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Arciero I, Buonvino S, Melino S. Slow H 2S-Releasing Donors and 3D Printable Arrays Cellular Models in Osteo-Differentiation of Mesenchymal Stem Cells for Personalized Therapies. Biomolecules 2024; 14:1380. [PMID: 39595557 PMCID: PMC11592188 DOI: 10.3390/biom14111380] [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: 09/24/2024] [Revised: 10/18/2024] [Accepted: 10/28/2024] [Indexed: 11/28/2024] Open
Abstract
The effects of the hydrogen sulfide (H2S) slow-releasing donor, named GSGa, a glutathione-conjugate water-soluble garlic extract, on human mesenchymal stem cells (hMSCs) in both bidimensional (2D) and three-dimensional (3D) cultures were investigated, demonstrating increased expression of the antioxidant enzyme HO-1 and decreased expression of the pro-inflammatory cytokine interleukin-6 (IL-6). The administration of the H2S donor can therefore increase the expression of antioxidant enzymes, which may have potential therapeutic applications in osteoarthritis (OA). Moreover, GSGa was able to promote the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), but not of cardiac mesenchymal stem cells (cMSCs) in a 2D culture system. This result highlights the varying sensitivity of hMSCs to the H2S donor GSGa, suggesting that the induction of osteogenic differentiation in stem cells by chemical factors is dependent on the tissue of origin. Additionally, a 3D-printable mesenchymal stem cells-bone matrix array (MSCBM), designed to closely mimic the stiffness of bone tissue, was developed to serve as a versatile tool for evaluating the effects of drugs and stem cells on bone repair in chronic diseases, such as OA. We demonstrated that the osteogenic differentiation process in cMSCs can be induced just by simulating bone stiffness in a 3D system. The expression of osteocalcin, RUNX2, and antioxidant enzymes was also assessed after treating MSCs with GSGa and/or increasing the stiffness of the culture environment. The printability of the array may enable better customization of the cavities, enabling an accurate replication of real bone defects. This could optimize the BM array to mimic bone defects not only in terms of stiffness, but also in terms of shape. This culture system may enable a rapid screening of antioxidant and anti-inflammatory compounds, facilitating a more personalized approach to regenerative therapy.
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Affiliation(s)
- Ilaria Arciero
- Department of Chemical Sciences and Technologies, University of Rome “Tor Vergata”, Via della Ricerca Scientifica, 00133 Rome, Italy;
| | - Silvia Buonvino
- Department of Experimental Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy;
| | - Sonia Melino
- Department of Experimental Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy;
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2
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Sun H, Li C, Shi Y, Wang Y, Li J, Fan L, Yu Y, Ji X, Gao X, Hou K, Li Y. Investigating the L-Glu-NMDA receptor-H 2S-NMDA receptor pathway that regulates gastric function in rats' nucleus ambiguus. Front Pharmacol 2024; 15:1389873. [PMID: 38751777 PMCID: PMC11094298 DOI: 10.3389/fphar.2024.1389873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 04/15/2024] [Indexed: 05/18/2024] Open
Abstract
Background In previous investigations, we explored the regulation of gastric function by hydrogen sulfide (H2S) and L-glutamate (L-Glu) injections in the nucleus ambiguus (NA). We also determined that both H2S and L-Glu have roles to play in the physiological activities of the body, and that NA is an important nucleus for receiving visceral sensations. The purpose of this study was to explore the potential pathway link between L-Glu and H2S, resulting in the regulation of gastric function. Methods Physiological saline (PS), L-glutamate (L-Glu, 2 nmol), NaHS (2 nmol), D-2-amino-5-phopho-novalerate (D-AP5, 2 nmol) + L-Glu (2 nmol), aminooxyacetic acid (AOAA, 2 nmol) + L-Glu (2 nmol), D-AP5 (2 nmol) + NaHS (2 nmol) were injected into the NA. A balloon was inserted into the stomach to observe gastric pressure and for recording the changes of gastric smooth muscle contraction curve. The gastric fluid was collected by esophageal perfusion and for recording the change of gastric pH value. Results Injecting L-Glu in NA was found to significantly inhibit gastric motility and promote gastric acid secretion in rats (p < 0.01). On the other hand, injecting the PS, pre-injection N-methyl-D-aspartate (NMDA) receptor blocker D-AP5, cystathionine beta-synthase (CBS) inhibitor AOAA and re-injection L-Glu did not result in significant changes (p > 0.05). The same injection NaHS significantly inhibit gastric motility and promote gastric acid secretion in rats (p < 0.01), but is eliminated by injection D-AP5 (p > 0.05). Conclusion The results indicate that both exogenous L-Glu and H2S injected in NA regulate gastric motility and gastric acid secretion through NMDA receptors. This suggests that NA has an L-Glu-NMDA receptor-CBS-H2S pathway that regulates gastric function.
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Martelli A, d'Emmanuele di Villa Bianca R, Cirino G, Sorrentino R, Calderone V, Bucci M. Hydrogen sulfide and sulfaceutic or sulfanutraceutic agents: Classification, differences and relevance in preclinical and clinical studies. Pharmacol Res 2023; 196:106947. [PMID: 37797660 DOI: 10.1016/j.phrs.2023.106947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/01/2023] [Accepted: 10/02/2023] [Indexed: 10/07/2023]
Abstract
Hydrogen sulfide (H2S) has been extensively studied as a signal molecule in the body for the past 30 years. Researchers have conducted studies using both natural and synthetic sources of H2S, known as H2S donors, which have different characteristics in terms of how they release H2S. These donors can be inorganic salts or have various organic structures. In recent years, certain types of sulfur compounds found naturally in foods have been characterized as H2S donors and explored for their potential health benefits. These compounds are referred to as "sulfanutraceuticals," a term that combines "nutrition" and "pharmaceutical". It is used to describe products derived from food sources that offer additional health advantages. By introducing the terms "sulfaceuticals" and "sulfanutraceuticals," we categorize sulfur-containing substances based on their origin and their use in both preclinical and clinical research, as well as in dietary supplements.
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Affiliation(s)
- A Martelli
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy; Interdepartmental Research Center "Nutrafood: Nutraceutica e Alimentazione per la Salute", University of Pisa, 56126 Pisa, Italy; Interdepartmental Research Center "Biology and Pathology of Ageing", University of Pisa, 56126 Pisa, Italy
| | - R d'Emmanuele di Villa Bianca
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
| | - G Cirino
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
| | - R Sorrentino
- Department of Molecular Medicine and Medical Biotechnologies, School of Medicine, University of Naples, Federico II, Via Pansini, 5, 80131 Naples, Italy
| | - V Calderone
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy; Interdepartmental Research Center "Nutrafood: Nutraceutica e Alimentazione per la Salute", University of Pisa, 56126 Pisa, Italy; Interdepartmental Research Center "Biology and Pathology of Ageing", University of Pisa, 56126 Pisa, Italy.
| | - M Bucci
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
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4
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Hydrogen sulfide as a neuromodulator of the vascular tone. Eur J Pharmacol 2023; 940:175455. [PMID: 36549499 DOI: 10.1016/j.ejphar.2022.175455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/29/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022]
Abstract
Hydrogen sulfide (H2S) is a unique signaling molecule that, along with carbon monoxide and nitric oxide, belongs to the gasotransmitters family. H2S is endogenously synthesized by enzymatic and non-enzymatic pathways. Three enzymatic pathways involving cystathionine-γ-lyase, cystathionine-β-synthetase, and 3-mercaptopyruvate sulfurtransferase are known as endogenous sources of H2S. This gaseous molecule has recently emerged as a regulator of many systems and physiological functions, including the cardiovascular system where it controls the vascular tone of small arteries. In this context, H2S leads to vasorelaxation by regulating the activity of vascular smooth muscle cells, endothelial cells, and perivascular nerves. Specifically, H2S modulates the functionality of different ion channels to inhibit the autonomic sympathetic outflow-by either central or peripheral mechanisms-or to stimulate perivascular sensory nerves. These mechanisms are particularly relevant for those pathological conditions associated with impaired neuromodulation of vascular tone. In this regard, exogenous H2S administration efficiently attenuates the increased activity of the sympathetic nervous system often seen in patients with certain pathologies. These effects of H2S on the autonomic sympathetic outflow will be the primary focus of this review. Thereafter, we will discuss the central and peripheral regulatory effects of H2S on vascular tone. Finally, we will provide the audience with a detailed summary of the current pathological implications of H2S modulation on the neural regulation of vascular tone.
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Comparative Study of Different H 2S Donors as Vasodilators and Attenuators of Superoxide-Induced Endothelial Damage. Antioxidants (Basel) 2023; 12:antiox12020344. [PMID: 36829903 PMCID: PMC9951978 DOI: 10.3390/antiox12020344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 01/25/2023] [Accepted: 01/30/2023] [Indexed: 02/04/2023] Open
Abstract
In the last years, research proofs have confirmed that hydrogen sulfide (H2S) plays an important role in various physio-pathological processes, such as oxidation, inflammation, neurophysiology, and cardiovascular protection; in particular, the protective effects of H2S in cardiovascular diseases were demonstrated. The interest in H2S-donating molecules as tools for biological and pharmacological studies has grown, together with the understanding of H2S importance. Here we performed a comparative study of a series of H2S donor molecules with different chemical scaffolds and H2S release mechanisms. The compounds were tested in human serum for their stability and ability to generate H2S. Their vasorelaxant properties were studied on rat aorta strips, and the capacity of the selected compounds to protect NO-dependent endothelium reactivity in an acute oxidative stress model was tested. H2S donors showed different H2S-releasing kinetic and produced amounts and vasodilating profiles; in particular, compound 6 was able to attenuate the dysfunction of relaxation induced by pyrogallol exposure, showing endothelial protective effects. These results may represent a useful basis for the rational development of promising H2S-releasing agents also conjugated with other pharmacophores.
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Huerta de la Cruz S, Santiago-Castañeda CL, Rodríguez-Palma EJ, Medina-Terol GJ, López-Preza FI, Rocha L, Sánchez-López A, Freeman K, Centurión D. Targeting hydrogen sulfide and nitric oxide to repair cardiovascular injury after trauma. Nitric Oxide 2022; 129:82-101. [PMID: 36280191 PMCID: PMC10644383 DOI: 10.1016/j.niox.2022.10.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 10/06/2022] [Accepted: 10/18/2022] [Indexed: 11/06/2022]
Abstract
The systemic cardiovascular effects of major trauma, especially neurotrauma, contribute to death and permanent disability in trauma patients and treatments are needed to improve outcomes. In some trauma patients, dysfunction of the autonomic nervous system produces a state of adrenergic overstimulation, causing either a sustained elevation in catecholamines (sympathetic storm) or oscillating bursts of paroxysmal sympathetic hyperactivity. Trauma can also activate innate immune responses that release cytokines and damage-associated molecular patterns into the circulation. This combination of altered autonomic nervous system function and widespread systemic inflammation produces secondary cardiovascular injury, including hypertension, damage to cardiac tissue, vascular endothelial dysfunction, coagulopathy and multiorgan failure. The gasotransmitters nitric oxide (NO) and hydrogen sulfide (H2S) are small gaseous molecules with potent effects on vascular tone regulation. Exogenous NO (inhaled) has potential therapeutic benefit in cardio-cerebrovascular diseases, but limited data suggests potential efficacy in traumatic brain injury (TBI). H2S is a modulator of NO signaling and autonomic nervous system function that has also been used as a drug for cardio-cerebrovascular diseases. The inhaled gases NO and H2S are potential treatments to restore cardio-cerebrovascular function in the post-trauma period.
