, they drive conditions like fibrosis and tumor metastasis/progression. To counter these pathologies, extensive efforts have been directed towards targeting TGF-βs, resulting in the development of a range of TGF-β inhibitors. Despite some clinical success, these agents have yet to reach their full potential in the treatment of cancers. A significant challenge rests in effectively targeting TGF-βs' pathological functions while preserving their physiological roles. Many existing approaches collectively target all three isoforms, failing to target just the specific deregulated ones. Additionally, most strategies tackle the entire TGF-β signaling pathway instead of focusing on disease-specific components or preferentially targeting tumors. This review gives a unique historical overview of the TGF-β field often missed in other reviews and provides a current landscape of TGF-β research, emphasizing isoform-specific functions and disease implications. The review then delves into ongoing therapeutic strategies in cancer, stressing the need for more tools that target specific isoforms and disease-related pathway components, advocating mechanism-based and refined approaches to enhance the effectiveness of TGF-β-targeted cancer therapies.
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Affiliation(s)
- David Danielpour
- Case Comprehensive Cancer Center Research Laboratories, The Division of General Medical Sciences-Oncology, Case Western Reserve University, Cleveland, OH 44106, USA; ; Tel.: +1-216-368-5670; Fax: +1-216-368-8919
- Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA
- Institute of Urology, University Hospitals, Cleveland, OH 44106, USA
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14
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Kaschina E, Lauer D, Lange C, Unger T. Angiotensin AT 2 receptors reduce inflammation and fibrosis in cardiovascular remodeling. Biochem Pharmacol 2024; 222:116062. [PMID: 38369211 DOI: 10.1016/j.bcp.2024.116062] [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: 10/05/2023] [Revised: 01/04/2024] [Accepted: 02/15/2024] [Indexed: 02/20/2024]
Abstract
The angiotensin AT2 receptor (AT2R), an important member of the "protective arm" of the renin-angiotensin system (RAS), has been recently defined as a therapeutic target in different pathological conditions. The AT2R activates complex signalling pathways linked to cellular proliferation, differentiation, anti-inflammation, antifibrosis, and induction or inhibition of apoptosis. The anti-inflammatory effect of AT2R activation is commonly associated with reduced fibrosis in different models. Current discoveries demonstrated a direct impact of AT2Rs on the regulation of cytokines, transforming growth factor beta1 (TGF-beta1), matrix metalloproteases (MMPs), and synthesis of the extracellular matrix components. This review article summarizes current knowledge on the AT2R in regard to immunity, inflammation and fibrosis in the heart and blood vessels. In particular, the differential influence of the AT2R on cardiovascular remodeling in preclinical models of myocardial infarction, heart failure and aneurysm formation are discussed. Overall, these studies demonstrate that AT2R stimulation represents a promising therapeutic approach to counteract myocardial and aortic damage in cardiovascular diseases.
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Affiliation(s)
- Elena Kaschina
- Charité - Universitätsmedizin Berlin, Institute of Pharmacology, Max Rubner Center for Cardiovascular Metabolic Renal Research (MRC), Berlin, Germany.
| | - Dilyara Lauer
- Charité - Universitätsmedizin Berlin, Institute of Pharmacology, Max Rubner Center for Cardiovascular Metabolic Renal Research (MRC), Berlin, Germany
| | - Christoph Lange
- Charité - Universitätsmedizin Berlin, Institute of Pharmacology, Max Rubner Center for Cardiovascular Metabolic Renal Research (MRC), Berlin, Germany
| | - Thomas Unger
- CARIM - School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands
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15
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Lei M, Salvage SC, Jackson AP, Huang CLH. Cardiac arrhythmogenesis: roles of ion channels and their functional modification. Front Physiol 2024; 15:1342761. [PMID: 38505707 PMCID: PMC10949183 DOI: 10.3389/fphys.2024.1342761] [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: 11/22/2023] [Accepted: 01/22/2024] [Indexed: 03/21/2024] Open
Abstract
Cardiac arrhythmias cause significant morbidity and mortality and pose a major public health problem. They arise from disruptions in the normally orderly propagation of cardiac electrophysiological activation and recovery through successive cardiomyocytes in the heart. They reflect abnormalities in automaticity, initiation, conduction, or recovery in cardiomyocyte excitation. The latter properties are dependent on surface membrane electrophysiological mechanisms underlying the cardiac action potential. Their disruption results from spatial or temporal instabilities and heterogeneities in the generation and propagation of cellular excitation. These arise from abnormal function in their underlying surface membrane, ion channels, and transporters, as well as the interactions between them. The latter, in turn, form common regulatory targets for the hierarchical network of diverse signaling mechanisms reviewed here. In addition to direct molecular-level pharmacological or physiological actions on these surface membrane biomolecules, accessory, adhesion, signal transduction, and cytoskeletal anchoring proteins modify both their properties and localization. At the cellular level of excitation-contraction coupling processes, Ca2+ homeostatic and phosphorylation processes affect channel activity and membrane excitability directly or through intermediate signaling. Systems-level autonomic cellular signaling exerts both acute channel and longer-term actions on channel expression. Further upstream intermediaries from metabolic changes modulate the channels both themselves and through modifying Ca2+ homeostasis. Finally, longer-term organ-level inflammatory and structural changes, such as fibrotic and hypertrophic remodeling, similarly can influence all these physiological processes with potential pro-arrhythmic consequences. These normal physiological processes may target either individual or groups of ionic channel species and alter with particular pathological conditions. They are also potentially alterable by direct pharmacological action, or effects on longer-term targets modifying protein or cofactor structure, expression, or localization. Their participating specific biomolecules, often clarified in experimental genetically modified models, thus constitute potential therapeutic targets. The insights clarified by the physiological and pharmacological framework outlined here provide a basis for a recent modernized drug classification. Together, they offer a translational framework for current drug understanding. This would facilitate future mechanistically directed therapeutic advances, for which a number of examples are considered here. The latter are potentially useful for treating cardiac, in particular arrhythmic, disease.
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Affiliation(s)
- Ming Lei
- Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| | - Samantha C. Salvage
- Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
| | - Antony P. Jackson
- Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
| | - Christopher L.-H. Huang
- Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
- Physiological Laboratory, University of Cambridge, Cambridge, United Kingdom
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16
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Siregar S, Rulianov R, Ksatriapraja RA, Stefanus D. The role of angiotensin receptor blocker (losartan) on decreasing fibrotic process of corpora cavernosa in priapism model of wistar rats. F1000Res 2024; 11:831. [PMID: 38046538 PMCID: PMC10690033 DOI: 10.12688/f1000research.123040.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/22/2024] [Indexed: 12/05/2023] Open
Abstract
Background Priapism induces regulation of Transforming Growth Factor-β1 (TGF-β1) expression and collagen-type-1 deposition. This will replace the normal corpora cavernosa with fibrotic tissue which eventually resulted in erectile dysfunction. It is also known that the fibrosis process of corpora cavernosa is related to Renin-Angiotensin II System (RAS). Angiotensin II receptor blockers (ARB), especially losartan, inhibit the inflammation process and fibrotic tissue formation. This study evaluated the effect of losartan in reducing fibrosis in priapism by evaluating TGF-β1 and collagen-type-1 in cavernous tissue and determined the effect of losartan in preventing fibrosis in priapism model of Wistar rats assessed by the metavir score. Methods A total of eighteen male Wistar rats mean were divided into five groups. For the priapism models, we applied negative pressure on the penis to make an artificial erection to mimic the priapism process. The control groups were observed and the treatment groups were orally given losartan 15 mg/kg/day. Corpora cavernosa was harvested for TGF-β1 and collagen-type-1 measurement using an enzyme-linked immunosorbent assay (ELISA). The fibrotic tissue of each rat was then collected and assessed histopathologically with the metavir scoring system. Results Penile TGF-β1 concentration in the losartan-treated group was not significantly different on day 10 and day 28 of observation (p10=0,30; p28=0,17). Meanwhile, collagen-type-1 concentration was significantly lower compared to control group (p10=0,002; p28=0,01). There was a significant difference in metavir scores in rats that received losartan and those who did not (p<0,05). Conclusion Losartan could suppress the fibrosis process in the priapism model. It could decrease the collagen type 1 deposition during corpora cavernosa tissue regeneration. Based on the metavir score, the group receiving losartan therapy was better than the control group.
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Affiliation(s)
- Safendra Siregar
- Department of Urology, Universitas Padjadjaran, Bandung, 40161, Indonesia
| | - Rulianov Rulianov
- Department of Urology, Universitas Padjadjaran, Bandung, 40161, Indonesia
| | | | - Dicky Stefanus
- Department of Urology, Universitas Padjadjaran, Bandung, 40161, Indonesia
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17
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Ferrasi AC, Lima SVG, Galvani AF, Delafiori J, Dias-Audibert FL, Catharino RR, Silva GF, Praxedes RR, Santos DB, Almeida DTDM, Lima EO. Metabolomics in chronic hepatitis C: Decoding fibrosis grading and underlying pathways. World J Hepatol 2023; 15:1237-1249. [DOI: 10.4254/wjh.v15.i11.1237] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 09/22/2023] [Accepted: 10/23/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Chronic Hepatitis C (CHC) affects 71 million people globally and leads to liver issues such as fibrosis, cirrhosis, cancer, and death. A better understanding and prognosis of liver involvement are vital to reduce morbidity and mortality. The accurate identification of the fibrosis stage is crucial for making treatment decisions and predicting outcomes. Tests used to grade fibrosis include histological analysis and imaging but have limitations. Blood markers such as molecular biomarkers can offer valuable insights into fibrosis.
AIM To identify potential biomarkers that might stratify these lesions and add information about the molecular mechanisms involved in the disease.
METHODS Plasma samples were collected from 46 patients with hepatitis C and classified into fibrosis grades F1 (n = 13), F2 (n = 12), F3 (n = 6), and F4 (n = 15). To ensure that the identified biomarkers were exclusive to liver lesions (CHC fibrosis), healthy volunteer participants (n = 50) were also included. An untargeted metabolomic technique was used to analyze the plasma metabolites using mass spectrometry and database verification. Statistical analyses were performed to identify differential biomarkers among groups.
RESULTS Six differential metabolites were identified in each grade of fibrosis. This six-metabolite profile was able to establish a clustering tendency in patients with the same grade of fibrosis; thus, they showed greater efficiency in discriminating grades.
CONCLUSION This study suggests that some of the observed biomarkers, once validated, have the potential to be applied as prognostic biomarkers. Furthermore, it suggests that liquid biopsy analyses of plasma metabolites are a good source of molecular biomarkers capable of stratifying patients with CHC according to fibrosis grade.
