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De Feo D, Massari F, Campanella C, Livrieri A, Ciccone MM, Caldarola P, De Palo M, Scicchitano P. Influence of Soluble Guanylate Cyclase on Cardiac, Vascular, and Renal Structure and Function: A Physiopathological Insight. Int J Mol Sci 2025; 26:4550. [PMID: 40429695 PMCID: PMC12110928 DOI: 10.3390/ijms26104550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2025] [Revised: 05/01/2025] [Accepted: 05/07/2025] [Indexed: 05/29/2025] Open
Abstract
The role of nitric oxide (NO), soluble guanylate cyclase (sGC), and the cyclic guanosine monophosphate (cGMP) pathway in cardiovascular and renal health and disease is a complex issue. The impact of these biochemical pathways on the vascular tree is well established: the activation of sGC by NO promotes vasodilation and modulates vascular tone. Indeed, additional characteristics exist that lead physicians to believe there is a pleiotropic influence of this pathway on the functional activities and structural characteristics of human tissues and cells. Recently, sGC stimulators have demonstrated clinical efficacy in patients with worsening heart failure with reduced ejection fraction, improving cardiovascular death risk, re-hospitalization for HF, and all-cause mortality. These new outcome data have increased interest in understanding the potential pathophysiological mechanisms. The NO-sGC-cGMP axis may influence endothelial function, kidney performance, and cardiac muscle cell activity. The synergy of these actions could explain the positive effects of vericiguat on worsening HF. The aim of this narrative review was to provide a comprehensive insight into the pathophysiological mechanisms of action of NO-sGC-cGMP axis stimulators on cardiac muscle, endothelial cells, and kidneys.
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Affiliation(s)
- Daniele De Feo
- Cardiology Section, University of Bari, 70121 Bari, Italy; (D.D.F.); (A.L.); (M.M.C.)
| | - Francesco Massari
- Cardiology Section, Hospital “F. Perinei” Altamura (BA), 70022 Altamura, Italy;
| | - Cosimo Campanella
- Cardiology Department, Hospital “San Paolo” Bari, 70132 Bari, Italy; (C.C.); (P.C.)
| | - Anna Livrieri
- Cardiology Section, University of Bari, 70121 Bari, Italy; (D.D.F.); (A.L.); (M.M.C.)
| | - Marco Matteo Ciccone
- Cardiology Section, University of Bari, 70121 Bari, Italy; (D.D.F.); (A.L.); (M.M.C.)
| | - Pasquale Caldarola
- Cardiology Department, Hospital “San Paolo” Bari, 70132 Bari, Italy; (C.C.); (P.C.)
| | - Micaela De Palo
- Cardiac Surgery Section, University of Bari, 70121 Bari, Italy;
| | - Pietro Scicchitano
- Cardiology Section, Hospital “F. Perinei” Altamura (BA), 70022 Altamura, Italy;
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Gu J, He Y, He C, Zhang Q, Huang Q, Bai S, Wang R, You Q, Wang L. Advances in the structures, mechanisms and targeting of molecular chaperones. Signal Transduct Target Ther 2025; 10:84. [PMID: 40069202 PMCID: PMC11897415 DOI: 10.1038/s41392-025-02166-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 11/25/2024] [Accepted: 01/15/2025] [Indexed: 03/15/2025] Open
Abstract
Molecular chaperones, a class of complex client regulatory systems, play significant roles in the prevention of protein misfolding and abnormal aggregation, the modulation of protein homeostasis, and the protection of cells from damage under constantly changing environmental conditions. As the understanding of the biological mechanisms of molecular chaperones has increased, their link with the occurrence and progression of disease has suggested that these proteins are promising targets for therapeutic intervention, drawing intensive interest. Here, we review recent advances in determining the structures of molecular chaperones and heat shock protein 90 (HSP90) chaperone system complexes. We also describe the features of molecular chaperones and shed light on the complicated regulatory mechanism that operates through interactions with various co-chaperones in molecular chaperone cycles. In addition, how molecular chaperones affect diseases by regulating pathogenic proteins has been thoroughly analyzed. Furthermore, we focus on molecular chaperones to systematically discuss recent clinical advances and various drug design strategies in the preclinical stage. Recent studies have identified a variety of novel regulatory strategies targeting molecular chaperone systems with compounds that act through different mechanisms from those of traditional inhibitors. Therefore, as more novel design strategies are developed, targeting molecular chaperones will significantly contribute to the discovery of new potential drugs.
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Affiliation(s)
- Jinying Gu
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yanyi He
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Chenxi He
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Qiuyue Zhang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Qifei Huang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Shangjun Bai
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Ruoning Wang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
- Jiangsu Provincial TCM Engineering Technology Research Center of Highly Efficient Drug Delivery Systems (DDSs), Nanjing, China.
| | - Qidong You
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
| | - Lei Wang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
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3
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Wang L, Tang Y, Buckley AF, Spurney RF. Podocyte specific knockout of the natriuretic peptide clearance receptor is podocyte protective in focal segmental glomerulosclerosis. PLoS One 2025; 20:e0319424. [PMID: 40063586 PMCID: PMC11892885 DOI: 10.1371/journal.pone.0319424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 01/31/2025] [Indexed: 05/13/2025] Open
Abstract
Natriuretic peptides (NPs) bind to glomerular podocytes and attenuate glomerular injury. The beneficial effects of NPs are negatively regulated by the NP clearance receptor (NPRC), which is highly expressed in podocytes. To determine if inhibiting NPRC is podocyte protective, we examined the effects of deleting NPRC in both cultured podocytes and in vivo. We found that: 1.Both atrial NP and C-type NP inhibit podocyte apoptosis in cultured podocytes, but these podocyte protective effects are significantly attenuated in cells expressing NPRC, and 2. Atrial NP was significantly more effective than CNP at inhibiting the apoptotic response. Consistent with the protective actions of NPs, podocyte specific knockout of NPRC reduced albuminuria, glomerular sclerosis and tubulointerstitial inflammation in a mouse model of focal segmental glomerulosclerosis. These beneficial actions were associated with: 1. Decreased expression of the myofibroblast marker alpha-smooth muscle actin, 2. Reduced expression of the extracellular matrix proteins collagen 4-alpha-1 and fibronectin, and 3. Preserved expression of the podocyte proteins nephrin and podocin. Inhibiting NP clearance may be a useful therapeutic approach to treat glomerular diseases.
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MESH Headings
- Podocytes/metabolism
- Podocytes/pathology
- Podocytes/drug effects
- Animals
- Glomerulosclerosis, Focal Segmental/pathology
- Glomerulosclerosis, Focal Segmental/metabolism
- Glomerulosclerosis, Focal Segmental/genetics
- Receptors, Atrial Natriuretic Factor/genetics
- Receptors, Atrial Natriuretic Factor/metabolism
- Receptors, Atrial Natriuretic Factor/deficiency
- Mice
- Apoptosis/drug effects
- Mice, Knockout
- Natriuretic Peptide, C-Type/pharmacology
- Natriuretic Peptide, C-Type/metabolism
- Disease Models, Animal
- Membrane Proteins/metabolism
- Albuminuria/genetics
- Male
- Intracellular Signaling Peptides and Proteins
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Affiliation(s)
- Liming Wang
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina, United States of America
| | - Yuping Tang
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina, United States of America
| | - Anne F. Buckley
- Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America
| | - Robert F. Spurney
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina, United States of America
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Liu YK, Dong YH, Liang XM, Qiang S, Li ME, Sun Z, Zhao X, Yan ZH, Zheng J. Application of integrated omics in aseptic loosening of prostheses after hip replacement. Mol Med Rep 2025; 31:65. [PMID: 39749710 PMCID: PMC11726296 DOI: 10.3892/mmr.2025.13430] [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: 07/12/2024] [Accepted: 11/06/2024] [Indexed: 01/04/2025] Open
Abstract
Aseptic loosening (AL) of artificial hip joints is the most common complication following hip replacement surgery. A total of eight patients diagnosed with AL following total hip arthroplasty (THA) undergoing total hip replacement and eight control patients diagnosed with avascular necrosis of femoral head (ANFH) or femoral neck fracture undergoing THA were enrolled. The samples of the AL group were from synovial tissue surrounding the lining/head/neck of the prosthesis, and the samples of the control group were from the synovium in the joint cavity. The present study utilized second‑generation high‑throughput sequencing and mass spectrometry to detect differentially expressed genes, proteins and metabolites in the samples, as well as Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Key genes cytokine receptor‑like factor‑1 (CRLF1) and glutathione‑S transferase µ1 (GSTM1) expression levels were verified by reverse transcription‑quantitative PCR and western blotting. The integrated transcriptomics, proteomics and untargeted metabolomics analyses revealed characteristic metabolite changes (biosynthesis of guanine, L‑glycine and adenosine) and decreased CRLF1 and GSTM1 in AL, which were primarily associated with amino acid metabolism and lipid metabolism. In summary, the present study may uncover the underlying mechanisms of AL pathology and provide stable and accurate biomarkers for early warning and diagnosis.
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Affiliation(s)
- Yun-Ke Liu
- Department of Orthopedics, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
- Department of Orthopedics, Henan University People's Hospital, Zhengzhou, Henan 450003, P.R. China
- Department of Orthopedics, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China
| | - Yong-Hui Dong
- Department of Orthopedics, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
- Department of Orthopedics, Henan University People's Hospital, Zhengzhou, Henan 450003, P.R. China
- Department of Orthopedics, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China
| | - Xia-Ming Liang
- Department of Orthopedics, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
- Department of Orthopedics, Henan University People's Hospital, Zhengzhou, Henan 450003, P.R. China
- Department of Orthopedics, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China
| | - Shuo Qiang
- Department of Orthopedics, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
- Department of Orthopedics, Henan University People's Hospital, Zhengzhou, Henan 450003, P.R. China
- Department of Orthopedics, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China
| | - Meng-En Li
- Department of Orthopedics, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
- Department of Orthopedics, Henan University People's Hospital, Zhengzhou, Henan 450003, P.R. China
- Department of Orthopedics, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China
| | - Zhuang Sun
- Department of Orthopedics, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
- Department of Orthopedics, Henan University People's Hospital, Zhengzhou, Henan 450003, P.R. China
- Department of Orthopedics, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China
| | - Xin Zhao
- Department of Orthopedics, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
- Department of Orthopedics, Henan University People's Hospital, Zhengzhou, Henan 450003, P.R. China
- Department of Orthopedics, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China
| | - Zhi-Hua Yan
- Department of Orthopedics, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
- Department of Orthopedics, Henan University People's Hospital, Zhengzhou, Henan 450003, P.R. China
- Department of Orthopedics, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China
| | - Jia Zheng
- Department of Orthopedics, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
- Department of Orthopedics, Henan University People's Hospital, Zhengzhou, Henan 450003, P.R. China
- Department of Orthopedics, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China
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5
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Ng MSY, Hawley CM. A golden year of innovative kidney disease therapeutics. Nat Rev Nephrol 2025; 21:75-76. [PMID: 39753690 DOI: 10.1038/s41581-024-00916-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2025]
Affiliation(s)
- Monica Suet Ying Ng
- Kidney Health Service, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
- Conjoint Internal Medicine Laboratory, Pathology Queensland, Herston, Queensland, Australia
- Faculty of Medicine, University of Queensland, Herston, Queensland, Australia
- Institute of Molecular Biosciences, University of Queensland, Saint Lucia, Queensland, Australia
| | - Carmel M Hawley
- Department of Kidney and Transplant Services, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia.
- Translational Research Institute, Woolloongabba, Queensland, Australia.
- Centre for Kidney Disease Research, University of Queensland, Woolloongabba, Queensland, Australia.
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6
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Lehners M, Schmidt H, Zaldivia MTK, Stehle D, Krämer M, Peter A, Adler J, Lukowski R, Feil S, Feil R. Single-cell analysis identifies the CNP/GC-B/cGMP axis as marker and regulator of modulated VSMCs in atherosclerosis. Nat Commun 2025; 16:429. [PMID: 39814746 PMCID: PMC11735800 DOI: 10.1038/s41467-024-55687-9] [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: 03/25/2024] [Accepted: 12/20/2024] [Indexed: 01/18/2025] Open
Abstract
A balanced activity of cGMP signaling contributes to the maintenance of cardiovascular homeostasis. Vascular smooth muscle cells (VSMCs) can generate cGMP via three ligand-activated guanylyl cyclases, the NO-sensitive guanylyl cyclase, the atrial natriuretic peptide (ANP)-activated GC-A, and the C-type natriuretic peptide (CNP)-stimulated GC-B. Here, we study natriuretic peptide signaling in murine VSMCs and atherosclerotic lesions. Correlative profiling of pathway activity and VSMC phenotype at the single-cell level shows that phenotypic modulation of contractile VSMCs to chondrocyte-like plaque cells during atherogenesis is associated with a switch from ANP/GC‑A to CNP/GC‑B signaling. Silencing of the CNP/GC-B axis in VSMCs results in an increase of chondrocyte-like plaque cells. These findings indicate that the CNP/GC-B/cGMP pathway is a marker and atheroprotective regulator of modulated VSMCs, limiting their transition to chondrocyte-like cells. Overall, this study highlights the plasticity of cGMP signaling in VSMCs and suggests analogies between CNP-dependent remodeling of bone and blood vessels.
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MESH Headings
- Animals
- Cyclic GMP/metabolism
- Natriuretic Peptide, C-Type/metabolism
- Natriuretic Peptide, C-Type/genetics
- Atherosclerosis/metabolism
- Atherosclerosis/pathology
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/cytology
- Signal Transduction
- Mice
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Receptors, Atrial Natriuretic Factor/metabolism
- Receptors, Atrial Natriuretic Factor/genetics
- Single-Cell Analysis
- Male
- Mice, Inbred C57BL
- Biomarkers/metabolism
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Affiliation(s)
- Moritz Lehners
- Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany
| | - Hannes Schmidt
- Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany
| | - Maria T K Zaldivia
- Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany
| | - Daniel Stehle
- Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany
| | - Michael Krämer
- Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany
| | - Andreas Peter
- Department for Diagnostic Laboratory Medicine, Institute for Clinical Chemistry and Pathobiochemistry, University Hospital Tübingen, Tübingen, Germany
| | - Julia Adler
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany
| | - Robert Lukowski
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany
| | - Susanne Feil
- Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany
| | - Robert Feil
- Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany.
