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Badr AM, Alotaibi HN, El-Orabi N. Dibenzazepine, a γ-Secretase Enzyme Inhibitor, Protects Against Doxorubicin-Induced Cardiotoxicity by Suppressing NF-κB, iNOS, and Hes1/Hey1 Expression. Inflammation 2025; 48:557-574. [PMID: 39078585 DOI: 10.1007/s10753-024-02046-x] [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: 03/29/2024] [Revised: 05/02/2024] [Accepted: 05/06/2024] [Indexed: 07/31/2024]
Abstract
Doxorubicin (DOX) is an effective chemotherapeutic drug; however, its cardiotoxicity and resistance compromise its therapeutic index. The Notch pathway was reported to contribute to DOX cancer resistance. The role of Notch pathway in DOX cardiotoxicity has not been identified yet. Notch receptors are characterized by their extracellular (NECD) and intracellular (NICD) domains (NICD). The γ-secretase enzyme helps in the release of NICD. Dibenzazepine (DBZ) is a γ-secretase inhibitor. The present study investigated the effect of Notch pathway inhibition on DOX cardiotoxicity. Twenty-four male Wistar rats were divided into four groups: control group, DOX group, acute cardiotoxicity was induced by a single dose of DOX (20 mg/kg) i.p., DOX (20 mg/kg) plus DBZ group, and DBZ group. The third and fourth groups received i.p. injection of DBZ daily for 14 days at 2 mg/kg dose. DOX cardiotoxicity increased the level of serum creatine kinase-MB and cardiac troponin I, and it was confirmed by the histopathological examination. Moreover, the antioxidants glutathione peroxidase and superoxide dismutase levels were markedly decreased, and the inflammatory markers, inducible nitric oxide synthase, nuclear factor-ķB, and tumor necrosis factor-α were markedly increased. Furthermore, DOX increased BAX protein and downregulated BCL-2. In addition, DOX upregulated Notch pathway-related parameters: Hes1 and Hey1 mRNA levels, and increased Hes1 protein levels. DBZ ameliorated DOX-induced cardiotoxicity, evidenced by reducing the cardiac injury biomarkers, improving cardiac histopathological changes, correcting antioxidant levels, and reducing inflammatory and apoptotic proteins. Our study indicates the protective effect of Notch inhibitor against DOX-induced cardiotoxicity.
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Affiliation(s)
- Amira M Badr
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Saud University, Riyadh, 11211, Saudi Arabia
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt
| | - Hind N Alotaibi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Saud University, Riyadh, 11211, Saudi Arabia
| | - Naglaa El-Orabi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt.
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2
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Akter R, Noor F, Tonmoy HS, Ahmed A. Potential of SIRT6 modulators in targeting molecular pathways involved in cardiovascular diseases and their treatment-A comprehensive review. Biochem Pharmacol 2025; 233:116787. [PMID: 39894306 DOI: 10.1016/j.bcp.2025.116787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 01/09/2025] [Accepted: 01/28/2025] [Indexed: 02/04/2025]
Abstract
Cardiovascular disease (CVD) is the leading cause of mortality and morbidity, accounting for major public health concerns worldwide. CVD poses an immense burden on the global healthcare system and economy. Ischemic heart disease, stroke, heart failure, atherosclerosis, and hypertension are the major diseases belonging to CVDs and ischemic heart diseases and stroke contribute to most CVD-induced deaths. Previously published review articles focused on the role of SIRT6 in CVDs but did not focus on the important role of SIRT6 in modulating the signaling pathways involved in CVDs and targeting them to treat CVDs. Thus, this review aims to identify and delineate the major signaling pathways that are involved in CVDs and whether SIRT6 can modulate those pathways to improve and treat CVDs. Alongside possible applications of small molecule modulators of SIRT6 in cardiovascular disease treatment have been comprehensively analyzed.
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Affiliation(s)
- Raushanara Akter
- School of Pharmacy, KHA 224 Bir Uttam Rafiqul Islam Avenue, Merul Badda, BRAC University, Dhaka 1212, Bangladesh.
| | - Fouzia Noor
- School of Pharmacy, KHA 224 Bir Uttam Rafiqul Islam Avenue, Merul Badda, BRAC University, Dhaka 1212, Bangladesh
| | - Hasan Shahriyer Tonmoy
- School of Pharmacy, KHA 224 Bir Uttam Rafiqul Islam Avenue, Merul Badda, BRAC University, Dhaka 1212, Bangladesh
| | - Ashfaq Ahmed
- School of Pharmacy, KHA 224 Bir Uttam Rafiqul Islam Avenue, Merul Badda, BRAC University, Dhaka 1212, Bangladesh
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3
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Yang H, Cao G, Li X, Zhao Z, Wang Y, Xu F. Berberine Intervention Mitigates Myocardial Ischemia-Reperfusion Injury in a Rat Model: Mechanistic Insights via miR-184 Signaling. Biologics 2025; 19:31-42. [PMID: 40026702 PMCID: PMC11871928 DOI: 10.2147/btt.s479430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 12/31/2024] [Indexed: 03/05/2025]
Abstract
Background Ischemia-reperfusion (I/R) injury is a major contributor to myocardial dysfunction and tissue damage. A natural alkaloid-Berberine having a wide range of pharmacological properties, has garnered interest for its potential cardioprotective properties. This study aimed to investigate the protective effects of berberine on myocardial tissue in a rat model of myocardial ischemia-reperfusion (I/R) injury. Additionally, the study explored the role of the miR-184/NOTCH1 signaling pathway in mediating these effects. Methods Male Wistar rats were randomly assigned to five groups: sham-operated control, I/R injury, I/R treated with berberine, I/R treated with inhibitor NC and I/R treated with a miR-184 inhibitor. The I/R injury was induced by ligating the left anterior descending (LAD) coronary artery for 30 minutes, followed by 2 hours of reperfusion. Berberine was administered orally at 100 mg/kg/day for 2 weeks, and the miR-184 inhibitor was administered via intraperitoneal injection. Hemodynamic parameters were recorded using a pressure sensor connected to a catheter inserted into the left ventricle. Myocardial infarct size was assessed using TTC staining, while histological and molecular changes were evaluated through H&E staining, TUNEL assay, and Western blotting. The expression levels of target genes were analyzed using quantitative real-time PCR (qRT-PCR). Results Berberine significantly reduced myocardial infarct size and improved hemodynamic parameters compared to the untreated I/R group. Additionally, berberine treatment attenuated apoptosis as evidenced by decreased TUNEL-positive cells. The miR-184 inhibitor also demonstrated protective effects by modulating key signaling pathways involved in myocardial injury. Western blot analysis revealed downregulation of NOTCH1 and HES1 expression in treated groups, indicating a potential mechanism for the observed cardio protection. Conclusion Berberine and miR-184 inhibition offer significant protection against myocardial ischemia-reperfusion injury. These findings suggest that targeting miR-184 and associated pathways may be a promising therapeutic strategy for reducing cardiac damage following ischemia-reperfusion.