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Affiliation(s)
| | | | - Aline Faria Galvani
- Department of Internal Medicine, Sao Paulo State University, Botucatu 18618-686, Brazil
| | - Jeany Delafiori
- Innovare Biomarkers Laboratory, University of Campinas, Campinas 13083-877, Brazil
| | | | | | - Giovanni Faria Silva
- Department of Internal Medicine, Sao Paulo State University, Botucatu 18618-686, Brazil
| | | | | | | | - Estela Oliveira Lima
- Department of Internal Medicine, Sao Paulo State University, Botucatu 18618-686, Brazil
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18
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Young ON, Bourke JE, Widdop RE. Catch your breath: The protective role of the angiotensin AT 2 receptor for the treatment of idiopathic pulmonary fibrosis. Biochem Pharmacol 2023; 217:115839. [PMID: 37778444 DOI: 10.1016/j.bcp.2023.115839] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/28/2023] [Accepted: 09/28/2023] [Indexed: 10/03/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease whereby excessive deposition of extracellular matrix proteins (ECM) ultimately leads to respiratory failure. While there have been advances in pharmacotherapies for pulmonary fibrosis, IPF remains an incurable and irreversible disease. There remains an unmet clinical need for treatments that reverse fibrosis, or at the very least have a more tolerable side effect profile than currently available treatments. Transforming growth factor β1(TGFβ1) is considered the main driver of fibrosis in IPF. However, as our understanding of the role of the pulmonary renin-angiotensin system (PRAS) in the pathogenesis of IPF increases, it is becoming clear that targeting angiotensin receptors represents a potential novel treatment strategy for IPF - in particular, via activation of the anti-fibrotic angiotensin type 2 receptor (AT2R). This review describes the current understanding of the pathophysiology of IPF and the mediators implicated in its pathogenesis; focusing on TGFβ1, angiotensin II and related peptides in the PRAS and their contribution to fibrotic processes in the lung. Preclinical and clinical assessment of currently available AT2R agonists and the development of novel, highly selective ligands for this receptor will also be described, with a focus on compound 21, currently in clinical trials for IPF. Collectively, this review provides evidence of the potential of AT2R as a novel therapeutic target for IPF.
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Affiliation(s)
- Olivia N Young
- Department of Pharmacology and Cardiovascular Disease Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Jane E Bourke
- Department of Pharmacology and Cardiovascular Disease Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Robert E Widdop
- Department of Pharmacology and Cardiovascular Disease Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
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19
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Hassani B, Attar Z, Firouzabadi N. The renin-angiotensin-aldosterone system (RAAS) signaling pathways and cancer: foes versus allies. Cancer Cell Int 2023; 23:254. [PMID: 37891636 PMCID: PMC10604988 DOI: 10.1186/s12935-023-03080-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 09/20/2023] [Indexed: 10/29/2023] Open
Abstract
The renin-angiotensin-aldosterone system (RAAS), is an old system with new fundamental roles in cancer biology which influences cell growth, migration, death, and metastasis. RAAS signaling enhances cell proliferation in malignancy directly and indirectly by affecting tumor cells and modulating angiogenesis. Cancer development may be influenced by the balance between the ACE/Ang II/AT1R and the ACE2/Ang 1-7/Mas receptor pathways. The interactions between Ang II/AT1R and Ang I/AT2R as well as Ang1-7/Mas and alamandine/MrgD receptors in the RAAS pathway can significantly impact the development of cancer. Ang I/AT2R, Ang1-7/Mas, and alamandine/MrgD interactions can have anticancer effects while Ang II/AT1R interactions can be involved in the development of cancer. Evidence suggests that inhibitors of the RAAS, which are conventionally used to treat cardiovascular diseases, may be beneficial in cancer therapies.Herein, we aim to provide a thorough description of the elements of RAAS and their molecular play in cancer. Alongside this, the role of RAAS components in sex-dependent cancers as well as GI cancers will be discussed with the hope of enlightening new venues for adjuvant cancer treatment.
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Affiliation(s)
- Bahareh Hassani
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zeinab Attar
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Negar Firouzabadi
- Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
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20
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Ghosh K, Shome DK, Kulkarni B, Ghosh MK, Ghosh K. Fibrosis and bone marrow: understanding causation and pathobiology. J Transl Med 2023; 21:703. [PMID: 37814319 PMCID: PMC10561412 DOI: 10.1186/s12967-023-04393-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 07/28/2023] [Indexed: 10/11/2023] Open
Abstract
Bone marrow fibrosis represents an important structural change in the marrow that interferes with some of its normal functions. The aetiopathogenesis of fibrosis is not well established except in its primary form. The present review consolidates current understanding of marrow fibrosis. We searched PubMed without time restriction using key words: bone marrow and fibrosis as the main stem against the terms: growth factors, cytokines and chemokines, morphology, megakaryocytes and platelets, myeloproliferative disorders, myelodysplastic syndrome, collagen biosynthesis, mesenchymal stem cells, vitamins and minerals and hormones, and mechanism of tissue fibrosis. Tissue marrow fibrosis-related papers were short listed and analysed for the review. It emerged that bone marrow fibrosis is the outcome of complex interactions between growth factors, cytokines, chemokines and hormones together with their facilitators and inhibitors. Fibrogenesis is initiated by mobilisation of special immunophenotypic subsets of mesenchymal stem cells in the marrow that transform into fibroblasts. Fibrogenic stimuli may arise from neoplastic haemopoietic or non-hematopoietic cells, as well as immune cells involved in infections and inflammatory conditions. Autoimmunity is involved in a small subset of patients with marrow fibrosis. Megakaryocytes and platelets are either directly involved or are important intermediaries in stimulating mesenchymal stem cells. MMPs, TIMPs, TGF-β, PDGRF, and basic FGF and CRCXL4 chemokines are involved in these processes. Genetic and epigenetic changes underlie many of these conditions.
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Affiliation(s)
- Kanjaksha Ghosh
- National Institute of Immunohaematology, 13 Th Fl KEM Hospital, Parel, Mumbai, 400012, India.
| | - Durjoy K Shome
- Department of Pathophysiology, American University of Antigua College of Medicine, Coolidge, Antigua and Barbuda
| | - Bipin Kulkarni
- Department of Molecular Biology and Haemostasis, National Institute of Immunohaematology, 13Th Fl KEM Hospital, Parel, Mumbai, 400012, India
| | - Malay K Ghosh
- Department of Haematology, Nilratan Sarkar Medical College, Kolkata, 700014, West Bengal, India
| | - Kinjalka Ghosh
- Department of Clinical Biochemistry, Tata Medical Centre and Homi Bhaba National Institute, Parel, Mumbai, 400012, India
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21
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Wegner E, Mickan T, Truffel S, Slotina E, Müller L, Wunderlich F, Harper A, Ritz U, Rommens PM, Gercek E, Drees P, Baranowski A. The effect of losartan on the development of post-traumatic joint stiffness in a rat model. Biomed Pharmacother 2023; 166:115291. [PMID: 37557010 DOI: 10.1016/j.biopha.2023.115291] [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: 04/08/2023] [Revised: 07/27/2023] [Accepted: 08/04/2023] [Indexed: 08/11/2023] Open
Abstract
Post-traumatic joint stiffness (PTJS) is accompanied by a multidimensional disturbance of joint architecture. Pharmacological approaches represent promising alternatives as the traumatic nature of current therapeutic standards may lead to PTJS' progression. Losartan is an auspicious candidate, as it has demonstrated an antifibrotic effect in other organs. Forty-eight Sprague Dawley rats were randomized into equally sized losartan or control groups. After a standardized knee trauma, the joint was immobilized for either 2 weeks (n = 16), 4 weeks (n = 16) or 4 weeks with re-mobilization for an additional 4 weeks (n = 16). Pharmacotherapy with losartan or placebo (30 mg/kg/day) was initiated on the day of trauma and continued for the entire course. Joint contracture was measured alongside histological and molecular biological assessments. There were no significant biomechanical changes in joint contracture over time, comparing short-term (2 weeks) with long-term losartan therapy (4 weeks). However, comparing the formation of PTJS with that of the control, there was a trend toward improvement of joint mobility of 10.5° (p 0.09) under the influence of losartan. During the re-mobilization phase, no significant effect of losartan on range of motion (ROM) was demonstrated. At a cellular level, losartan significantly reduced myofibroblast counts by up to 72 % (4 weeks, p ≤ 0.001) without effecting the capsular configuration. Differences in expression levels of profibrotic factors (TGF-β, CTGF, Il-6) were most pronounced at week 4. The antifibrotic properties of losartan are not prominent enough to completely prevent the development of PTJS after severe joint injury.
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Affiliation(s)
- Erik Wegner
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Tim Mickan
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Sebastian Truffel
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Ekaterina Slotina
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Lukas Müller
- Department of Diagnostic and Interventional Radiology, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany; Mainz Research School of Translational Biomedicine, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Felix Wunderlich
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Austin Harper
- St. George's University School of Medicine, True Blue, St. George, Grenada
| | - Ulrike Ritz
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Pol M Rommens
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Erol Gercek
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Philipp Drees
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Andreas Baranowski
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany.
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Ahmed AA, Mohamed SK, Nofal S, El Morsy EM, Ahmed AAE. Targeting the adenosine monophosphate-activated protein kinase signalling pathway by bempedoic acid attenuates Angiotensin II-induced cardiac remodelling in renovascular hypertension in rats. Life Sci 2023; 329:121963. [PMID: 37473803 DOI: 10.1016/j.lfs.2023.121963] [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: 06/11/2023] [Revised: 07/09/2023] [Accepted: 07/17/2023] [Indexed: 07/22/2023]
Abstract
The crosstalk between the renin-angiotensin system and Adenosine monophosphate-activated protein kinase (AMPK) gained significant interest due to their involvement in the pathogenesis of several cardiovascular diseases. Angiotensin II (Ang II) plays a crucial role in developing cardiac remodelling by inducing energy imbalance, inflammation, oxidative and endoplasmic reticulum stress, and transforming growth factor-β (TGF-β)-induced fibrosis. Ang II directly or through extracellular signal-regulated kinase (ERK) activation impairs AMPK signalling with well-known antioxidant, anti-inflammatory, and anti-fibrotic effects. AIM This study aimed to investigate the role of bempedoic acid, a novel antihyperlipidemic drug, in attenuating hypertension-induced cardiac remodelling in rats by modulating Ang II-induced damage and activating the AMPK signalling pathway. METHOD Sixty adult male Sprague Dawley rats were randomly allocated into the Sham control group, Hypertensive group, Captopril group (30 mg/kg), and Bempedoic acid group (30 mg/kg). Hypertension was induced by left renal artery ligation in all groups except the Sham control group. Treatment with captopril and bempedoic acid started 14 days post-surgy and lasted two weeks. Finally, Hemodynamic measurements and electrocardiographic examination were done followed by heart tissue samples collection for biochemical, histopathological, and immunohistochemical examinations. KEY FINDINGS Bempedoic acid preserved the cardiac function and electrocardiogram patterns. It inhibited endoplasmic reticulum stress, exhibited antioxidant activity, and increased endothelial nitric oxide synthase activity. Bempedoic acid interfered with ERK signalling pathways, including nuclear factor-κB and TGF-β, exerting anti-inflammatory and anti-fibrotic effects. SIGNIFICANCE These findings indicate the cardioprotective and antihypertrophic activity of bempedoic acid, which are suggested to result from energy-independent AMPK downstream signalling activation.