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Rager C, Klöpper T, Tasch S, Whittaker MR, Exintaris B, Mietens A, Middendorff R. The Influence of Cell Isolation and Culturing on Natriuretic Peptide Receptors in Aortic Vascular Smooth Muscle Cells. Cells 2025; 14:51. [PMID: 39791752 PMCID: PMC11720613 DOI: 10.3390/cells14010051] [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: 10/24/2024] [Revised: 12/22/2024] [Accepted: 01/02/2025] [Indexed: 01/12/2025] Open
Abstract
Vascular smooth muscle cell (SMC) relaxation by guanylyl cyclases (GCs) and cGMP is mediated by NO and its receptor soluble GC (sGC) or natriuretic peptides (NPs) ANP/BNP and CNP with the receptors GC-A and GC-B, respectively. It is commonly accepted that cultured SMCs differ from those in intact vessels. Nevertheless, cell culture often remains the first step for signaling investigations and drug testing. Previously, we showed that even popular reference genes changed dramatically after SMC isolation from aorta. Regarding NP receptors, a substantial amount of data relies on cell culture. We hypothesize that the NP/cGMP system in intact aortic tunica media differs from isolated and cultured aortic SMCs. Therefore, we studied isolation and culturing effects on the expression of NP receptors GC-A, GC-B, and NP clearance receptor (NPRC) compared to sGC. We investigated intact tunica media and primary SMCs from the longitudinal halves of the same rat aorta. GC activity was monitored by cyclic guanosine monophosphate (cGMP). In addition, we hypothesize that there are sex-dependent differences in the NP/cGMP cascade in both intact tissue and cultured cells. We, therefore, analyzed a male and female cohort. Expression was quantified by RT-qPCR comparing aortic media and SMCs with our recently validated reference gene (RG) small nuclear ribonucleoprotein 2 (U2). Only GC-A was stably expressed. In intact media, GC-A exceeded GC-B and NPRC. However, GC-B, NPRC, and sGC were dramatically upregulated in cultured SMCs of the same aortae different from the stable GC-A. The expression was mirrored by NP-induced GC activity. In cultured cells, changes in GC activity were delayed compared to receptor expression. Minor differences between both sexes could also be revealed. Thus, isolation and culture fundamentally alter the cGMP system in vascular SMCs with potential impact on drug testing and scRNAseq. Especially, the dramatic increase in the clearance receptor NPRC in culture might distort all physiological ANP, BNP, and CNP effects.
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MESH Headings
- Animals
- Muscle, Smooth, Vascular/cytology
- Muscle, Smooth, Vascular/metabolism
- Receptors, Atrial Natriuretic Factor/metabolism
- Receptors, Atrial Natriuretic Factor/genetics
- Male
- Rats
- Female
- Aorta/cytology
- Aorta/metabolism
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/cytology
- Cells, Cultured
- Cyclic GMP/metabolism
- Cell Separation
- Rats, Wistar
- Cell Culture Techniques/methods
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Affiliation(s)
- Christine Rager
- Institute of Anatomy & Cell Biology, Faculty of Medicine, Justus-Liebig-University, Aulweg 123, 35392 Giessen, Germany; (C.R.)
- Drug Delivery, Disposition, and Dynamics (D4), Monash Institute of Pharmacy & Pharmaceutical Sciences (MIPS), Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia;
| | - Tobias Klöpper
- Institute of Anatomy & Cell Biology, Faculty of Medicine, Justus-Liebig-University, Aulweg 123, 35392 Giessen, Germany; (C.R.)
| | - Sabine Tasch
- Institute of Anatomy & Cell Biology, Faculty of Medicine, Justus-Liebig-University, Aulweg 123, 35392 Giessen, Germany; (C.R.)
| | - Michael Raymond Whittaker
- Drug Delivery, Disposition, and Dynamics (D4), Monash Institute of Pharmacy & Pharmaceutical Sciences (MIPS), Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia;
| | - Betty Exintaris
- Pharmacy and Pharmaceutical Sciences Education, Monash Institute of Pharmacy & Pharmaceutical Sciences (MIPS), Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia
| | - Andrea Mietens
- Institute of Anatomy & Cell Biology, Faculty of Medicine, Justus-Liebig-University, Aulweg 123, 35392 Giessen, Germany; (C.R.)
| | - Ralf Middendorff
- Institute of Anatomy & Cell Biology, Faculty of Medicine, Justus-Liebig-University, Aulweg 123, 35392 Giessen, Germany; (C.R.)
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8
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Gormley AR, Duarte ME, Deng Z, Kim SW. Saccharomyces yeast postbiotics mitigate mucosal damages from F18 + Escherichia coli challenges by positively balancing the mucosal microbiota in the jejunum of young pigs. Anim Microbiome 2024; 6:73. [PMID: 39707576 DOI: 10.1186/s42523-024-00363-y] [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: 11/12/2024] [Accepted: 12/03/2024] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND Enterotoxigenic Escherichia coli (E. coli) is one of the most prevalent causes of diarrhea in young animals. Postbiotics derived from yeast have the potential to positively influence the mucosal microbiota in the jejunum, therefore it was hypothesized that Saccharomyces yeast postbiotics could enhance the microbiota and mucosal immune response in the jejunum, mitigating the effects of infection with enterotoxigenic E. coli. The purpose of this study was to investigate the effects of a Saccharomyces yeast postbiotic on the mucosal microbiota and mucosal immune response in the jejunum of newly weaned pigs challenged with F18+ E. coli. RESULTS Thirty-six individually housed nursery pigs were allotted into three treatments utilizing a randomized complete block design; negative control (NC: basal diet, no challenge), positive control (PC: basal diet, challenge), and SYP (basal diet + Saccharomyces yeast postbiotics at 175 g/ton, challenge). On d 7, PC and SYP were orally inoculated with F18+ E. coli, whereas NC received saline. On d 28, pigs were euthanized for sampling of the jejunum to analyze the mucosal microbiota, oxidative stress, immune status, and intestinal morphology. The PC reduced (P < 0.05) growth performance compared to NC. The SYP improved (P < 0.05) fecal score from d 7-18 when compared with PC. SYP reduced (P < 0.05) protein carbonyl, reduced (P < 0.05) gene expression of Toll-like receptor 4, and increased (P < 0.05) gene expression of mammalian target of rapamycin, compared with PC. CONCLUSIONS Challenge with F18+ E. coli negatively impacted jejunal mucosa-associated microbiota and jejunal morphology, affecting growth performance. Saccharomyces yeast postbiotics could reduce the negative effects associated with F18+ E. coli infection.
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Affiliation(s)
- Alexa R Gormley
- Department of Animal Science, North Carolina State University, 116 Polk Hall, 120 W Broughton Dr, Raleigh, NC, 27695, USA
| | - Marcos Elias Duarte
- Department of Animal Science, North Carolina State University, 116 Polk Hall, 120 W Broughton Dr, Raleigh, NC, 27695, USA
| | - Zixiao Deng
- Department of Animal Science, North Carolina State University, 116 Polk Hall, 120 W Broughton Dr, Raleigh, NC, 27695, USA
| | - Sung Woo Kim
- Department of Animal Science, North Carolina State University, 116 Polk Hall, 120 W Broughton Dr, Raleigh, NC, 27695, USA.
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9
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Xu Y, Huang C, Xu H, Xu J, Cheng KW, Mok HL, Lyu C, Zhu L, Lin C, Tan HY, Bian Z. Modified Zhenwu Decoction improved intestinal barrier function of experimental colitis through activation of sGC-mediated cGMP/PKG signaling. JOURNAL OF ETHNOPHARMACOLOGY 2024; 334:118570. [PMID: 39002824 DOI: 10.1016/j.jep.2024.118570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 06/13/2024] [Accepted: 07/09/2024] [Indexed: 07/15/2024]
Abstract
BACKGROUND The invasion of luminal antigens and an aberrant immune response resulting from a disrupted physical epithelial barrier are the key characteristics of ulcerative colitis (UC). The restoration of damaged epithelial function is crucial for maintaining mucosal homeostasis and disease quiescence. Current therapies for UC primarily focus on suppressing inflammation. However, most patients fail to respond to therapy or develop secondary resistance over time, emphasizing the need to develop novel therapeutic targets for UC. Our study aimed to identify the potential targets of a novel modified herbal formula from the Zhen Wu Decoction, namely CDD-2103, which has demonstrated promising efficacy in treating chronic colitis. METHODS The effect of CDD-2103 on epithelial barrier function was examined using in vitro and ex vivo models of tissue injury, as well as a chronic colitis C57BL/6 mouse model. Transcriptomic analysis was employed to profile gene expression changes in colonic tissues following treatment with CDD-2103. RESULTS Our in vivo experiments demonstrated that CDD-2103 dose-dependently reduced disease severity in mice with chronic colitis. The efficacy of CDD-2103 was mediated by a reduction in goblet cell loss and the enhancement of tight junction protein integrity. Mechanistically, CDD-2103 suppressed epithelial cell apoptosis and tight junction protein breakdown by activating the soluble guanynyl cyclase (sGC)-mediated cyclic guanosine monophosphate (cGMP)/PKG signaling cascade. Molecular docking analysis revealed strong sGC ligand recognition by the CDD-2103-derived molecules, warranting further investigation. CONCLUSION Our study revealed a novel formulation CDD-2103 that restores intestinal barrier function through the activation of sGC-regulated cGMP/PKG signaling. Furthermore, our findings suggest that targeting sGC can be an effective approach for promoting mucosal healing in the management of UC.
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Affiliation(s)
- Yiqi Xu
- Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong SAR, China
| | - Chunhua Huang
- Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong SAR, China; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Hengyue Xu
- Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China
| | - Jiaruo Xu
- Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong SAR, China
| | - Ka Wing Cheng
- Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong SAR, China; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Heung Lam Mok
- Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong SAR, China
| | - Cheng Lyu
- Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong SAR, China
| | - Lin Zhu
- Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong SAR, China
| | - Chengyuan Lin
- Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong SAR, China
| | - Hor Yue Tan
- Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong SAR, China; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.
| | - Zhaoxiang Bian
- Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong SAR, China; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.
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10
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Zhang K, Xu Y, Zheng Y, Zhang T, Wu Y, Yan Y, Lei Y, Cao X, Wang X, Yan F, Lei Z, Brugger D, Chen Y, Deng L, Yang Y. Bifidobacterium pseudolongum-Derived Bile Acid from Dietary Carvacrol and Thymol Supplementation Attenuates Colitis via cGMP-PKG-mTORC1 Pathway. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2406917. [PMID: 39308187 DOI: 10.1002/advs.202406917] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 09/09/2024] [Indexed: 11/22/2024]
Abstract
Carvacrol and thymol (CAT) have been widely recognized for their antimicrobial and anti-inflammatory properties, yet their specific effects on colitis and the mechanisms involved remain insufficiently understood. This study establishes a causative link between CAT administration and colitis mitigation, primarily through the enhancement of Bifidobacterium pseudolongum abundance in the colon. This increase promotes the production of secondary bile acids, particularly hyodeoxycholic acid (HDCA) and 12-ketodeoxycholic acid (12-KCAC), which exert anti-inflammatory effects. Notably, CAT does not alleviate colitis symptoms in germ-free mice, indicating the necessity of gut microbiota. This research uncovers a novel regulatory mechanism where HDCA and 12-KCAC inhibit colonic inflammation by reducing the expression of transmembrane guanylate cyclase 1A in the colonic epithelium. This downregulation elevates intracellular Ca2+ and cGMP levels, activating protein kinase G (PKG). Activated PKG subsequently suppresses the mTOR signaling pathway, thereby ameliorating dextran sulfate sodium (DSS)-induced colonic damage. These findings highlight potential metabolites and therapeutic targets for preventing and treating colitis. Bifidobacterium pseudolongum, HDCA, and 12-KCAC emerge as promising candidates for therapeutic interventions in colitis and related disorders characterized by impaired tight junction function.
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Affiliation(s)
- Ke Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Yangbin Xu
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Yining Zheng
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Ting Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Yujiang Wu
- Institute of Animal Sciences, Tibet Academy of Agricultural and Animal Husbandry Sciences, Lhasa, 850009, China
| | - Yiting Yan
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Yu Lei
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Xi Cao
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Xiaolong Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Frances Yan
- Novus International Inc, Research Park Drive, Saint Charles, MO, 63304, USA
| | - Zhaomin Lei
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China
| | - Daniel Brugger
- Institute of Animal Nutrition and Dietetics, Vetsuisse-Faculty, University of Zurich, Zurich, 8057, Switzerland
| | - Yulin Chen
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Lu Deng
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Yuxin Yang
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
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11
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Douma EH, Stoop J, Lingl MVR, Smidt MP, van der Heide LP. Phosphodiesterase inhibition and Gucy2C activation enhance tyrosine hydroxylase Ser40 phosphorylation and improve 6-hydroxydopamine-induced motor deficits. Cell Biosci 2024; 14:132. [PMID: 39456033 PMCID: PMC11515495 DOI: 10.1186/s13578-024-01312-7] [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: 02/20/2024] [Accepted: 10/14/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND Parkinson's disease is characterized by a progressive loss of dopaminergic neurons in the nigrostriatal pathway, leading to dopamine deficiency and motor impairments. Current treatments, such as L-DOPA, provide symptomatic relief but result in off-target effects and diminished efficacy over time. This study explores an alternative approach by investigating the activation of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. Specifically, we explore the effects of phosphodiesterase (PDE) inhibition and guanylate cyclase-C (GUCY2C) activation on tyrosine hydroxylase Ser40 phosphorylation and their impact on motor behavior in a 6-hydroxydopamine (6-OHDA) Parkinson's disease model. RESULTS Our findings demonstrate that increasing cyclic nucleotide levels through PDE inhibition and GUCY2C activation significantly enhances tyrosine hydroxylase Ser40 phosphorylation. In a Pitx3-deficient mouse model, which mimics the loss of dopaminergic neurons seen in Parkinson's disease, Ser40 phosphorylation remained manipulable despite reduced tyrosine hydroxylase protein levels. Moreover, we observed no evidence of tyrosine hydroxylase degradation due to Ser40 phosphorylation, challenging previous reports. Furthermore, both PDE inhibition and GUCY2C activation resulted in improved motor behavior in the 6-OHDA Parkinson's disease mouse model, highlighting the potential therapeutic benefits of these approaches. CONCLUSIONS This study underscores the therapeutic potential of enhancing tyrosine hydroxylase Ser40 phosphorylation to improve motor function in Parkinson's disease. Both PDE inhibition and GUCY2C activation represent promising non-invasive strategies to modulate endogenous dopamine biosynthesis and address motor deficits. These findings suggest that targeting cyclic nucleotide pathways could lead to novel therapeutic approaches, either as standalone treatments or in combination with existing therapies like L-DOPA, aiming to provide more durable symptom relief and potentially mitigate neurodegeneration in Parkinson's disease.