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Affiliation(s)
- Saúl Huerta de la Cruz
- Departamento de Farmacobiología, Cinvestav-Coapa, Mexico City, Mexico; Department of Pharmacology, University of Vermont, Burlington, VT, USA.
| | | | - Erick J Rodríguez-Palma
- Neurobiology of Pain Laboratory, Departamento de Farmacobiología, Cinvestav, Sede Sur, Mexico City, Mexico.
| | | | | | - Luisa Rocha
- Departamento de Farmacobiología, Cinvestav-Coapa, Mexico City, Mexico.
| | | | - Kalev Freeman
- Department of Emergency Medicine, University of Vermont, Burlington, VT, USA.
| | - David Centurión
- Departamento de Farmacobiología, Cinvestav-Coapa, Mexico City, Mexico.
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Huerta de la Cruz S, Rodríguez-Palma EJ, Santiago-Castañeda CL, Beltrán-Ornelas JH, Sánchez-López A, Rocha L, Centurión D. Exogenous hydrogen sulfide restores CSE and CBS but no 3-MST protein expression in the hypothalamus and brainstem after severe traumatic brain injury. Metab Brain Dis 2022; 37:1863-1874. [PMID: 35759072 DOI: 10.1007/s11011-022-01033-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 06/10/2022] [Indexed: 02/07/2023]
Abstract
Hydrogen sulfide (H2S) is a gasotransmitter endogenously synthesized by cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), and 3-mercaptopiruvate sulfurtransferase (3-MST) enzymes. H2S exogenous administration prevents the development of hemodynamic impairments after traumatic brain injury (TBI). Since the hypothalamus and the brainstem highly regulate the cardiovascular system, this study aimed to evaluate the effect of NaHS subchronic treatment on the changes of H2S-sythesizing enzymes in those brain areas after TBI and in physiological conditions. For that purpose, animals were submitted to a lateral fluid percussion injury, and the changes in CBS, CSE, and 3-MST protein expression were measured by western blot at days 1, 2, 3, 7, and 28 in the vehicle group, and 7 and 28 days after NaHS treatment. After severe TBI induction, we found a decrease in CBS and CSE protein expression in the hypothalamus and brainstem; meanwhile, 3-MST protein expression diminished only in the hypothalamus compared to the Sham group. Remarkably, i.p. daily injections of NaHS, an H2S donor, (3.1 mg/kg) during seven days: (1) restored CBS and CSE but no 3-MST protein expression in the hypothalamus at day 28 post-TBI; (2) reestablished only CSE in brainstem 7 and 28 days after TBI; and (3) did not modify H2S-sythesizing enzymes protein expression in uninjured animals. Mainly, our results show that the NaHS effect on CBS and CSE protein expression is observed in a time- and tissue-dependent manner with no effect on 3-MST expression, which may suggest a potential role of H2S synthesis in hypothalamus and brainstem impairments observed after TBI.
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Affiliation(s)
| | - Erick J Rodríguez-Palma
- Neurobiology of Pain Laboratory, Departamento de Farmacobiología, Cinvestav, Sede Sur, Mexico City, Mexico
| | | | | | | | - Luisa Rocha
- Departamento de Farmacobiología, Cinvestav-Coapa, Mexico City, Mexico
| | - David Centurión
- Departamento de Farmacobiología, Cinvestav-Coapa, Mexico City, Mexico.
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Li C, Sun H, Shi Y, Yu Y, Ji X, Li E, Zhou X, Liu X, Xue X, Sun H. Effects of Exogenous Hydrogen Sulfide in the Hypothalamic Paraventricular Nucleus on Gastric Function in Rats. Front Pharmacol 2022; 12:806012. [PMID: 35095514 PMCID: PMC8793780 DOI: 10.3389/fphar.2021.806012] [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: 10/31/2021] [Accepted: 12/01/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Hydrogen sulfide (H2S) is a new type of gas neurotransmitter discovered in recent years. It plays an important role in various physiological activities. The hypothalamus paraventricular nucleus (PVN) is an important nucleus that regulates gastric function. This study aimed to clarify the role of H2S in the paraventricular nucleus of the hypothalamus on the gastric function of rats. Methods: An immunofluorescence histochemistry double-labelling technique was used to determine whether cystathionine-beta-synthase (CBS) and c-Fos neurons are involved in PVN stress. Through microinjection of different concentrations of NaHS, physiological saline (PS), D-2-Amino-5-phosphonovaleric acid (D-AP5), and pyrrolidine dithiocarbamate (PDTC), we observed gastric motility and gastric acid secretion. Results: c-Fos and CBS co-expressed the most positive neurons after 1 h of restraint and immersion, followed by 3 h, and the least was at 0 h. After injection of different concentrations of NaHS into the PVN, gastric motility and gastric acid secretion in rats were significantly inhibited and promoted, respectively (p < 0.01); however, injection of normal saline, D-AP5, and PDTC did not cause any significant change (p > 0.05). The suppressive effect of NaHS on gastrointestinal motility and the promotional effect of NaHS on gastric acid secretion could be prevented by D-AP5, a specific N-methyl-D-aspartic acid (NMDA) receptor antagonist, and PDTC, an NF-κB inhibitor. Conclusion: There are neurons co-expressing CBS and c-Fos in the PVN, and the injection of NaHS into the PVN can inhibit gastric motility and promote gastric acid secretion in rats. This effect may be mediated by NMDA receptors and the NF-κB signalling pathway.
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Affiliation(s)
- Chenyu Li
- School of Life Science, Qilu Normal University, Jinan, China.,Key Laboratory of Animal Resistance, School of Life Science, Shandong Normal University, Jinan, China
| | - Hongzhao Sun
- School of Life Science, Qilu Normal University, Jinan, China
| | - Yuan Shi
- School of Life Science, Qilu Normal University, Jinan, China
| | - Yan Yu
- School of Life Science, Qilu Normal University, Jinan, China
| | - Xiaofeng Ji
- School of Life Science, Qilu Normal University, Jinan, China
| | - Enguang Li
- School of Life Science, Qilu Normal University, Jinan, China
| | - Xiaofan Zhou
- School of Life Science, Qilu Normal University, Jinan, China
| | - Xiaomeng Liu
- School of Life Science, Qilu Normal University, Jinan, China
| | - Xikang Xue
- School of Life Science, Qilu Normal University, Jinan, China
| | - Haiji Sun
- Key Laboratory of Animal Resistance, School of Life Science, Shandong Normal University, Jinan, China
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McCook O, Denoix N, Radermacher P, Waller C, Merz T. H 2S and Oxytocin Systems in Early Life Stress and Cardiovascular Disease. J Clin Med 2021; 10:jcm10163484. [PMID: 34441780 PMCID: PMC8397059 DOI: 10.3390/jcm10163484] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/02/2021] [Accepted: 08/03/2021] [Indexed: 02/07/2023] Open
Abstract
Today it is well established that early life stress leads to cardiovascular programming that manifests in cardiovascular disease, but the mechanisms by which this occurs, are not fully understood. This perspective review examines the relevant literature that implicates the dysregulation of the gasomediator hydrogen sulfide and the neuroendocrine oxytocin systems in heart disease and their putative mechanistic role in the early life stress developmental origins of cardiovascular disease. Furthermore, interesting hints towards the mutual interaction of the hydrogen sulfide and OT systems are identified, especially with regards to the connection between the central nervous and the cardiovascular system, which support the role of the vagus nerve as a communication link between the brain and the heart in stress-mediated cardiovascular disease.
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Affiliation(s)
- Oscar McCook
- Institute for Anesthesiological Pathophysiology and Process Engineering, Ulm University Medical Center, 89081 Ulm, Germany; (N.D.); (P.R.); (T.M.)
- Correspondence: ; Tel.: +49-731-500-60185; Fax: +49-731-500-60162
| | - Nicole Denoix
- Institute for Anesthesiological Pathophysiology and Process Engineering, Ulm University Medical Center, 89081 Ulm, Germany; (N.D.); (P.R.); (T.M.)
- Clinic for Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, 89081 Ulm, Germany
| | - Peter Radermacher
- Institute for Anesthesiological Pathophysiology and Process Engineering, Ulm University Medical Center, 89081 Ulm, Germany; (N.D.); (P.R.); (T.M.)
| | - Christiane Waller
- Department of Psychosomatic Medicine and Psychotherapy, Nuremberg General Hospital, Paracelsus Medical University, 90471 Nuremberg, Germany;
| | - Tamara Merz
- Institute for Anesthesiological Pathophysiology and Process Engineering, Ulm University Medical Center, 89081 Ulm, Germany; (N.D.); (P.R.); (T.M.)
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Design of an Innovative Methodology for Cerebrospinal Fluid Analysis: Preliminary Results. SENSORS 2021; 21:s21113767. [PMID: 34071694 PMCID: PMC8198196 DOI: 10.3390/s21113767] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 05/25/2021] [Accepted: 05/27/2021] [Indexed: 11/17/2022]
Abstract
Cerebrospinal fluid (CSF) analysis supports diagnosis of neurodegenerative diseases (NDs), however a number of issues limits its potentialities in clinical practice. Here, a newly developed technique for fluid voltammetry, relying on a simple sensor (BIOsensor-based multisensorial system for mimicking Nose, Tongue and Eyes, BIONOTE), was used to test the applicability for CSF analysis. BIONOTE was initially calibrated on an artificial CSF-like solution and then applied on human CSF, either immediately after collection or after refrigerated storage. Following optimization, it was used to evaluate 11 CSF samples correlating the electrochemical dataset with CSF routine parameters and biomarkers of neurodegeneration. Multivariate data analysis was performed for model elaboration and calibration using principal component analysis and partial least squares discriminant analysis. BIONOTE presented a high capacity to predict both physiological and pathological constituents of artificial CSF. It differentiated distinct fresh human CSF samples well but lost accuracy after refrigerated storage. The electrochemical analysis-derived data correlated with either CSF routine cytochemical indexes or a biomarker of neurodegeneration. BIONOTE resulted as being a reliable system for electrochemical analysis of CSF. The CSF fingerprint provided by the sensor has shown itself to be sensitive to CSF modification, thus it is potentially representative of CSF alteration. This result opens the way to its testing in further study addressed at assessing the clinical relevance of the methodology. Because of its advantages due to the ease and rapidity of the methodology, a validation study is now required to translate the technique into clinical practice and improve diagnostic workup of NDs.
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Trends in H 2S-Donors Chemistry and Their Effects in Cardiovascular Diseases. Antioxidants (Basel) 2021; 10:antiox10030429. [PMID: 33799669 PMCID: PMC8002049 DOI: 10.3390/antiox10030429] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 02/26/2021] [Accepted: 03/08/2021] [Indexed: 12/15/2022] Open
Abstract
Hydrogen sulfide (H2S) is an endogenous gasotransmitter recently emerged as an important regulatory mediator of numerous human cell functions in health and in disease. In fact, much evidence has suggested that hydrogen sulfide plays a significant role in many physio-pathological processes, such as inflammation, oxidation, neurophysiology, ion channels regulation, cardiovascular protection, endocrine regulation, and tumor progression. Considering the plethora of physiological effects of this gasotransmitter, the protective role of H2S donors in different disease models has been extensively studied. Based on the growing interest in H2S-releasing compounds and their importance as tools for biological and pharmacological studies, this review is an exploration of currently available H2S donors, classifying them by the H2S-releasing-triggered mechanism and highlighting those potentially useful as promising drugs in the treatment of cardiovascular diseases.