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Affiliation(s)
- Asmaa A Ahmed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Helwan University, Ein Helwan, Egypt.
| | - Shimaa K Mohamed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Helwan University, Ein Helwan, Egypt.
| | - Shahira Nofal
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Helwan University, Ein Helwan, Egypt.
| | - Engy M El Morsy
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Helwan University, Ein Helwan, Egypt.
| | - Amany A E Ahmed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Helwan University, Ein Helwan, Egypt.
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23
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Martins L, Amorim WW, Gregnani MF, de Carvalho Araújo R, Qadri F, Bader M, Pesquero JB. Kinin receptors regulate skeletal muscle regeneration: differential effects for B1 and B2 receptors. Inflamm Res 2023; 72:1583-1601. [PMID: 37464053 PMCID: PMC10499706 DOI: 10.1007/s00011-023-01766-4] [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: 05/20/2023] [Revised: 06/20/2023] [Accepted: 07/02/2023] [Indexed: 07/20/2023] Open
Abstract
OBJECTIVE AND DESIGN After traumatic skeletal muscle injury, muscle healing is often incomplete and produces extensive fibrosis. Bradykinin (BK) reduces fibrosis in renal and cardiac damage models through the B2 receptor. The B1 receptor expression is induced by damage, and blocking of the kallikrein-kinin system seems to affect the progression of muscular dystrophy. We hypothesized that both kinin B1 and B2 receptors could play a differential role after traumatic muscle injury, and the lack of the B1 receptor could produce more cellular and molecular substrates for myogenesis and fewer substrates for fibrosis, leading to better muscle healing. MATERIAL AND METHODS To test this hypothesis, tibialis anterior muscles of kinin receptor knockout animals were subjected to traumatic injury. Myogenesis, angiogenesis, fibrosis, and muscle functioning were evaluated. RESULTS Injured B1KO mice showed a faster healing progression of the injured area with a larger amount of central nucleated fiber post-injury when compared to control mice. In addition, they exhibited higher neovasculogenic capacity, maintaining optimal tissue perfusion for the post-injury phase; had higher amounts of myogenic markers with less inflammatory infiltrate and tissue destruction. This was followed by higher amounts of SMAD7 and lower amounts of p-SMAD2/3, which resulted in less fibrosis. In contrast, B2KO and B1B2KO mice showed more severe tissue destruction and excessive fibrosis. B1KO animals had better results in post-injury functional tests compared to control animals. CONCLUSIONS We demonstrate that injured skeletal muscle tissues have a better repair capacity with less fibrosis in the presence of B2 receptor and absence of B1 receptor, including better performances in functional tests.
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Affiliation(s)
- Leonardo Martins
- Division of Medical Sciences, Laboratory of Transcriptional Regulation, Institute of Medical Biology of Polish Academy of Sciences (IMB-PAN), 3a Tylna St., 90-364, Łódź, Poland.
- Center for Research and Molecular Diagnosis of Genetic Diseases, Federal University of São Paulo, Rua Pedro de Toledo 669, 9th Floor, São Paulo, 04039032, Brazil.
- Department of Biochemistry and Molecular Biology, Federal University of São Paulo, Rua Três de Maio 100, 4th Floor, São Paulo, 04044-020, Brazil.
| | - Weslley Wallace Amorim
- Center for Research and Molecular Diagnosis of Genetic Diseases, Federal University of São Paulo, Rua Pedro de Toledo 669, 9th Floor, São Paulo, 04039032, Brazil
| | - Marcos Fernandes Gregnani
- Laboratory of Exercise Genetics and Metabolism, Federal University of São Paulo, Rua Pedro de Toledo 669, 9th Floor, São Paulo, 04039032, Brazil
| | - Ronaldo de Carvalho Araújo
- Laboratory of Exercise Genetics and Metabolism, Federal University of São Paulo, Rua Pedro de Toledo 669, 9th Floor, São Paulo, 04039032, Brazil
| | - Fatimunnisa Qadri
- Max-Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany
| | - Michael Bader
- Max-Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany
- Institute for Biology, University of Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany
- Charité University Medicine Berlin, Charitéplatz 1, 10117, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Potsdamer Str. 58, 10785, Berlin, Germany
| | - João Bosco Pesquero
- Center for Research and Molecular Diagnosis of Genetic Diseases, Federal University of São Paulo, Rua Pedro de Toledo 669, 9th Floor, São Paulo, 04039032, Brazil.
- Department of Biophysics, Federal University of São Paulo, Rua Botucatu 862, 6th Floor, São Paulo, 04023-062, Brazil.
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24
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Colin M, Delaitre C, Foulquier S, Dupuis F. The AT 1/AT 2 Receptor Equilibrium Is a Cornerstone of the Regulation of the Renin Angiotensin System beyond the Cardiovascular System. Molecules 2023; 28:5481. [PMID: 37513355 PMCID: PMC10383525 DOI: 10.3390/molecules28145481] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 07/11/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
The AT1 receptor has mainly been associated with the pathological effects of the renin-angiotensin system (RAS) (e.g., hypertension, heart and kidney diseases), and constitutes a major therapeutic target. In contrast, the AT2 receptor is presented as the protective arm of this RAS, and its targeting via specific agonists is mainly used to counteract the effects of the AT1 receptor. The discovery of a local RAS has highlighted the importance of the balance between AT1/AT2 receptors at the tissue level. Disruption of this balance is suggested to be detrimental. The fine tuning of this balance is not limited to the regulation of the level of expression of these two receptors. Other mechanisms still largely unexplored, such as S-nitrosation of the AT1 receptor, homo- and heterodimerization, and the use of AT1 receptor-biased agonists, may significantly contribute to and/or interfere with the settings of this AT1/AT2 equilibrium. This review will detail, through several examples (the brain, wound healing, and the cellular cycle), the importance of the functional balance between AT1 and AT2 receptors, and how new molecular pharmacological approaches may act on its regulation to open up new therapeutic perspectives.
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Affiliation(s)
- Mélissa Colin
- CITHEFOR, Université de Lorraine, F-54000 Nancy, France
- Department of Pharmacology and Toxicology, MHeNS-School for Mental Health and Neuroscience, Maastricht University, 6200 MD Maastricht, The Netherlands
| | | | - Sébastien Foulquier
- Department of Pharmacology and Toxicology, MHeNS-School for Mental Health and Neuroscience, Maastricht University, 6200 MD Maastricht, The Netherlands
- CARIM-School for Cardiovascular Diseases, Maastricht University, 6200 MD Maastricht, The Netherlands
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25
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Confalonieri F, Lumi X, Petrovski G. Spontaneous Epiretinal Membrane Resolution and Angiotensin Receptor Blockers: Case Observation, Literature Review and Perspectives. Biomedicines 2023; 11:1976. [PMID: 37509613 PMCID: PMC10377102 DOI: 10.3390/biomedicines11071976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/05/2023] [Accepted: 06/21/2023] [Indexed: 07/30/2023] Open
Abstract
INTRODUCTION Epiretinal membrane (ERM) is a relatively common condition affecting the macula. When symptoms become apparent and compromise a patient's quality of vision, the only therapeutic approach available today is surgery with a vitrectomy and peeling of the ERM. Angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACE-Is) reduce the effect of angiotensin II, limit the amount of fibrosis, and demonstrate consequences on fibrinogenesis in the human body. Case Description and Materials and Methods: A rare case of spontaneous ERM resolution with concomitant administration of ARB is reported. The patient was set on ARB treatment for migraines and arterial hypertension, and a posterior vitreous detachment was already present at the first diagnosis of ERM. The scientific literature addressing the systemic relationship between ARB, ACE-Is, and fibrosis in the past 25 years was searched in the PubMed, Medline, and EMBASE databases. RESULTS In total, 38 and 16 original articles have been selected for ARBs and ACE-Is, respectively, in regard to fibrosis modulation. CONCLUSION ARBs and ACE-Is might have antifibrotic activity on ERM formation and resolution. Further clinical studies are necessary to explore this phenomenon.
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Affiliation(s)
- Filippo Confalonieri
- Department of Ophthalmology, Oslo University Hospital, Kirkeveien 166, 0450 Oslo, Norway
- Center for Eye Research and Innovative Diagnostics, Department of Ophthalmology, Institute for Clinical Medicine, University of Oslo, Kirkeveien 166, 0450 Oslo, Norway
| | - Xhevat Lumi
- Department of Ophthalmology, Oslo University Hospital, Kirkeveien 166, 0450 Oslo, Norway
- Eye Hospital, University Medical Centre Ljubljana, Zaloška Cesta 2, 1000 Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Goran Petrovski
- Department of Ophthalmology, Oslo University Hospital, Kirkeveien 166, 0450 Oslo, Norway
- Center for Eye Research and Innovative Diagnostics, Department of Ophthalmology, Institute for Clinical Medicine, University of Oslo, Kirkeveien 166, 0450 Oslo, Norway
- Department of Ophthalmology, University of Split School of Medicine and University Hospital Centre, 21000 Split, Croatia
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26
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Zou L, Zhou Y, Yu X, Chen C, Xiao G. Angiotensin I-Converting Enzyme Inhibitory Activity of Two Peptides Derived from In Vitro Digestion Products of Pork Sausage with Partial Substitution of NaCl by KCl. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023. [PMID: 37406188 DOI: 10.1021/acs.jafc.3c01149] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/07/2023]
Abstract
This study aimed to identify angiotensin I-converting enzyme (ACE) from in vitro digestion products of pork sausage with partial substitution of NaCl by KCl (PSRK). Peptides from in vitro digestion products of PSRK were identified through liquid chromatography with tandem mass spectrometry analysis coupled with de novo sequencing. Subsequently, the ACE inhibitory peptides LIVGFPAYGH and IVGFPAYGH were screened based on PeptideRanker, in silico absorption, molecular docking, and the determination of ACE inhibitory activity. In addition, the ACE inhibitory peptides LIVGFPAYGH and IVGFPAYGH were mixed-type inhibitors; these peptides' ACE inhibitory activities were expressed as the 50% inhibitory concentration (IC50) values in vitro, which were 196.16 and 150.88 μM, respectively. After 2 h of incubation, LIVGFPAYGH and IVGFPAYGH could be transported through Caco-2 cell monolayers with paracellular passive diffusion. Furthermore, LIVGFPAYGH and IVGFPAYGH significantly increased the levels of ACE2 and nitric oxide while decreasing the levels of ACE, angiotensin II, and endothelin-1 in Ang I-treated human umbilical vein endothelial cells, indicating the ACE inhibitory effect of LIVGFPAYGH and IVGFPAYGH. In summary, LIVGFPAYGH and IVGFPAYGH from PSRK can be used as functional foods with antihypertensive activity.