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Affiliation(s)
- Erik H Douma
- Macrobian-Biotech B.V., Science Park 904, 1098 XH, Amsterdam, The Netherlands
- Parkinnova Therapeutics B.V., Science Park 904, 1098 XH, Amsterdam, The Netherlands
| | - Jesse Stoop
- Macrobian-Biotech B.V., Science Park 904, 1098 XH, Amsterdam, The Netherlands
| | - Matthijs V R Lingl
- Swammerdam Institute for Life Sciences, University of Amsterdam, Room C3.104, Science Park 904, 1098 XH, Amsterdam, The Netherlands
| | - Marten P Smidt
- Swammerdam Institute for Life Sciences, University of Amsterdam, Room C3.104, Science Park 904, 1098 XH, Amsterdam, The Netherlands
| | - Lars P van der Heide
- Swammerdam Institute for Life Sciences, University of Amsterdam, Room C3.104, Science Park 904, 1098 XH, Amsterdam, The Netherlands.
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12
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Douma EH, Smidt MP, van der Heide LP. Boosting endogenous dopamine production: a novel therapeutic approach for Parkinson's disease. Trends Mol Med 2024; 30:800-803. [PMID: 38926032 DOI: 10.1016/j.molmed.2024.06.002] [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: 03/31/2024] [Revised: 06/03/2024] [Accepted: 06/04/2024] [Indexed: 06/28/2024]
Abstract
Innovative therapeutic strategies are urgently needed for Parkinson's disease due to limited efficacy of current treatments and a weak therapeutic pipeline. In this forum article, we propose targeting tyrosine hydroxylase phosphorylation as a novel mechanism of action to address this critical need.
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Affiliation(s)
- Erik H Douma
- Parkinnova Therapeutics, Science Park 904, 1098 XH, Amsterdam, The Netherlands
| | - Marten P Smidt
- Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands
| | - Lars P van der Heide
- Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands.
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13
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Bekmez H, Kocak MN, Tavaci T, Halici H, Toktay E, Celik M, Bagci HH. Inflammation in cerebral ischemia reperfusion improved by avanafil via nod-like receptor protein-3 inflammasome: an experimental study in rats. Brain Inj 2024; 38:708-715. [PMID: 38676710 DOI: 10.1080/02699052.2024.2346147] [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: 04/16/2023] [Accepted: 04/17/2024] [Indexed: 04/29/2024]
Abstract
OBJECTIVE The aim of study was to investigate the effect of avanafil, a second-generation phosphodiesterase-5 (PDE5) inhibitor, on cerebral ischemia reperfusion (CI/R) model. METHODS 32 male albino Wistar rats were used. Four groups were constituted, as I: the healthy (sham), II: the CI/R group, III: the CI/R +I 10 mg/kg avanafil group, and IV: the CI/R + 20 mg/kg avanafil group. Avanafil was administered twice via oral gavage, first shortly after ischemia reperfusion and once more after 12 h. The rats were euthanized after 24 h. Histopathological and Real Time PCR analyzes were performed on cerebral tissues. RESULTS IL-1β, NLRP3 and TNF-α mRNA expressions were statistically higher in the CI/R group when compared to healthy (sham) group. Conversely, the IL-1β, NLRP3, and TNF-α mRNA expressions were significantly decreased in both of the avanafil-treated groups when compared to CI/R group. Histopathological results showed that both doses of avanafil also decreased cellular damage in cerebral tissue that occurred after CI/R. CONCLUSION Avanafil, was found to have ameliorated inflammatory response and cellular injury caused by CI/R. The mRNA expression of IL-1β, NLRP3, and TNF-α decreased in the I/R groups and approached the control group levels with a high dose of avanafil.
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Affiliation(s)
- Huseyin Bekmez
- Faculty of Medicine, Department of Pharmacology, Ataturk University, Erzurum, Turkey
| | - Mehmet Nuri Kocak
- Faculty of Medicine, Department of Neurology, Ataturk University, Erzurum, Turkey
| | - Taha Tavaci
- Faculty of Medicine, Department of Pharmacology, Ataturk University, Erzurum, Turkey
| | - Hamza Halici
- Faculty of Medicine, Department of Pharmacology, Ataturk University, Erzurum, Turkey
- Department of Hınıs Vocational Training School, Ataturk University, Erzurum, Turkey
| | - Erdem Toktay
- Faculty of Medicine, Department of Embryology and Histology, Kafkas University, Kars, Turkey
| | - Muhammet Celik
- Department of Medical Biochemistry, Faculty of Medicine, Ataturk University, Erzurum, Turkey
| | - Hamit Harun Bagci
- General Directorate of Administrative Services, Republic of Türkiye Ministry of Health, Ankara, Turkey
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14
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Ednacot EMQ, Nabhani A, Dinh DM, Morehouse BR. Pharmacological potential of cyclic nucleotide signaling in immunity. Pharmacol Ther 2024; 258:108653. [PMID: 38679204 DOI: 10.1016/j.pharmthera.2024.108653] [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: 01/07/2024] [Revised: 03/16/2024] [Accepted: 04/17/2024] [Indexed: 05/01/2024]
Abstract
Cyclic nucleotides are important signaling molecules that play many critical physiological roles including controlling cell fate and development, regulation of metabolic processes, and responding to changes in the environment. Cyclic nucleotides are also pivotal regulators in immune signaling, orchestrating intricate processes that maintain homeostasis and defend against pathogenic threats. This review provides a comprehensive examination of the pharmacological potential of cyclic nucleotide signaling pathways within the realm of immunity. Beginning with an overview of the fundamental roles of cAMP and cGMP as ubiquitous second messengers, this review delves into the complexities of their involvement in immune responses. Special attention is given to the challenges associated with modulating these signaling pathways for therapeutic purposes, emphasizing the necessity for achieving cell-type specificity to avert unintended consequences. A major focus of the review is on the recent paradigm-shifting discoveries regarding specialized cyclic nucleotide signals in the innate immune system, notably the cGAS-STING pathway. The significance of cyclic dinucleotides, exemplified by 2'3'-cGAMP, in controlling immune responses against pathogens and cancer, is explored. The evolutionarily conserved nature of cyclic dinucleotides as antiviral agents, spanning across diverse organisms, underscores their potential as targets for innovative immunotherapies. Findings from the last several years have revealed a striking diversity of novel bacterial cyclic nucleotide second messengers which are involved in antiviral responses. Knowledge of the existence and precise identity of these molecules coupled with accurate descriptions of their associated immune defense pathways will be essential to the future development of novel antibacterial therapeutic strategies. The insights presented herein may help researchers navigate the evolving landscape of immunopharmacology as it pertains to cyclic nucleotides and point toward new avenues or lines of thinking about development of therapeutics against the pathways they regulate.
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Affiliation(s)
- Eirene Marie Q Ednacot
- Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California Irvine, Irvine, CA 92697, USA; Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of California Irvine, Irvine, CA 92697, USA
| | - Ali Nabhani
- Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California Irvine, Irvine, CA 92697, USA
| | - David M Dinh
- Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California Irvine, Irvine, CA 92697, USA
| | - Benjamin R Morehouse
- Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California Irvine, Irvine, CA 92697, USA; Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of California Irvine, Irvine, CA 92697, USA; Institute for Immunology, University of California Irvine, Irvine, CA 92697, USA; Center for Virus Research, University of California Irvine, Irvine, CA 92697, USA.
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15
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Ogawa H, Kodama M. Structural insight into hormone recognition by the natriuretic peptide receptor-A. FEBS J 2024; 291:2273-2286. [PMID: 38437249 DOI: 10.1111/febs.17104] [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: 06/19/2023] [Revised: 11/21/2023] [Accepted: 02/16/2024] [Indexed: 03/06/2024]
Abstract
Atrial natriuretic peptide (ANP) plays a central role in the regulation of blood pressure and volume. ANP activities are mediated by natriuretic peptide receptor-A (NPR-A), a single-pass transmembrane receptor harboring intrinsic guanylate cyclase activity. This study investigated the mechanism underlying NPR-A-dependent hormone recognition through the determination of the crystal structures of the NPR-A extracellular hormone-binding domain complexed with full-length ANP, truncated mutants of ANP, and dendroaspis natriuretic peptide (DNP) isolated from the venom of the green Mamba snake, Dendroaspis angusticeps. The bound peptides possessed pseudo-two-fold symmetry, despite the lack of two-fold symmetry in the primary sequences, which enabled the tight coupling of the peptide to the receptor, and evidently contributes to guanylyl cyclase activity. The binding of DNP to the NPR-A was essentially identical to that of ANP; however, the affinity of DNP for NPR-A was higher than that of ANP owing to the additional interactions between distinctive sequences in the DNP and NPR-A. Consequently, our findings provide valuable insights that can be applied to the development of novel agonists for the treatment of various human diseases.
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Affiliation(s)
- Haruo Ogawa
- Department of Structural Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan
| | - Masami Kodama
- Department of Bio-informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Japan
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16
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Hill TJ, Sengupta P. Feedforward and feedback mechanisms cooperatively regulate rapid experience-dependent response adaptation in a single thermosensory neuron type. Proc Natl Acad Sci U S A 2024; 121:e2321430121. [PMID: 38530893 PMCID: PMC10998601 DOI: 10.1073/pnas.2321430121] [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: 12/05/2023] [Accepted: 02/27/2024] [Indexed: 03/28/2024] Open
Abstract
Sensory adaptation allows neurons to adjust their sensitivity and responses based on recent experience. The mechanisms that mediate continuous adaptation to stimulus history over seconds- to hours-long timescales, and whether these mechanisms can operate within a single sensory neuron type, are unclear. The single pair of AFD thermosensory neurons in Caenorhabditis elegans exhibits experience-dependent plasticity in their temperature response thresholds on both minutes- and hours-long timescales upon a temperature upshift. While long-term response adaptation requires changes in gene expression in AFD, the mechanisms driving rapid response plasticity are unknown. Here, we show that rapid thermosensory response adaptation in AFD is mediated via cGMP and calcium-dependent feedforward and feedback mechanisms operating at the level of primary thermotransduction. We find that either of two thermosensor receptor guanylyl cyclases (rGCs) alone is sufficient to drive rapid adaptation, but that each rGC drives adaptation at different rates. rGC-driven adaptation is mediated in part via phosphorylation of their intracellular domains, and calcium-dependent feedback regulation of basal cGMP levels via a neuronal calcium sensor protein. In turn, cGMP levels feedforward via cGMP-dependent protein kinases to phosphorylate a specific subunit of the cGMP-gated thermotransduction channel to further regulate rapid adaptation. Our results identify multiple molecular pathways that act in AFD to ensure rapid adaptation to a temperature change and indicate that the deployment of both transcriptional and nontranscriptional mechanisms within a single sensory neuron type can contribute to continuous sensory adaptation.
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Affiliation(s)
- Tyler J. Hill
- Department of Biology, Brandeis University, Waltham, MA02454
| | - Piali Sengupta
- Department of Biology, Brandeis University, Waltham, MA02454
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17
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Metkar SK, Yan Y, Lu Y, Lu J, Zhu X, Du F, Xu Y. Phosphodiesterase 2 and Its Isoform A as Therapeutic Targets in the Central Nervous System Disorders. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2024; 23:941-955. [PMID: 37855295 DOI: 10.2174/1871527323666230811093126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 06/15/2023] [Accepted: 07/07/2023] [Indexed: 10/20/2023]
Abstract
Cyclic adenosine monophosphates (cAMP) and cyclic guanosine monophosphate (cGMP) are two essential second messengers, which are hydrolyzed by phosphodiesterase's (PDEs), such as PDE-2. Pharmacological inhibition of PDE-2 (PDE2A) in the central nervous system improves cAMP and cGMP signaling, which controls downstream proteins related to neuropsychiatric, neurodegenerative, and neurodevelopmental disorders. Considering that there are no specific treatments for these disorders, PDE-2 inhibitors' development has gained more attention in the recent decade. There is high demand for developing new-generation drugs targeting PDE2 for treating diseases in the central nervous and peripheral systems. This review summarizes the relationship between PDE-2 with neuropsychiatric, neurodegenerative, and neurodevelopmental disorders as well as its possible treatment, mainly involving inhibitors of PDE2.
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Affiliation(s)
- Sanjay K Metkar
- Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA
| | - Yuqing Yan
- Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA
| | - Yue Lu
- Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA
| | - Jianming Lu
- Codex BioSolutions Inc. 12358 Parklawn Drive, Suite 250A, Rockville, MD 20852, Maryland
| | - Xiongwei Zhu
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106; USA
| | - Fu Du
- FD NeuroTechnologies Consulting & Services, Inc., Columbia, MD 21046, Maryland
| | - Ying Xu
- Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA
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18
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Hill TJ, Sengupta P. Feedforward and feedback mechanisms cooperatively regulate rapid experience-dependent response adaptation in a single thermosensory neuron type. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.05.570166. [PMID: 38168209 PMCID: PMC10760192 DOI: 10.1101/2023.12.05.570166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Sensory adaptation allows neurons to adjust their sensitivity and responses based on recent experience. The mechanisms that mediate continuous adaptation to stimulus history over seconds to hours long timescales, and whether these mechanisms can operate within a single sensory neuron type, are unclear. The single pair of AFD thermosensory neurons in C. elegans exhibits experience-dependent plasticity in their temperature response thresholds on both minutes- and hours-long timescales upon a temperature upshift. While long-term response adaptation requires changes in gene expression in AFD, the mechanisms driving rapid response plasticity are unknown. Here, we show that rapid thermosensory response adaptation in AFD is mediated via cGMP and calcium-dependent feedforward and feedback mechanisms operating at the level of primary thermotransduction. We find that either of two thermosensor receptor guanylyl cyclases (rGCs) alone is sufficient to drive rapid adaptation, but that each rGC drives adaptation at different rates. rGC-driven adaptation is mediated in part via phosphorylation of their intracellular domains, and calcium-dependent feedback regulation of basal cGMP levels via a neuronal calcium sensor protein. In turn, cGMP levels feedforward via cGMP-dependent protein kinases to phosphorylate a specific subunit of the cGMP-gated thermotransduction channel to further regulate rapid adaptation. Our results identify multiple molecular pathways that act in AFD to ensure rapid adaptation to a temperature change, and indicate that the deployment of both transcriptional and non-transcriptional mechanisms within a single sensory neuron type can contribute to continuous sensory adaptation.