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Trautwein B, Merz T, Denoix N, Szabo C, Calzia E, Radermacher P, McCook O. ΔMST and the Regulation of Cardiac CSE and OTR Expression in Trauma and Hemorrhage. Antioxidants (Basel) 2021; 10:233. [PMID: 33546491 PMCID: PMC7913715 DOI: 10.3390/antiox10020233] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/01/2021] [Accepted: 02/01/2021] [Indexed: 12/19/2022] Open
Abstract
Genetic deletion of 3-mercaptopyruvate sulfurtransferase (MST) is known to result in hypertension and cardiac hypertrophy in older mice, and is associated with increased anxiety-like behaviors. Endogenous hydrogen sulfide (H2S) produced by MST in the mitochondria is also known to be involved in physiological and cellular bioenergetics, and its dysfunction associated with depressive behavior and increased cardiovascular morbidity. Interestingly, early life stress has been shown to lead to a significant loss of cystathionine-γ-lyase (CSE) and oxytocin receptor (OTR) expression in the heart. Thus, we were interested in testing the hypothesis of whether genetic MST mutation (ΔMST) would affect cardiac CSE and OTR expression and affect the mitochondrial respiration in a clinically relevant, resuscitated, mouse model of trauma and hemorrhagic shock. In ΔMST mice, we found a reduction of CSE and OTR in both the naive as well as injured state, in contrast to the wild type (wt) controls. Interestingly, the ΔMST showed a different complex IV response to injury than the wt controls, although our claims are based on the non-demonstrated assumption that naive wt and naive ΔMST mice have comparable complex IV activity. Finally, hemorrhagic shock led to a reduction of CSE and OTR, confirming previous results in the injured mouse heart. To date, the exact mechanisms of the cardiac interaction between H2S and OT are not clear, but they point the way to potential cardioprotective therapies.
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Affiliation(s)
- Britta Trautwein
- Institute for Anesthesiological Pathophysiology and Process Engineering, Ulm University Medical Center, 89081 Um, Germany; (B.T.); (T.M.); (N.D.); (E.C.); (P.R.)
| | - Tamara Merz
- Institute for Anesthesiological Pathophysiology and Process Engineering, Ulm University Medical Center, 89081 Um, Germany; (B.T.); (T.M.); (N.D.); (E.C.); (P.R.)
| | - Nicole Denoix
- Institute for Anesthesiological Pathophysiology and Process Engineering, Ulm University Medical Center, 89081 Um, Germany; (B.T.); (T.M.); (N.D.); (E.C.); (P.R.)
- Clinic for Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, 89070 Ulm, Germany
| | - Csaba Szabo
- Department of Science and Medicine, University of Fribourg, 1700 Fribourg, Switzerland;
| | - Enrico Calzia
- Institute for Anesthesiological Pathophysiology and Process Engineering, Ulm University Medical Center, 89081 Um, Germany; (B.T.); (T.M.); (N.D.); (E.C.); (P.R.)
| | - Peter Radermacher
- Institute for Anesthesiological Pathophysiology and Process Engineering, Ulm University Medical Center, 89081 Um, Germany; (B.T.); (T.M.); (N.D.); (E.C.); (P.R.)
| | - Oscar McCook
- Clinic for Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, 89070 Ulm, Germany
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Manandhar S, Sinha P, Ejiwale G, Bhatia M. Hydrogen Sulfide and its Interaction with Other Players in Inflammation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1315:129-159. [PMID: 34302691 DOI: 10.1007/978-981-16-0991-6_6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hydrogen sulfide (H2S) plays a vital role in human physiology and in the pathophysiology of several diseases. In addition, a substantial role of H2S in inflammation has emerged. This chapter will discuss the involvement of H2S in various inflammatory diseases. Furthermore, the contribution of reactive oxygen species (ROS), adhesion molecules, and leukocyte recruitment in H2S-mediated inflammation will be discussed. The interrelationship of H2S with other gasotransmitters in inflammation will also be examined. There is mixed literature on the contribution of H2S to inflammation due to studies reporting both pro- and anti-inflammatory actions. These apparent discrepancies in the literature could be resolved with further studies.
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Affiliation(s)
- Sumeet Manandhar
- Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
| | - Priyanka Sinha
- Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
| | - Grace Ejiwale
- Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
| | - Madhav Bhatia
- Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
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14
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Denoix N, McCook O, Ecker S, Wang R, Waller C, Radermacher P, Merz T. The Interaction of the Endogenous Hydrogen Sulfide and Oxytocin Systems in Fluid Regulation and the Cardiovascular System. Antioxidants (Basel) 2020; 9:E748. [PMID: 32823845 PMCID: PMC7465147 DOI: 10.3390/antiox9080748] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/10/2020] [Accepted: 08/11/2020] [Indexed: 12/11/2022] Open
Abstract
The purpose of this review is to explore the parallel roles and interaction of hydrogen sulfide (H2S) and oxytocin (OT) in cardiovascular regulation and fluid homeostasis. Their interaction has been recently reported to be relevant during physical and psychological trauma. However, literature reports on H2S in physical trauma and OT in psychological trauma are abundant, whereas available information regarding H2S in psychological trauma and OT in physical trauma is much more limited. This review summarizes recent direct and indirect evidence of the interaction of the two systems and their convergence in downstream nitric oxide-dependent signaling pathways during various types of trauma, in an effort to better understand biological correlates of psychosomatic interdependencies.
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Affiliation(s)
- Nicole Denoix
- Clinic for Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, 89081 Ulm, Germany;
- Institute for Anesthesiological Pathophysiology and Process Engineering, Ulm University Medical Center, 89081 Ulm, Germany; (S.E.); (P.R.); (T.M.)
| | - Oscar McCook
- Institute for Anesthesiological Pathophysiology and Process Engineering, Ulm University Medical Center, 89081 Ulm, Germany; (S.E.); (P.R.); (T.M.)
| | - Sarah Ecker
- Institute for Anesthesiological Pathophysiology and Process Engineering, Ulm University Medical Center, 89081 Ulm, Germany; (S.E.); (P.R.); (T.M.)
| | - Rui Wang
- Faculty of Science, York University, Toronto, ON M3J 1P3, Canada;
| | - Christiane Waller
- Department of Psychosomatic Medicine and Psychotherapy, Nuremberg General Hospital, Paracelsus Medical University, 90419 Nuremberg, Germany;
| | - Peter Radermacher
- Institute for Anesthesiological Pathophysiology and Process Engineering, Ulm University Medical Center, 89081 Ulm, Germany; (S.E.); (P.R.); (T.M.)
| | - Tamara Merz
- Institute for Anesthesiological Pathophysiology and Process Engineering, Ulm University Medical Center, 89081 Ulm, Germany; (S.E.); (P.R.); (T.M.)
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Zuhra K, Augsburger F, Majtan T, Szabo C. Cystathionine-β-Synthase: Molecular Regulation and Pharmacological Inhibition. Biomolecules 2020; 10:E697. [PMID: 32365821 PMCID: PMC7277093 DOI: 10.3390/biom10050697] [Citation(s) in RCA: 132] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 04/24/2020] [Accepted: 04/27/2020] [Indexed: 12/11/2022] Open
Abstract
Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in the transsulfuration pathway, is an important mammalian enzyme in health and disease. Its biochemical functions under physiological conditions include the metabolism of homocysteine (a cytotoxic molecule and cardiovascular risk factor) and the generation of hydrogen sulfide (H2S), a gaseous biological mediator with multiple regulatory roles in the vascular, nervous, and immune system. CBS is up-regulated in several diseases, including Down syndrome and many forms of cancer; in these conditions, the preclinical data indicate that inhibition or inactivation of CBS exerts beneficial effects. This article overviews the current information on the expression, tissue distribution, physiological roles, and biochemistry of CBS, followed by a comprehensive overview of direct and indirect approaches to inhibit the enzyme. Among the small-molecule CBS inhibitors, the review highlights the specificity and selectivity problems related to many of the commonly used "CBS inhibitors" (e.g., aminooxyacetic acid) and provides a comprehensive review of their pharmacological actions under physiological conditions and in various disease models.
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Affiliation(s)
- Karim Zuhra
- Chair of Pharmacology, Section of Medicine, University of Fribourg, 1702 Fribourg, Switzerland; (K.Z.); (F.A.)
| | - Fiona Augsburger
- Chair of Pharmacology, Section of Medicine, University of Fribourg, 1702 Fribourg, Switzerland; (K.Z.); (F.A.)
| | - Tomas Majtan
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;
| | - Csaba Szabo
- Chair of Pharmacology, Section of Medicine, University of Fribourg, 1702 Fribourg, Switzerland; (K.Z.); (F.A.)
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Santos BM, Francescato HDC, Turcato FC, Antunes‐Rodrigues J, Coimbra TM, Branco LGS. Increased hypothalamic hydrogen sulphide contributes to endotoxin tolerance by down-modulating PGE 2 production. Acta Physiol (Oxf) 2020; 228:e13373. [PMID: 31483934 DOI: 10.1111/apha.13373] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 08/13/2019] [Accepted: 08/28/2019] [Indexed: 02/01/2023]
Abstract
AIM Whereas some patients have important changes in body core temperature (Tb) during systemic inflammation, others maintain a normal Tb, which is intrinsically associated to immune paralysis. One classical model to study immune paralysis is the use of repeated administration of lipopolysaccharide (LPS), the so-called endotoxin tolerance. However, the neuroimmune mechanisms of endotoxin tolerance remain poorly understood. Hydrogen sulphide (H2 S) is a gaseous neuromodulator produced in the brain by the enzyme cystathionine β-synthase (CBS). The present study assessed whether endotoxin tolerance is modulated by hypothalamic H2 S. METHODS Rats with central cannulas (drug microinjection) and intraperitoneal datalogger (temperature record) received a low-dose of lipopolysaccharide (LPS; 100 µg kg-1 ) daily for four consecutive days. Hypothalamic CBS expression and H2 S production rate were assessed, together with febrigenic signalling. Tolerant rats received an inhibitor of H2 S synthesis (AOA, 100 pmol 1 µL-1 icv) or its vehicle in the last day. RESULTS Antero-ventral preoptic area of the hypothalamus (AVPO) H2 S production rate and CBS expression were increased in endotoxin-tolerant rats. Additionally, hypothalamic H2 S inhibition reversed endotoxin tolerance reestablishing fever, AVPO and plasma PGE2 levels without altering the absent plasma cytokines surges. CONCLUSION Endotoxin tolerance is not simply a reflection of peripheral reduced cytokines release but actually results from a complex set of mechanisms acting at multiple levels. Hypothalamic H2 S production modulates most of these mechanisms.