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Affiliation(s)
- Haichen Yang
- Department of Emergency, The Affiliated Huai’an Hospital of Xuzhou Medical University and Huai’an second People’s Hospital, Huai’an, People’s Republic of China
| | - Gang Cao
- Department of Respiratory Medicine, Hongze District People’s Hospital, Hongze, Jiangsu, People’s Republic of China
| | - Xia Li
- Department of Geriatric, The Affiliated Huai’an Hospital of Xuzhou Medical University and Huai’an Second People’s Hospital, Huai’an, People’s Republic of China
| | - Zhikun Zhao
- Department of Intensive Care Unit, The Affiliated Huai’an Hospital of Xuzhou Medical University and Huai’an Second People’s Hospital, Huai’an, People’s Republic of China
| | - Yong Wang
- Department of Cardiology, The Affiliated Huai’an Hospital of Xuzhou Medical University and Huai’an Second People’s Hospital, Huai’an, People’s Republic of China
| | - Fei Xu
- Department of Intensive Care Unit, Lianshui County People’s Hospital, Huai’an, People’s Republic of China
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Sivan S, Vijayakumar G, Pillai IC. Non-coding RNAs mediating the regulation of genes and signaling pathways in aortic valve calcification. Gene 2025; 936:149117. [PMID: 39580125 DOI: 10.1016/j.gene.2024.149117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 11/15/2024] [Accepted: 11/18/2024] [Indexed: 11/25/2024]
Affiliation(s)
- Silpa Sivan
- Stem Cells and Regenerative Biology Lab, Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Clappana PO, Kollam 690 525, Kerala, India
| | - Gayathri Vijayakumar
- Stem Cells and Regenerative Biology Lab, Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Clappana PO, Kollam 690 525, Kerala, India
| | - Indulekha Cl Pillai
- Stem Cells and Regenerative Biology Lab, Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Clappana PO, Kollam 690 525, Kerala, India.
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Tayal R, Mannan A, Singh S, Dhiman S, Singh TG. Unveiling the Complexities: Exploring Mechanisms of Anthracyclineinduced Cardiotoxicity. Curr Cardiol Rev 2025; 21:42-77. [PMID: 39484769 PMCID: PMC12060933 DOI: 10.2174/011573403x322928241021100631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 08/27/2024] [Accepted: 08/27/2024] [Indexed: 11/03/2024] Open
Abstract
The coexistence of cancer and heart disease, both prominent causes of illness and death, is further exacerbated by the detrimental impact of chemotherapy. Anthracycline-induced cardiotoxicity is an unfortunate side effect of highly effective therapy in treating different types of cancer; it presents a significant challenge for both clinicians and patients due to the considerable risk of cardiotoxicity. Despite significant progress in understanding these mechanisms, challenges persist in identifying effective preventive and therapeutic strategies, rendering it a subject of continued research even after three decades of intensive global investigation. The molecular targets and signaling pathways explored provide insights for developing targeted therapies, emphasizing the need for continued research to bridge the gap between preclinical understanding and clinical applications. This review provides a comprehensive exploration of the intricate mechanisms underlying anthracycline-induced cardiotoxicity, elucidating the interplay of various signaling pathways leading to adverse cellular events, including cardiotoxicity and death. It highlights the extensive involvement of pathways associated with oxidative stress, inflammation, apoptosis, and cellular stress responses, offering insights into potential and unexplored targets for therapeutic intervention in mitigating anthracycline-induced cardiac complications. A comprehensive understanding of the interplay between anthracyclines and these complexes signaling pathways is crucial for developing strategies to prevent or mitigate the associated cardiotoxicity. Further research is needed to outline the specific contributions of these pathways and identify potential therapeutic targets to improve the safety and efficacy of anthracycline-based cancer treatment. Ultimately, advancements in understanding anthracycline-induced cardiotoxicity mechanisms will facilitate the development of more efficacious preventive and treatment approaches, thereby improving outcomes for cancer patients undergoing anthracycline-based chemotherapy.
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Affiliation(s)
- Rohit Tayal
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Shareen Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Sonia Dhiman
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
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Fortini F, Vieceli Dalla Sega F, Lazzarini E, Aquila G, Sysa-Shah P, Bertero E, Ascierto A, Severi P, Ouambo Talla AW, Schirone A, Gabrielson K, Morciano G, Patergnani S, Pedriali G, Pinton P, Ferrari R, Tremoli E, Ameri P, Rizzo P. ErbB2-NOTCH1 axis controls autophagy in cardiac cells. Biofactors 2025; 51:e2091. [PMID: 38994725 DOI: 10.1002/biof.2091] [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: 11/30/2023] [Accepted: 06/16/2024] [Indexed: 07/13/2024]
Abstract
Although the epidermal growth factor receptor 2 (ErbB2) and Notch1 signaling pathways have both significant roles in regulating cardiac biology, their interplay in the heart remains poorly investigated. Here, we present evidence of a crosstalk between ErbB2 and Notch1 in cardiac cells, with effects on autophagy and proliferation. Overexpression of ErbB2 in H9c2 cardiomyoblasts induced Notch1 activation in a post-transcriptional, p38-dependent manner, while ErbB2 inhibition with the specific inhibitor, lapatinib, reduced Notch1 activation. Moreover, incubation of H9c2 cells with lapatinib resulted in stalled autophagic flux and decreased proliferation, consistent with the established cardiotoxicity of this and other ErbB2-targeting drugs. Confirming the findings in H9c2 cells, exposure of primary neonatal mouse cardiomyocytes to exogenous neuregulin-1, which engages ErbB2, stimulated proliferation, and this effect was abrogated by concomitant inhibition of the enzyme responsible for Notch1 activation. Furthermore, the hearts of transgenic mice specifically overexpressing ErbB2 in cardiomyocytes had increased levels of active Notch1 and of Notch-related genes. These data expand the knowledge of ErbB2 and Notch1 functions in the heart and may allow better understanding the mechanisms of the cardiotoxicity of ErbB2-targeting cancer treatments.