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Affiliation(s)
- Lifang Zou
- China Light Industry Key Laboratory of Meat Microbial Control and Utilization, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
| | - Yu Zhou
- China Light Industry Key Laboratory of Meat Microbial Control and Utilization, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
| | - Xia Yu
- China Light Industry Key Laboratory of Meat Microbial Control and Utilization, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
| | - Conggui Chen
- China Light Industry Key Laboratory of Meat Microbial Control and Utilization, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
- Engineering Research Center of Bio-process from Ministry of Education, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
| | - Guiran Xiao
- China Light Industry Key Laboratory of Meat Microbial Control and Utilization, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
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27
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Wang E, Zhou R, Li T, Hua Y, Zhou K, Li Y, Luo S, An Q. The Molecular Role of Immune Cells in Dilated Cardiomyopathy. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1246. [PMID: 37512058 PMCID: PMC10385992 DOI: 10.3390/medicina59071246] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/29/2023] [Accepted: 07/03/2023] [Indexed: 07/30/2023]
Abstract
Dilated cardiomyopathy (DCM) is a rare and severe condition characterized by chamber dilation and impaired contraction of the left ventricle. It constitutes a fundamental etiology for profound heart failure and abrupt cardiac demise, rendering it a prominent clinical indication for heart transplantation (HTx) among both adult and pediatric populations. DCM arises from various etiologies, including genetic variants, epigenetic disorders, infectious insults, autoimmune diseases, and cardiac conduction abnormalities. The maintenance of cardiac function involves two distinct types of immune cells: resident immune cells and recruited immune cells. Resident immune cells play a crucial role in establishing a harmonious microenvironment within the cardiac tissue. Nevertheless, in response to injury, cardiomyocytes initiate a cytokine cascade that attracts peripheral immune cells, thus perturbing this intricate equilibrium and actively participating in the initiation and pathological remodeling of dilated cardiomyopathy (DCM), particularly during the progression of myocardial fibrosis. Additionally, immune cells assume a pivotal role in orchestrating the inflammatory processes, which are intimately linked to the prognosis of DCM. Consequently, understanding the molecular role of various immune cells and their regulation mechanisms would provide an emerging era for managing DCM. In this review, we provide a summary of the most recent advancements in our understanding of the molecular mechanisms of immune cells in DCM. Additionally, we evaluate the effectiveness and limitations of immunotherapy approaches for the treatment of DCM, with the aim of optimizing future immunotherapeutic strategies for this condition.
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Affiliation(s)
- Enping Wang
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Ruofan Zhou
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Tiange Li
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Yimin Hua
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Kaiyu Zhou
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Yifei Li
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Shuhua Luo
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Qi An
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
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28
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Brown S, Nores GDG, Sarker A, Ly C, Li C, Park HJ, Hespe GE, Gardenier J, Kuonqui K, Campbell A, Shin J, Kataru RP, Aras O, Mehrara BJ. Topical captopril: a promising treatment for secondary lymphedema. Transl Res 2023; 257:43-53. [PMID: 36736951 PMCID: PMC10192126 DOI: 10.1016/j.trsl.2023.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 01/15/2023] [Accepted: 01/25/2023] [Indexed: 02/04/2023]
Abstract
Transforming growth factor-beta 1 (TGF-β1)-mediated tissue fibrosis is an important regulator of lymphatic dysfunction in secondary lymphedema. However, TGF-β1 targeting can cause toxicity and autoimmune complications, limiting clinical utility. Angiotensin II (Ang II) modulates intracellular TGF-β1 signaling, and inhibition of Ang II production using angiotensin-converting enzyme (ACE) inhibitors, such as captopril, has antifibrotic efficacy in some pathological settings. Therefore, we analyzed the expression of ACE and Ang II in clinical lymphedema biopsy specimens from patients with unilateral breast cancer-related lymphedema (BCRL) and mouse models, and found that cutaneous ACE expression is increased in lymphedematous tissues. Furthermore, topical captopril decreases fibrosis, activation of intracellular TGF-β1 signaling pathways, inflammation, and swelling in mouse models of lymphedema. Captopril treatment also improves lymphatic function and immune cell trafficking by increasing collecting lymphatic pumping. Our results show that the renin-angiotensin system in the skin plays an important role in the regulation of fibrosis in lymphedema, and inhibition of this signaling pathway may hold merit for treating lymphedema.
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Affiliation(s)
- Stav Brown
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Gabriela D G Nores
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ananta Sarker
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Catherine Ly
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Claire Li
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Hyeung Ju Park
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Geoffrey E Hespe
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jason Gardenier
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Kevin Kuonqui
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Adana Campbell
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jinyeon Shin
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Raghu P Kataru
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Omer Aras
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Babak J Mehrara
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York.
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29
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Russo E, Corrao S, Di Gaudio F, Alberti G, Caprnda M, Kubatka P, Kruzliak P, Miceli V, Conaldi PG, Borlongan CV, La Rocca G. Facing the Challenges in the COVID-19 Pandemic Era: From Standard Treatments to the Umbilical Cord-Derived Mesenchymal Stromal Cells as a New Therapeutic Strategy. Cells 2023; 12:1664. [PMID: 37371134 PMCID: PMC10297457 DOI: 10.3390/cells12121664] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/10/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19), the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which counts more than 650 million cases and more than 6.6 million of deaths worldwide, affects the respiratory system with typical symptoms such as fever, cough, sore throat, acute respiratory distress syndrome (ARDS), and fatigue. Other nonpulmonary manifestations are related with abnormal inflammatory response, the "cytokine storm", that could lead to a multiorgan disease and to death. Evolution of effective vaccines against SARS-CoV-2 provided multiple options to prevent the infection, but the treatment of the severe forms remains difficult to manage. The cytokine storm is usually counteracted with standard medical care and anti-inflammatory drugs, but researchers moved forward their studies on new strategies based on cell therapy approaches. The perinatal tissues, such as placental membranes, amniotic fluid, and umbilical cord derivatives, are enriched in mesenchymal stromal cells (MSCs) that exert a well-known anti-inflammatory role, immune response modulation, and tissue repair. In this review, we focused on umbilical-cord-derived MSCs (UC-MSCs) used in in vitro and in vivo studies in order to evaluate the weakening of the severe symptoms, and on recent clinical trials from different databases, supporting the favorable potential of UC-MSCs as therapeutic strategy.
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Affiliation(s)
- Eleonora Russo
- Section of Histology and Embryology, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (E.R.); (G.A.)
| | - Simona Corrao
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per per i Trapianti e Terapie Ad Alta Specializzazione), 90127 Palermo, Italy; (S.C.); (V.M.); (P.G.C.)
| | | | - Giusi Alberti
- Section of Histology and Embryology, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (E.R.); (G.A.)
| | - Martin Caprnda
- 1st Department of Internal Medicine, Faculty of Medicine, Comenius University, University Hospital Bratislava, 81499 Bratislava, Slovakia;
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03649 Martin, Slovakia;
| | - Peter Kruzliak
- Research and Development Services, Pradlacka 18, 61300 Brno, Czech Republic;
| | - Vitale Miceli
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per per i Trapianti e Terapie Ad Alta Specializzazione), 90127 Palermo, Italy; (S.C.); (V.M.); (P.G.C.)
| | - Pier Giulio Conaldi
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per per i Trapianti e Terapie Ad Alta Specializzazione), 90127 Palermo, Italy; (S.C.); (V.M.); (P.G.C.)
| | - Cesario Venturina Borlongan
- Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Giampiero La Rocca
- Section of Histology and Embryology, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (E.R.); (G.A.)
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30
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Huang CLH, Lei M. Cardiomyocyte electrophysiology and its modulation: current views and future prospects. Philos Trans R Soc Lond B Biol Sci 2023; 378:20220160. [PMID: 37122224 PMCID: PMC10150219 DOI: 10.1098/rstb.2022.0160] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 03/10/2023] [Indexed: 05/02/2023] Open
Abstract
Normal and abnormal cardiac rhythms are of key physiological and clinical interest. This introductory article begins from Sylvio Weidmann's key historic 1950s microelectrode measurements of cardiac electrophysiological activity and Singh & Vaughan Williams's classification of cardiotropic targets. It then proceeds to introduce the insights into cardiomyocyte function and its regulation that subsequently emerged and their therapeutic implications. We recapitulate the resulting view that surface membrane electrophysiological events underlying cardiac excitation and its initiation, conduction and recovery constitute the final common path for the cellular mechanisms that impinge upon this normal or abnormal cardiac electrophysiological activity. We then consider progress in the more recently characterized successive regulatory hierarchies involving Ca2+ homeostasis, excitation-contraction coupling and autonomic G-protein signalling and their often reciprocal interactions with the surface membrane events, and their circadian rhythms. Then follow accounts of longer-term upstream modulation processes involving altered channel expression, cardiomyocyte energetics and hypertrophic and fibrotic cardiac remodelling. Consideration of these developments introduces each of the articles in this Phil. Trans. B theme issue. The findings contained in these articles translate naturally into recent classifications of cardiac electrophysiological targets and drug actions, thereby encouraging future iterations of experimental cardiac electrophysiological discovery, and testing directed towards clinical management. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.
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Affiliation(s)
- Christopher L.-H. Huang
- Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK
- Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK
| | - Ming Lei
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK
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31
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Sinha A, Vaggu RG, Swain R, Patnaik S. Repurposing of RAS-Pathway Mediated Drugs for Intestinal Inflammation Related Diseases for Treating SARS-CoV-2 Infection. Curr Microbiol 2023; 80:194. [PMID: 37106165 PMCID: PMC10136399 DOI: 10.1007/s00284-023-03304-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 04/16/2023] [Indexed: 04/29/2023]
Abstract
Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) is an emerging zoonotic virus, which causes Coronavirus Disease 2019 (COVID-19). Entry of coronaviruses into the cell depends on binding of the viral spike (S) proteins to cellular receptors Angiotensin-converting enzyme 2 (ACE2). The virus-mediated reduction of ACE2/Ang1-7 causes flooding of inflammatory cytokines. A similar scenario of hyper immunologic reaction has been witnessed in the context of Intestinal Inflammatory Diseases (IIDs) with the deregulation of ACE2. This review summarizes several IIDs that lead to such susceptible conditions. It discusses suitable mechanisms of how ACE2, being a crucial regulator of the Renin-Angiotensin System (RAS) signaling pathway, can affect the physiology of intestine as well as lungs, the primary site of SARS-CoV-2 infection. ACE2, as a SARS-CoV-2 receptor, establishes a critical link between COVID-19 and IIDs. Intercessional studies targeting the RAS signaling pathway in patients may provide a novel strategy for addressing the COVID-19 crisis. Hence, the modulation of these key RAS pathway members can be beneficial in both instances. However, it's difficult to say how beneficial are the ACE inhibitors (ACEI)/ Angiotensin II type-1 receptor blockers (ARBs) during COVID-19. As a result, much more research is needed to better understand the relationship between the RAS and SARS-CoV-2 infection.