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Affiliation(s)
- Bruna M. Santos
- Department of Physiology Medical School of Ribeirão Preto University of São Paulo Ribeirão Preto Brazil
| | - Heloísa D. C. Francescato
- Department of Physiology Medical School of Ribeirão Preto University of São Paulo Ribeirão Preto Brazil
| | - Flávia C. Turcato
- Department of Physiology Medical School of Ribeirão Preto University of São Paulo Ribeirão Preto Brazil
| | - José Antunes‐Rodrigues
- Department of Physiology Medical School of Ribeirão Preto University of São Paulo Ribeirão Preto Brazil
| | - Terezila M. Coimbra
- Department of Physiology Medical School of Ribeirão Preto University of São Paulo Ribeirão Preto Brazil
| | - Luiz G. S. Branco
- Department of Basic and Oral Biology Dental School of Ribeirão Preto University of São Paulo Ribeirão Preto Brazil
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Glutathione-Allylsulfur Conjugates as Mesenchymal Stem Cells Stimulating Agents for Potential Applications in Tissue Repair. Int J Mol Sci 2020; 21:ijms21051638. [PMID: 32121252 PMCID: PMC7084915 DOI: 10.3390/ijms21051638] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 02/24/2020] [Accepted: 02/25/2020] [Indexed: 12/23/2022] Open
Abstract
The endogenous gasotransmitter H2S plays an important role in the central nervous, respiratory and cardiovascular systems. Accordingly, slow-releasing H2S donors are powerful tools for basic studies and innovative pharmaco-therapeutic agents for cardiovascular and neurodegenerative diseases. Nonetheless, the effects of H2S-releasing agents on the growth of stem cells have not been fully investigated. H2S preconditioning can enhance mesenchymal stem cell survival after post-ischaemic myocardial implantation; therefore, stem cell therapy combined with H2S may be relevant in cell-based therapy for regenerative medicine. Here, we studied the effects of slow-releasing H2S agents on the cell growth and differentiation of cardiac Lin− Sca1+ human mesenchymal stem cells (cMSC) and on normal human dermal fibroblasts (NHDF). In particular, we investigated the effects of water-soluble GSH–garlic conjugates (GSGa) on cMSC compared to other H2S-releasing agents, such as Na2S and GYY4137. GSGa treatment of cMSC and NHDF increased their cell proliferation and migration in a concentration dependent manner with respect to the control. GSGa treatment promoted an upregulation of the expression of proteins involved in oxidative stress protection, cell–cell adhesion and commitment to differentiation. These results highlight the effects of H2S-natural donors as biochemical factors that promote MSC homing, increasing their safety profile and efficacy after transplantation, and the value of these donors in developing functional 3D-stem cell delivery systems for cardiac muscle tissue repair and regeneration.
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Sunzini F, De Stefano S, Chimenti MS, Melino S. Hydrogen Sulfide as Potential Regulatory Gasotransmitter in Arthritic Diseases. Int J Mol Sci 2020; 21:ijms21041180. [PMID: 32053981 PMCID: PMC7072783 DOI: 10.3390/ijms21041180] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 01/30/2020] [Accepted: 02/09/2020] [Indexed: 01/12/2023] Open
Abstract
The social and economic impact of chronic inflammatory diseases, such as arthritis, explains the growing interest of the research in this field. The antioxidant and anti-inflammatory properties of the endogenous gasotransmitter hydrogen sulfide (H2S) were recently demonstrated in the context of different inflammatory diseases. In particular, H2S is able to suppress the production of pro-inflammatory mediations by lymphocytes and innate immunity cells. Considering these biological effects of H2S, a potential role in the treatment of inflammatory arthritis, such as rheumatoid arthritis (RA), can be postulated. However, despite the growing interest in H2S, more evidence is needed to understand the pathophysiology and the potential of H2S as a therapeutic agent. Within this review, we provide an overview on H2S biological effects, on its role in immune-mediated inflammatory diseases, on H2S releasing drugs, and on systems of tissue repair and regeneration that are currently under investigation for potential therapeutic applications in arthritic diseases.
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Affiliation(s)
- Flavia Sunzini
- Institute of Infection Immunity and Inflammation, University of Glasgow, 120 University, Glasgow G31 8TA, UK;
- Rheumatology, Allergology and clinical immunology, University of Rome Tor Vergata, via Montpelier, 00133 Rome, Italy;
| | - Susanna De Stefano
- Department of Chemical Science and Technologies, University of Rome Tor Vergata, via della Ricerca Scientifica 1, 00133 Rome, Italy;
| | - Maria Sole Chimenti
- Rheumatology, Allergology and clinical immunology, University of Rome Tor Vergata, via Montpelier, 00133 Rome, Italy;
| | - Sonia Melino
- Department of Chemical Science and Technologies, University of Rome Tor Vergata, via della Ricerca Scientifica 1, 00133 Rome, Italy;
- Correspondence: ; Tel.: +39-0672594410
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Natural Hydrogen Sulfide Donors from Allium sp. as a Nutraceutical Approach in Type 2 Diabetes Prevention and Therapy. Nutrients 2019; 11:nu11071581. [PMID: 31336965 PMCID: PMC6682899 DOI: 10.3390/nu11071581] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Revised: 06/30/2019] [Accepted: 07/10/2019] [Indexed: 12/30/2022] Open
Abstract
Type 2 diabetes mellitus (DM) is a socially relevant chronic disease with high prevalence worldwide. DM may lead to several vascular, macrovascular, and microvascular complications (cerebrovascular, coronary artery, and peripheral arterial diseases, retinopathy, neuropathy, and nephropathy), often accelerating the progression of atherosclerosis. Dietary therapy is generally considered to be the first step in the treatment of diabetic patients. Among the current therapeutic options, such as insulin therapy and hypoglycemic drugs, in recent years, attention has been shifting to the effects and properties-that are still not completely known-of medicinal plants as valid and inexpensive therapeutic supports with limited side effects. In this review, we report the relevant effects of medicinal plants and nutraceuticals in diabetes. In particular, we paid attention to the organosulfur compounds (OSCs) present in plant extracts that due to their antioxidant, hypoglycemic, anti-inflammatory, and immunomodulatory effects, can contribute as cardioprotective agents in type 2 DM. OSCs derived from garlic (Allium sp.), due to their properties, can represent a valuable support to the diet in type 2 DM, as outlined in this manuscript based on both in vitro and in vivo studies. Moreover, a relevant characteristic of garlic OSCs is their ability to produce the gasotransmitter H2S, and many of their effects can be explained by this property. Indeed, in recent years, several studies have demonstrated the relevant effects of endogenous and exogenous H2S in human DM, including by in vitro and in vivo experiments and clinical trials; therefore, here, we summarize the effects and the underlying molecular mechanisms of H2S and natural H2S donors.
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20
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Cacciotti I, Ciocci M, Di Giovanni E, Nanni F, Melino S. Hydrogen Sulfide-Releasing Fibrous Membranes: Potential Patches for Stimulating Human Stem Cells Proliferation and Viability under Oxidative Stress. Int J Mol Sci 2018; 19:E2368. [PMID: 30103516 PMCID: PMC6121677 DOI: 10.3390/ijms19082368] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 08/07/2018] [Accepted: 08/08/2018] [Indexed: 01/04/2023] Open
Abstract
The design of biomaterial platforms able to release bioactive molecules is mandatory in tissue repair and regenerative medicine. In this context, electrospinning is a user-friendly, versatile and low-cost technique, able to process different kinds of materials in micro- and nano-fibers with a large surface area-to-volume ratio for an optimal release of gaseous signaling molecules. Recently, the antioxidant and anti-inflammatory properties of the endogenous gasotramsmitter hydrogen sulfide (H₂S), as well as its ability to stimulate relevant biochemical processes on the growth of mesenchymal stem cells (MSC), have been investigated. Therefore, in this work, new poly(lactic) acid fibrous membranes (PFM), doped and functionalized with H₂S slow-releasing donors extracted from garlic, were synthetized. These innovative H₂S-releasing mats were characterized for their morphological, thermal, mechanical, and biological properties. Their antimicrobial activity and effects on the in vitro human cardiac MSC growth, either in the presence or in the absence of oxidative stress, were here assessed. On the basis of the results here presented, these new H₂S-releasing PFM could represent promising and low-cost scaffolds or patches for biomedical applications in tissue repair.
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Affiliation(s)
- Ilaria Cacciotti
- Department of Engineering, University of Rome "Niccolò Cusano", via Don Carlo Gnocchi 3, 00166 Rome, Italy.
- Italian Interuniversity Consortium on Materials Science and Technology (INSTM), 50121 Florence, Italy.
- CIMER Center for Regenerative Medicine, University of Rome Tor Vergata, via Montpellier 1, 00133 Rome, Italy.
| | - Matteo Ciocci
- Department of Chemical Science and Technologies, University of Rome "Tor Vergata", via della Ricerca Scientifica1, 00133 Rome, Italy.
| | - Emilia Di Giovanni
- Department of Chemical Science and Technologies, University of Rome "Tor Vergata", via della Ricerca Scientifica1, 00133 Rome, Italy.
| | - Francesca Nanni
- Italian Interuniversity Consortium on Materials Science and Technology (INSTM), 50121 Florence, Italy.
- Enterprise Engineering Department, University of Rome "Tor Vergata", via del Politecnico 1, 00133 Rome, Italy.
| | - Sonia Melino
- CIMER Center for Regenerative Medicine, University of Rome Tor Vergata, via Montpellier 1, 00133 Rome, Italy.
- Department of Chemical Science and Technologies, University of Rome "Tor Vergata", via della Ricerca Scientifica1, 00133 Rome, Italy.
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Vellecco V, Armogida C, Bucci M. Hydrogen sulfide pathway and skeletal muscle: an introductory review. Br J Pharmacol 2018; 175:3090-3099. [PMID: 29767441 PMCID: PMC6031874 DOI: 10.1111/bph.14358] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 04/18/2018] [Accepted: 04/30/2018] [Indexed: 12/13/2022] Open
Abstract
The presence of the H2 S pathway in skeletal muscle (SKM) has recently been established. SKM expresses the three constitutive H2 S-generating enzymes in animals and humans, and it actively produces H2 S. The main, recognized molecular targets of H2 S, that is, potassium channels and PDEs, have been evaluated in SKM physiology in order to hypothesize a role for H2 S signalling. SKM dysfunctions, including muscular dystrophy and malignant hyperthermia, have also been evaluated as conditions in which the H2 S and transsulfuration pathways have been suggested to be involved. The intrinsic complexity of the molecular mechanisms involved in excitation-contraction (E-C) coupling together with the scarcity of preclinical models of SKM-related disorders have hampered any advances in the knowledge of SKM function. Here, we have addressed the role of the H2 S pathway in E-C coupling and the relative importance of cystathionine β-synthase, cistathionine γ-lyase and 3-mercaptopyruvate sulfurtransferase in SKM diseases.
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Affiliation(s)
- Valentina Vellecco
- Department of Pharmacy, School of Medicine, University of Naples 'Federico II', Naples, 80131, Italy
| | - Chiara Armogida
- Department of Pharmacy, School of Medicine, University of Naples 'Federico II', Naples, 80131, Italy
| | - Mariarosaria Bucci
- Department of Pharmacy, School of Medicine, University of Naples 'Federico II', Naples, 80131, Italy
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Abstract
SIGNIFICANCE Among many endogenous mediators, the gasotransmitter hydrogen sulfide (H2S) plays an important role in the regulation of glucose homeostasis. In this article we discuss different functional roles of H2S in several metabolic organs/tissues required in the maintenance of glucose homeostasis. Recent Advances: New evidence has emerged revealing the insulin sensitizing role of H2S in adipose tissue and skeletal muscle biology. In addition, H2S was demonstrated to be a potent stimulator of gluconeogenesis via the induction and stimulation of various glucose-producing pathways in the liver. CRITICAL ISSUES Similar to its other physiological effects, H2S exhibits paradoxical characteristics in the regulation of glucose homeostasis: (1) H2S stimulates glucose production via activation of gluconeogenesis and glycogenolysis in hepatocytes, yet inhibits lipolysis in adipocytes; (2) H2S stimulates glucose uptake into adipocytes and skeletal muscle but inhibits glucose uptake into hepatocytes; (3) H2S inhibits insulin secretion from pancreatic β cells, yet sensitizes insulin signaling and insulin-triggered response in adipose tissues and skeletal muscle. It is also unclear the impact H2S may have on glucose metabolism and utilization by other vital organs, such as the brain. FUTURE DIRECTIONS Recent reports and ongoing studies lay the foundation for a general, although highly incomplete, understanding of the effect of H2S on regulating glucose homeostasis. In this review, we describe the molecular mechanisms and physiological outcomes of the gasotransmitter H2S on organs and tissues required for homeostatic maintenance of blood glucose. Future directions highlighting the H2S-mediated homeostatic control of glucose metabolism under physiological and insulin-resistant conditions are also discussed. Antioxid. Redox Signal. 28, 1463-1482.