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Affiliation(s)
| | | | - Edoardo Lazzarini
- Laboratory for Cardiovascular Theranostics, Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale Lugano, Lugano, Switzerland
- Euler Institute, Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland
| | - Giorgio Aquila
- Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
| | - Polina Sysa-Shah
- The Brady Urological Institute and Department of Urology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA
| | - Edoardo Bertero
- Department of Internal Medicine and Specialties (Di.M.I.), University of Genova, Genova, Italy
| | - Alessia Ascierto
- Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
| | - Paolo Severi
- Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
| | - Achille Wilfred Ouambo Talla
- Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
| | - Alessio Schirone
- Oncology and Hematology Department, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara, Italy
| | - Kathleen Gabrielson
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA
| | - Giampaolo Morciano
- GVM Care & Research, Maria Cecilia Hospital, Ravenna, Italy
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Simone Patergnani
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Gaia Pedriali
- GVM Care & Research, Maria Cecilia Hospital, Ravenna, Italy
| | - Paolo Pinton
- GVM Care & Research, Maria Cecilia Hospital, Ravenna, Italy
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Roberto Ferrari
- Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
| | - Elena Tremoli
- GVM Care & Research, Maria Cecilia Hospital, Ravenna, Italy
| | - Pietro Ameri
- Department of Internal Medicine and Specialties (Di.M.I.), University of Genova, Genova, Italy
- Cardiac, Thoracic, and Vascular Department, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Paola Rizzo
- GVM Care & Research, Maria Cecilia Hospital, Ravenna, Italy
- Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
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7
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Severi P, Ascierto A, Marracino L, Ouambo Talla AW, Aquila G, Martino V, Dalessandro F, Scarpante I, Minghini G, Haffreingue L, Vieceli Dalla Sega F, Fortini F, Rizzo P. 17β-estradiol inhibits Notch1 activation in murine macrophage cell line RAW 264.7. Mol Biol Rep 2024; 51:1134. [PMID: 39514048 DOI: 10.1007/s11033-024-10058-x] [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: 05/31/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Macrophages are major effectors in regulating immune response and inflammation. The pro-inflammatory phenotype (M1) is induced by the activation of the Toll-like receptor 4 (TLR4) on the macrophage surface, which recognizes lipopolysaccharide (LPS), a component of Gram-negative bacterial wall, and by the binding of interferon-gamma (IFNγ), a cytokine released by activated T lymphocytes, to its receptor (IFNGR). Among the pathways activated by LPS/IFNγ is the Notch pathway, which promotes the M1 phenotype. Conversely, 17β-estradiol (E2) has been shown to blunt LPS-mediated inflammatory response. While it has been shown that E2 regulates the activity of the Notch1 receptor in human endothelial cells, there is no evidence of estrogen-mediated regulation of Notch1 in macrophages. METHODS AND RESULTS In this study, RAW 264.7 cells were stimulated with LPS/IFNγ in the presence or absence of E2 and/or N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), an inhibitor of γ-secretase, the enzyme involved in Notch activation. The effects of treatment on inducible nitric oxide synthase (iNOS), on components of the Notch pathway, and MAPK (mitogen-activated protein kinase) were assessed by quantitative PCR and Western blotting. We found that E2, through a mechanism involving the inhibition of p38 phosphorylation, reduces the activation of Notch1 induced by LPS/IFNγ. On the contrary, Notch1 exerts a negative control on the estrogen receptor α (ERα) since Notch1 inhibition increases the protein levels of this receptor. CONCLUSION In conclusion, we report for the first time a Notch-ERα interaction in macrophages. Our data suggest that E2 may reduce LPS/IFNγ-mediated M1 pro-inflammatory phenotype in macrophages by inhibiting Notch1. This finding encourages further studies on Notch1 inhibitors as novel treatments for inflammation-related diseases.
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Affiliation(s)
- Paolo Severi
- Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy
| | - Alessia Ascierto
- Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy
| | - Luisa Marracino
- Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy
| | - Achille Wilfred Ouambo Talla
- Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy
| | - Giorgio Aquila
- Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy
| | - Valeria Martino
- Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy
| | - Francesca Dalessandro
- Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy
| | - Irene Scarpante
- Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy
| | - Giada Minghini
- Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy
| | - Louis Haffreingue
- Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy
| | | | - Francesca Fortini
- GVM Care & Research, Maria Cecilia Hospital, Cotignola, 48033, Italy
| | - Paola Rizzo
- Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy.
- GVM Care & Research, Maria Cecilia Hospital, Cotignola, 48033, Italy.
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8
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Sachan N, Sharma V, Mutsuddi M, Mukherjee A. Notch signalling: multifaceted role in development and disease. FEBS J 2024; 291:3030-3059. [PMID: 37166442 DOI: 10.1111/febs.16815] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 02/08/2023] [Accepted: 05/10/2023] [Indexed: 05/12/2023]
Abstract
Notch pathway is an evolutionarily conserved signalling system that operates to influence an astonishing array of cell fate decisions in different developmental contexts. Notch signalling plays important roles in many developmental processes, making it difficult to name a tissue or a developing organ that does not depend on Notch function at one stage or another. Thus, dysregulation of Notch signalling is associated with many developmental defects and various pathological conditions, including cancer. Although many recent advances have been made to reveal different aspects of the Notch signalling mechanism and its intricate regulation, there are still many unanswered questions related to how the Notch signalling pathway functions in so many developmental events. The same pathway can be deployed in numerous cellular contexts to play varied and critical roles in an organism's development and this is only possible because of the complex regulatory mechanisms of the pathway. In this review, we provide an overview of the mechanism and regulation of the Notch signalling pathway along with its multifaceted functions in different aspects of development and disease.