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Affiliation(s)
- Tyler J. Hill
- Department of Biology, Brandeis University, Waltham, MA 02454
| | - Piali Sengupta
- Department of Biology, Brandeis University, Waltham, MA 02454
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19
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Ahsan R, Khan MM, Mishra A, Noor G, Ahmad U. Protein Kinases and their Inhibitors Implications in Modulating Disease Progression. Protein J 2023; 42:621-632. [PMID: 37768476 DOI: 10.1007/s10930-023-10159-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/14/2023] [Indexed: 09/29/2023]
Abstract
Protein phosphorylation plays an important role in cellular pathways, including cell cycle regulation, metabolism, differentiation and survival. The protein kinase superfamily network consists of 518 members involved in intrinsic or extrinsic interaction processes. Protein kinases are divided into two categories based on their ability to phosphorylate tyrosine, serine, and threonine residues. The complexity of the system implies its vulnerability. Any changes in the pathways of protein kinases may be implicated in pathological processes. Therefore, they are regarded as having an important role in human diseases and represent prospective therapeutic targets. This article provides a review of the protein kinase inhibitors approved by the FDA. Finally, we summarize the mechanism of action of protein kinases, including their role in the development and progression of protein kinase-related roles in various pathological conditions and the future therapeutic potential of protein kinase inhibitors, along with links to protein kinase databases. Further clinical studies aimed at examining the sequence of protein kinase inhibitor availability would better utilize current protein kinase inhibitors in diseases. Additionally, this review may help researchers and biochemists find new potent and selective protein kinase inhibitors and provide more indications for using existing drugs.
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Affiliation(s)
- Rabiya Ahsan
- Department of pharmacology, Faculty of Pharmacy, Integral University, Lucknow, India
| | - Mohd Muazzam Khan
- Department of pharmacology, Faculty of Pharmacy, Integral University, Lucknow, India.
| | - Anuradha Mishra
- Department of pharmacology, Amity Institute of Pharmacy, Amity University, sector 125, Noida, Uttar Pradesh, 201313, India
| | - Gazala Noor
- Department of pharmacology, Faculty of Pharmacy, Integral University, Lucknow, India
| | - Usama Ahmad
- Department of pharmaceutics, Faculty of Pharmacy, Integral University, Lucknow, India
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20
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Badawi S, Varghese DS, Raj A, John A, Al-Musafir HS, Al-Ghamari AJ, Alshamsi AR, Ouda SH, Al-Dirbashi G, Ali BR. Unveiling the pathogenic mechanisms of NPR2 missense variants: insights into the genotype-associated severity in acromesomelic dysplasia and short stature. Front Cell Dev Biol 2023; 11:1294748. [PMID: 38078000 PMCID: PMC10702138 DOI: 10.3389/fcell.2023.1294748] [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: 09/15/2023] [Accepted: 11/10/2023] [Indexed: 01/14/2025] Open
Abstract
Introduction: Natriuretic peptide receptor 2 (NPR2 or NPR-B) plays a central role in growth development and bone morphogenesis and therefore loss-of-function variations in NPR2 gene have been reported to cause Acromesomelic Dysplasia, Maroteaux type 1 and short stature. While several hypotheses have been proposed to underlie the pathogenic mechanisms responsible for these conditions, the exact mechanisms, and functional characteristics of many of those variants and their correlations with the clinical manifestations have not been fully established. Methods: In this study, we examined eight NPR2 genetic missense variants (p.Leu51Pro, p.Gly123Val, p.Leu314Arg, p.Arg318Gly, p.Arg388Gln, p.Arg495Cys, p.Arg557His, and p.Arg932Cys) Acromesomelic Dysplasia, Maroteaux type 1 and short stature located on diverse domains and broadly classified as variants of uncertain significance. The evaluated variants are either reported in patients with acromesomelic dysplasia in the homozygous state or short stature in the heterozygous state. Our investigation included the evaluation of their expression, subcellular trafficking and localization, N-glycosylation profiles, and cyclic guanosine monophosphate (cGMP) production activity. Results and Discussion: Our results indicate that variants p.Leu51Pro, p.Gly123Val, p.Leu314Arg, p.Arg388Gln have defective cellular trafficking, being sequestered within the endoplasmic reticulum (ER), and consequently impaired cGMP production ability. Conversely, variants p.Arg318Gly, p.Arg495Cys, and p.Arg557His seem to display a non-statistically significant behavior that is slightly comparable to WT-NPR2. On the other hand, p.Arg932Cys which is located within the guanylyl cyclase active site displayed normal cellular trafficking profile albeit with defective cGMP. Collectively, our data highlights the genotype-phenotype relationship that might be responsible for the milder symptoms observed in short stature compared to acromesomelic dysplasia. This study enhances our understanding of the functional consequences of several NPR2 variants, shedding light on their mechanisms and roles in related genetic disorders which might also help in their pathogenicity re-classification.
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Affiliation(s)
- Sally Badawi
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Divya Saro Varghese
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Anjana Raj
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Anne John
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Hamda S. Al-Musafir
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Ahmed J. Al-Ghamari
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Alreem R. Alshamsi
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Sara H. Ouda
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Ghayth Al-Dirbashi
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Bassam R. Ali
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al-Ain, United Arab Emirates
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21
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Cheslow L, Byrne M, Kopenhaver JS, Iacovitti L, Smeyne RJ, Snook AE, Waldman SA. GUCY2C signaling limits dopaminergic neuron vulnerability to toxic insults. RESEARCH SQUARE 2023:rs.3.rs-3416338. [PMID: 37886524 PMCID: PMC10602097 DOI: 10.21203/rs.3.rs-3416338/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/28/2023]
Abstract
Mitochondrial dysfunction and reactive oxygen species (ROS) accumulation within the substantia nigra pars compacta (SNpc) are central drivers of dopaminergic (DA) neuron death in Parkinson's disease (PD). Guanylyl cyclases, and their second messengers cyclic (c)GMP, support mitochondrial function, protecting against ROS and promoting cell survival in a number of tissues. However, the role of the guanylyl cyclase-cGMP axis in defining the vulnerability of DA neurons in the SNpc in PD remains unclear, in part due to the challenge of manipulating cGMP levels selectively in midbrain DA neurons. In that context, guanylyl cyclase C (GUCY2C), a receptor primarily expressed by intestinal epithelial cells, was discovered recently in midbrain DA neurons. Here, we demonstrate that GUCY2C promotes mitochondrial function, reducing oxidative stress and protecting DA neurons from degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of neurodegeneration. GUCY2C is overexpressed in the SNpc in PD patients and in mice treated with MPTP, possibly reflecting a protective response to oxidative stress. Moreover, cGMP signaling protects against oxidative stress, mitochondrial impairment, and cell death in cultured DA neurons. These observations reveal a previously unexpected role for the GUCY2C-cGMP signaling axis in controlling mitochondrial dysfunction and toxicity in nigral DA neurons, highlighting the therapeutic potential of targeting DA neuron GUCY2C to prevent neurodegeneration in PD.
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Affiliation(s)
- Lara Cheslow
- Department of Pharmacology, Physiology, & Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Department of Neurosciences, Thomas Jefferson University, Philadelphia, PA, USA
| | - Matthew Byrne
- Department of Neurosciences, Thomas Jefferson University, Philadelphia, PA, USA
| | - Jessica S. Kopenhaver
- Department of Pharmacology, Physiology, & Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Lorraine Iacovitti
- Department of Neurosciences, Thomas Jefferson University, Philadelphia, PA, USA
| | - Richard J. Smeyne
- Department of Neurosciences, Thomas Jefferson University, Philadelphia, PA, USA
| | - Adam E. Snook
- Department of Pharmacology, Physiology, & Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Department of Microbiology & Immunology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Scott A. Waldman
- Department of Pharmacology, Physiology, & Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
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22
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Montoya-Durango D, Walter MN, Rodriguez W, Wang Y, Chariker JH, Rouchka EC, Maldonado C, Barve S, McClain CJ, Gobejishvili L. Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies. BIOLOGY 2023; 12:1321. [PMID: 37887031 PMCID: PMC10604143 DOI: 10.3390/biology12101321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 09/29/2023] [Accepted: 10/09/2023] [Indexed: 10/28/2023]
Abstract
BACKGROUND Cyclic nucleotides are second messengers, which play significant roles in numerous biological processes. Previous work has shown that cAMP and cGMP signaling regulates various pathways in liver cells, including Kupffer cells, hepatocytes, hepatic stellate cells, and cellular components of hepatic sinusoids. Importantly, it has been shown that cAMP levels and enzymes involved in cAMP homeostasis are affected by alcohol. Although the role of cyclic nucleotide signaling is strongly implicated in several pathological pathways in liver diseases, studies describing the changes in genes regulating cyclic nucleotide metabolism in ALD are lacking. METHODS Male C57B/6 mice were used in an intragastric model of alcohol-associated steatohepatitis (ASH). Liver injury, inflammation, and fibrogenesis were evaluated by measuring plasma levels of injury markers, liver tissue cytokines, and gene expression analyses. Liver transcriptome analysis was performed to examine the effects of alcohol on regulators of cyclic AMP and GMP levels and signaling. cAMP and cGMP levels were measured in mouse livers as well as in livers from healthy human donors and patients with alcohol-associated hepatitis (AH). RESULTS Our results show significant changes in several phosphodiesterases (PDEs) with specificity to degrade cAMP (Pde4a, Pde4d, and Pde8a) and cGMP (Pde5a, Pde6d, and Pde9a), as well as dual-specificity PDEs (Pde1a and Pde10a) in ASH mouse livers. Adenylyl cyclases (ACs) 7 and 9, which are responsible for cAMP generation, were also affected by alcohol. Importantly, adenosine receptor 1, which has been implicated in the pathogenesis of liver diseases, was significantly increased by alcohol. Adrenoceptors 1 and 3 (Adrb), which couple with stimulatory G protein to regulate cAMP and cGMP signaling, were significantly decreased. Additionally, beta arrestin 2, which interacts with cAMP-specific PDE4D to desensitize G-protein-coupled receptor to generate cAMP, was significantly increased by alcohol. Notably, we observed that cAMP levels are much higher than cGMP levels in the livers of humans and mice; however, alcohol affected them differently. Specifically, cGMP levels were higher in patients with AH and ASH mice livers compared with controls. As expected, these changes in liver cyclic nucleotide signaling were associated with increased inflammation, steatosis, apoptosis, and fibrogenesis. CONCLUSIONS These data strongly implicate dysregulated cAMP and cGMP signaling in the pathogenesis of ASH. Future studies to identify changes in these regulators in a cell-specific manner could lead to the development of novel targeted therapies for ASH.
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Affiliation(s)
- Diego Montoya-Durango
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40290, USA; (D.M.-D.); (M.N.W.); (W.R.); (Y.W.); (C.M.)
| | - Mary Nancy Walter
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40290, USA; (D.M.-D.); (M.N.W.); (W.R.); (Y.W.); (C.M.)
| | - Walter Rodriguez
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40290, USA; (D.M.-D.); (M.N.W.); (W.R.); (Y.W.); (C.M.)
| | - Yali Wang
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40290, USA; (D.M.-D.); (M.N.W.); (W.R.); (Y.W.); (C.M.)
| | - Julia H. Chariker
- Department of Neuroscience Training, University of Louisville, Louisville, KY 40290, USA;
- KY INBRE Bioinformatics Core, University of Louisville, Louisville, KY 40290, USA;
| | - Eric C. Rouchka
- KY INBRE Bioinformatics Core, University of Louisville, Louisville, KY 40290, USA;
- Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY 40292, USA
| | - Claudio Maldonado
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40290, USA; (D.M.-D.); (M.N.W.); (W.R.); (Y.W.); (C.M.)
| | - Shirish Barve
- Department of Medicine, School of Medicine, University of Louisville, Louisville, KY 40290, USA; (S.B.); (C.J.M.)
- Alcohol Research Center, University of Louisville, Louisville, KY 40290, USA
| | - Craig J. McClain
- Department of Medicine, School of Medicine, University of Louisville, Louisville, KY 40290, USA; (S.B.); (C.J.M.)
- Alcohol Research Center, University of Louisville, Louisville, KY 40290, USA
- Robley Rex VA Medical Center, Louisville, KY 40206, USA
- Department of Pharmacology & Toxicology, School of Medicine, University of Louisville, Louisville, KY 40290, USA
| | - Leila Gobejishvili
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40290, USA; (D.M.-D.); (M.N.W.); (W.R.); (Y.W.); (C.M.)
- Department of Medicine, School of Medicine, University of Louisville, Louisville, KY 40290, USA; (S.B.); (C.J.M.)