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Affiliation(s)
- Anupriya Sinha
- School of Biotechnology, KIIT University, Campus-XI, Bhubaneswar, Odisha, 751024, India
| | | | - Ramakrushna Swain
- School of Biotechnology, KIIT University, Campus-XI, Bhubaneswar, Odisha, 751024, India
| | - Srinivas Patnaik
- School of Biotechnology, KIIT University, Campus-XI, Bhubaneswar, Odisha, 751024, India.
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32
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Bianchi LMG, Irmici G, Cè M, D'Ascoli E, Della Pepa G, Di Vita F, Casati O, Soresina M, Menozzi A, Khenkina N, Cellina M. Diagnosis and Treatment of Post-Prostatectomy Lymphedema: What's New? Curr Oncol 2023; 30:4512-4526. [PMID: 37232799 DOI: 10.3390/curroncol30050341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/24/2023] [Accepted: 04/24/2023] [Indexed: 05/27/2023] Open
Abstract
Lymphedema is a chronic progressive disorder that significantly compromises patients' quality of life. In Western countries, it often results from cancer treatment, as in the case of post-radical prostatectomy lymphedema, where it can affect up to 20% of patients, with a significant disease burden. Traditionally, diagnosis, assessment of severity, and management of disease have relied on clinical assessment. In this landscape, physical and conservative treatments, including bandages and lymphatic drainage have shown limited results. Recent advances in imaging technology are revolutionizing the approach to this disorder: magnetic resonance imaging has shown satisfactory results in differential diagnosis, quantitative classification of severity, and most appropriate treatment planning. Further innovations in microsurgical techniques, based on the use of indocyanine green to map lymphatic vessels during surgery, have improved the efficacy of secondary LE treatment and led to the development of new surgical approaches. Physiologic surgical interventions, including lymphovenous anastomosis (LVA) and vascularized lymph node transplant (VLNT), are going to face widespread diffusion. A combined approach to microsurgical treatment provides the best results: LVA is effective in promoting lymphatic drainage, bridging VLNT delayed lymphangiogenic and immunological effects in the lymphatic impairment site. Simultaneous VLNT and LVA are safe and effective for patients with both early and advanced stages of post-prostatectomy LE. A new perspective is now represented by the combination of microsurgical treatments with the positioning of nano fibrillar collagen scaffolds (BioBridgeTM) to favor restoring the lymphatic function, allowing for improved and sustained volume reduction. In this narrative review, we proposed an overview of new strategies for diagnosing and treating post-prostatectomy lymphedema to get the most appropriate and successful patient treatment with an overview of the main artificial intelligence applications in the prevention, diagnosis, and management of lymphedema.
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Affiliation(s)
| | - Giovanni Irmici
- Postgraduation School in Radiodiagnostics, University of Milan, 20122 Milan, Italy
| | - Maurizio Cè
- Postgraduation School in Radiodiagnostics, University of Milan, 20122 Milan, Italy
| | - Elisa D'Ascoli
- Postgraduation School in Radiodiagnostics, University of Milan, 20122 Milan, Italy
| | - Gianmarco Della Pepa
- Postgraduation School in Radiodiagnostics, University of Milan, 20122 Milan, Italy
| | - Filippo Di Vita
- Postgraduation School in Plastic Surgery, University of Milan, Via Festa del Perdono, 7, 20122 Milan, Italy
| | - Omar Casati
- Postgraduation School in Plastic Surgery, University of Milan, Via Festa del Perdono, 7, 20122 Milan, Italy
| | - Massimo Soresina
- Plastic Surgery Department, Fatebenefratelli Hospital, ASST Fatebenefratelli Sacco, 20121 Milan, Italy
| | - Andrea Menozzi
- Plastic Surgery Department, Fatebenefratelli Hospital, ASST Fatebenefratelli Sacco, 20121 Milan, Italy
| | - Natallia Khenkina
- Postgraduation School in Radiodiagnostics, University of Milan, 20122 Milan, Italy
| | - Michaela Cellina
- Radiology Department, Fatebenefratelli Hospital, ASST Fatebenefratelli Sacco, 20121 Milan, Italy
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33
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Lee SY, Kuo YH, Du CX, Huang CW, Ku HC. A novel caffeic acid derivative prevents angiotensin II-induced cardiac remodeling. Biomed Pharmacother 2023; 162:114709. [PMID: 37084559 DOI: 10.1016/j.biopha.2023.114709] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 04/12/2023] [Accepted: 04/12/2023] [Indexed: 04/23/2023] Open
Abstract
Differentiation of cardiac fibroblasts into myofibroblasts is a critical event in the progression of cardiac fibrosis that causes pathological cardiac remodeling. Cardiac fibrosis is a hallmark of heart disease and is associated with a stiff myocardium and heart failure. This study investigated the effect of caffeic acid ethanolamide (CAEA), a novel caffeic acid derivative, on cardiac remodeling. Angiotensin (Ang) II was used to induce cardiac remodeling both in cell and animal studies. Treating cardiac fibroblast with CAEA in Ang II-exposed cell cultures reduced the expression of fibrotic marker α-smooth muscle actin (α-SMA) and collagen and the production of superoxide, indicating that CAEA inhibited the differentiation of fibroblast into myofibroblast after Ang II exposure. CAEA protects against Ang II-induced cardiac fibrosis and dysfunction in vivo, characterized by the alleviation of collagen accumulation and the recovery of ejection fraction. In addition, CAEA decreased Ang II-induced transforming growth factor-β (TGF-β) expression and reduced NOX4 expression and oxidative stress in a SMAD-dependent pathway. CAEA participated in the regulation of Ang II-induced TGF-β/SMAD/NOX4 signaling to prevent the differentiation of fibroblast into myofibroblast and thus exerted a cardioprotective effect. Our data support the administration of CAEA as a viable method for preventing the progression of Ang II-induced cardiac remodeling.
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Affiliation(s)
- Shih-Yi Lee
- Division of Pulmonary and Critical Care Medicine, MacKay Memorial Hospital, Taipei, Taiwan; MacKay Junior College of Medicine, Nursing and Management, Taipei, Taiwan
| | - Yueh-Hsiung Kuo
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan; Department of Biotechnology, Asia University, Taichung, Taiwan
| | - Chen-Xuan Du
- Department of Life Science, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Cheng-Wei Huang
- Department of Life Science, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Hui-Chun Ku
- Department of Life Science, Fu Jen Catholic University, New Taipei City, Taiwan.
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34
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Duangrat R, Parichatikanond W, Mangmool S. Dual Blockade of TGF-β Receptor and Endothelin Receptor Synergistically Inhibits Angiotensin II-Induced Myofibroblast Differentiation: Role of AT 1R/G αq-Mediated TGF-β1 and ET-1 Signaling. Int J Mol Sci 2023; 24:ijms24086972. [PMID: 37108136 PMCID: PMC10138810 DOI: 10.3390/ijms24086972] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 03/30/2023] [Accepted: 04/07/2023] [Indexed: 04/29/2023] Open
Abstract
Angiotensin II (Ang II) upregulates transforming growth factor-beta1 (TGF-β1) and endothelin-1 (ET-1) in various types of cells, and all of them act as profibrotic mediators. However, the signal transduction of angiotensin II receptor (ATR) for upregulation of TGF-β1 and ET-1, and their effectors that play an essential role in myofibroblast differentiation, are not fully understood. Therefore, we investigated the ATR networking with TGF-β1 and ET-1 and identified the signal transduction of these mediators by measuring the mRNA expression of alpha-smooth muscle actin (α-SMA) and collagen I using qRT-PCR. Myofibroblast phenotypes were monitored by α-SMA and stress fiber formation with fluorescence microscopy. Our findings suggested that Ang II induced collagen I and α-SMA synthesis and stress fiber formation through the AT1R/Gαq axis in adult human cardiac fibroblasts (HCFs). Following AT1R stimulation, Gαq protein, not Gβγ subunit, was required for upregulation of TGF-β1 and ET-1. Moreover, dual inhibition of TGF-β and ET-1 signaling completely inhibited Ang II-induced myofibroblast differentiation. The AT1R/Gαq cascade transduced signals to TGF-β1, which in turn upregulated ET-1 via the Smad- and ERK1/2-dependent pathways. ET-1 consecutively bound to and activated endothelin receptor type A (ETAR), leading to increases in collagen I and α-SMA synthesis and stress fiber formation. Remarkably, dual blockade of TGF-β receptor and ETR exhibited the restorative effects to reverse the myofibroblast phenotype induced by Ang II. Collectively, TGF-β1 and ET-1 are major effectors of AT1R/Gαq cascade, and therefore, negative regulation of TGF-β and ET-1 signaling represents a targeted therapeutic strategy for the prevention and restoration of cardiac fibrosis.
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Affiliation(s)
- Ratchanee Duangrat
- Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
- Molecular Medicine Graduate Program, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Warisara Parichatikanond
- Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand
- Centre of Biopharmaceutical Science for Healthy Ageing (BSHA), Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand
| | - Supachoke Mangmool
- Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
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35
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Gan PXL, Liao W, Linke KM, Mei D, Wu XD, Wong WSF. Targeting the renin angiotensin system for respiratory diseases. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2023; 98:111-144. [PMID: 37524485 DOI: 10.1016/bs.apha.2023.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/03/2023]
Abstract
Renin-angiotensin system (RAS) plays an indispensable role in regulating blood pressure through its effects on fluid and electrolyte balance. As an aside, cumulative evidence from experimental to clinical studies supports the notion that dysregulation of RAS contributes to the pro-inflammatory, pro-oxidative, and pro-fibrotic processes that occur in pulmonary diseases like asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and acute lung injury (ALI). Pharmacological intervention of the various RAS components can be a novel therapeutic strategy for the treatment of these respiratory diseases. In this chapter, we first give a recent update on the RAS, and then compile, review, and analyse recent reports on targeting RAS components as treatments for respiratory diseases. Inhibition of the pro-inflammatory renin, angiotensin-converting enzyme (ACE), angiotensin (Ang) II, and Ang II type 1 receptor (AT1R) axis, and activation of the protective ACE2, AT2R, Ang (1-7), and Mas receptor axis have demonstrated varying degrees of efficacies in experimental respiratory disease models or in human trials. The newly identified alamandine/Mas-related G-protein-coupled receptor member D pathway has shown some therapeutic promise as well. However, our understanding of the RAS ligand-and-receptor interactions is still inconclusive, and the modes of action and signaling cascade mediating the newly identified RAS receptors remain to be better characterized. Clinical data are obviously lacking behind the promising pre-clinical findings of certain well-established molecules targeting at different pathways of the RAS in respiratory diseases. Translational human studies should be the focus for RAS drug development in lung diseases in the next decade.