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Affiliation(s)
- Nalani Sachan
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, India
- Department of Cell Biology, NYU Grossman School of Medicine, New York, NY, USA
| | - Vartika Sharma
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Mousumi Mutsuddi
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Ashim Mukherjee
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, India
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Chen S, Wang K, Fan Z, Zhou T, Li R, Zhang B, Chen J, Chi J, Wei K, Liu J, Liu Z, Ma J, Dong N, Liu J. Modulation of anti-cardiac fibrosis immune responses by changing M2 macrophages into M1 macrophages. Mol Med 2024; 30:88. [PMID: 38879491 PMCID: PMC11179216 DOI: 10.1186/s10020-024-00858-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 06/10/2024] [Indexed: 06/19/2024] Open
Abstract
BACKGROUND Macrophages play a crucial role in the development of cardiac fibrosis (CF). Although our previous studies have shown that glycogen metabolism plays an important role in macrophage inflammatory phenotype, the role and mechanism of modifying macrophage phenotype by regulating glycogen metabolism and thereby improving CF have not been reported. METHODS Here, we took glycogen synthetase kinase 3β (GSK3β) as the target and used its inhibitor NaW to enhance macrophage glycogen metabolism, transform M2 phenotype into anti-fibrotic M1 phenotype, inhibit fibroblast activation into myofibroblasts, and ultimately achieve the purpose of CF treatment. RESULTS NaW increases the pH of macrophage lysosome through transmembrane protein 175 (TMEM175) and caused the release of Ca2+ through the lysosomal Ca2+ channel mucolipin-2 (Mcoln2). At the same time, the released Ca2+ activates TFEB, which promotes glucose uptake by M2 and further enhances glycogen metabolism. NaW transforms the M2 phenotype into the anti-fibrotic M1 phenotype, inhibits fibroblasts from activating myofibroblasts, and ultimately achieves the purpose of treating CF. CONCLUSION Our data indicate the possibility of modifying macrophage phenotype by regulating macrophage glycogen metabolism, suggesting a potential macrophage-based immunotherapy against CF.
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Affiliation(s)
- Shiqi Chen
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Kan Wang
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zhengfeng Fan
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Tingwen Zhou
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Rui Li
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Bingxia Zhang
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jie Chen
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jiangyang Chi
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Keke Wei
- Department of Immunology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, China
| | - Jincheng Liu
- Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, China
| | - Zongtao Liu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jingwei Ma
- Department of Immunology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, China.
| | - Nianguo Dong
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
| | - Junwei Liu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Pagliaro P, Penna C. Inhibitors of NLRP3 Inflammasome in Ischemic Heart Disease: Focus on Functional and Redox Aspects. Antioxidants (Basel) 2023; 12:1396. [PMID: 37507935 PMCID: PMC10376505 DOI: 10.3390/antiox12071396] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 07/03/2023] [Accepted: 07/05/2023] [Indexed: 07/30/2023] Open
Abstract
Myocardial ischemia-reperfusion injury (MIRI) is caused by several mechanisms, including the production of reactive oxygen species (ROS), altered cellular osmolarity, and inflammatory response. Calcium overload, altered oxygen levels, and mitochondrial ROS are also involved in these MIRI processes, resulting in the irreversible opening of the mitochondrial permeability transition pore (mPTP). These mechanisms and processes are associated with NLRP3 inflammasome priming and activation, which can also induce cell death by pyroptosis through the up-regulation of the caspase-1 pathway and IL-18 release. In addition, endothelial dysfunction, both in the presence and absence of MIRI, is also accompanied by altered oxygen levels, decreased nitric oxide production, and ROS overproduction, resulting in the expression of adhesion molecules and leukocyte infiltration in which the NLRP3 inflammasome plays a central role, thus contributing, through endothelial dysfunction, to the alteration of coronary flow, typical of ischemic heart disease. Given the intricate interrelationship between ROS and NLRP3, ROS inhibitors can reduce NLRP3 inflammasome activation, while NLRP3 inhibitors can reduce oxidative stress and inflammation. NLRP3 inhibitors have been intensively studied as anti-inflammatory agents in basic cardiovascular sciences. In this review, we analyze the interrelation between ROS and NLRP3 in ischemic heart disease and the effects of some NLRP3 inhibitors as possible therapeutic agents in this disease condition. All compounds considered in this review need larger studies to confirm their appropriate use in clinical scenarios as anti-ischemic drugs.