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Affiliation(s)
- Ashley Untereiner
- 1 Department of Anesthesiology, University of Texas Medical Branch , Galveston, Texas
| | - Lingyun Wu
- 2 Cardiovascular & Metabolic Research Unit and School of Human Kinetics, Laurentian University , Sudbury, Canada .,3 Health Sciences North Research Institute , Sudbury, Canada
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Ciocci M, Iorio E, Carotenuto F, Khashoggi HA, Nanni F, Melino S. H2S-releasing nanoemulsions: a new formulation to inhibit tumor cells proliferation and improve tissue repair. Oncotarget 2018; 7:84338-84358. [PMID: 27741519 PMCID: PMC5356665 DOI: 10.18632/oncotarget.12609] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Accepted: 10/07/2016] [Indexed: 12/16/2022] Open
Abstract
The improvement of solubility and/or dissolution rate of poorly soluble natural compounds is an ideal strategy to make them optimal candidates as new potential drugs. Accordingly, the allyl sulfur compounds and omega-3 fatty acids are natural hydrophobic compounds that exhibit two important combined properties: cardiovascular protection and antitumor activity. Here, we have synthesized and characterized a novel formulation of diallyl disulfide (DADS) and α-linolenic acid (ALA) as protein-nanoemulsions (BAD-NEs), using ultrasounds. BAD-NEs are stable over time at room temperature and show antioxidant and radical scavenging property. These NEs are also optimal H2S slow-release donors and show a significant anti-proliferative effect on different human cancer cell lines: MCF-7 breast cancer and HuT 78 T-cell lymphoma cells. BAD-NEs are able to regulate the ERK1/2 pathway, inducing apoptosis and cell cycle arrest at the G0/G1 phase. We have also investigated their effect on cell proliferation of human adult stem/progenitor cells. Interestingly, BAD-NEs are able to improve the Lin- Sca1+ human cardiac progenitor cells (hCPC) proliferation. This stem cell growth stimulation is combined with the expression and activation of proteins involved in tissue-repair, such as P-AKT, α-sma and connexin 43. Altogether, our results suggest that these antioxidant nanoemulsions might have potential application in selective cancer therapy and for promoting the muscle tissue repair.
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Affiliation(s)
- Matteo Ciocci
- Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, Rome, Italy
| | - Egidio Iorio
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
| | - Felicia Carotenuto
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Haneen A Khashoggi
- Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, Rome, Italy
| | - Francesca Nanni
- Department of Industrial Engineering, University of Rome Tor Vergata, Rome, Italy
| | - Sonia Melino
- Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, Rome, Italy
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Shefa U, Kim MS, Jeong NY, Jung J. Antioxidant and Cell-Signaling Functions of Hydrogen Sulfide in the Central Nervous System. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:1873962. [PMID: 29507650 PMCID: PMC5817206 DOI: 10.1155/2018/1873962] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 11/13/2017] [Accepted: 12/11/2017] [Indexed: 12/13/2022]
Abstract
Hydrogen sulfide (H2S), a toxic gaseous molecule, plays a physiological role in regulating homeostasis and cell signaling. H2S is produced from cysteine by enzymes, such as cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), cysteine aminotransferase (CAT), and 3-mercaptopyruvate sulfurtransferase (3MST). These enzymes regulate the overall production of H2S in the body. H2S has a cell-signaling function in the CNS and plays important roles in combating oxidative species such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the body. H2S is crucial for maintaining balanced amounts of antioxidants to protect the body from oxidative stress, and appropriate amounts of H2S are required to protect the CNS in particular. The body regulates CBS, 3MST, and CSE levels in the CNS, and higher or lower levels of these enzymes cause various neurodegenerative diseases. This review discusses how H2S protects the CNS by acting as an antioxidant that reduces excessive amounts of ROS and RNS. Additionally, H2S regulates cell signaling to combat neuroinflammation and protect against central neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS).
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Affiliation(s)
- Ulfuara Shefa
- Department of Biomedical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - Min-Sik Kim
- Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Deogyeong-daero, Giheung-gu, Yongin-si, Gyeonggi-do 17104, Republic of Korea
| | - Na Young Jeong
- Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, 32 Daesingongwon-ro, Seo-gu, Busan 49201, Republic of Korea
| | - Junyang Jung
- Department of Biomedical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
- East-West Medical Research Institute, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
- Department of Anatomy and Neurobiology, College of Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
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Bai X, Ihara E, Hirano K, Tanaka Y, Nakano K, Kita S, Iwamoto T, Ogino H, Hirano M, Oda Y, Nakamura K, Ogawa Y. Endogenous Hydrogen Sulfide Contributes to Tone Generation in Porcine Lower Esophageal Sphincter Via Na +/Ca 2+ Exchanger. Cell Mol Gastroenterol Hepatol 2017; 5:209-221. [PMID: 29379856 PMCID: PMC5782486 DOI: 10.1016/j.jcmgh.2017.11.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 11/14/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Hydrogen sulfide (H2S) is a major physiologic gastrotransmitter. Its role in the regulation of the lower esophageal sphincter (LES) function remains unknown. The present study addresses this question. METHODS Isometric contraction was monitored in circular smooth muscle strips of porcine LES. Changes in cytosolic Ca2+ concentration ([Ca2+]i) and force were simultaneously monitored in fura-2-loaded strips with front-surface fluorometry. The contribution of endogenous H2S to LES contractility was investigated by examining the effects of inhibitors of H2S-generating enzymes, including cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, on the LES function. RESULTS Porcine LES strips myogenically maintained a tetrodotoxin-resistant basal tone. Application of AOA (cystathionine-β-synthase inhibitor) or L-aspartic acid (L-Asp; 3-mercaptopyruvate sulfurtransferase inhibitor) but not DL-PAG (cystathionine-γ-lyase inhibitor), decreased this basal tone. The relaxant effects of AOA and L-Asp were additive. Maximum relaxation was obtained by combination of 1 mM AOA and 3 mM L-Asp. Immunohistochemical analyses revealed that cystathionine-β-synthase and 3-mercaptopyruvate sulfurtransferase, but not cystathionine-γ-lyase, were expressed in porcine LES. AOA+L-Asp-induced relaxation was accompanied by a decrease in [Ca2+]i and inversely correlated with the extracellular Na+ concentration ([Na+]o) (25-137.4 mM), indicating involvement of an Na+/Ca2+ exchanger. The reduction in the basal [Ca2+]i level by AOA was significantly augmented in the antral smooth muscle sheets of Na+/Ca2+ exchanger transgenic mice compared with wild-type mice. CONCLUSIONS Endogenous H2S regulates the LES myogenic tone by maintaining the basal [Ca2+]i via Na+/Ca2+ exchanger. H2S-generating enzymes may be a potential therapeutic target for esophageal motility disorders, such as achalasia.
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Key Words
- 3MST, 3-mercaptopyruvate sulfurtransferase
- AOA, amino-oxyacetic acid
- CBS, cystathionine-β-synthase
- CCh, carbachol
- CSE, cystathionine-γ-lyase
- ES, extracellular solution
- H2S, hydrogen sulfide
- Hydrogen Sulfate
- KATP channels, ATP-sensitive K+ channels
- KES, K+ extracellular solution
- L-Asp, L-aspartic acid
- L-Cys, L-cysteine
- L-NAME, Nω-nitro-L-arginine methyl ester
- LES, lower esophageal sphincter
- Lower Esophageal Sphincter
- Myogenic Tone Regulation
- NCX, Na+/Ca2+ exchanger
- NES, normal extracellular solution
- Na+/Ca2+ Exchanger
- PAG, propargylglycine
- TEA, tetraethylammonium
- TG, transgenic
- TTX, tetrodotoxin
- [Ca2+]i, cytosolic Ca2+ concentration
- [Na+]o, extracellular Na+ concentration
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Affiliation(s)
- Xiaopeng Bai
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eikichi Ihara
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan,Correspondence Address correspondence to: Eikichi Ihara, MD, PhD, Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. fax +81-92-642-5287.Department of Medicine and Bioregulatory ScienceGraduate School of Medical SciencesKyushu University3-1-1 Maidashi, Higashi-kuFukuoka812-8582Japan
| | - Katsuya Hirano
- Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University, Kagawa Prefecture, Japan
| | - Yoshimasa Tanaka
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kayoko Nakano
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Satomi Kita
- Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan,Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
| | - Takahiro Iwamoto
- Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Haruei Ogino
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Mayumi Hirano
- Division of Molecular Cardiology, Research Institute of Angiocardiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazuhiko Nakamura
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan,Department of Molecular and Cellular Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
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Szabo C, Papapetropoulos A. International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H 2S Levels: H 2S Donors and H 2S Biosynthesis Inhibitors. Pharmacol Rev 2017; 69:497-564. [PMID: 28978633 PMCID: PMC5629631 DOI: 10.1124/pr.117.014050] [Citation(s) in RCA: 304] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Over the last decade, hydrogen sulfide (H2S) has emerged as an important endogenous gasotransmitter in mammalian cells and tissues. Similar to the previously characterized gasotransmitters nitric oxide and carbon monoxide, H2S is produced by various enzymatic reactions and regulates a host of physiologic and pathophysiological processes in various cells and tissues. H2S levels are decreased in a number of conditions (e.g., diabetes mellitus, ischemia, and aging) and are increased in other states (e.g., inflammation, critical illness, and cancer). Over the last decades, multiple approaches have been identified for the therapeutic exploitation of H2S, either based on H2S donation or inhibition of H2S biosynthesis. H2S donation can be achieved through the inhalation of H2S gas and/or the parenteral or enteral administration of so-called fast-releasing H2S donors (salts of H2S such as NaHS and Na2S) or slow-releasing H2S donors (GYY4137 being the prototypical compound used in hundreds of studies in vitro and in vivo). Recent work also identifies various donors with regulated H2S release profiles, including oxidant-triggered donors, pH-dependent donors, esterase-activated donors, and organelle-targeted (e.g., mitochondrial) compounds. There are also approaches where existing, clinically approved drugs of various classes (e.g., nonsteroidal anti-inflammatories) are coupled with H2S-donating groups (the most advanced compound in clinical trials is ATB-346, an H2S-donating derivative of the non-steroidal anti-inflammatory compound naproxen). For pharmacological inhibition of H2S synthesis, there are now several small molecule compounds targeting each of the three H2S-producing enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase. Although many of these compounds have their limitations (potency, selectivity), these molecules, especially in combination with genetic approaches, can be instrumental for the delineation of the biologic processes involving endogenous H2S production. Moreover, some of these compounds (e.g., cell-permeable prodrugs of the CBS inhibitor aminooxyacetate, or benserazide, a potentially repurposable CBS inhibitor) may serve as starting points for future clinical translation. The present article overviews the currently known H2S donors and H2S biosynthesis inhibitors, delineates their mode of action, and offers examples for their biologic effects and potential therapeutic utility.
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Affiliation(s)
- Csaba Szabo
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas (C.S.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Zografou, Greece (A.P.); and Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (A.P.)
| | - Andreas Papapetropoulos
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas (C.S.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Zografou, Greece (A.P.); and Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (A.P.)