- Alcohol Research Center, University of Louisville, Louisville, KY 40290, USA
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Gutiérrez-Rodelo C, Martínez-Tolibia SE, Morales-Figueroa GE, Velázquez-Moyado JA, Olivares-Reyes JA, Navarrete-Castro A. Modulating cyclic nucleotides pathways by bioactive compounds in combatting anxiety and depression disorders. Mol Biol Rep 2023; 50:7797-7814. [PMID: 37486442 PMCID: PMC10460744 DOI: 10.1007/s11033-023-08650-8] [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: 02/14/2023] [Accepted: 06/28/2023] [Indexed: 07/25/2023]
Abstract
Anxiety and depression disorders are highly prevalent neurological disorders (NDs) that impact up to one in three individuals during their lifetime. Addressing these disorders requires reducing their frequency and impact, understanding molecular causes, implementing prevention strategies, and improving treatments. Cyclic nucleotide monophosphates (cNMPs) like cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), cyclic uridine monophosphate (cUMP), and cyclic cytidine monophosphate (cCMP) regulate the transcription of genes involved in neurotransmitters and neurological functions. Evidence suggests that cNMP pathways, including cAMP/cGMP, cAMP response element binding protein (CREB), and Protein kinase A (PKA), play a role in the physiopathology of anxiety and depression disorders. Plant and mushroom-based compounds have been used in traditional and modern medicine due to their beneficial properties. Bioactive compound metabolism can activate key pathways and yield pharmacological outcomes. This review focuses on the molecular mechanisms of bioactive compounds from plants and mushrooms in modulating cNMP pathways. Understanding these processes will support current treatments and aid in the development of novel approaches to reduce the prevalence of anxiety and depression disorders, contributing to improved outcomes and the prevention of associated complications.
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Affiliation(s)
- Citlaly Gutiérrez-Rodelo
- Department of Pharmacy, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City, ZIP 04510, Mexico.
| | | | - Guadalupe Elide Morales-Figueroa
- Department of Physiology, Biophysics, and Neurosciences of the Center for Research, Advanced Studies of the National Polytechnic Institute (CINVESTAV-IPN), Mexico City, ZIP, 07360, Mexico
| | - Josué Arturo Velázquez-Moyado
- Department of Pharmacy, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City, ZIP 04510, Mexico
| | - J Alberto Olivares-Reyes
- Department of Biochemistry, Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV-IPN) Mexico City, Mexico City, ZIP 07360, Mexico
| | - Andrés Navarrete-Castro
- Department of Pharmacy, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City, ZIP 04510, Mexico.
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24
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Friebe A, Kraehling JR, Russwurm M, Sandner P, Schmidtko A. The 10th International Conference on cGMP 2022: recent trends in cGMP research and development-meeting report. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:1669-1686. [PMID: 37079081 PMCID: PMC10338386 DOI: 10.1007/s00210-023-02484-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 03/31/2023] [Indexed: 04/21/2023]
Abstract
Increasing cGMP is a unique therapeutic principle, and drugs inhibiting cGMP-degrading enzymes or stimulating cGMP production are approved for the treatment of various diseases such as erectile dysfunction, coronary artery disease, pulmonary hypertension, chronic heart failure, irritable bowel syndrome, or achondroplasia. In addition, cGMP-increasing therapies are preclinically profiled or in clinical development for quite a broad set of additional indications, e.g., neurodegenerative diseases or different forms of dementias, bone formation disorders, underlining the pivotal role of cGMP signaling pathways. The fundamental understanding of the signaling mediated by nitric oxide-sensitive (soluble) guanylyl cyclase and membrane-associated receptor (particulate) guanylyl cyclase at the molecular and cellular levels, as well as in vivo, especially in disease models, is a key prerequisite to fully exploit treatment opportunities and potential risks that could be associated with an excessive increase in cGMP. Furthermore, human genetic data and the clinical effects of cGMP-increasing drugs allow back-translation into basic research to further learn about signaling and treatment opportunities. The biannual international cGMP conference, launched nearly 20 years ago, brings all these aspects together as an established and important forum for all topics from basic science to clinical research and pivotal clinical trials. This review summarizes the contributions to the "10th cGMP Conference on cGMP Generators, Effectors and Therapeutic Implications," which was held in Augsburg in 2022 but will also provide an overview of recent key achievements and activities in the field of cGMP research.
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Affiliation(s)
- Andreas Friebe
- Institute of Physiology, University of Würzburg, Röntgenring 9, D-97070 Würzburg, Germany
| | - Jan R. Kraehling
- Pharmaceuticals, Research and Early Development, Pharma Research Center, Bayer AG, Aprather Weg 18a, D-42096 Wuppertal, Germany
| | - Michael Russwurm
- Institute of Pharmacology, Ruhr-University Bochum, Universitätsstr. 150, D-44801 Bochum, Germany
| | - Peter Sandner
- Pharmaceuticals, Research and Early Development, Pharma Research Center, Bayer AG, Aprather Weg 18a, D-42096 Wuppertal, Germany
- Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany
| | - Achim Schmidtko
- Institute of Pharmacology and Clinical Pharmacy, Goethe University, Max-Von-Laue-Str. 9, D-60438 Frankfurt Am Main, Germany
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25
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Locascio A, Annona G, Caccavale F, D'Aniello S, Agnisola C, Palumbo A. Nitric Oxide Function and Nitric Oxide Synthase Evolution in Aquatic Chordates. Int J Mol Sci 2023; 24:11182. [PMID: 37446358 DOI: 10.3390/ijms241311182] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 07/03/2023] [Accepted: 07/04/2023] [Indexed: 07/15/2023] Open
Abstract
Nitric oxide (NO) is a key signaling molecule in almost all organisms and is active in a variety of physiological and pathological processes. Our understanding of the peculiarities and functions of this simple gas has increased considerably by extending studies to non-mammal vertebrates and invertebrates. In this review, we report the nitric oxide synthase (Nos) genes so far characterized in chordates and provide an extensive, detailed, and comparative analysis of the function of NO in the aquatic chordates tunicates, cephalochordates, teleost fishes, and amphibians. This comprehensive set of data adds new elements to our understanding of Nos evolution, from the single gene commonly found in invertebrates to the three genes present in vertebrates.
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Affiliation(s)
- Annamaria Locascio
- Department of Biology and Evolution of Marine Organisms, Stazione Zoologica Anton Dohrn, Villa Comunale, 80121 Naples, Italy
| | - Giovanni Annona
- Department of Biology and Evolution of Marine Organisms, Stazione Zoologica Anton Dohrn, Villa Comunale, 80121 Naples, Italy
- Department of Research Infrastructure for Marine Biological Resources (RIMAR), Stazione Zoologica Anton Dohrn, Villa Comunale, 80121 Naples, Italy
| | - Filomena Caccavale
- Department of Biology and Evolution of Marine Organisms, Stazione Zoologica Anton Dohrn, Villa Comunale, 80121 Naples, Italy
| | - Salvatore D'Aniello
- Department of Biology and Evolution of Marine Organisms, Stazione Zoologica Anton Dohrn, Villa Comunale, 80121 Naples, Italy
| | - Claudio Agnisola
- Department of Biology, University of Naples Federico II, Via Cinthia 4, 80126 Naples, Italy
| | - Anna Palumbo
- Department of Biology and Evolution of Marine Organisms, Stazione Zoologica Anton Dohrn, Villa Comunale, 80121 Naples, Italy
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Pellesi L. The human NTG model of migraine in drug discovery and development. Expert Opin Drug Discov 2023; 18:1077-1085. [PMID: 37439036 DOI: 10.1080/17460441.2023.2236545] [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: 03/07/2023] [Accepted: 07/11/2023] [Indexed: 07/14/2023]
Abstract
INTRODUCTION Various triggers can originate a migraine attack. In healthy volunteers and patients with migraine, the nitroglycerin (NTG) provocation model induces a headache that resembles migraine in pain characteristics and vascular manifestations. This headache is reversible and treatable in monitored conditions, providing an opportunity to test novel antimigraine medications in early clinical development. AREAS COVERED This perspective covers the main characteristics and applications of the human NTG model of migraine with effective and ineffective antimigraine therapies. EXPERT OPINION The NTG model represents a potential de-risking strategy to test novel hypotheses for antimigraine mechanisms in humans. Considering previous studies conducted with effective and ineffective antimigraine therapies, the sensitivity of the model was 71% while the specificity was 100%. The probability that following an analgesic effect, that compound would truly be efficacious in individuals with migraine was 100%. Following a negative result, the probability that such compound would truly be ineffective in patients with individuals was 33%. A clinical trial testing the analgesic properties of novel compounds after a sublingual and/or intravenous NTG challenge in migraine patients may support a subsequent phase 2 trial for the treatment of migraine.
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Affiliation(s)
- Lanfranco Pellesi
- Department of Clinical Pharmacology, H. Lundbeck A/S, Copenhagen, Denmark
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27
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Baudet S, Zagar Y, Roche F, Gomez-Bravo C, Couvet S, Bécret J, Belle M, Vougny J, Uthayasuthan S, Ros O, Nicol X. Subcellular second messenger networks drive distinct repellent-induced axon behaviors. Nat Commun 2023; 14:3809. [PMID: 37369692 PMCID: PMC10300027 DOI: 10.1038/s41467-023-39516-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
Second messengers, including cAMP, cGMP and Ca2+ are often placed in an integrating position to combine the extracellular cues that orient growing axons in the developing brain. This view suggests that axon repellents share the same set of cellular messenger signals and that axon attractants evoke opposite cAMP, cGMP and Ca2+ changes. Investigating the confinement of these second messengers in cellular nanodomains, we instead demonstrate that two repellent cues, ephrin-A5 and Slit1, induce spatially segregated signals. These guidance molecules activate subcellular-specific second messenger crosstalk, each signaling network controlling distinct axonal morphology changes in vitro and pathfinding decisions in vivo.
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Affiliation(s)
- Sarah Baudet
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012, Paris, France
| | - Yvrick Zagar
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012, Paris, France
| | - Fiona Roche
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012, Paris, France
| | - Claudia Gomez-Bravo
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012, Paris, France
| | - Sandrine Couvet
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012, Paris, France
| | - Johann Bécret
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012, Paris, France
| | - Morgane Belle
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012, Paris, France
| | - Juliette Vougny
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012, Paris, France
| | | | - Oriol Ros
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012, Paris, France
- Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, 08028, Barcelona, Catalonia, Spain
| | - Xavier Nicol
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012, Paris, France.
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28
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Kuehnel RM, Ganga E, Balestra AC, Suarez C, Wyss M, Klages N, Brusini L, Maco B, Brancucci N, Voss TS, Soldati D, Brochet M. A Plasmodium membrane receptor platform integrates cues for egress and invasion in blood forms and activation of transmission stages. SCIENCE ADVANCES 2023; 9:eadf2161. [PMID: 37327340 PMCID: PMC10275601 DOI: 10.1126/sciadv.adf2161] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 05/11/2023] [Indexed: 06/18/2023]
Abstract
Critical events in the life cycle of malaria-causing parasites depend on cyclic guanosine monophosphate homeostasis by guanylyl cyclases (GCs) and phosphodiesterases, including merozoite egress or invasion of erythrocytes and gametocyte activation. These processes rely on a single GCα, but in the absence of known signaling receptors, how this pathway integrates distinct triggers is unknown. We show that temperature-dependent epistatic interactions between phosphodiesterases counterbalance GCα basal activity preventing gametocyte activation before mosquito blood feed. GCα interacts with two multipass membrane cofactors in schizonts and gametocytes: UGO (unique GC organizer) and SLF (signaling linking factor). While SLF regulates GCα basal activity, UGO is essential for GCα up-regulation in response to natural signals inducing merozoite egress and gametocyte activation. This work identifies a GC membrane receptor platform that senses signals triggering processes specific to an intracellular parasitic lifestyle, including host cell egress and invasion to ensure intraerythrocytic amplification and transmission to mosquitoes.
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Affiliation(s)
- Ronja Marie Kuehnel
- Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, 1 Rue Michel Servet, 12111 Geneva, Switzerland
| | - Emma Ganga
- Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, 1 Rue Michel Servet, 12111 Geneva, Switzerland
| | - Aurélia C. Balestra
- Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, 1 Rue Michel Servet, 12111 Geneva, Switzerland
| | - Catherine Suarez
- Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, 1 Rue Michel Servet, 12111 Geneva, Switzerland
| | - Matthias Wyss
- Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, 4123 Allschwil, Switzerland
- University of Basel, 4001 Basel, Switzerland
| | - Natacha Klages
- Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, 1 Rue Michel Servet, 12111 Geneva, Switzerland
| | - Lorenzo Brusini
- Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, 1 Rue Michel Servet, 12111 Geneva, Switzerland
| | - Bohumil Maco
- Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, 1 Rue Michel Servet, 12111 Geneva, Switzerland
| | - Nicolas Brancucci
- Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, 4123 Allschwil, Switzerland
- University of Basel, 4001 Basel, Switzerland
| | - Till S. Voss
- Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, 4123 Allschwil, Switzerland
- University of Basel, 4001 Basel, Switzerland
| | - Dominique Soldati
- Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, 1 Rue Michel Servet, 12111 Geneva, Switzerland
| | - Mathieu Brochet
- Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, 1 Rue Michel Servet, 12111 Geneva, Switzerland
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Della Corte V, Pacinella G, Todaro F, Pecoraro R, Tuttolomondo A. The Natriuretic Peptide System: A Single Entity, Pleiotropic Effects. Int J Mol Sci 2023; 24:ijms24119642. [PMID: 37298592 DOI: 10.3390/ijms24119642] [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: 04/17/2023] [Revised: 05/29/2023] [Accepted: 05/29/2023] [Indexed: 06/12/2023] Open
Abstract
In the modern scientific landscape, natriuretic peptides are a complex and interesting network of molecules playing pleiotropic effects on many organs and tissues, ensuring the maintenance of homeostasis mainly in the cardiovascular system and regulating the water-salt balance. The characterization of their receptors, the understanding of the molecular mechanisms through which they exert their action, and the discovery of new peptides in the last period have made it possible to increasingly feature the physiological and pathophysiological role of the members of this family, also allowing to hypothesize the possible settings for using these molecules for therapeutic purposes. This literature review traces the history of the discovery and characterization of the key players among the natriuretic peptides, the scientific trials performed to ascertain their physiological role, and the applications of this knowledge in the clinical field, leaving a glimpse of new and exciting possibilities for their use in the treatment of diseases.