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Affiliation(s)
- Pasquale Pagliaro
- Department of Clinical and Biological Sciences, Turin University, Orbassano, 10043 Turin, Italy
- National Institute for Cardiovascular Research (INRC), 40126 Bologna, Italy
| | - Claudia Penna
- Department of Clinical and Biological Sciences, Turin University, Orbassano, 10043 Turin, Italy
- National Institute for Cardiovascular Research (INRC), 40126 Bologna, Italy
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11
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Sæther JC, Vesterbekkmo EK, Taraldsen MD, Gigante B, Follestad T, Røsjø HR, Omland T, Wiseth R, Madssen E, Bye A. Associations between circulating microRNAs and lipid-rich coronary plaques measured with near-infrared spectroscopy. Sci Rep 2023; 13:7580. [PMID: 37165064 PMCID: PMC10172303 DOI: 10.1038/s41598-023-34642-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Accepted: 05/04/2023] [Indexed: 05/12/2023] Open
Abstract
Lipid-rich coronary atherosclerotic plaques often cause myocardial infarction (MI), and circulating biomarkers that reflect lipid content may predict risk of MI. We investigated the association between circulating microRNAs (miRs) are lipid-rich coronary plaques in 47 statin-treated patients (44 males) with stable coronary artery disease undergoing percutaneous coronary intervention. We assessed lipid content in non-culprit coronary artery lesions with near-infrared spectroscopy and selected the 4 mm segment with the highest measured lipid core burden index (maxLCBI4mm). Lipid-rich plaques were predefined as a lesion with maxLCBI4mm ≥ 324.7. We analyzed 177 circulating miRs with quantitative polymerase chain reaction in plasma samples. The associations between miRs and lipid-rich plaques were analyzed with elastic net. miR-133b was the miR most strongly associated with lipid-rich coronary plaques, with an estimated 18% increase in odds of lipid-rich plaques per unit increase in miR-133b. Assessing the uncertainty by bootstrapping, miR-133b was present in 82.6% of the resampled dataset. Inclusion of established cardiovascular risk factors did not attenuate the association. No evidence was found for an association between the other analyzed miRs and lipid-rich coronary plaques. Even though the evidence for an association was modest, miR-133b could be a potential biomarker of vulnerable coronary plaques and risk of future MI. However, the prognostic value and clinical relevance of miR-133b needs to be assessed in larger cohorts.
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Affiliation(s)
- Julie Caroline Sæther
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway.
- Department of Cardiology, St. Olavs Hospital, Trondheim, Norway.
| | - Elisabeth Kleivhaug Vesterbekkmo
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Cardiology, St. Olavs Hospital, Trondheim, Norway
- National Advisory Unit on Exercise Training as Medicine for Cardiopulmonary Conditions, Trondheim, Norway
| | - Maria Dalen Taraldsen
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
| | - Bruna Gigante
- Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Turid Follestad
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- Clinical Research Unit Central Norway, St. Olavs Hospital, Trondheim, Norway
| | - Helge Rørvik Røsjø
- Division of Research and Innovation, Akershus University Hospital, Lørenskog, Norway
- K. G. Jebsen Center for Cardiac Biomarkers, University of Oslo, Oslo, Norway
| | - Torbjørn Omland
- Division of Research and Innovation, Akershus University Hospital, Lørenskog, Norway
- K. G. Jebsen Center for Cardiac Biomarkers, University of Oslo, Oslo, Norway
- Department of Cardiology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway
| | - Rune Wiseth
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Cardiology, St. Olavs Hospital, Trondheim, Norway
| | - Erik Madssen
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Cardiology, St. Olavs Hospital, Trondheim, Norway
| | - Anja Bye
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Cardiology, St. Olavs Hospital, Trondheim, Norway
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12
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Li G, Shen N, Deng H, Wang Y, Kong G, Shi J, Dong N, Deng C. Abnormal mechanical stress on bicuspid aortic valve induces valvular calcification and inhibits Notch1/NICD/Runx2 signal. PeerJ 2023; 11:e14950. [PMID: 36908813 PMCID: PMC9997191 DOI: 10.7717/peerj.14950] [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: 09/26/2022] [Accepted: 02/03/2023] [Indexed: 03/08/2023] Open
Abstract
Background Bicuspid aortic valve (BAV) is a congenital cardiac deformity, increasing the risk of developing calcific aortic valve disease (CAVD). The disturbance of hemodynamics can induce valvular calcification, but the mechanism has not been fully identified. Methods We constructed a finite element model (FEM) of the aortic valve based on the computed tomography angiography (CTA) data from BAV patients and tricuspid aortic valve (TAV) individuals. We analyzed the hemodynamic properties based on our model and investigated the characteristics of mechanical stimuli on BAV. Further, we detected the expression of Notch, NICD and Runx2 in valve samples and identified the association between mechanical stress and the Notch1 signaling pathway. Results Finite element analysis showed that at diastole phase, the equivalent stress on the root of BAV was significantly higher than that on the TAV leaflet. Correspondingly, the expression of Notch1 and NICH decreased and the expression of Runx2 elevated significantly on large BAV leaflet belly, which is associated with equivalent stress on leaflet. Our findings indicated that the root of BAV suffered higher mechanical stress due to the abnormal hemodynamic environment, and the disturbance of the Notch1/NICD/Runx2 signaling pathway caused by mechanical stimuli contributed to valvular calcification.
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Affiliation(s)
- Guangzhou Li
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Na Shen
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huifang Deng
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yixuan Wang
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gangcheng Kong
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jiawei Shi
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Nianguo Dong
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cheng Deng
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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13
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Rajendran NK, Liu W, Cahill PA, Redmond EM. Caveolin-1 inhibition mediates the opposing effects of alcohol on γ-secretase activity in arterial endothelial and smooth muscle cells. Physiol Rep 2023; 11:e15544. [PMID: 36635975 PMCID: PMC9837422 DOI: 10.14814/phy2.15544] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/01/2022] [Accepted: 12/04/2022] [Indexed: 04/18/2023] Open
Abstract
Notch is important to vessel homeostasis. We investigated the mechanistic role of caveolin-1 (Cav-1) in mediating the effects of alcohol (Ethanol/EtOH) on the γ-secretase proteolytic activity necessary for Notch signaling in vascular cells. Human coronary artery endothelial cells (HCAEC) were treated with EtOH (0-50 mM), Notch ligand delta-like ligand 4 (Dll4), and the γ-secretase inhibitor DAPT. EtOH stimulated Notch signaling in HCAEC as evidenced by increased Notch receptor (N1, N4) and target gene (hrt2, hrt3) mRNA levels with the most robust response achieved at 25 mM EtOH. Ethanol (25 mM) stimulated γ-secretase proteolytic activity, to the same extent as Dll4, in HCAEC membranes. Ethanol inhibited Cav-1 mRNA and protein levels in HCAEC. Caveolin-1 negatively regulated γ-secretase activity in HCAEC as Cav-1 knockdown stimulated it, while Cav-1 overexpression inhibited it. Moreover, Cav-1 overexpression blocked the stimulatory effect of EtOH on γ-secretase activity in HCAEC. Although EtOH also inhibited Cav-1 expression in human coronary artery smooth muscle cells (HCASMC), EtOH inhibited γ-secretase activity in HCASMC in contrast to its effect in HCAEC. The inhibitory effect of EtOH on γ-secretase in HCASMC was mimicked by Cav-1 knockdown and prevented by Cav-1 overexpression, suggesting that in these cells Cav-1 positively regulates γ-secretase activity. In conclusion, EtOH differentially regulates γ-secretase activity in arterial EC and SMC, being stimulatory and inhibitory, respectively. These effects are both mediated by caveolin-1 inhibition which itself has opposite effects on γ-secretase in the two cell types. This mechanism may underlie, in part, the effects of moderate drinking on atherosclerosis.