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27
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Wei W, Wang C, Li D. The content of hydrogen sulfide in plasma of cirrhosis rats combined with portal hypertension and the correlation with indexes of liver function and liver fibrosis. Exp Ther Med 2017; 14:5022-5026. [PMID: 29201208 PMCID: PMC5704297 DOI: 10.3892/etm.2017.5133] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 09/12/2017] [Indexed: 12/15/2022] Open
Abstract
The purpose of this study is to investigate the content of hydrogen sulfide (H2S) in plasma of cirrhosis rats combined with portal hypertension and the correlation with indexes of liver function and liver fibrosis. Thirty female Sprague-Dawley rats were randomly divided into normal control group (NC), liver cirrhosis group (LC) and cirrhosis + propargylglycine (PPG) group (LC+PPG). Cirrhosis and portal hypertension were induced by carbon tetrachloride. Rats in LC+PPG group were intraperitoneally injected with H2S synthase inhibitor PPG for one week. Portal vein catheterization was used to measure portal vein pressure (PVP), and plasma H2S content was determined by deproteinization. Liver function was measured by automatic biochemical analyzer, and the fibrosis index was determined by radioimmunoassay. Real-time PCR was used to detect the expression levels of type I and type III collagen mRNA in liver tissue. Compared with NC group, levels of plasma H2S were significantly decreased (P<0.01), while PVP, alanine aminotransferase (ALT), aspartate aminotransferase (AST), laminin (LN), hyaluronic acid (HA), and expression levels of type III procollagen (PC III) and type I and type III collagen mRNAs were significantly increased in LC and LC+PPG groups (P<0.01). Compared with LC group, levels of plasma H2S were significantly decreased (P<0.01), while PVP, ALT, AST, LN, HA, and expression levels of PC III and type I and type III collagen mRNAs in LC+PPG group (P<0.05 or P<0.01). In conclusion, level of H2S was decreased and PVP was increased in cirrhosis rats, and H2S has the function of protecting liver function and anti-fibrosis.
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Affiliation(s)
- Weiwei Wei
- Department of General Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Chao Wang
- Department of General Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Dongjian Li
- Department of General Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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28
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Diligustilide releases H2S and stabilizes S-nitrosothiols in ethanol-induced lesions on rat gastric mucosa. Inflammopharmacology 2017; 26:611-619. [DOI: 10.1007/s10787-017-0392-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 08/19/2017] [Indexed: 11/25/2022]
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29
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Zhang JY, Ding YP, Wang Z, Kong Y, Gao R, Chen G. Hydrogen sulfide therapy in brain diseases: from bench to bedside. Med Gas Res 2017; 7:113-119. [PMID: 28744364 PMCID: PMC5510292 DOI: 10.4103/2045-9912.208517] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Hydrogen sulfide (H2S) has been recognized and studied for nearly 300 years, but past researches mainly focus on its toxicity effect. During the past two decades, the majority of researches have reported that H2S is a novel endogenous gaseous signal molecule in organisms, and play an important role in various systems and diseases. H2S is mainly produced by three enzymes, including cystathionine β-synthase, cystathionine γ-lyase and 3-mercaptopyruvate sulfurtransferase along with cysteine aminotransferase. H2S had been firstly reported as a neuromodulator in the brain, because of its essential role in the facilitating hippocampal long-term potentiation at physiological concentration. It is subsequently reported that H2S may have relevance to neurologic disorders through antioxidative, anti-inflammatory, anti-apoptotic and additional effects. Recent basic medical studies and preclinical studies on neurologic diseases have demonstrated that the administration of H2S at physiological or pharmacological levels attenuates brain injury. However, the neuroprotective effect of H2S is concentration-dependent, only a comparatively low dose of H2S can provide beneficial effect. Herein, we review the neuroprotevtive role of H2S therapy in brain diseases from its mechanism to clinical application in animal and human subjects, and therefore provide the potential strategies for further clinical treatment.
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Affiliation(s)
- Ju-Yi Zhang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Yi-Ping Ding
- Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Zhong Wang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Yan Kong
- Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Rong Gao
- Department of Neurosurgery, Zhangjiagang First People's Hospital, Soochow University, Zhangjiagang, Jiangsu Province, China
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.,Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.,Department of Neurosurgery, Zhangjiagang First People's Hospital, Soochow University, Zhangjiagang, Jiangsu Province, China.,Department of Neurosurgery, Huaian Hospital Affiliated of Xuzhou Medical University and Huaian Second People's Hospital, Huaian, Jiangsu Province, China
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30
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Hydrogen sulfide in paraventricular nucleus attenuates blood pressure by regulating oxidative stress and inflammatory cytokines in high salt-induced hypertension. Toxicol Lett 2017; 270:62-71. [DOI: 10.1016/j.toxlet.2017.02.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 01/22/2017] [Accepted: 02/05/2017] [Indexed: 11/21/2022]
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31
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Sun HZ, Zheng S, Lu K, Hou FT, Bi JX, Liu XL, Wang SS. Hydrogen sulfide attenuates gastric mucosal injury induced by restraint water-immersion stress via activation of K ATP channel and NF-κB dependent pathway. World J Gastroenterol 2017; 23:87-92. [PMID: 28104983 PMCID: PMC5221289 DOI: 10.3748/wjg.v23.i1.87] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Revised: 10/19/2016] [Accepted: 11/16/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the effect of hydrogen sulfide (H2S) on restraint water-immersion stress (RWIS)-induced gastric lesions in rats and the influence of adenosine triphosphate (ATP)-sensitive potassium (KATP) channels and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway on such an effect.
METHODS Male Wistar rats were randomly divided into a control group, a physiological saline (PS) group, a sodium hydrosulfide (NaHS) group, a glibenclamide (Gl) group, Gl plus NaHS group, a pyrrolidine dithiocarbamate (PDTC) group, and a PDTC plus NaHS group. Gastric mucosal injury was induced by RWIS for 3 h in rats, and gastric mucosal damage was analyzed after that. The PS, NaHS (100 μmol/kg body weight), Gl (100 μmol/kg body weight), Gl (100 μmol/kg or 150 μmol/kg body weight) plus NaHS (100 μmol/kg body weight), PDTC (100 μmol/kg body weight), and PDTC (100 μmol/kg body weight) plus NaHS (100 μmol/kg body weight) were respectively injected intravenously before RWIS.
RESULTS RWIS induced serious gastric lesions in the rats in the PS pretreatment group. The pretreatment of NaHS (a H2S donor) significantly reduced the damage induced by RWIS. The gastric protective effect of the NaHS during RWIS was attenuated by PDTC, an NF-κB inhibitor, and also by glibenclamide, an ATP-sensitive potassium channel blocker, in a dose-dependent manner.
CONCLUSION These results suggest that exogenous H2S plays a protective role against RWIS injury in rats, possibly through modulation of KATP channel opening and the NF-κB dependent pathway.
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32
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WANG XL, WANG ZY, LING JJ, ZHANG YH, YIN J. Synthesis and biological evaluation of nitric oxide (NO)-hydrogen sulfide (H 2 S) releasing derivatives of ( S )-3- n -butylphthalide as potential antiplatelet agents. Chin J Nat Med 2016; 14:946-953. [DOI: 10.1016/s1875-5364(17)30021-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Indexed: 12/17/2022]
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33
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Tomasova L, Dobrowolski L, Jurkowska H, Wróbel M, Huc T, Ondrias K, Ostaszewski R, Ufnal M. Intracolonic hydrogen sulfide lowers blood pressure in rats. Nitric Oxide 2016; 60:50-58. [DOI: 10.1016/j.niox.2016.09.007] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 09/13/2016] [Accepted: 09/20/2016] [Indexed: 02/07/2023]
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34
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Liu X, Zhang N, Ding Y, Cao D, Huang Y, Chen X, Wang R, Lu N. Hydrogen Sulfide Regulates the [Ca 2+] i Level in the Primary Medullary Neurons. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:2735347. [PMID: 27840667 PMCID: PMC5093289 DOI: 10.1155/2016/2735347] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Revised: 09/12/2016] [Accepted: 09/27/2016] [Indexed: 02/07/2023]
Abstract
In the present study, we attempted to elucidate mechanisms for the regulation of intracellular calcium levels by H2S in primary rat medullary neurons. Our results showed that NaHS significantly increased the level of [Ca2+]i in rat medullary neurons in a concentration-dependent manner. L-Cysteine and SAM significantly raised the level of [Ca2+]i in the medullary neurons while HA and/or AOAA produced a reversal effect. In addition, L-cysteine and SAM significantly increased but HA and/or AOAA decreased the production of H2S in the cultured neurons. The [Ca2+]i elevation induced by H2S was significantly diminished by EGTA-Ca2+-free solutions, and this elevation was also reduced by nifedipine or nimodipine and mibefradil, suggesting the role of L-type and/or T-type Ca2+ channels. Moreover, the effect of H2S on [Ca2+]i level in neurons was significantly attenuated by BAPTA-AM and thapsigargin, suggesting the source of Ca2+. Therefore, we concluded that both exogenous and endogenous H2S elevates [Ca2+]i level in primarily cultured rat medullary neurons via both increasing calcium influx and mobilizing intracellular Ca2+ stores from ER.
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Affiliation(s)
- Xiaoni Liu
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Nana Zhang
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yingjiong Ding
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Dongqing Cao
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Ying Huang
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xiangjun Chen
- Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Rui Wang
- The Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, ON, Canada P3E 2C6
| | - Ning Lu
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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35
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Sabino JPJ, Traslaviña GAA, Branco LG. Role of central hydrogen sulfide on ventilatory and cardiovascular responses to hypoxia in spontaneous hypertensive rats. Respir Physiol Neurobiol 2016; 231:21-7. [DOI: 10.1016/j.resp.2016.05.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 05/23/2016] [Accepted: 05/26/2016] [Indexed: 11/24/2022]
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Lee YN, Okumura K, Iwata T, Takahashi K, Hattori T, Ishida M, Sawada K. Development of an ATP and hydrogen ion image sensor using a patterned apyrase-immobilized membrane. Talanta 2016; 161:419-424. [PMID: 27769427 DOI: 10.1016/j.talanta.2016.08.070] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 08/26/2016] [Accepted: 08/26/2016] [Indexed: 01/01/2023]
Abstract
A bio-image sensor using a patterned apyrase-immobilized membrane was developed to visualize the activities of adenosine triphosphate (ATP) and H+ ion in real-time. An enzymatic membrane patterning technique was suggested to immobilize apyrase on a specific sensing area of a charge coupled device (CCD)-type image sensor. It was able to observe the spatiotemporal information of ATP and H+ ion. The smallest size of a patterned membrane is 250×250µm2. The fabrication parameters of the patterned membrane, such as its thickness and the intensity of the incident light used for photolithography, were optimized experimentally. The sensing area under the patterned apyrase-immobilized membrane revealed a linear response up to 0.6mM of ATP concentration with a sensitivity of 37.8mV/mM. Meanwhile, another sensing area without the patterned membrane measured the diffused H+ ion from nearby membranes. This diffusion characteristics were analyzed to determine a measurement time that can minimize the undesirable impact of the diffused ions. In addition, the newly developed bio-image sensor successfully reconstructed ATP and H+ ion dynamics into sequential 2-dimensional images.