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Affiliation(s)
- Phyllis X L Gan
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore
| | - W Liao
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore; Singapore-HUJ Alliance for Research Enterprise, National University of Singapore, Singapore, Singapore
| | - Kira M Linke
- Department of Pharmacology, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - D Mei
- Department of Respiratory and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, P.R. China
| | - X D Wu
- Department of Respiratory and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, P.R. China
| | - W S Fred Wong
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore; Singapore-HUJ Alliance for Research Enterprise, National University of Singapore, Singapore, Singapore; Drug Discovery and Optimization Platform, National University Health System, Singapore, Singapore.
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36
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Bekedam FT, Goumans MJ, Bogaard HJ, de Man FS, Llucià-Valldeperas A. Molecular mechanisms and targets of right ventricular fibrosis in pulmonary hypertension. Pharmacol Ther 2023; 244:108389. [PMID: 36940790 DOI: 10.1016/j.pharmthera.2023.108389] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 02/19/2023] [Accepted: 03/16/2023] [Indexed: 03/23/2023]
Abstract
Right ventricular fibrosis is a stress response, predominantly mediated by cardiac fibroblasts. This cell population is sensitive to increased levels of pro-inflammatory cytokines, pro-fibrotic growth factors and mechanical stimulation. Activation of fibroblasts results in the induction of various molecular signaling pathways, most notably the mitogen-activated protein kinase cassettes, leading to increased synthesis and remodeling of the extracellular matrix. While fibrosis confers structural protection in response to damage induced by ischemia or (pressure and volume) overload, it simultaneously contributes to increased myocardial stiffness and right ventricular dysfunction. Here, we review state-of-the-art knowledge of the development of right ventricular fibrosis in response to pressure overload and provide an overview of all published preclinical and clinical studies in which right ventricular fibrosis was targeted to improve cardiac function.
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Affiliation(s)
- F T Bekedam
- Amsterdam UMC location Vrije Universiteit Amsterdam, PHEniX laboratory, Department of Pulmonary Medicine, De Boelelaan 1117, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Pulmonary Hypertension and Thrombosis, Amsterdam, the Netherlands
| | - M J Goumans
- Department of Cell and Chemical Biology, Leiden UMC, 2300 RC Leiden, the Netherlands
| | - H J Bogaard
- Amsterdam UMC location Vrije Universiteit Amsterdam, PHEniX laboratory, Department of Pulmonary Medicine, De Boelelaan 1117, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Pulmonary Hypertension and Thrombosis, Amsterdam, the Netherlands
| | - F S de Man
- Amsterdam UMC location Vrije Universiteit Amsterdam, PHEniX laboratory, Department of Pulmonary Medicine, De Boelelaan 1117, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Pulmonary Hypertension and Thrombosis, Amsterdam, the Netherlands.
| | - A Llucià-Valldeperas
- Amsterdam UMC location Vrije Universiteit Amsterdam, PHEniX laboratory, Department of Pulmonary Medicine, De Boelelaan 1117, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Pulmonary Hypertension and Thrombosis, Amsterdam, the Netherlands.
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37
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Dow T, Selman T, Williams J, Bezuhly M. The Role of ACE-Inhibitors and ARBs in reducing hypertrophic scarring following bilateral breast reduction. J Plast Reconstr Aesthet Surg 2023; 78:1-3. [PMID: 36669236 DOI: 10.1016/j.bjps.2022.11.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/20/2022] [Accepted: 11/17/2022] [Indexed: 01/13/2023]
Abstract
BACKGROUND The angiotensin-renin system (ARS) has been shown to play a role in the promotion of tissue fibrosis through angiotensin II activation of the angiotensin-receptor 1 and subsequently transforming growth factor beta-1 (TGF- β1). Breast reduction surgery is known to have a potential complication of hypertrophic scarring. The primary objective of this study is to assess whether the use of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blockers (ARBs) by patients undergoing bilateral reduction mammoplasty is correlated with a reduction in hypertrophic scarring complications post-operatively. METHODS A retrospective chart review of all patients who received bilateral breast reduction surgery in our province over a 10-year period was performed. Patient charts were reviewed for post-operative hypertrophic scarring as well as medications being used around the time of surgery. The rate of hypertrophic scarring within patients treated with an ACEi or ARB for existing hypertension were compared with the rest of the population. RESULTS A total of 981 patients met the inclusion criteria of the study. The overall incidence of hypertrophic scarring was 6%. Within the population, 132 (14%) of patients had a clinical diagnosis of hypertension. Of the patients who were managed with an ACEi or ARB, one (2%) patient developed hypertrophic scarring post-operatively. This was significantly less than the total population and the remainder of the population with hypertension treated with a medication other than an ACEi or ARB. CONCLUSIONS This study investigated the impact of routine ACEi or ARB use by patients undergoing bilateral reduction mammoplasty and demonstrated a statistically significant reduction in the incidence of hypertrophic scarring. This study is one of the first to investigate ACEi or ARB use in humans to reduce rates of unsightly scarring. LEVEL OF EVIDENCE Level III.
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Affiliation(s)
- Todd Dow
- Division of Plastic Surgery and Reconstructive Surgery, Dalhousie University, Halifax, Nova Scotia, Canada.
| | - Tamara Selman
- Division of Plastic Surgery and Reconstructive Surgery, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Jason Williams
- Division of Plastic Surgery and Reconstructive Surgery, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Michael Bezuhly
- Division of Plastic Surgery and Reconstructive Surgery, Dalhousie University, Halifax, Nova Scotia, Canada
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Khan SM, Martin RD, Bayne A, Pétrin D, Bourque K, Jones-Tabah J, Bouazza C, Blaney J, Lau J, Martins-Cannavino K, Gora S, Zhang A, MacKinnon S, Trieu P, Clarke PBS, Trempe JF, Tanny JC, Hébert TE. Gβγ subunits colocalize with RNA polymerase II and regulate transcription in cardiac fibroblasts. J Biol Chem 2023; 299:103064. [PMID: 36841480 PMCID: PMC10060754 DOI: 10.1016/j.jbc.2023.103064] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 02/08/2023] [Accepted: 02/09/2023] [Indexed: 02/26/2023] Open
Abstract
Gβγ subunits mediate many different signaling processes in various compartments of the cell, including the nucleus. To gain insight into the functions of nuclear Gβγ signaling, we investigated the functional role of Gβγ signaling in the regulation of GPCR-mediated gene expression in primary rat neonatal cardiac fibroblasts. We identified a novel, negative, regulatory role for the Gβ1γ dimer in the fibrotic response. Depletion of Gβ1 led to derepression of the fibrotic response at the mRNA and protein levels under basal conditions and an enhanced fibrotic response after sustained stimulation of the angiotensin II type I receptor. Our genome-wide chromatin immunoprecipitation experiments revealed that Gβ1 colocalized and interacted with RNA polymerase II on fibrotic genes in an angiotensin II-dependent manner. Additionally, blocking transcription with inhibitors of Cdk9 prevented association of Gβγ with transcription complexes. Together, our findings suggest that Gβ1γ is a novel transcriptional regulator of the fibrotic response that may act to restrict fibrosis to conditions of sustained fibrotic signaling. Our work expands the role for Gβγ signaling in cardiac fibrosis and may have broad implications for the role of nuclear Gβγ signaling in other cell types.
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Affiliation(s)
- Shahriar M Khan
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Ryan D Martin
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Andrew Bayne
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada; Centre de Recherche en Biologie Structurale, McGill University, Montréal, Québec, Canada
| | - Darlaine Pétrin
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Kyla Bourque
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Jace Jones-Tabah
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Celia Bouazza
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Jacob Blaney
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Jenny Lau
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | | | - Sarah Gora
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Andy Zhang
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Sarah MacKinnon
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Phan Trieu
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Paul B S Clarke
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Jean-François Trempe
- Centre de Recherche en Biologie Structurale, McGill University, Montréal, Québec, Canada
| | - Jason C Tanny
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
| | - Terence E Hébert
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
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39
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Duangrat R, Parichatikanond W, Morales NP, Pinthong D, Mangmool S. Sustained AT1R stimulation induces upregulation of growth factors in human cardiac fibroblasts via Gαq/TGF-β/ERK signaling that influences myocyte hypertrophy. Eur J Pharmacol 2022; 937:175384. [DOI: 10.1016/j.ejphar.2022.175384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/03/2022] [Accepted: 11/04/2022] [Indexed: 11/13/2022]
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40
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Wang EY, Zhao Y, Okhovatian S, Smith JB, Radisic M. Intersection of stem cell biology and engineering towards next generation in vitro models of human fibrosis. Front Bioeng Biotechnol 2022; 10:1005051. [PMID: 36338120 PMCID: PMC9630603 DOI: 10.3389/fbioe.2022.1005051] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 09/26/2022] [Indexed: 08/31/2023] Open
Abstract
Human fibrotic diseases constitute a major health problem worldwide. Fibrosis involves significant etiological heterogeneity and encompasses a wide spectrum of diseases affecting various organs. To date, many fibrosis targeted therapeutic agents failed due to inadequate efficacy and poor prognosis. In order to dissect disease mechanisms and develop therapeutic solutions for fibrosis patients, in vitro disease models have gone a long way in terms of platform development. The introduction of engineered organ-on-a-chip platforms has brought a revolutionary dimension to the current fibrosis studies and discovery of anti-fibrotic therapeutics. Advances in human induced pluripotent stem cells and tissue engineering technologies are enabling significant progress in this field. Some of the most recent breakthroughs and emerging challenges are discussed, with an emphasis on engineering strategies for platform design, development, and application of machine learning on these models for anti-fibrotic drug discovery. In this review, we discuss engineered designs to model fibrosis and how biosensor and machine learning technologies combine to facilitate mechanistic studies of fibrosis and pre-clinical drug testing.
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Affiliation(s)
- Erika Yan Wang
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
| | - Yimu Zhao
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Sargol Okhovatian
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Jacob B. Smith
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada
| | - Milica Radisic
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada
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Prospects and Challenges of Electrospun Cell and Drug Delivery Vehicles to Correct Urethral Stricture. Int J Mol Sci 2022; 23:ijms231810519. [PMID: 36142432 PMCID: PMC9502833 DOI: 10.3390/ijms231810519] [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: 07/30/2022] [Revised: 08/30/2022] [Accepted: 09/01/2022] [Indexed: 11/17/2022] Open
Abstract
Current therapeutic modalities to treat urethral strictures are associated with several challenges and shortcomings. Therefore, significant strides have been made to develop strategies with minimal side effects and the highest therapeutic potential. In this framework, electrospun scaffolds incorporated with various cells or bioactive agents have provided promising vistas to repair urethral defects. Due to the biomimetic nature of these constructs, they can efficiently mimic the native cells’ niches and provide essential microenvironmental cues for the safe transplantation of multiple cell types. Furthermore, these scaffolds are versatile platforms for delivering various drug molecules, growth factors, and nucleic acids. This review discusses the recent progress, applications, and challenges of electrospun scaffolds to deliver cells or bioactive agents during the urethral defect repair process. First, the current status of electrospinning in urethral tissue engineering is presented. Then, the principles of electrospinning in drug and cell delivery applications are reviewed. Finally, the recent preclinical studies are summarized and the current challenges are discussed.