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Affiliation(s)
- Naresh K. Rajendran
- Department of SurgeryUniversity of Rochester Medical CenterRochesterNew YorkUSA
| | - Weimin Liu
- Department of SurgeryUniversity of Rochester Medical CenterRochesterNew YorkUSA
| | - Paul A. Cahill
- Vascular Biology and Therapeutics Laboratory, School of BiotechnologyDublin City UniversityDublinIreland
| | - Eileen M. Redmond
- Department of SurgeryUniversity of Rochester Medical CenterRochesterNew YorkUSA
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14
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Wronska A. The Role of microRNA in the Development, Diagnosis, and Treatment of Cardiovascular Disease: Recent Developments. J Pharmacol Exp Ther 2023; 384:123-132. [PMID: 35779862 DOI: 10.1124/jpet.121.001152] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 05/12/2022] [Accepted: 05/13/2022] [Indexed: 01/13/2023] Open
Abstract
Since their discovery in 1993, microRNAs (miRNAs) have emerged as important regulators of many crucial cellular processes, and their dysregulation have been shown to contribute to multiple pathologic conditions, including cardiovascular disease (CVD). miRNAs have been found to regulate the expression of various genes involved in cardiac development and function and in the development and progression of CVD. Many miRNAs are master regulators fine-tuning the expression of multiple, often interrelated, genes involved in inflammation, apoptosis, fibrosis, senescence, and other processes crucial for the development of different forms of CVD. This article presents a review of recent developments in our understanding of the role of miRNAs in the development of CVD and surveys their potential applicability as therapeutic targets and biomarkers to facilitate CVD diagnosis, prognosis, and treatment. There are currently multiple potential miRNA-based therapeutic agents in different stages of development, which can be grouped into two classes: miRNA mimics (replicating the sequence and activity of their corresponding miRNAs) and antagomiRs (antisense inhibitors of specific miRNAs). However, in spite of promising preliminary data and our ever-increasing knowledge about the mechanisms of action of specific miRNAs, miRNA-based therapeutics and biomarkers have yet to be approved for clinical applications. SIGNIFICANCE STATEMENT: Over the last few years microRNAs have emerged as crucial, specific regulators of the cardiovascular system and in the development of cardiovascular disease, by posttranscriptional regulation of their target genes. The minireview presents the most recent developments in this area of research, including the progress in diagnostic and therapeutic applications of microRNAs. microRNAs seem very promising candidates for biomarkers and therapeutic agents, although some challenges, such as efficient delivery and unwanted effects, need to be resolved.
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Affiliation(s)
- Anetta Wronska
- Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York
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15
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Liu Z, Li W, Cao Y, Zhang X, Yang K, Yin F, Yang M, Peng P. Effects of the interaction of Notch and TLR4 pathways on inflammation and heart function in septic heart. Open Life Sci 2022; 17:744-755. [PMID: 35891967 PMCID: PMC9281592 DOI: 10.1515/biol-2022-0076] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 03/22/2022] [Accepted: 04/07/2022] [Indexed: 11/15/2022] Open
Abstract
We investigated the role of the interaction between the Notch and Toll-like receptor 4 (TLR4) pathways in septic myocardial injury. The sepsis model was induced in rats with lipopolysaccharide (LPS). Rats were divided into control, LPS, LPS + TAK242 ((6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate) and LPS + DAPT (N-[N-(3,5-difluorophenacetyl)-l-alanyl]-s-phenylglycinetbutylester) groups. Heart function was evaluated with a Cardiac Doppler ultrasound. Myocardial morphological changes were detected by hematoxylin-eosin staining (H&E). Apoptosis was assessed by a TUNEL assay. The mRNA and protein levels were detected with real-time PCR, Western blot, and immunohistochemistry analysis. We found that heart function in the LPS + TAK242 group was significantly improved, but not in the LPS + DAPT group. LPS + TAK242 had a lower level of degeneration and necrosis of cardiomyocytes and inflammatory cell infiltration, as well as lower apoptosis and caspase-3 expression than the LPS group. Compared with the LPS group, the inflammatory cell infiltration was reduced in the LPS + DAPT group, while the degeneration and necrosis of cardiomyocytes were not obviously improved. Additionally, the expression levels of tumor necrosis factor-α and Interleukin-6, the protein contents of Notch intracellular domain and Hes1, and the P65 nuclear factor kappa-B (NF-κB) to P-P65 NF-κB ratio in LPS + TAK242 group and LPS + DAPT group were significantly lower than those in LPS group. Conclusively, the interaction between TLR4 and Notch signaling pathways enhances the inflammatory response in the septic heart by activating NF-κB. Blocking the TLR4 pathway with TAK242 can improve heart dysfunction and myocardial damage in sepsis, while blocking the Notch pathway with DAPT cannot effectively prevent heart dysfunction and myocardial damage in sepsis.