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Affiliation(s)
- You-Na Lee
- Electrical & Electronic Information Eng., Toyohashi University of Technology, Hibarigaoka 1-1, Tempaku-cho, Toyohashi 441-8580, Japan.
| | - Koichi Okumura
- Electrical & Electronic Information Eng., Toyohashi University of Technology, Hibarigaoka 1-1, Tempaku-cho, Toyohashi 441-8580, Japan; Electronics-Inspired Interdisciplinary Research Institute, Toyohashi University of Technology, Hibarigaoka 1-1, Tempaku-cho, Toyohashi 441-8580, Japan
| | - Tatsuya Iwata
- Electrical & Electronic Information Eng., Toyohashi University of Technology, Hibarigaoka 1-1, Tempaku-cho, Toyohashi 441-8580, Japan
| | - Kazuhiro Takahashi
- Electrical & Electronic Information Eng., Toyohashi University of Technology, Hibarigaoka 1-1, Tempaku-cho, Toyohashi 441-8580, Japan
| | - Toshiaki Hattori
- Electrical & Electronic Information Eng., Toyohashi University of Technology, Hibarigaoka 1-1, Tempaku-cho, Toyohashi 441-8580, Japan
| | - Makoto Ishida
- Electrical & Electronic Information Eng., Toyohashi University of Technology, Hibarigaoka 1-1, Tempaku-cho, Toyohashi 441-8580, Japan; Electronics-Inspired Interdisciplinary Research Institute, Toyohashi University of Technology, Hibarigaoka 1-1, Tempaku-cho, Toyohashi 441-8580, Japan
| | - Kazuaki Sawada
- Electrical & Electronic Information Eng., Toyohashi University of Technology, Hibarigaoka 1-1, Tempaku-cho, Toyohashi 441-8580, Japan; Electronics-Inspired Interdisciplinary Research Institute, Toyohashi University of Technology, Hibarigaoka 1-1, Tempaku-cho, Toyohashi 441-8580, Japan
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H2S-induced thiol-based redox switches: Biochemistry and functional relevance for inflammatory diseases. Pharmacol Res 2016; 111:642-651. [PMID: 27468648 DOI: 10.1016/j.phrs.2016.07.026] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 07/19/2016] [Accepted: 07/22/2016] [Indexed: 02/08/2023]
Abstract
During the last decades, small inorganic molecules like reactive oxygen species (ROS), nitric oxide (NO), carbon monoxide (CO) and even the highly toxic hydrogen sulfide (H2S) have been evolved as important signaling molecules that trigger crucial cellular processes by regulating the activity of kinases, phosphatases and transcription factors. These redox molecules use similar target structures and therefore, the composition of the complex "redox environment" determines the final outcome of signaling processes and may subsequently also affect the behavior of a cell in an inflammatory environment. Here, we discuss the role of H2S in this complex interplay with a focus on the transcription factors Nrf2 and NFκB.
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38
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Mauretti A, Neri A, Kossover O, Seliktar D, Nardo PD, Melino S. Design of a Novel Composite H2 S-Releasing Hydrogel for Cardiac Tissue Repair. Macromol Biosci 2016; 16:847-58. [PMID: 26857526 DOI: 10.1002/mabi.201500430] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Revised: 01/12/2016] [Indexed: 12/21/2022]
Abstract
The design of 3D scaffolds is a crucial step in the field of regenerative medicine. Scaffolds should be degradable and bioresorbable as well as display good porosity, interconnecting pores, and topographic features; these properties favour tissue integration and vascularization. These requirements could be fulfilled by hybrid hydrogels using a combination of natural and synthetic components. Here, the mechanical and biological properties of a polyethylene glycol-fibrinogen hydrogel (PFHy) are improved in order to favour the proliferation and differentiation of human Sca-1(pos) cardiac progenitor cells (hCPCs). PFHys are modified by embedding air- or perfluorohexane-filled bovine serum albumin microbubbles (MBs) and characterized. Changes in cell morphology are observed in MBs-PFHys, suggesting that MBs could enhance the formation of bundles of cells and influence the direction of the spindle growth. The properties of MBs as carriers of active macromolecules are also exploited. For the first time, enzyme-coated MBs have been used as systems for the production of hydrogen sulfide (H2 S)-releasing scaffolds. Novel H2 S-releasing PFHys are produced, which are able to improve the growth of hCPCs. This novel 3D cell-scaffold system will allow the assessment of the effects of H2 S on the cardiac muscle regeneration with its potential applications in tissue repair.
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Affiliation(s)
- Arianna Mauretti
- Department of Sciences and Chemical Technologies, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133, Rome, Italy
| | - Annalisa Neri
- Department of Sciences and Chemical Technologies, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133, Rome, Italy
| | - Olga Kossover
- Department of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa, 32000, Israel
| | - Dror Seliktar
- Department of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa, 32000, Israel
| | - Paolo Di Nardo
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
| | - Sonia Melino
- Department of Sciences and Chemical Technologies, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133, Rome, Italy
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Pharmacological evidence that NaHS inhibits the vasopressor responses induced by stimulation of the preganglionic sympathetic outflow in pithed rats. Eur J Pharmacol 2016; 770:40-5. [DOI: 10.1016/j.ejphar.2015.11.057] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Revised: 11/25/2015] [Accepted: 11/27/2015] [Indexed: 11/18/2022]
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40
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Malik R, Ferguson AV. Hydrogen sulfide depolarizes neurons in the nucleus of the solitary tract of the rat. Brain Res 2015; 1633:1-9. [PMID: 26721687 DOI: 10.1016/j.brainres.2015.12.029] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 10/28/2015] [Accepted: 12/15/2015] [Indexed: 12/17/2022]
Abstract
Hydrogen sulfide (H2S) is a gasotransmitter that has been described to affect the membrane potential of neurons in a number of brain areas. Using whole cell patch-clamp electrophysiological techniques, we investigated the effects of H2S on the membrane potential of neurons in the nucleus of the solitary tract (NTS). Whole cell patch clamp recordings were obtained from 300 µm coronal NTS brain slices and bath application of the H2S donor, sodium hydrosulfide (NaHS)(1mM, 5mM and 10mM) was shown to have clear concentration-dependent, reversible, depolarizing effects on the membrane potential of 95% of neurons tested (72/76), an effect which in 64% (46/72) of these responding neurons was followed by a hyperpolarization. In the presence of the voltage-gated sodium channel blocker tetrodotoxin (TTX) and the glutamate receptor antagonist kynurenic acid (KA), these depolarizing effects of 5 mM NaHS (5.0 ± 2.2 mV (n=7)) were still observed, although they were significantly reduced compared to regular aCSF (7.7 ± 2.0 mV (n=7), p*<0.05, paired t-test). We also demonstrated that hyperpolarizations in response to 5mM NaHS resulted from modulation of the KATP channel with recordings showing that following KATP channel block with glibenclamide these hyperpolarizing effects were abolished (Control -7.9 ± 1.2 mV, Glibenclamide -1.9 ± 0.9 mV (n=8) p<0.05, paired t-test). This study has for the first time described post-synaptic effects of this gasotransmitter on the membrane potential of NTS neurons and thus implicates this transmitter in regulating the diverse autonomic systems controlled by the NTS.
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Affiliation(s)
- Rishi Malik
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada K7L 3N6
| | - Alastair V Ferguson
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada K7L 3N6.
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41
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Yanchuk PI, Slobodianyk LA. [THE ROLE OF HYDROGEN SULFIDE IN REGULATION OF CIRCULATION BLOOD LIVER]. ACTA ACUST UNITED AC 2015; 61:28-34. [PMID: 26495733 DOI: 10.15407/fz61.03.028] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
It was shown in acute experiments on laboratory rats that intraportalinjectionof hydrogen sulfide's precursor L-cysteine (15 mg/kg)caused dilatation of the intrahepatic vessels. As a result, systemic blood pressure (SBP) and blood pressure in the portal vein (PVP) significantly decreased on 17,6 and 24,5%, respectively, and the rate of local blood flow in the liver (LF) and its blood filling (BF) increased on 28,2 and 24,4% respectively. Application of hydrogen sulfide donor NaHS (7 mg/kg) resulted in similarly directed changes: SBP and PVP decreased on 20,8% i 26,2% respectively,LF and BF increased on 16,4% and 30,9% respectively. Application of L-cysteine in the conditions of tsystationin-gamma-lyase blockade by LD-proparhilhlitsyn led to an increase in SBP on 20,4 % and PVP on 26,6% and a decrease of BF on 21,5% and LF in the liver on 11,7% comparing with baseline values of these parameters. So, blockade of tsystationin-gamma-lyase not only completely removed the effects of L-cysteine, but also inhibited synthesis of H2S from its endogenous predecessors,which led to vasoconstriction of liver's blood vessels and, consequently, to an increase of blood pressure and a decrease of liver blood flow rat's and volume of blood deposited in liver.
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42
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Ruginsk SG, Mecawi ADS, da Silva MP, Reis WL, Coletti R, de Lima JBM, Elias LLK, Antunes-Rodrigues J. Gaseous modulators in the control of the hypothalamic neurohypophyseal system. Physiology (Bethesda) 2015; 30:127-38. [PMID: 25729058 DOI: 10.1152/physiol.00040.2014] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) are gaseous molecules produced by the brain. Within the hypothalamus, gaseous molecules have been highlighted as autocrine and paracrine factors regulating endocrine function. Therefore, in the present review, we briefly discuss the main findings linking NO, CO, and H2S to the control of body fluid homeostasis at the hypothalamic level, with particular emphasis on the regulation of neurohypophyseal system output.
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Affiliation(s)
- Silvia Graciela Ruginsk
- Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil; and
| | - Andre de Souza Mecawi
- Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil; and
| | - Melina Pires da Silva
- Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil; and
| | - Wagner Luis Reis
- Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil; and Physiology Department, Georgia Regents University, Augusta, Georgia
| | - Ricardo Coletti
- Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil; and
| | | | - Lucila Leico Kagohara Elias
- Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil; and
| | - Jose Antunes-Rodrigues
- Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil; and
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43
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Wang X, Wang L, Sheng X, Huang Z, Li T, Zhang M, Xu J, Ji H, Yin J, Zhang Y. Design, synthesis and biological evaluation of hydrogen sulfide releasing derivatives of 3-n-butylphthalide as potential antiplatelet and antithrombotic agents. Org Biomol Chem 2015; 12:5995-6004. [PMID: 24988475 DOI: 10.1039/c4ob00830h] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
In the present study, a series of hydrogen sulfide (H2S) releasing derivatives (8a–g and 9a–f) of 3-n-butylphthalide (NBP) were designed, synthesized and biologically evaluated. The most promising compound 8e significantly inhibited the adenosine diphosphate (ADP) and arachidonic acid (AA)-induced platelet aggregation in vitro, superior to NBP, ticlopidine hydrochloride and aspirin. Furthermore, 8e could slowly produce moderate levels of H2S in vitro, which could be beneficial for improving cardiovascular and cerebral circulation. Most importantly, 8e protected against the collagen and adrenaline induced thrombosis in mice, and exhibited greater antithrombotic activity than NBP and aspirin in rats. Overall, 8e could warrant further investigation for the treatment of thrombosis-related ischemic stroke.
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Affiliation(s)
- Xiaoli Wang
- The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Lihu Avenue 1800, Wuxi 214122, P. R. China.
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Yu H, Xu H, Liu X, Zhang N, He A, Yu J, Lu N. Superoxide Mediates Depressive Effects Induced by Hydrogen Sulfide in Rostral Ventrolateral Medulla of Spontaneously Hypertensive Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2015:927686. [PMID: 26078823 PMCID: PMC4442288 DOI: 10.1155/2015/927686] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 01/04/2015] [Accepted: 01/04/2015] [Indexed: 12/02/2022]
Abstract
Hydrogen sulfide (H2S) plays a crucial role in the regulation of blood pressure and oxidative stress. In the present study, we tested the hypothesis that H2S exerts its cardiovascular effects by reducing oxidative stress via inhibition of NADPH oxidase activity in the rostral ventrolateral medulla (RVLM). We examined cell distributions of cystathionine-β-synthase (CBS) and effects of H2S on reactive oxygen species (ROS) and mean arterial blood pressure (MAP) in spontaneously hypertensive rats (SHRs). We found that CBS was expressed in neurons of the RVLM, and the expression was lower in SHRs than in Wistar-Kyoto rats. Microinjection of NaHS (H2S donor), S-adenosyl-l-methionine (SAM, a CBS agonist), or Apocynin (NADPH oxidase inhibitor) into the RVLM reduced the ROS level, NADPH oxidase activity, and MAP, whereas microinjection of hydroxylamine hydrochloride (HA, a CBS inhibitor) increased MAP. Furthermore, intracerebroventricular infusion of NaHS inhibited phosphorylation of p47(phox), a key step of NADPH oxidase activation. Since decreasing ROS level in the RVLM reduces MAP and heart rate and increasing H2S reduces ROS production, we conclude that H2S exerts an antihypertensive effect via suppressing ROS production. H2S, as an antioxidant, may be a potential target for cardiovascular diseases.