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Affiliation(s)
- Vittoriano Della Corte
- Internal Medicine and Stroke Care Ward, Department of Health Promotion, Maternal and Infant Care, Internal Medicine and Medical Specialities (PROMISE) "G. D'Alessandro", University of Palermo, 90127 Palermo, Italy
| | - Gaetano Pacinella
- Internal Medicine and Stroke Care Ward, Department of Health Promotion, Maternal and Infant Care, Internal Medicine and Medical Specialities (PROMISE) "G. D'Alessandro", University of Palermo, 90127 Palermo, Italy
| | - Federica Todaro
- Internal Medicine and Stroke Care Ward, Department of Health Promotion, Maternal and Infant Care, Internal Medicine and Medical Specialities (PROMISE) "G. D'Alessandro", University of Palermo, 90127 Palermo, Italy
| | - Rosaria Pecoraro
- Internal Medicine and Stroke Care Ward, Department of Health Promotion, Maternal and Infant Care, Internal Medicine and Medical Specialities (PROMISE) "G. D'Alessandro", University of Palermo, 90127 Palermo, Italy
| | - Antonino Tuttolomondo
- Internal Medicine and Stroke Care Ward, Department of Health Promotion, Maternal and Infant Care, Internal Medicine and Medical Specialities (PROMISE) "G. D'Alessandro", University of Palermo, 90127 Palermo, Italy
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Sadeghi MA, Nassireslami E, Yousefi Zoshk M, Hosseini Y, Abbasian K, Chamanara M. Phosphodiesterase inhibitors in psychiatric disorders. Psychopharmacology (Berl) 2023; 240:1201-1219. [PMID: 37060470 DOI: 10.1007/s00213-023-06361-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 03/27/2023] [Indexed: 04/16/2023]
Abstract
RATIONALE Challenges in drug development for psychiatric disorders have left much room for the introduction of novel treatments with better therapeutic efficacies and indices. As a result, intense research has focused on identifying new targets for developing such pharmacotherapies. One of these targets may be the phosphodiesterase (PDE) class of enzymes, which play important roles in intracellular signaling. Due to their critical roles in cellular pathways, these enzymes affect diverse neurobiological functions from learning and memory formation to neuroinflammation. OBJECTIVES In this paper, we reviewed studies on the use of PDE inhibitors (PDEIs) in preclinical models and clinical trials of psychiatric disorders including depression, anxiety, schizophrenia, post-traumatic stress disorder (PTSD), bipolar disorder (BP), sexual dysfunction, and feeding disorders. RESULTS PDEIs are able to improve symptoms of psychiatric disorders in preclinical models through activating the cAMP-PKA-CREB and cGMP-PKG pathways, attenuating neuroinflammation and oxidative stress, and stimulating neural plasticity. The most promising therapeutic candidates to emerge from these preclinical studies are PDE2 and PDE4 inhibitors for depression and anxiety and PDE1 and PDE10 inhibitors for schizophrenia. Furthermore, PDE3 and 4 inhibitors have shown promising results in clinical trials in patients with depression and schizophrenia. CONCLUSIONS Larger and better designed clinical studies of PDEIs in schizophrenia, depression, and anxiety are warranted to facilitate their translation into the clinic. Regarding the other conditions discussed in this review (most notably PTSD and BP), better characterization of the effects of PDEIs in preclinical models is required before clinical studies.
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Affiliation(s)
- Mohammad Amin Sadeghi
- Toxicology Research Center, AJA University of Medical Sciences, Tehran, Iran
- Department of Pharmacology, School of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Ehsan Nassireslami
- Toxicology Research Center, AJA University of Medical Sciences, Tehran, Iran
- Department of Pharmacology, School of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Mojtaba Yousefi Zoshk
- Trauma Research Center, AJA University of Medical Sciences, Tehran, Iran
- Department of Pediatrics, AJA University of Medical Sciences, Tehran, Iran
| | - Yasaman Hosseini
- Cognitive Neuroscience Center, School of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Kourosh Abbasian
- Management and Health Economics Department, AJA University of Medical Sciences, Tehran, Iran
| | - Mohsen Chamanara
- Toxicology Research Center, AJA University of Medical Sciences, Tehran, Iran.
- Department of Pharmacology, School of Medicine, AJA University of Medical Sciences, Tehran, Iran.
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Caveney NA, Tsutsumi N, Garcia KC. Structural insight into guanylyl cyclase receptor hijacking of the kinase-Hsp90 regulatory mechanism. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.14.528495. [PMID: 36824799 PMCID: PMC9948968 DOI: 10.1101/2023.02.14.528495] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
Abstract
Membrane receptor guanylyl cyclases play a role in many important facets of human physiology, ranging from regulation of blood pressure to the regulation of intestinal fluid secretion. The structural mechanisms which influence the regulation of these important physiological effects have yet to be explored. We present the 3.9 Å resolution cryoEM structure of the human membrane receptor guanylyl cyclase GC-C in complex with Hsp90 and its co-chaperone Cdc37, providing insight into the mechanism of Cdc37 mediated binding of GC-C to the Hsp90 regulatory complex. As a membrane protein and non-kinase client of Hsp90-Cdc37, this work shows remarkable plasticity of Cdc37 to interact with a broad array of clients having significant sequence variation. Further, this work shows how membrane receptor guanylyl cyclases hijack the regulatory mechanisms used for active kinases to facilitate their regulation. Given the known druggability of Hsp90, these insights can guide the further development of mGC targeted therapeutics and lead to new avenues to treat hypertension, inflammatory bowel disease, and other mGC related conditions.
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Bon-Mathier AC, Déglise T, Rignault-Clerc S, Bielmann C, Mazzolai L, Rosenblatt-Velin N. Brain Natriuretic Peptide Protects Cardiomyocytes from Apoptosis and Stimulates Their Cell Cycle Re-Entry in Mouse Infarcted Hearts. Cells 2022; 12:cells12010007. [PMID: 36611800 PMCID: PMC9818267 DOI: 10.3390/cells12010007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/02/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022] Open
Abstract
Brain Natriuretic Peptide (BNP) supplementation after infarction increases heart function and decreases heart remodeling. BNP receptors, NPR-A and NPR-B are expressed on adult cardiomyocytes (CMs). We investigated whether a part of the BNP cardioprotective effect in infarcted and unmanipulated hearts is due to modulation of the CM fate. For this purpose, infarcted adult male mice were intraperitoneally injected every two days during 2 weeks with BNP or saline. Mice were sacrificed 1 and 14 days after surgery. BNP or saline was also injected intraperitoneally every two days into neonatal pups (3 days after birth) for 10 days and in unmanipulated 8-week-old male mice for 2 weeks. At sacrifice, CMs were isolated, counted, measured, and characterized by qRT-PCR. The proportion of mononucleated CMs was determined. Immunostainings aimed to detect CM re-entry in the cell cycle were performed on the different hearts. Finally, the signaling pathway activated by BNP treatment was identified in in vitro BNP-treated adult CMs and in CMs isolated from BNP-treated hearts. An increased number of CMs was detected in the hypoxic area of infarcted hearts, and in unmanipulated neonatal and adult hearts after BNP treatment. Accordingly, Troponin T plasma concentration was significantly reduced 1 and 3 days after infarction in BNP-treated mice, demonstrating less CM death. Furthermore, higher number of small, dedifferentiated and mononucleated CMs were identified in adult BNP-treated hearts when compared to saline-treated hearts. BNP-treated CMs express higher levels of mRNAs coding for hif1 alpha and for the different cyclins than CMs isolated from saline-treated hearts. Higher percentages of CMs undergoing DNA synthesis, expressing Ki67, phospho histone3 and Aurora B were detected in all BNP-treated hearts, demonstrating that CMs re-enter into the cell cycle. BNP effect on adult CMs in vivo is mediated by NPR-A binding and activation of the ERK MAP kinase pathway. Interestingly, an increased number of CMs was also detected in adult infarcted hearts treated with LCZ696, an inhibitor of the natriuretic peptide degradation. Altogether, our results identified BNP and all therapies aimed to increase BNP's bioavailability as new cardioprotective targets as BNP treatment leads to an increased number of CMs in neonatal, adult unmanipulated and infarcted hearts.
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Otto NM, Potter LR. Vicinal glutamates are better phosphomimetics: Phosphorylation is required for allosteric activation of guanylyl cyclase-A. Front Mol Neurosci 2022; 15:1012784. [DOI: 10.3389/fnmol.2022.1012784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 09/22/2022] [Indexed: 11/06/2022] Open
Abstract
Multisite phosphorylation of guanylyl cyclase (GC)-A, also known as NPR-A or NPR1, is required for receptor activation by natriuretic peptides (NPs) because alanine substitutions for the first four GC-A phosphorylation sites produce an enzyme that cannot be stimulated by NPs. In contrast, single Glu substitutions for the first six chemically identified GC-A phosphorylation sites to mimic the negative charge of phosphate produced an enzyme that is activated by NPs but had an elevated Michaelis constant (Km), resulting in low activity. Here, we show that vicinal (double adjacent) Glu substitutions for the same sites to mimic the two negative charges of phosphate produced a near wild type (WT) enzyme with a low Km. Unlike the enzyme with single glutamate substitutions, the vicinally substituted enzyme did not require the functionally identified Ser-473-Glu substitution to achieve WT-like activity. Importantly, the negative charge associated with either phosphorylation or glutamate substitutions was required for allosteric activation of GC-A by ATP. We conclude that vicinal Glu substitutions are better phosphomimetics than single Glu substitutions and that phosphorylation is required for allosteric activation of GC-A in the absence and presence of NP. Finally, we suggest that the putative functionally identified phosphorylation sites, Ser-473 in GC-A and Ser-489 in GC-B, are not phosphorylation sites at all.
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Wagner BM, Robinson JW, Prickett TCR, Espiner EA, Khosla S, Gaddy D, Suva LJ, Potter LR. Guanylyl Cyclase-B Dependent Bone Formation in Mice is Associated with Youth, Increased Osteoblasts, and Decreased Osteoclasts. Calcif Tissue Int 2022; 111:506-518. [PMID: 35947145 DOI: 10.1007/s00223-022-01014-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 07/15/2022] [Indexed: 11/02/2022]
Abstract
C-type natriuretic peptide (CNP) activation of guanylyl cyclase-B (GC-B) catalyzes the synthesis of cGMP in chondrocytes and osteoblasts. Elevated cGMP stimulates long bone growth, and inactivating mutations in CNP or GC-B reduce cGMP, which causes dwarfism. GC-B7E/7E mice that express a GC-B mutant that cannot be inactivated by dephosphorylation exhibit increased CNP-dependent GC-B activity, which increases bone length, as well as bone mass and strength. Importantly, how GC-B increases bone mass is not known. Here, we injected 12-week-old, wild type mice once daily for 28 days with or without BMN-111 (Vosoritide), a proteolytically resistant CNP analog. We found that BMN-111 treated mice had elevated levels of osteocalcin and collagen 1 C-terminal telopeptide (CTX) as well as increased osteoblasts and osteoclasts. In BMN-111 injected mice, tibial mRNAs for Rank ligand and osteoprotegrin were increased and decreased, respectively, whereas sclerostin mRNA was elevated 400-fold, consistent with increased osteoclast activity and decreased osteoblast activity. Mineral apposition rates and trabecular bone mass were not elevated in response to BMN-111. Because 9-week-old male GC-B7E/7E mice have increased bone mass but do not exhibit increased mineral apposition rates, we examined 4-week-old male GC-B7E/7E mice and found that these animals had increased serum osteocalcin, but not CTX. Importantly, tibias from these mice had 37% more osteoblasts, 26% fewer osteoclasts as well as 36% and 40% higher mineral apposition and bone formation rates, respectively. We conclude that GC-B-dependent bone formation is coupled to an early juvenile process that requires both increased osteoblasts and decreased osteoclasts.
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Affiliation(s)
- Brandon M Wagner
- Departments of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA
| | - Jerid W Robinson
- Departments of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church Street, Minneapolis, MN, USA
| | | | - Eric A Espiner
- Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Sundeep Khosla
- Robert and Arlene Kogod Center on Aging and Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Dana Gaddy
- Departments of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA
| | - Larry J Suva
- Departments of Physiology and Pharmacology, Texas A&M University, College Station, TX, USA
| | - Lincoln R Potter
- Departments of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA.
- Departments of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church Street, Minneapolis, MN, USA.
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Calmodulin in Paramecium: Focus on Genomic Data. Microorganisms 2022; 10:microorganisms10101915. [PMID: 36296191 PMCID: PMC9608856 DOI: 10.3390/microorganisms10101915] [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: 07/15/2022] [Revised: 09/14/2022] [Accepted: 09/22/2022] [Indexed: 11/26/2022] Open
Abstract
Calcium (Ca2+) is a universal second messenger that plays a key role in cellular signaling. However, Ca2+ signals are transduced with the help of Ca2+-binding proteins, which serve as sensors, transducers, and elicitors. Among the collection of these Ca2+-binding proteins, calmodulin (CaM) emerged as the prototypical model in eukaryotic cells. This is a small protein that binds four Ca2+ ions and whose functions are multiple, controlling many essential aspects of cell physiology. CaM is universally distributed in eukaryotes, from multicellular organisms, such as human and land plants, to unicellular microorganisms, such as yeasts and ciliates. Here, we review most of the information gathered on CaM in Paramecium, a group of ciliates. We condense the information here by mentioning that mature Paramecium CaM is a 148 amino acid-long protein codified by a single gene, as in other eukaryotic microorganisms. In these ciliates, the protein is notoriously localized and regulates cilia function and can stimulate the activity of some enzymes. When Paramecium CaM is mutated, cells show flawed locomotion and/or exocytosis. We further widen this and additional information in the text, focusing on genomic data.
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Ang WF, Koh CY, Kini RM. From Snake Venoms to Therapeutics: A Focus on Natriuretic Peptides. Pharmaceuticals (Basel) 2022; 15:ph15091153. [PMID: 36145374 PMCID: PMC9502559 DOI: 10.3390/ph15091153] [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: 08/29/2022] [Revised: 09/07/2022] [Accepted: 09/13/2022] [Indexed: 11/26/2022] Open
Abstract
Snake venom is a cocktail of multifunctional biomolecules that has evolved with the purpose of capturing prey and for defense. These biomolecules are classified into different classes based on their functions. They include three-finger toxins, natriuretic peptides, phospholipases and metalloproteinases. The focus for this review is on the natriuretic peptide (NP), which is an active component that can be isolated from the venoms of vipers and mambas. In these venoms, NPs contribute to the lowering of blood pressure, causing a rapid loss of consciousness in the prey such that its mobility is reduced, paralyzing the prey, and often death follows. Over the past 30 years since the discovery of the first NP in the venom of the green mamba, venom NPs have shown potential in the development of drug therapy for heart failure. Venom NPs have long half-lives, different pharmacological profiles, and may also possess different functions in comparison to the mammalian NPs. Understanding their mechanisms of action provides the strategies needed to develop new NPs for treatment of heart failure. This review summarizes the venom NPs that have been identified over the years and how they can be useful in drug development.