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Flournoy J, Ashkanani S, Chen Y. Mechanical regulation of signal transduction in angiogenesis. Front Cell Dev Biol 2022; 10:933474. [PMID: 36081909 PMCID: PMC9447863 DOI: 10.3389/fcell.2022.933474] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 07/28/2022] [Indexed: 11/21/2022] Open
Abstract
Biophysical and biochemical cues work in concert to regulate angiogenesis. These cues guide angiogenesis during development and wound healing. Abnormal cues contribute to pathological angiogenesis during tumor progression. In this review, we summarize the known signaling pathways involved in mechanotransduction important to angiogenesis. We discuss how variation in the mechanical microenvironment, in terms of stiffness, ligand availability, and topography, can modulate the angiogenesis process. We also present an integrated view on how mechanical perturbations, such as stretching and fluid shearing, alter angiogenesis-related signal transduction acutely, leading to downstream gene expression. Tissue engineering-based approaches to study angiogenesis are reviewed too. Future directions to aid the efforts in unveiling the comprehensive picture of angiogenesis are proposed.
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Affiliation(s)
- Jennifer Flournoy
- Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, United States
- Center for Cell Dynamics, Johns Hopkins University, Baltimore, MD, United States
- Institute for NanoBio Technology, Johns Hopkins University, Baltimore, MD, United States
| | - Shahad Ashkanani
- Center for Cell Dynamics, Johns Hopkins University, Baltimore, MD, United States
- Institute for NanoBio Technology, Johns Hopkins University, Baltimore, MD, United States
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, United States
| | - Yun Chen
- Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, United States
- Center for Cell Dynamics, Johns Hopkins University, Baltimore, MD, United States
- Institute for NanoBio Technology, Johns Hopkins University, Baltimore, MD, United States
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Yu Q, Zhu D, Zou Y, Wang K, Rao P, Shen Y. Catalpol Attenuates Pulmonary Fibrosis by Inhibiting Ang II/AT1 and TGF-β/Smad-Mediated Epithelial Mesenchymal Transition. Front Med (Lausanne) 2022; 9:878601. [PMID: 35685407 PMCID: PMC9171363 DOI: 10.3389/fmed.2022.878601] [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: 04/01/2022] [Accepted: 04/25/2022] [Indexed: 11/25/2022] Open
Abstract
Background Idiopathic pulmonary fibrosis (IPF) is a progressive and devastating chronic lung condition affecting over 3 million people worldwide with a high mortality rate and there are no effective drugs. Angiotensin II (Ang II), as a major effector peptide of the renin angiotensin aldosterone system, has been shown to act in tandem with the transforming growth factor-β (TGF-β) signaling pathway to promote the infiltration of inflammatory cells, production of reactive oxygen species (ROS) and profibrotic factors after lung injury, and to participate in the process of epithelial mesenchymal transition (EMT). Catalpol (CAT) has been shown to have anti-inflammatory and antifibrotic effects. However, the effects and mechanisms of CAT on pulmonary fibrosis are not clear. Purpose To assess the effects and mechanisms of catalpol on bleomycin-induced pulmonary fibrosis in mice. Methods We used bleomycin-induced mouse model of pulmonary fibrosis to evaluate the alleviation effect of CAT at 7, 14, 28d, respectively. Next, enzyme-linked immunosorbent assay, hematoxylin-eosin staining, immunofluorescence, Masson trichrome staining and western blotting were used to study the underlying mechanism of CAT on bleomycin-induced pulmonary fibrosis. Results It's demonstrated that CAT exerted a potent anti-fibrotic function in BLM-induced mice pulmonary fibrosis via alleviating inflammatory, ameliorating collagen deposition, reducing the level of Ang II and HYP and alleviating the degree of EMT. Moreover, CAT attenuate BLM-induced fibrosis by targeting Ang II/AT1 and TGF-β/Smad signaling in vivo. Conclusion CAT may serve as a novel therapeutic candidate for the simultaneous blockade of Ang II and TGF-β pathway to attenuate pulmonary fibrosis.
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Affiliation(s)
- Qun Yu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Dewei Zhu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yang Zou
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Kai Wang
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Peili Rao
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yunhui Shen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Yunhui Shen
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Kilmister EJ, Tan ST. Insights Into Vascular Anomalies, Cancer, and Fibroproliferative Conditions: The Role of Stem Cells and the Renin-Angiotensin System. Front Surg 2022; 9:868187. [PMID: 35574555 PMCID: PMC9091963 DOI: 10.3389/fsurg.2022.868187] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 03/22/2022] [Indexed: 12/15/2022] Open
Abstract
Cells exhibiting embryonic stem cell (ESC) characteristics have been demonstrated in vascular anomalies (VAs), cancer, and fibroproliferative conditions, which are commonly managed by plastic surgeons and remain largely unsolved. The efficacy of the mTOR inhibitor sirolimus, and targeted therapies that block the Ras/BRAF/MEK/ERK1/2 and PI3KCA/AKT/mTOR pathways in many types of cancer and VAs, further supports the critical role of ESC-like cells in the pathogenesis of these conditions. ESC-like cells in VAs, cancer, and fibroproliferative conditions express components of the renin-angiotensin system (RAS) – a homeostatic endocrine signaling cascade that regulates cells with ESC characteristics. ESC-like cells are influenced by the Ras/BRAF/MEK/ERK1/2 and PI3KCA/AKT/mTOR pathways, which directly regulate cellular proliferation and stemness, and interact with the RAS at multiple points. Gain-of-function mutations affecting these pathways have been identified in many types of cancer and VAs, that have been treated with targeted therapies with some success. In cancer, the RAS promotes tumor progression, treatment resistance, recurrence, and metastasis. The RAS modulates cellular invasion, migration, proliferation, and angiogenesis. It also indirectly regulates ESC-like cells via its direct influence on the tissue microenvironment and by its interaction with the immune system. In vitro studies show that RAS inhibition suppresses the hallmarks of cancer in different experimental models. Numerous epidemiological studies show a reduced incidence of cancer and improved survival outcomes in patients taking RAS inhibitors, although some studies have shown no such effect. The discovery of ESC-like cells that express RAS components in infantile hemangioma (IH) underscores the paradigm shift in the understanding of its programmed biologic behavior and accelerated involution induced by β-blockers and angiotensin-converting enzyme inhibitors. The findings of SOX18 inhibition by R-propranolol suggests the possibility of targeting ESC-like cells in IH without β-adrenergic blockade, and its associated side effects. This article provides an overview of the current knowledge of ESC-like cells and the RAS in VAs, cancer, and fibroproliferative conditions. It also highlights new lines of research and potential novel therapeutic approaches for these unsolved problems in plastic surgery, by targeting the ESC-like cells through manipulation of the RAS, its bypass loops and converging signaling pathways using existing low-cost, commonly available, and safe oral medications.
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Affiliation(s)
| | - Swee T. Tan
- Gillies McIndoe Research Institute, Wellington, New Zealand
- Wellington Regional Plastic, Maxillofacial & Burns Unit, Hutt Hospital, Lower Hutt, New Zealand
- Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia
- *Correspondence: Swee T. Tan
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Pathak E, Atri N, Mishra R. Single-Cell Transcriptome Analysis Reveals the Role of Pancreatic Secretome in COVID-19 Associated Multi-organ Dysfunctions. Interdiscip Sci 2022; 14:863-878. [PMID: 35394619 PMCID: PMC8990272 DOI: 10.1007/s12539-022-00513-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/16/2022] [Accepted: 03/17/2022] [Indexed: 01/09/2023]
Abstract
The SARS-CoV-2 infection affects the lungs, heart, kidney, intestine, olfactory epithelia, liver, and pancreas and brings forward multi-organ dysfunctions (MODs). However, mechanistic details of SARS-CoV-2-induced MODs are unclear. Here, we have investigated the role of pancreatic secretory proteins to mechanistically link COVID-19 with MODs using single-cell transcriptome analysis. Secretory proteins were identified using the Human Protein Atlas. Gene ontology, pathway, and disease enrichment analyses were used to highlight the role of upregulated pancreatic secretory proteins (secretome). We show that SARS-CoV-2 infection shifts the expression profile of pancreatic endocrine cells to acinar and ductal cell-specific profiles, resulting in increased expression of acinar and ductal cell-specific genes. Among all the secretory proteins, the upregulated expression of IL1B, AGT, ALB, SPP1, CRP, SERPINA1, C3, TFRC, TNFSF10, and MIF was mainly associated with disease of diverse organs. Extensive literature and experimental evidence are used to validate the association of the upregulated pancreatic secretome with the coagulation cascade, complement activation, renin-angiotensinogen system dysregulation, endothelial cell injury and thrombosis, immune system dysregulation, and fibrosis. Our finding suggests the influence of an upregulated secretome on multi-organ systems such as nervous, cardiovascular, immune, digestive, and urogenital systems. Our study provides evidence that an upregulated pancreatic secretome is a possible cause of SARS-CoV-2-induced MODs. This finding may have a significant impact on the clinical setting regarding the prevention of SARS-CoV-2-induced MODs.
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Affiliation(s)
- Ekta Pathak
- Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India.
| | - Neelam Atri
- Bioinformatics Department, MMV, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
- Department of Botany, MMV, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Rajeev Mishra
- Bioinformatics Department, MMV, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
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Hussien NI, El-Kerdasy HI, Sorour SM, Shoman AA. Chronic oestrogen deficiency induced by ovariectomy may cause lung fibrosis through activation of the renin-angiotensin system in rats. Arch Physiol Biochem 2022; 128:290-299. [PMID: 31608713 DOI: 10.1080/13813455.2019.1676262] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
CONTEXT Oestrogen deficiency is linked with pulmonary fibrosis. Additionally, it may lead to over-activation of the renin-angiotensin system (RAS), which worsens lung fibrosis. OBJECTIVE The present study aims to investigate the role of RAS on lung fibrosis associated with oestrogen deficiency in ovariectomised rats. MATERIALS AND METHODS Serum 17β-oestradiol (E2), arterial blood gases, plasma angiotensin II levels, lung tissue hydroxyproline content, and transforming growth factor beta 1 (TGF-β1) concentration, the mRNA expression of angiotensin type 1 receptor (AT1R), and angiotensin-converting enzyme (ACE1) were evaluated. Moreover, lung tissues were examined by histopathology and immunohistochemistry. RESULTS Hydroxyproline content, TGF-β1 concentration, plasma angiotensin II, the relative mRNA expression of ACE1, and AT1R is found to increase in ovariectomised rats. The mentioned changes can be largely rescued by administration of RAS blockers. CONCLUSION Oestrogen deficiency activates RAS, which consequently increases the expression of pro-fibrotic factors and stimulates the fibrotic cascade causing lung fibrosis.