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Affiliation(s)
- Haiyun Yu
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Yixueyuan Road 138, Xuhui District, Shanghai 200032, China
- Beijing Electric Power Hospital, Capital Medical University, China
| | - Haiyan Xu
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Yixueyuan Road 138, Xuhui District, Shanghai 200032, China
| | - Xiaoni Liu
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Yixueyuan Road 138, Xuhui District, Shanghai 200032, China
| | - Nana Zhang
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Yixueyuan Road 138, Xuhui District, Shanghai 200032, China
| | - Anqi He
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Yixueyuan Road 138, Xuhui District, Shanghai 200032, China
| | - Jerry Yu
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Yixueyuan Road 138, Xuhui District, Shanghai 200032, China
- Department of Medicine, University of Louisville, KY, USA
| | - Ning Lu
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Yixueyuan Road 138, Xuhui District, Shanghai 200032, China
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45
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Sun HZ, Yu KH, Ai HB. Role of hydrogen sulfide within the dorsal motor nucleus of the vagus in the control of gastric function in rats. Neurogastroenterol Motil 2015; 27:618-26. [PMID: 25773343 DOI: 10.1111/nmo.12530] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Accepted: 01/22/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND Hydrogen sulfide (H2 S) is a gaseous messenger and serves as an important neuromodulator in the central nervous system. This study aimed to clarify the role of H2 S within the dorsal motor nucleus of the vagus (DMV) in the control of gastric function in rats. METHODS Cystathionine β-synthetase (CBS) is an important generator of endogenous H2 S in the brain. We investigated the distribution of CBS in the DMV using immunohistochemical method, and the effects of H2 S on gastric motility and on gastric acid secretion. KEY RESULTS CBS-immunoreactive (IR) neurons were detected in the rostral, intermediate and caudal DMV, with the highest number of CBS-IR neurons in the caudal DMV, and the lowest in the intermediate DMV. We also found that microinjection of the exogenous H2 S donor NaHS (0.04 and 0.08 mol/L; 0.1 μL; n = 6; p < 0.05) into the DMV significantly inhibited gastric motility with a dose-dependent trend, and promoted gastric acid secretion in Wistar rats. Microinjection of the same volume of physiological saline (PS; 0.1 μL, n = 6, p > 0.05) at the same location did not noticeably change gastric motility and acid secretion. CONCLUSIONS & INFERENCES The data from these experiments suggest that the CBS that produces H2 S is present in the DMV, and microinjection of NaHS into the DMV inhibited gastric motility and enhanced gastric acid secretion in rats.
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Affiliation(s)
- H-Z Sun
- College of Life Science, Qi Lu Normal University, Jinan, China
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46
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Hydrogen sulfide-based therapeutics: exploiting a unique but ubiquitous gasotransmitter. Nat Rev Drug Discov 2015; 14:329-45. [PMID: 25849904 DOI: 10.1038/nrd4433] [Citation(s) in RCA: 624] [Impact Index Per Article: 62.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Hydrogen sulfide (H2S) has become recognized as an important signalling molecule throughout the body, contributing to many physiological and pathological processes. In recent years, improved methods for measuring H2S levels and the availability of a wider range of H2S donors and more selective inhibitors of H2S synthesis have helped to more accurately identify the many biological effects of this highly reactive gaseous mediator. Animal studies of several H2S-releasing drugs have demonstrated considerable promise for the safe treatment of a wide range of disorders. Several such drugs are now in clinical trials.
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47
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Kulkarni-Chitnis M, Njie-Mbye YF, Mitchell L, Robinson J, Whiteman M, Wood ME, Opere CA, Ohia SE. Inhibitory action of novel hydrogen sulfide donors on bovine isolated posterior ciliary arteries. Exp Eye Res 2015; 134:73-9. [PMID: 25845295 DOI: 10.1016/j.exer.2015.04.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 03/02/2015] [Accepted: 04/02/2015] [Indexed: 01/11/2023]
Abstract
In the present study, we investigate the inhibitory effect of novel H2S donors, AP67 and AP72 on isolated bovine posterior ciliary arteries (PCAs) under conditions of tone induced by an adrenoceptor agonist. Furthermore, we examined the possible mechanisms underlying the AP67- and AP72-induced relaxations. Isolated bovine PCA were set up for measurement of isometric tension in organ baths containing oxygenated Krebs solution. The relaxant action of H2S donors was studied on phenylephrine-induced tone in the absence or presence of enzyme inhibitors for the following pathways: cyclooxygenase (COX); H2S; nitric oxide and the ATP-sensitive K(+) (KATP) channel. The H2S donors, NaSH (1 nM - 10 μM), AP67 (1 nM - 10 μM) and AP72 (10 nM - 1 μM) elicited a concentration-dependent relaxation of phenylephrine-induced tone in isolated bovine PCA. While the COX inhibitor, flurbiprofen (3 μM) blocked significantly (p < 0.05) the inhibitory response elicited by AP67, it had no effect on relaxations induced by NaSH and AP72. Both aminooxyacetic acid (30 μM) and propargylglycine (1 mM), enzyme inhibitors of H2S biosynthesis caused significant (p < 0.05) rightward shifts in the concentration-response curve to AP67 and AP72. Furthermore, the KATP channel antagonist, glibenclamide (300 μM) and the NO synthase inhibitor, l-NAME (100 μM) significantly attenuated (p < 0.05) the relaxation effect induced by AP67 and AP72 on PCA. We conclude that H2S donors can relax pre-contracted isolated bovine PCA, an effect dependent on endogenous production of H2S. The inhibitory action of only AP67 on pre-contracted PCA may involve the production of inhibitory endogenous prostanoids. Furthermore, the observed inhibitory action of H2S donors on PCA may depend on the endogenous biosynthesis of NO and by an action of KATP channels.
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Affiliation(s)
- Madhura Kulkarni-Chitnis
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA
| | - Ya Fatou Njie-Mbye
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA
| | - Leah Mitchell
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA
| | - Jenaye Robinson
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA
| | - Matthew Whiteman
- University of Exeter Medical School, St. Luke's Campus, Magdalen Road, Exeter EX1 2LU, UK
| | - Mark E Wood
- Department of Biosciences, College of Life and Environmental Sciences, University of Exeter, UK
| | - Catherine A Opere
- Department of Pharmacy Sciences, School of Pharmacy and Health Professions, Creighton University, Omaha, NE 68178, USA
| | - Sunny E Ohia
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA.
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48
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Duan XC, Guo R, Liu SY, Xiao L, Xue HM, Guo Q, Jin S, Wu YM. Gene transfer of cystathionine β-synthase into RVLM increases hydrogen sulfide-mediated suppression of sympathetic outflow via KATP channel in normotensive rats. Am J Physiol Heart Circ Physiol 2015; 308:H603-11. [PMID: 25599573 DOI: 10.1152/ajpheart.00693.2014] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Hydrogen sulfide has been shown to have a sympathoinhibitory effect in the rostral ventrolateral medulla (RVLM). The present study examined the function of cystathionine β-synthase (CBS)/hydrogen sulfide system in the RVLM, which plays a crucial role in the control of blood pressure and sympathetic nerve activity. Adenovirus vectors encoding CBS (AdCBS) or enhanced green fluorescent protein (AdEGFP) were transfected into the RVLM in normotensive rats. Identical microinjection of AdCBS into the RVLM had no effect on systolic blood pressure and heart rate (HR) in conscious rats. Acute experiments were performed at day 7 after gene transfer in anesthetized rats. Microinjection of the CBS inhibitors hydroxylamine (HA) or amino-oxyacetate into the RVLM produced an increase in the renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and HR. There was a potentiation of the increases in RSNA, MAP, and HR because of the CBS inhibitors in AdCBS-injected rats compared with AdEGFP-injected rats. Pretreatment with pinacidil, a ATP-sensitive potassium (KATP) channel activator, abolished the effects of HA in two groups. Microinjection of glibenclamide, a KATP channel blocker, produced increases in RSNA, MAP, and HR in AdCBS-injected rats. No changes in behavior were observed in AdEGFP-injected rats. Furthermore, Western blot analysis indicated an increase in the expression of sulfonylurea receptor 2 and inward rectifier K(+) 6.1 in AdCBS-injected rats. These results suggest that the increase in KATP channels in the RVLM may be responsible for the greater sympathetic outflow and pressor effect of HA in AdCBS-injected rats compared with AdEGFP-injected rats.
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Affiliation(s)
- Xiao-cui Duan
- Department of Physiology, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, China; Hebei Key Lab of Laboratory Animal Science, Department of Laboratory Animal Science, Hebei Medical University, Shijiazhuang, China; and
| | - Rong Guo
- Dean's Office of the Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Shang-yu Liu
- Department of Physiology, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, China
| | - Lin Xiao
- Department of Physiology, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, China
| | - Hong-mei Xue
- Department of Physiology, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, China
| | - Qi Guo
- Department of Physiology, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, China
| | - Sheng Jin
- Department of Physiology, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, China
| | - Yu-ming Wu
- Department of Physiology, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, China;
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49
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Coletti R, Almeida-Pereira G, Elias LLK, Antunes-Rodrigues J. Effects of hydrogen sulfide (H2S) on water intake and vasopressin and oxytocin secretion induced by fluid deprivation. Horm Behav 2015; 67:12-20. [PMID: 25436932 DOI: 10.1016/j.yhbeh.2014.11.008] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 10/10/2014] [Accepted: 11/11/2014] [Indexed: 10/24/2022]
Abstract
During dehydration, responses of endocrine and autonomic control systems are triggered by central and peripheral osmoreceptors and peripheral baroreceptors to stimulate thirst and sodium appetite. Specifically, it is already clear that endocrine system acts by secreting vasopressin (AVP), oxytocin (OT) and angiotensin II (ANG II), and that gaseous molecules, such as nitric oxide (NO) and carbon monoxide (CO), play an important role in modulating the neurohypophyseal secretion as well as ANG II production and thirst. More recently, another gas-hydrogen sulfide (H2S)-has been studied as a neuronal modulator, which is involved in hypothalamic control of blood pressure, heart frequency and temperature. In this study, we aimed to investigate whether H2S and its interaction with NO system could participate in the modulatory responses of thirst and hormonal secretion induced by fluid deprivation. For this purpose, Wistar male rats were deprived of water for 12 and 24h, and the activity of sulfide-generating enzymes was measured. Surprisingly, 24-h water deprivation increased the activity of sulfide-generating enzymes in the medial basal hypothalamus (MBH). Furthermore, the icv injection of sodium sulfide (Na2S, 260nmol), a H2S donor, reduced water intake, increased AVP, OT and CORT plasma concentrations and decreased MBH nitrate/nitrite (NOX) content of 24-h water-deprived animals compared to controls. We thus suggest that H2S system has an important role in the modulation of hormonal and behavioral responses induced by 24-h fluid deprivation.
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Affiliation(s)
- R Coletti
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - G Almeida-Pereira
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - L L K Elias
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - J Antunes-Rodrigues
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
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50
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Branco LG, Soriano RN, Steiner AA. Gaseous Mediators in Temperature Regulation. Compr Physiol 2014; 4:1301-38. [DOI: 10.1002/cphy.c130053] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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