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Affiliation(s)
- Wei Fong Ang
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117558, Singapore
- NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore 119077, Singapore
| | - Cho Yeow Koh
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117559, Singapore
- Correspondence: (C.Y.K.); (R.M.K.); Tel.: +65-6601-1387 (C.Y.K.); +65-6516-5235 (R.M.K.)
| | - R. Manjunatha Kini
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117558, Singapore
- NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore 119077, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298-0614, USA
- Correspondence: (C.Y.K.); (R.M.K.); Tel.: +65-6601-1387 (C.Y.K.); +65-6516-5235 (R.M.K.)
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Pleiotropic Roles of Atrial Natriuretic Peptide in Anti-Inflammation and Anti-Cancer Activity. Cancers (Basel) 2022; 14:cancers14163981. [PMID: 36010974 PMCID: PMC9406604 DOI: 10.3390/cancers14163981] [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: 05/16/2022] [Revised: 08/07/2022] [Accepted: 08/15/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary The relationship between inflammation and carcinogenesis, as well as the response to anti-tumor therapy, is intimate. Atrial natriuretic peptides (ANPs) play a pivotal role in the homeostatic control of blood pressure, electrolytes, and water balance. In addition, ANPs exert immune-modulatory effects in the tissue microenvironment, thus exhibiting a fascinating ability to prevent inflammation-related tumorigenesis and cancer recurrence. In cancers, ANPs show anti-proliferative effects through several molecular pathways. Furthermore, ANPs attenuate the side effects of cancer therapy. Therefore, ANPs have potential therapeutic value in tumors. Here, we summarized the roles of ANPs in diverse aspects of the immune system and the molecular mechanisms underlying the anti-cancer effects of ANPs, contributing to the development of ANP-based anti-cancer agents. Abstract The atrial natriuretic peptide (ANP), a cardiovascular hormone, plays a pivotal role in the homeostatic control of blood pressure, electrolytes, and water balance and is approved to treat congestive heart failure. In addition, there is a growing realization that ANPs might be related to immune response and tumor growth. The anti-inflammatory and immune-modulatory effects of ANPs in the tissue microenvironment are mediated through autocrine or paracrine mechanisms, which further suppress tumorigenesis. In cancers, ANPs show anti-proliferative effects through several molecular pathways. Furthermore, ANPs attenuate the side effects of cancer therapy. Therefore, ANPs act on several hallmarks of cancer, such as inflammation, angiogenesis, sustained tumor growth, and metastasis. In this review, we summarized the contributions of ANPs in diverse aspects of the immune system and the molecular mechanisms underlying the anti-cancer effects of ANPs.
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Petraina A, Nogales C, Krahn T, Mucke H, Lüscher TF, Fischmeister R, Kass DA, Burnett JC, Hobbs AJ, Schmidt HHHW. Cyclic GMP modulating drugs in cardiovascular diseases: mechanism-based network pharmacology. Cardiovasc Res 2022; 118:2085-2102. [PMID: 34270705 PMCID: PMC9302891 DOI: 10.1093/cvr/cvab240] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 07/14/2021] [Indexed: 12/13/2022] Open
Abstract
Mechanism-based therapy centred on the molecular understanding of disease-causing pathways in a given patient is still the exception rather than the rule in medicine, even in cardiology. However, recent successful drug developments centred around the second messenger cyclic guanosine-3'-5'-monophosphate (cGMP), which is regulating a number of cardiovascular disease modulating pathways, are about to provide novel targets for such a personalized cardiovascular therapy. Whether cGMP breakdown is inhibited or cGMP synthesis is stimulated via guanylyl cyclases or their upstream regulators in different cardiovascular disease phenotypes, the outcomes seem to be so far uniformly protective. Thus, a network of cGMP-modulating drugs has evolved that act in a mechanism-based, possibly causal manner in a number of cardiac conditions. What remains a challenge is the detection of cGMPopathy endotypes amongst cardiovascular disease phenotypes. Here, we review the growing clinical relevance of cGMP and provide a glimpse into the future on how drugs interfering with this pathway may change how we treat and diagnose cardiovascular diseases altogether.
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Affiliation(s)
- Alexandra Petraina
- Department of Pharmacology and Personalised Medicine, School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands
| | - Cristian Nogales
- Department of Pharmacology and Personalised Medicine, School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands
| | - Thomas Krahn
- Department of Pharmacology and Personalised Medicine, School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands
| | - Hermann Mucke
- H.M. Pharma Consultancy, Enenkelstrasse 28/32, A-1160, Vienna, Austria
| | - Thomas F Lüscher
- Royal Brompton & Harefield Hospitals, Heart Division and National Heart and Lung Institute, Guy Scadding Building, Imperial College, Dovehouse Street London SW3 6LY, United Kingdom
- Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistreet 12, CH-8952 Schlieren, Switzerland
| | - Rodolphe Fischmeister
- INSERM UMR-S 1180, Faculty of Pharmacy, Université Paris-Saclay, F-92296 Châtenay-Malabry, France
| | - David A Kass
- Division of Cardiology, Department of Medicine, Ross Research Building, Rm 858, Johns Hopkins Medical Institutions, 720 Rutland Avenue, Baltimore, MD 21205, USA
| | - John C Burnett
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA
| | - Adrian J Hobbs
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, EC1M 6BQ, London, UK
| | - Harald H H W Schmidt
- Department of Pharmacology and Personalised Medicine, School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands
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Molecular Mechanism of Induction of Bone Growth by the C-Type Natriuretic Peptide. Int J Mol Sci 2022; 23:ijms23115916. [PMID: 35682595 PMCID: PMC9180634 DOI: 10.3390/ijms23115916] [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: 04/12/2022] [Revised: 05/17/2022] [Accepted: 05/21/2022] [Indexed: 12/10/2022] Open
Abstract
The skeletal development process in the body occurs through sequential cellular and molecular processes called endochondral ossification. Endochondral ossification occurs in the growth plate where chondrocytes differentiate from resting, proliferative, hypertrophic to calcified zones. Natriuretic peptides (NPTs) are peptide hormones with multiple functions, including regulation of blood pressure, water-mineral balance, and many metabolic processes. NPTs secreted from the heart activate different tissues and organs, working in a paracrine or autocrine manner. One of the natriuretic peptides, C-type natriuretic peptide-, induces bone growth through several mechanisms. This review will summarize the knowledge, including the newest discoveries, of the mechanism of CNP activation in bone growth.
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Bose A, Visweswariah SS. The pseudokinase domain in receptor guanylyl cyclases. Methods Enzymol 2022; 667:535-574. [PMID: 35525553 DOI: 10.1016/bs.mie.2022.03.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Cyclic GMP is produced by enzymes called guanylyl cyclases, of which the membrane-associated forms contain an intracellular pseudokinase domain that allosterically regulates the C-terminal guanylyl cyclase domain. Ligand binding to the extracellular domain of these single transmembrane-spanning domain receptors elicits an increase in cGMP levels in the cell. The pseudokinase domain (or kinase-homology domain) in these receptors appears to be critical for ligand-mediated activation. While the pseudokinase domain does not possess kinase activity, biochemical evidence indicates that the domain can bind ATP and thereby allosterically regulate the catalytic activity of these receptors. The pseudokinase domain also appears to be the site of interaction of regulatory proteins, as seen in the retinal guanylyl cyclases that are involved in visual signal transduction. In the absence of structural information on the pseudokinase-guanylyl cyclase domain organization of any member of this family of receptors, biochemical evidence has provided clues to the physical interaction of the pseudokinase and guanylyl cyclase domain. An α-helical linker region between the pseudokinase domain and the guanylyl cyclase domain regulates the basal activity of these receptors in the absence of a stimulatory ligand and is important for stabilizing the structure of the pseudokinase domain that can bind ATP. Here, we present an overview of salient features of ATP-mediated regulation of receptor guanylyl cyclases and describe biochemical approaches that allow a clearer understanding of the intricate interplay between the pseudokinase domain and catalytic domain in these proteins.
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Affiliation(s)
- Avipsa Bose
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
| | - Sandhya S Visweswariah
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India.
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Zhou L, Hu C, Li Y, Wang B. Sulforaphane alleviates hypoxic vestibular vertigo (HVV) by increasing NO production via upregulating the expression of NRF2. Bioengineered 2022; 13:10351-10361. [PMID: 35441581 PMCID: PMC9161921 DOI: 10.1080/21655979.2022.2030592] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Sulforaphane (SFP) treatment represses oxidative stress by activating NRF2. Meanwhile, SFP may also increase the production of nitric oxide (NO) and activate the signaling pathway of cyclic guanosine monophosphate (cGMP), which is involved in the pathogenesis of hypoxic vestibular vertigo (HVV). However, it remains unknown as whether SFP plays a therapeutic role in the treatment of HVV. A rat model of HVV was established to measure the levels of escape latency, malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD) in the aorta tissues. Quantitative real-time PCR was performed to evaluate the expression of NRF2 mRNA, and Western blot and immunohistochemistry were carried out to analyze the expression of NRF2 protein. ELISA was used to examine the production of NO and cGMP. SFP treatment helped to maintain the escape latency and MDA, GSH, SOD concentrations in the brain of HVV rats, and recovered the expression of NRF2 inhibited in the brain of HVV rats. SFP treatment also elevated NO and cGMP production that was down-regulated in the brain of HVV rats. On the cellular level, SFP enhanced the expression of NRF2, reduced the concentrations of MDA, GSH and SOD, and promoted the production of NO and cGMP in a dose-dependent manner. In this study, we treated an animal model of HVV with SFP to investigate its effect on NO production and oxidative stress. Our work provided a mechanistic insight into the therapeutic effect of SFP on the treatment of HVV.
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Affiliation(s)
- Liyuan Zhou
- Department of Otolaryngology, Head Neck Surgery, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China.,Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, Taiyuan, Shanxi, China
| | - Changchen Hu
- Department of Neurosurgery, Shanxi Provincial People's Hospital, Shanxi Medical University, Taiyuan, China.,Department of Neurosurgery, Shuozhou People's Hospital, Shuozhou, China
| | - Yujun Li
- Department of Otolaryngology, Head Neck Surgery, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China.,Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, Taiyuan, Shanxi, China
| | - Binquan Wang
- Department of Otolaryngology, Head Neck Surgery, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China.,Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, Taiyuan, Shanxi, China
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42
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Modulation of Inflammatory Cytokine Production in Human Monocytes by cGMP and IRAK3. Int J Mol Sci 2022; 23:ijms23052552. [PMID: 35269704 PMCID: PMC8909980 DOI: 10.3390/ijms23052552] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 02/23/2022] [Accepted: 02/24/2022] [Indexed: 12/13/2022] Open
Abstract
Interleukin-1 receptor-associated kinase-3 (IRAK3) is a critical checkpoint molecule of inflammatory responses in the innate immune system. The pseudokinase domain of IRAK3 contains a guanylate cyclase (GC) centre that generates small amounts of cyclic guanosine monophosphate (cGMP) associated with IRAK3 functions in inflammation. However, the mechanisms of IRAK3 actions are poorly understood. The effects of low cGMP levels on inflammation are unknown, therefore a dose–response effect of cGMP on inflammatory markers was assessed in THP-1 monocytes challenged with lipopolysaccharide (LPS). Sub-nanomolar concentrations of membrane permeable 8-Br-cGMP reduced LPS-induced NFκB activity, IL-6 and TNF-α cytokine levels. Pharmacologically upregulating cellular cGMP levels using a nitric oxide donor reduced cytokine secretion. Downregulating cellular cGMP using a soluble GC inhibitor increased cytokine levels. Knocking down IRAK3 in THP-1 cells revealed that unlike the wild type cells, 8-Br-cGMP did not suppress inflammatory responses. Complementation of IRAK3 knockdown cells with wild type IRAK3 suppressed cytokine production while complementation with an IRAK3 mutant at GC centre only partially restored this function. Together these findings indicate low levels of cGMP form a critical component in suppressing cytokine production and in mediating IRAK3 action, and this may be via a cGMP enriched nanodomain formed by IRAK3 itself.
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43
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Calamera G, Moltzau LR, Levy FO, Andressen KW. Phosphodiesterases and Compartmentation of cAMP and cGMP Signaling in Regulation of Cardiac Contractility in Normal and Failing Hearts. Int J Mol Sci 2022; 23:2145. [PMID: 35216259 PMCID: PMC8880502 DOI: 10.3390/ijms23042145] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/09/2022] [Accepted: 02/11/2022] [Indexed: 02/01/2023] Open
Abstract
Cardiac contractility is regulated by several neural, hormonal, paracrine, and autocrine factors. Amongst these, signaling through β-adrenergic and serotonin receptors generates the second messenger cyclic AMP (cAMP), whereas activation of natriuretic peptide receptors and soluble guanylyl cyclases generates cyclic GMP (cGMP). Both cyclic nucleotides regulate cardiac contractility through several mechanisms. Phosphodiesterases (PDEs) are enzymes that degrade cAMP and cGMP and therefore determine the dynamics of their downstream effects. In addition, the intracellular localization of the different PDEs may contribute to regulation of compartmented signaling of cAMP and cGMP. In this review, we will focus on the role of PDEs in regulating contractility and evaluate changes in heart failure.
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Affiliation(s)
| | | | | | - Kjetil Wessel Andressen
- Department of Pharmacology, Institute of Clinical Medicine, Oslo University Hospital, University of Oslo, P.O. Box 1057 Blindern, 0316 Oslo, Norway; (G.C.); (L.R.M.); (F.O.L.)