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Affiliation(s)
- Noha I Hussien
- Department of Physiology, Faculty of Medicine, Benha University, Benha, Egypt
| | - Hanan I El-Kerdasy
- Department of Anatomy, Faculty of Medicine, Benha University, Benha, Egypt
| | - Safwa M Sorour
- Department of Clinical Pharmacology, Faculty of Medicine, Benha University, Benha, Egypt
| | - Abeer A Shoman
- Department of Physiology, Faculty of Medicine, Benha University, Benha, Egypt
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Shabanian S, Khazaie M, Ferns GA, Arjmand MH. Local renin-angiotensin system molecular mechanisms in intrauterine adhesions formation following gynecological operations, new strategy for novel treatment. J OBSTET GYNAECOL 2022; 42:1613-1618. [PMID: 35260037 DOI: 10.1080/01443615.2022.2036972] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
It has recently been proposed that local tissue renin-angiotensin system activation has a role in post-surgical adhesion. Intrauterine adhesions are scar tissues that form in the endometrial cavity causing the walls of the uterine to adhere together. Women, undergoing major gynecological surgery, are exposed to a high risk of adhesion formation. Post-operative uterine adhesion is associated with chronic pain and infertility that are important problems following post-operation uterine adhesion. A local renin-angiotensin system has been found in the organs of the female reproductive system, for example in the endometrium. Data about the physiological roles of local RAS in the gynecological tract are largely unknown, but dysfunctional local RAS in the endometrium may contribute to this pathological condition. Local AngII/AT1R may be over-activated after surgical injury or hypoxia leading to an up-regulation of the molecular mechanisms that may lead to a chronic immune response, oxidative stress, and increase the expression of fibrotic molecules like TGF-β to induce the risk of connective fibrotic tissues. Based on AngII/AT1R pathological potential to induce pelvic and uterine adhesions, using angiotensin receptor blockers could be a therapeutic strategy for the prevention and treatment of post-surgical adhesions.IMPACT STATEMENTWhat is already known on this subject? Intrauterine adhesions are described as fibrotic scar tissues following gynecological surgeries. It's reported that 55-100% of women are at risk of intrauterine adhesion after gynecological surgeries. Injury to tissues and hypoxia during the surgery, promote molecular mechanisms to contribute post-surgical adhesion. Recently evidence supports the existence of renin-angiotensin system components in the gynecological tract. Abnormal expression of local angiotensin II and AT1R in uterus tissue following gynecological surgeries up-regulate molecular mechanisms to induce post-operative adhesions.What do the results of this study add? Recently there has been an increased focus on the role of the local renin-angiotensin system in organ fibrosis. The results of this Mini-review article refer to the pathological roles of the local renin-angiotensin system in fibrotic bands formation after gynecological operations. Over-activation of local renin-angiotensin systems up-regulate molecular mechanisms such as inflammation and the TGF-β1 signalling pathway. TGF-β as a profibrotic molecule strongly induces the expression of some fibrotic molecules such as PAI and TIMP to increase the risk of intrauterine adhesions.What are the implications of these findings for clinical practice and/or further research? According to the biological roles of local renin-angiotensin system and AT1R following injuries to develop post-operative adhesion, the administration of ARBs may be considered as a new therapeutic strategy for the prevention of IUA.
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Affiliation(s)
- Sheida Shabanian
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Majid Khazaie
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton and Sussex Medical School, Brighton, UK
| | - Mohammad-Hassan Arjmand
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.,Cancer Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
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González-Blázquez R, Alcalá M, Cárdenas-Rebollo JM, Viana M, Steckelings UM, Boisvert WA, Unger T, Fernández-Alfonso MS, Somoza B, Gil-Ortega M. AT2R stimulation with C21 prevents arterial stiffening and endothelial dysfunction in the abdominal aorta from mice fed a high-fat diet. Clin Sci (Lond) 2021; 135:2763-2780. [PMID: 34854902 DOI: 10.1042/cs20210971] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 11/25/2021] [Accepted: 12/02/2021] [Indexed: 12/16/2022]
Abstract
The aim of the present study was to evaluate the effect of Compound 21 (C21), a selective AT2R agonist, on the prevention of endothelial dysfunction, extracellular matrix (ECM) remodeling and arterial stiffness associated with diet-induced obesity (DIO). Five-week-old male C57BL/6J mice were fed a standard (Chow) or high-fat diet (HF) for 6 weeks. Half of the animals of each group were simultaneously treated with C21 (1 mg/kg/day, in the drinking water), generating four groups: Chow C, Chow C21, HF C, and HF C21. Vascular function and mechanical properties were determined in the abdominal aorta. To evaluate ECM remodeling, collagen deposition and TGF-β1 concentrations were determined in the abdominal aorta and the activity of metalloproteinases (MMP) 2 and 9 was analyzed in the plasma. Abdominal aortas from HF C mice showed endothelial dysfunction as well as enhanced contractile but reduced relaxant responses to Ang II. This effect was abrogated with C21 treatment by preserving NO availability. A left-shift in the tension-stretch relationship, paralleled by an augmented β-index (marker of intrinsic arterial stiffness), and enhanced collagen deposition and MMP-2/-9 activities were also detected in HF mice. However, when treated with C21, HF mice exhibited lower TGF-β1 levels in abdominal aortas together with reduced MMP activities and collagen deposition compared with HF C mice. In conclusion, these data demonstrate that AT2R stimulation by C21 in obesity preserves NO availability and prevents unhealthy vascular remodeling, thus protecting the abdominal aorta in HF mice against the development of endothelial dysfunction, ECM remodeling and arterial stiffness.
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Affiliation(s)
- Raquel González-Blázquez
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28925, Madrid, Spain
| | - Martín Alcalá
- Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad CEU-San Pablo, CEU Universities, 28925, Madrid, Spain
| | - José Miguel Cárdenas-Rebollo
- Departamento de Matemática Aplicada y Estadística. Facultad de Ciencias Económicas y Empresariales. Universidad San Pablo-CEU, CEU Universities, 28925, Madrid, Spain
| | - Marta Viana
- Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad CEU-San Pablo, CEU Universities, 28925, Madrid, Spain
| | - Ulrike Muscha Steckelings
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - William A Boisvert
- Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, 651 Ilalo Street, BSB311, Honolulu, HI 96813, USA
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlevskaya Str., Kazan 420008, Russia
| | - Thomas Unger
- CARIM - School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands
| | - María S Fernández-Alfonso
- Instituto Pluridisciplinar, Unidad de Cartografía Cerebral, Universidad Complutense de Madrid, 28040 Madrid, Spain
- Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Beatriz Somoza
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28925, Madrid, Spain
| | - Marta Gil-Ortega
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28925, Madrid, Spain
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Protective effects of galangin against H 2O 2/UVB-induced dermal fibroblast collagen degradation via hsa-microRNA-4535-mediated TGFβ/Smad signaling. Aging (Albany NY) 2021; 13:25342-25364. [PMID: 34890367 PMCID: PMC8714160 DOI: 10.18632/aging.203750] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 11/23/2021] [Indexed: 12/14/2022]
Abstract
This study aimed to investigate the mechanism underlying the protective effects of galangin against H2O2/UVB-induced damage using in vitro and in vivo models of photodamage. Moreover, we identified the involvement of miRNA regulation in this process. The H2O2/UVB-treated HS68 human dermal fibroblasts and UVB-induced C57BL/6J nude mice were used as in vitro and in vivo models of photodamage. The results showed that galangin treatment alleviated H2O2/UVB-induced reduction in cell viability, TGFβ/Smad signaling impairment, and dermal aging. Based on the results of microRNA array analyses and database searches, hsa-miR-4535 was identified as a potential candidate miRNA that targets Smad4. In vitro, galangin treatment activated Smad2/3/4 complex and inhibited hsa-miR-4535 expression in H2O2/UVB-exposed cells. In vivo, topical application of low (12 mg/kg) and high doses (24 mg/kg) of galangin to the dorsal skin of C57BL/6J nude mice significantly alleviated UVB-induced skin photodamage by promoting TGFβ/Smad collagen synthesis signaling, reducing epidermal hyperplasia, wrinkle formation, and skin senescence, as well as inhibiting hsa-miR-4535 expression. Taken together, our findings indicate a link between hsa-miR-4535 and TGFβ/Smad collagen synthesis signaling and suggest these factors to be involved in the photo-protective mechanism of galangin in dermal fibroblasts against H2O2/UVB-induced aging. The evidence indicated that galangin with anti-aging properties can be considered as a supplement in skin care products.
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Kilmister EJ, Tan ST. The Role of the Renin-Angiotensin System in the Cancer Stem Cell Niche. J Histochem Cytochem 2021; 69:835-847. [PMID: 34165363 PMCID: PMC8647629 DOI: 10.1369/00221554211026295] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 05/28/2021] [Indexed: 02/08/2023] Open
Abstract
Cancer stem cells (CSCs) drive metastasis, treatment resistance, and tumor recurrence. CSCs reside within a niche, an anatomically distinct site within the tumor microenvironment (TME) that consists of malignant and non-malignant cells, including immune cells. The renin-angiotensin system (RAS), a critical regulator of stem cells and key developmental processes, plays a vital role in the TME. Non-malignant cells within the CSC niche and stem cell signaling pathways such as the Wnt, Hedgehog, and Notch pathways influence CSCs. Components of the RAS and cathepsins B and D that constitute bypass loops of the RAS are expressed on CSCs in many cancer types. There is extensive in vitro and in vivo evidence showing that RAS inhibition reduces tumor growth, cell proliferation, invasion, and metastasis. However, there is inconsistent epidemiological data on the effect of RAS inhibitors on cancer incidence and survival outcomes, attributed to different patient characteristics and methodologies used between studies. Further mechanistic studies are warranted to investigate the precise effects of the RAS on CSCs directly and/or the CSC niche. Targeting the RAS, its bypass loops, and convergent signaling pathways participating in the TME and other key stem cell pathways that regulate CSCs may be a novel approach to cancer treatment.
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Affiliation(s)
| | - Swee T. Tan
- Gillies McIndoe Research Institute, Wellington,
New Zealand
- Wellington Regional Plastic, Maxillofacial and
Burns Unit, Hutt Hospital, Wellington, New Zealand
- Department of Surgery, The University of
Melbourne, Parkville, Victoria, Australia
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