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Affiliation(s)
- Ziyang Liu
- Intensive Care Unit, Emergency Trauma Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang, China
| | - Wenli Li
- Emergency Department of Internal Medicine, Emergency Trauma Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang, China
| | - Yang Cao
- Intensive Care Unit, Emergency Trauma Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang, China
| | - Xiaoxia Zhang
- Intensive Care Unit, Emergency Trauma Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang, China
| | - Kai Yang
- Intensive Care Unit, Emergency Trauma Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang, China
| | - Fukang Yin
- Intensive Care Unit, Emergency Trauma Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang, China
| | - Meng Yang
- Intensive Care Unit, Emergency Trauma Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang, China
| | - Peng Peng
- Intensive Care Unit, Emergency Trauma Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang, China
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16
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A “notch” in the cellular communication network in response to anoxia by wood frog (Rana sylvatica). Cell Signal 2022; 93:110305. [DOI: 10.1016/j.cellsig.2022.110305] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/06/2022] [Accepted: 03/07/2022] [Indexed: 12/12/2022]
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17
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Varzideh F, Kansakar U, Donkor K, Wilson S, Jankauskas SS, Mone P, Wang X, Lombardi A, Santulli G. Cardiac Remodeling After Myocardial Infarction: Functional Contribution of microRNAs to Inflammation and Fibrosis. Front Cardiovasc Med 2022; 9:863238. [PMID: 35498051 PMCID: PMC9043126 DOI: 10.3389/fcvm.2022.863238] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 03/08/2022] [Indexed: 01/12/2023] Open
Abstract
After an ischemic injury, the heart undergoes a complex process of structural and functional remodeling that involves several steps, including inflammatory and fibrotic responses. In this review, we are focusing on the contribution of microRNAs in the regulation of inflammation and fibrosis after myocardial infarction. We summarize the most updated studies exploring the interactions between microRNAs and key regulators of inflammation and fibroblast activation and we discuss the recent discoveries, including clinical applications, in these rapidly advancing fields.
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Affiliation(s)
- Fahimeh Varzideh
- Department of Medicine, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, New York, NY, United States
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Wilf Family Cardiovascular Research Institute, Institute for Neuroimmunology and Inflammation (INI), New York, NY, United States
| | - Urna Kansakar
- Department of Medicine, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, New York, NY, United States
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Wilf Family Cardiovascular Research Institute, Institute for Neuroimmunology and Inflammation (INI), New York, NY, United States
| | - Kwame Donkor
- Department of Medicine, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, New York, NY, United States
| | - Scott Wilson
- Department of Medicine, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, New York, NY, United States
| | - Stanislovas S. Jankauskas
- Department of Medicine, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, New York, NY, United States
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Wilf Family Cardiovascular Research Institute, Institute for Neuroimmunology and Inflammation (INI), New York, NY, United States
| | - Pasquale Mone
- Department of Medicine, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, New York, NY, United States
| | - Xujun Wang
- Department of Medicine, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, New York, NY, United States
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Wilf Family Cardiovascular Research Institute, Institute for Neuroimmunology and Inflammation (INI), New York, NY, United States
| | - Angela Lombardi
- Department of Medicine, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, New York, NY, United States
| | - Gaetano Santulli
- Department of Medicine, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, New York, NY, United States
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Wilf Family Cardiovascular Research Institute, Institute for Neuroimmunology and Inflammation (INI), New York, NY, United States
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18
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Fermentation of Vaccinium floribundum Berries with Lactiplantibacillus plantarum Reduces Oxidative Stress in Endothelial Cells and Modulates Macrophages Function. Nutrients 2022; 14:nu14081560. [PMID: 35458122 PMCID: PMC9027973 DOI: 10.3390/nu14081560] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 04/04/2022] [Accepted: 04/05/2022] [Indexed: 12/15/2022] Open
Abstract
Accumulating evidence suggests that high consumption of natural antioxidants promotes health by reducing oxidative stress and, thus, the risk of developing cardiovascular diseases. Similarly, fermentation of natural compounds with lactic acid bacteria (LAB), such as Lactiplantibacillus plantarum, enhances their beneficial properties as regulators of the immune, digestive, and cardiovascular system. We investigated the effects of fermentation with Lactiplantibacillus plantarum on the antioxidant and immunomodulatory effects of Pushgay berries (Vaccinium floribundum, Ericaceae family) in human umbilical vein endothelial cells (HUVECs) and macrophage cell line RAW264.7. Polyphenol content was assayed by Folin–Ciocalteu and HPLC-MS/MS analysis. The effects of berries solutions on cell viability or proliferation were assessed by WST8 (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt and Lactate dehydrogenase (LDH) release, Trypan blue exclusion test, and Alamar blue assay. Antioxidant activity was evaluated by a cell-based chemiluminescent probe for the detection of intracellular H2O2 production in HUVECs. Heme oxygenase-1 (HO-1) expression levels were investigated by RT-qPCR. Glutathione reductase (GR), glutathione peroxidase (Gpx), superoxide dismutase (SOD), and catalase (CAT) activities, as markers of intracellular antioxidant defense, were evaluated by spectrophotometric analysis. The immunomodulatory activity was examined in RAW 264.7 by quantification of inducible nitric oxide synthase (iNOS) and Tumor Necrosis Factor—alpha (TNFα) by RT-qPCR. Data showed that fermentation of Pushgay berries (i) enhances the content of quercetin aglycone, and (ii) increases their intracellular antioxidant activity, as indicated by the reduction in H2O2-induced cell death and the decrease in H2O2-induced HO-1 gene expression in HUVECs treated for 24 h with fermented berries solution (10 µg/mL). Moreover, treatment with Pushgay berries for 72 h (10 µg/mL) promotes cells growth in RAW 264.7, and only fermented Pushgay berries increase the expression of iNOS in the same cell line. Taken together, our results show that LAB fermentation of Pushgay berries enhances their antioxidant and immunomodulatory properties.