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44
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NO rapidly mobilizes cellular heme to trigger assembly of its own receptor. Proc Natl Acad Sci U S A 2022; 119:2115774119. [PMID: 35046034 PMCID: PMC8795550 DOI: 10.1073/pnas.2115774119] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/17/2021] [Indexed: 12/11/2022] Open
Abstract
Nitric oxide (NO) performs many biological functions, but how it operates at the molecular and cellular levels is not fully understood. We discovered that cell NO generation at physiologic levels triggers a rapid redeployment of intracellular heme, an iron-containing cofactor, and we show that this drives the assembly of the natural NO receptor protein, soluble guanylyl cyclase, which is needed for NO to perform its biological signaling functions. Our study uncovers a way that NO can shape biological signaling processes and a way that cells may use NO to control their hemeprotein activities through deployment of the heme cofactor. These concepts broaden our understanding of NO function in biology and medicine. Nitric oxide (NO) signaling in biology relies on its activating cyclic guanosine monophosphate (cGMP) production by the NO receptor soluble guanylyl cyclase (sGC). sGC must obtain heme and form a heterodimer to become functional, but paradoxically often exists as an immature heme-free form in cells and tissues. Based on our previous finding that NO can drive sGC maturation, we investigated its basis by utilizing a fluorescent sGC construct whose heme level can be monitored in living cells. We found that NO generated at physiologic levels quickly triggered cells to mobilize heme to immature sGC. This occurred when NO was generated within cells or by neighboring cells, began within seconds of NO exposure, and led cells to construct sGC heterodimers and thus increase their active sGC level by several-fold. The NO-triggered heme deployment involved cellular glyceraldehyde-3-phosphate dehydrogenase (GAPDH)–heme complexes and required the chaperone hsp90, and the newly formed sGC heterodimers remained functional long after NO generation had ceased. We conclude that NO at physiologic levels triggers assembly of its own receptor by causing a rapid deployment of cellular heme. Redirecting cellular heme in response to NO is a way for cells and tissues to modulate their cGMP signaling and to more generally tune their hemeprotein activities wherever NO biosynthesis takes place.
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45
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Fischer P, Mukherjee S, Schiewer E, Broser M, Bartl F, Hegemann P. The inner mechanics of rhodopsin guanylyl cyclase during cGMP-formation revealed by real-time FTIR spectroscopy. eLife 2021; 10:e71384. [PMID: 34665128 PMCID: PMC8575461 DOI: 10.7554/elife.71384] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 10/18/2021] [Indexed: 01/01/2023] Open
Abstract
Enzymerhodopsins represent a recently discovered class of rhodopsins which includes histidine kinase rhodopsin, rhodopsin phosphodiesterases, and rhodopsin guanylyl cyclases (RGCs). The regulatory influence of the rhodopsin domain on the enzyme activity is only partially understood and holds the key for a deeper understanding of intra-molecular signaling pathways. Here, we present a UV-Vis and FTIR study about the light-induced dynamics of a RGC from the fungus Catenaria anguillulae, which provides insights into the catalytic process. After the spectroscopic characterization of the late rhodopsin photoproducts, we analyzed truncated variants and revealed the involvement of the cytosolic N-terminus in the structural rearrangements upon photo-activation of the protein. We tracked the catalytic reaction of RGC and the free GC domain independently by UV-light induced release of GTP from the photolabile NPE-GTP substrate. Our results show substrate binding to the dark-adapted RGC and GC alike and reveal differences between the constructs attributable to the regulatory influence of the rhodopsin on the conformation of the binding pocket. By monitoring the phosphate rearrangement during cGMP and pyrophosphate formation in light-activated RGC, we were able to confirm the M state as the active state of the protein. The described setup and experimental design enable real-time monitoring of substrate turnover in light-activated enzymes on a molecular scale, thus opening the pathway to a deeper understanding of enzyme activity and protein-protein interactions.
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Affiliation(s)
- Paul Fischer
- Institute for Biology, Experimental Biophysics, Humboldt-Universität zu BerlinBerlinGermany
| | - Shatanik Mukherjee
- Institute of Biology, Biophysical Chemistry, Humboldt University of BerlinBerlinGermany
| | - Enrico Schiewer
- Institute for Biology, Experimental Biophysics, Humboldt-Universität zu BerlinBerlinGermany
| | - Matthias Broser
- Institute for Biology, Experimental Biophysics, Humboldt-Universität zu BerlinBerlinGermany
| | - Franz Bartl
- Institute of Biology, Biophysical Chemistry, Humboldt University of BerlinBerlinGermany
| | - Peter Hegemann
- Institute for Biology, Experimental Biophysics, Humboldt-Universität zu BerlinBerlinGermany
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Hansen FB, Esteves GV, Mogensen S, Prat-Duran J, Secher N, Løfgren B, Granfeldt A, Simonsen U. Increased cerebral endothelium-dependent vasodilation in rats in the postcardiac arrest period. J Appl Physiol (1985) 2021; 131:1311-1327. [PMID: 34435510 DOI: 10.1152/japplphysiol.00373.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Cardiovascular lability is common after cardiac arrest. We investigated whether altered endothelial function is present in cerebral and mesenteric arteries 2 and 4 h after resuscitation. Male Sprague-Dawley rats were anesthetized, intubated, ventilated, and intravascularly catheterized whereupon rats were randomized into four groups. Following 7 min of asphyxial cardiac arrest and subsequent resuscitation, cardiac arrest and sham rats were observed for either 2 or 4 h. Neuron-specific enolase levels were measured in blood samples. Middle cerebral artery segments and small mesenteric arteries were isolated and examined in microvascular myographs. qPCR and immunofluorescence analysis were performed on cerebral arteries. In cerebral arteries, bradykinin-induced vasodilation was inhibited in the presence of either calcium-activated K+ channel blockers (UCL1684 and senicapoc) or the nitric oxide (NO) synthase inhibitor, Nω-nitro-L-arginine methyl ester hydrochloride (l-NAME), whereas the combination abolished bradykinin-induced vasodilation across groups. Neuron-specific enolase levels were significantly increased in cardiac arrest rats. Cerebral vasodilation was comparable between the 2-h groups, but markedly enhanced in response to bradykinin, NS309 (an opener of small and intermediate calcium-activated K+ channels), and sodium nitroprusside 4 h after cardiac arrest. Endothelial NO synthase and guanylyl cyclase subunit α-1 mRNA expression was unaltered after 2 h, but significantly decreased 4 h after resuscitation. In mesenteric arteries, the endothelium-dependent vasodilation was comparable between corresponding groups at both 2 and 4 h. Our findings show enhanced cerebral endothelium-dependent vasodilation 4 h after cardiac arrest mediated by potentiated endothelial-derived hyperpolarization and NO pathways. Altered cerebral endothelium-dependent vasodilation may contribute to disturbed cerebral perfusion after cardiac arrest.NEW & NOTEWORTHY This is the first study, to our knowledge, to demonstrate enhanced endothelium-dependent vasodilation in middle cerebral arteries in a cardiac arrest rat model. The increased endothelium-dependent vasodilation was a result of potentiated endothelium-derived hyperpolarization and endothelial nitric oxide pathways. Immunofluorescence microscopy confirmed the presence of relevant receptors and eNOS in cerebral arteries, whereas qPCR showed altered expression of genes related to guanylyl cyclase and eNOS. Altered endothelium-dependent vasoregulation may contribute to disturbed cerebral blood flow in the postcardiac arrest period.
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Affiliation(s)
- Frederik Boe Hansen
- Department of Biomedicine, Aarhus University, Aarhus, Denmark.,Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | | | - Susie Mogensen
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | | | - Niels Secher
- Department of Anesthesiology and Intensive Care, Aarhus University Hospital, Aarhus, Denmark
| | - Bo Løfgren
- Research Center for Emergency Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Asger Granfeldt
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.,Department of Anesthesiology and Intensive Care, Aarhus University Hospital, Aarhus, Denmark
| | - Ulf Simonsen
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
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In Silico Prediction, Molecular Docking and Dynamics Studies of Steroidal Alkaloids of Holarrhena pubescens Wall. ex G. Don to Guanylyl Cyclase C: Implications in Designing of Novel Antidiarrheal Therapeutic Strategies. Molecules 2021; 26:molecules26144147. [PMID: 34299422 PMCID: PMC8305770 DOI: 10.3390/molecules26144147] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/24/2021] [Accepted: 06/25/2021] [Indexed: 01/08/2023] Open
Abstract
The binding of heat stable enterotoxin (STa) secreted by enterotoxigenic Escherichia coli (ETEC) to the extracellular domain of guanylyl cyclase c (ECDGC-C) causes activation of a signaling cascade, which ultimately results in watery diarrhea. We carried out this study with the objective of finding ligands that would interfere with the binding of STa on ECDGC-C. With this view in mind, we tested the biological activity of a alkaloid rich fraction of Holarrhena pubescens against ETEC under in vitro conditions. Since this fraction showed significant antibacterial activity against ETEC, we decided to test the screen binding affinity of nine compounds of steroidal alkaloid type from Holarrhena pubescens against extracellular domain (ECD) by molecular docking and identified three compounds with significant binding energy. Molecular dynamics simulations were performed for all the three lead compounds to establish the stability of their interaction with the target protein. Pharmacokinetics and toxicity profiling of these leads demonstrated that they possessed good drug-like properties. Furthermore, the ability of these leads to inhibit the binding of STa to ECD was evaluated. This was first done by identifying amino acid residues of ECDGC-C binding to STa by protein-protein docking. The results were matched with our molecular docking results. We report here that holadysenterine, one of the lead compounds that showed a strong affinity for the amino acid residues on ECDGC-C, also binds to STa. This suggests that holadysenterine has the potential to inhibit binding of STa on ECD and can be considered for future study, involving its validation through in vitro assays and animal model studies.
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48
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Redox Regulation of Lipid Mobilization in Adipose Tissues. Antioxidants (Basel) 2021; 10:antiox10071090. [PMID: 34356323 PMCID: PMC8301038 DOI: 10.3390/antiox10071090] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/30/2021] [Accepted: 07/01/2021] [Indexed: 12/14/2022] Open
Abstract
Lipid mobilization in adipose tissues, which includes lipogenesis and lipolysis, is a paramount process in regulating systemic energy metabolism. Reactive oxygen and nitrogen species (ROS and RNS) are byproducts of cellular metabolism that exert signaling functions in several cellular processes, including lipolysis and lipogenesis. During lipolysis, the adipose tissue generates ROS and RNS and thus requires a robust antioxidant response to maintain tight regulation of redox signaling. This review will discuss the production of ROS and RNS within the adipose tissue, their role in regulating lipolysis and lipogenesis, and the implications of antioxidants on lipid mobilization.
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49
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Widiyanti P, Suryohudoyo P. The role of hyperbaric oxygen to platelet aggregation in noninsulin-dependent diabetes mellitus (NIDDM). J Basic Clin Physiol Pharmacol 2021; 32:617-621. [PMID: 34214305 DOI: 10.1515/jbcpp-2020-0481] [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: 11/29/2020] [Accepted: 04/08/2021] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Hyperglycemia in diabetes mellitus (DM) could cause rheological disorder, such as platelet aggregation and blood hyperviscosity. Hyperbaric oxygen (HBO) could decrease collagen as platelet aggregation agonist. This study aimed to explore the effect of HBO treatment to platelet aggregation parameters (latency time(LT), aggregation speed, aggregation index, and aggregation percentage) with the collagen aggregator in the noninsulin dependent diabetes mellitus (NIDDM). METHODS The number of subjects in this study were 16 for each group normoxia normobaric (NONB) and HBO. NIDDM patients from DM polyclinic in Rumah Sakit Angkatan Laut (RSAL) Dr Ramelan Surabaya which was fulfilled inclusion criteria would receive HBO Therapy. Control Group/NONB were treated with NONB condition (20% O2 1 ATA) for 90 min and treatment group/HBO were treated with hyperoxia hyperbaric condition (100% O2 2.4 ATA) for 3 × 30 min with interval of 2 × 5 min for inhaling fresh air. Subject has been blood taken for platelet aggregation test before and after HBO Therapy. The length of treatment was 5 days for both condition (NONB and HBO). RESULTS The data from both groups, NONB and HBO were tested first by normality test, homogenity test, correlation test, analysis of covariance, and paired t-test. Based on paired t-test, the decrease on platelet aggregation speed, aggregation index, and aggregation percentage after HBO treatment was showed significant difference on the LT and aggregation index while in aggregation speed and aggregation percentage was not significant. NONB group after 5 days was showed a significant difference on the aggregation speed and aggregation index while in LT and aggregation percentage was not significant. CONCLUSIONS The utilization of HBO 2.4 ATA 100% O2 3 × 30 min, once a day, for 5 days could decrease the platelet aggregation parameters (LT, aggregation speed, aggregation index, and aggregation percentage) in patients with NIDDM.
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Affiliation(s)
- Prihartini Widiyanti
- Biomedical Engineering Study Program, Faculty of Science and Technology, Universitas Airlangga, Surabaya, Indonesia
- Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
| | - Purnomo Suryohudoyo
- Biochemistry Department, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
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50
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Hofmann F. The cGMP system: components and function. Biol Chem 2021; 401:447-469. [PMID: 31747372 DOI: 10.1515/hsz-2019-0386] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 10/30/2019] [Indexed: 12/29/2022]
Abstract
The cyclic guanosine monophosphate (cGMP) signaling system is one of the most prominent regulators of a variety of physiological and pathophysiological processes in many mammalian and non-mammalian tissues. Targeting this pathway by increasing cGMP levels has been a very successful approach in pharmacology as shown for nitrates, phosphodiesterase (PDE) inhibitors and stimulators of nitric oxide-guanylyl cyclase (NO-GC) and particulate GC (pGC). This is an introductory review to the cGMP signaling system intended to introduce those readers to this system, who do not work in this area. This article does not intend an in-depth review of this system. Signal transduction by cGMP is controlled by the generating enzymes GCs, the degrading enzymes PDEs and the cGMP-regulated enzymes cyclic nucleotide-gated ion channels, cGMP-dependent protein kinases and cGMP-regulated PDEs. Part A gives a very concise introduction to the components. Part B gives a very concise introduction to the functions modulated by cGMP. The article cites many recent reviews for those who want a deeper insight.
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Affiliation(s)
- Franz Hofmann
- Pharmakologisches Institut, Technische Universität München, Biedersteiner Str. 29, D-80802 München, Germany
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