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Liu M, Zhong W, Li C, Su W. Fluoxetine attenuates apoptosis in early brain injury after subarachnoid hemorrhage through Notch1/ASK1/p38 MAPK signaling pathway. Bioengineered 2022; 13:8396-8411. [PMID: 35383529 PMCID: PMC9162017 DOI: 10.1080/21655979.2022.2037227] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Subarachnoid hemorrhage (SAH) is a severe brain condition associated with a significantly high incidence and mortality. As a consequence of SAH, early brain injury (EBI) may contribute to poor SAH patient outcomes. Apoptosis is a signaling pathway contributing to post-SAH early brain injury and the diagnosis of the disease. Fluoxetine is a well-studied serotonin selective reuptake inhibitor (SSRI). However, its role in apoptosis has not been clearly understood. The present investigation assessed the effects of Fluoxetine in apoptosis and the potential Notch1/ASK1/p38 MAPK signaling pathway in EBI after SAH. Adult C57BL/6 J mice were subjected to SAH. Study mice (56) were randomly divided into 4 groups: the surgery without SAH (sham (n = 8), SAH+ vehicle; (SAH+V) (n = 16), surgery+ Fluoxetine (Fluox), (n = 16) and SAH+ Fluoxetine (n = 16). Various parameters were investigated 12, 24, 48, and 72 h after induction of SAH. Western blot analysis, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining, Immunohistochemistry (IHC), and flow cytometry were carried out in every experimental group. According to the findings, the SAH downregulated NOTCH1 signaling pathway, Jlk6 inhibited Notch1, Notch1 inactivation increased apoptotic protein expression and suppressed Bax, and cytochrome C. Fluoxetine reversed the effects of notch1 inhibition in SAH. The Neuroprotective Fluoxetine effects involved suppression of apoptosis post-SAH. In summary, early Fluoxetine treatment significantly attenuates apoptosis and the expression of apoptosis-related proteins after 72 h post-SAH. Fluoxetine may ameliorate early brain injury after subarachnoid hemorrhage through anti-apoptotic effects and Notch1/ASK1/p38 MAPK signaling pathway.
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Affiliation(s)
- Ming Liu
- Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan City, Shandong Province, China
| | - Weiying Zhong
- Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan City, Shandong Province, China
| | - Chao Li
- Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan City, Shandong Province, China
| | - Wandong Su
- Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan City, Shandong Province, China
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20
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Application of OpenArray RT-qPCR for identification of microRNA expression signatures of lower extremity artery disease. J Appl Genet 2022; 63:497-512. [DOI: 10.1007/s13353-022-00692-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 03/19/2022] [Accepted: 03/24/2022] [Indexed: 12/24/2022]
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21
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Herron CM, O’Connor A, Robb E, McCammick E, Hill C, Marks NJ, Robinson MW, Maule AG, McVeigh P. Developmental Regulation and Functional Prediction of microRNAs in an Expanded Fasciola hepatica miRNome. Front Cell Infect Microbiol 2022; 12:811123. [PMID: 35223544 PMCID: PMC8867070 DOI: 10.3389/fcimb.2022.811123] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 01/14/2022] [Indexed: 12/20/2022] Open
Abstract
The liver fluke, Fasciola hepatica, is a global burden on the wellbeing and productivity of farmed ruminants, and a zoonotic threat to human health. Despite the clear need for accelerated discovery of new drug and vaccine treatments for this pathogen, we still have a relatively limited understanding of liver fluke biology and host interactions. Noncoding RNAs, including micro (mi)RNAs, are key to transcriptional regulation in all eukaryotes, such that an understanding of miRNA biology can shed light on organismal function at a systems level. Four previous publications have reported up to 89 mature miRNA sequences from F. hepatica, but our data show that this does not represent a full account of this species miRNome. We have expanded on previous studies by sequencing, for the first time, miRNAs from multiple life stages (adult, newly excysted juvenile (NEJ), metacercariae and adult-derived extracellular vesicles (EVs)). These experiments detected an additional 61 high-confidence miRNAs, most of which have not been described in any other species, expanding the F. hepatica miRNome to 150 mature sequences. We used quantitative (q)PCR assays to provide the first developmental profile of miRNA expression across metacercariae, NEJ, adult and adult-derived Evs. The majority of miRNAs were expressed most highly in metacercariae, with at least six distinct expression clusters apparent across life stages. Intracellular miRNAs were functionally analyzed to identify target mRNAs with inversely correlated expression in F. hepatica tissue transcriptomes, highlighting regulatory interactions with key virulence transcripts including cathepsin proteases, and neuromuscular genes that control parasite growth, development and motility. We also linked 28 adult-derived EV miRNAs with downregulation of 397 host genes in F. hepatica-infected transcriptomes from ruminant lymph node, peripheral blood mononuclear cell (PBMC) and liver tissue transcriptomes. These included genes involved in signal transduction, immune and metabolic pathways, adding to the evidence for miRNA-based immunosuppression during fasciolosis. These data expand our understanding of the F. hepatica miRNome, provide the first data on developmental miRNA regulation in this species, and provide a set of testable hypotheses for functional genomics interrogations of liver fluke miRNA biology.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Paul McVeigh
- School of Biological Sciences, Queen’s University Belfast, Belfast, United Kingdom
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22
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E3 Ubiquitin Ligase Regulators of Notch Receptor Endocytosis: From Flies to Humans. Biomolecules 2022; 12:biom12020224. [PMID: 35204725 PMCID: PMC8961608 DOI: 10.3390/biom12020224] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/18/2022] [Accepted: 01/21/2022] [Indexed: 02/04/2023] Open
Abstract
Notch is a developmental receptor, conserved in the evolution of the metazoa, which regulates cell fate proliferation and survival in numerous developmental contexts, and also regulates tissue renewal and repair in adult organisms. Notch is activated by proteolytic removal of its extracellular domain and the subsequent release of its intracellular domain, which then acts in the nucleus as part of a transcription factor complex. Numerous regulatory mechanisms exist to tune the amplitude, duration and spatial patterning of this core signalling mechanism. In Drosophila, Deltex (Dx) and Suppressor of dx (Su(dx)) are E3 ubiquitin ligases which interact with the Notch intracellular domain to regulate its endocytic trafficking, with impacts on both ligand-dependent and ligand-independent signal activation. Homologues of Dx and Su(dx) have been shown to also interact with one or more of the four mammalian Notch proteins and other target substrates. Studies have shown similarities, specialisations and diversifications of the roles of these Notch regulators. This review collates together current research on vertebrate Dx and Su(dx)-related proteins, provides an overview of their various roles, and discusses their contributions to cell fate regulation and disease.
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