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Lu J, Wang J, Ni H, Li B, Yang J, Zhu J, Qian J, Gao R, Xu R. Activation of the melanocortin-1 receptor attenuates neuronal apoptosis after traumatic brain injury by upregulating Merlin expression. Brain Res Bull 2024; 207:110870. [PMID: 38185389 DOI: 10.1016/j.brainresbull.2024.110870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 12/30/2023] [Accepted: 01/04/2024] [Indexed: 01/09/2024]
Abstract
Traumatic brain injury (TBI) is a common disease worldwide with high mortality and disability rates. Besides the primary mechanical injury, the secondary injury associated with TBI can also induce numerous pathological changes, such as brain edema, nerve apoptosis, and neuroinflammation, which further aggravates neurological dysfunction and even causes the death due to the primary injury. Among them, neuronal apoptosis is a key link in the injury. Melanocortin-1 receptor (MC1R) is a G protein coupled receptor, belonging to the melanocortin receptor family. Studies have shown that activation of MC1R inhibits oxidative stress and apoptosis, and confers neuroprotective effects against various neurological diseases. Merlin is a protein product of the NF2 gene, which is widely expressed in the central nervous system (CNS) of mice, rats, and humans. Studies have indicated that Merlin is associated with MC1R. In this study, we explored the anti-apoptotic effects and potential mechanisms of MC1R. A rat model of TBI was established through controlled cortical impact. The MC1R-specific agonist Nle4-D-Phe7-α-Melanocyte (NDP-MSH) and the inhibitor MSG-606 were employed to explore the effects of MC1R and Merlin following TBI and investigated the associated mechanisms. The results showed that the expression levels of MC1R and Merlin were upregulated after TBI, and activation of MC1R promoted Merlin expression. Further, we found that MC1R activation significantly improved neurological dysfunction and reduced brain edema and neuronal apoptosis induced by TBI in rats. Mechanistically, its neuroprotective function and anti-apoptotic were partly associated with MC1R activation. In conclusion, we demonstrated that MC1R activation after TBI may inhibit apoptosis and confer neuroprotection by upregulating the expression of Merlin.
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Affiliation(s)
- Jinqi Lu
- Department of Pathology, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China
| | - Jin Wang
- Department of Orthopaedic Surgery, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China
| | - Haibo Ni
- Department of Neurosurgery, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China
| | - Bing Li
- Department of Neurosurgery, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China
| | - Jingjing Yang
- Department of Pathology, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China
| | - Jie Zhu
- Department of Pathology, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China
| | - Jie Qian
- Department of Pathology, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China
| | - Rong Gao
- Department of Neurosurgery, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China.
| | - Rong Xu
- Department of Pathology, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China.
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Dinparastisaleh R, Mirsaeidi M. Antifibrotic and Anti-Inflammatory Actions of α-Melanocytic Hormone: New Roles for an Old Player. Pharmaceuticals (Basel) 2021; 14:ph14010045. [PMID: 33430064 PMCID: PMC7827684 DOI: 10.3390/ph14010045] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 01/04/2021] [Accepted: 01/06/2021] [Indexed: 12/16/2022] Open
Abstract
The melanocortin system encompasses melanocortin peptides, five receptors, and two endogenous antagonists. Besides pigmentary effects generated by α-Melanocytic Hormone (α-MSH), new physiologic roles in sexual activity, exocrine secretion, energy homeostasis, as well as immunomodulatory actions, exerted by melanocortins, have been described recently. Among the most common and burdensome consequences of chronic inflammation is the development of fibrosis. Depending on the regenerative capacity of the affected tissue and the quality of the inflammatory response, the outcome is not always perfect, with the development of some fibrosis. Despite the heterogeneous etiology and clinical presentations, fibrosis in many pathological states follows the same path of activation or migration of fibroblasts, and the differentiation of fibroblasts to myofibroblasts, which produce collagen and α-SMA in fibrosing tissue. The melanocortin agonists might have favorable effects on the trajectories leading from tissue injury to inflammation, from inflammation to fibrosis, and from fibrosis to organ dysfunction. In this review we briefly summarized the data on structure, receptor signaling, and anti-inflammatory and anti-fibrotic properties of α-MSH and proposed that α-MSH analogues might be promising future therapeutic candidates for inflammatory and fibrotic diseases, regarding their favorable safety profile.
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Affiliation(s)
- Roshan Dinparastisaleh
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21218, USA;
| | - Mehdi Mirsaeidi
- Division of Pulmonary and Critical Care, University of Miami, Miami, FL 33146, USA
- Correspondence: ; Tel.: +1-305-243-1377
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Alawamlh OAH, Flannigan R, Hayden R, Goldstein M, Li PS, Lee RK. Testicular Torsion and Spermatogenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1288:287-306. [PMID: 34453742 DOI: 10.1007/978-3-030-77779-1_14] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Testicular torsion (TT) is a common urologic emergency that can occur at any age. It is most common in newborns and during puberty. Prompt evaluation and management is required to salvage the testis following an episode of torsion. TT brings about damage to testicular tissue and spermatogenesis through various hypothesized mechanisms; however there is a consensus that the effects of ischemia, ischemia-reperfusion injury, and oxidative stress account for the most destructive effects. Numerous studies have examined the effects of various agents and therapies in limiting the effects of TT on the testis.
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Affiliation(s)
- Omar Al Hussein Alawamlh
- James Buchanan Brady Foundation, Department of Urology, Weill Cornell Medical College of Cornell University, New York, NY, USA
| | - Ryan Flannigan
- James Buchanan Brady Foundation, Department of Urology, Weill Cornell Medical College of Cornell University, New York, NY, USA
| | - Russell Hayden
- James Buchanan Brady Foundation, Department of Urology, Weill Cornell Medical College of Cornell University, New York, NY, USA
| | - Marc Goldstein
- James Buchanan Brady Foundation, Department of Urology, Weill Cornell Medical College of Cornell University, New York, NY, USA
| | - Philip S Li
- James Buchanan Brady Foundation, Department of Urology, Weill Cornell Medical College of Cornell University, New York, NY, USA
| | - Richard K Lee
- James Buchanan Brady Foundation, Department of Urology, Weill Cornell Medical College of Cornell University, New York, NY, USA.
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Wei SM, Wang RY, Chen YS. Sesamol Protects Testis from Ischemia-Reperfusion Injury through Scavenging Reactive Oxygen Species and Upregulating CREM τ Expression. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:9043806. [PMID: 32655774 PMCID: PMC7320277 DOI: 10.1155/2020/9043806] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 05/25/2020] [Accepted: 06/01/2020] [Indexed: 02/06/2023]
Abstract
Testicular torsion/detorsion-induced damage is considered as a typical ischemia-reperfusion injury attributed to excessive reactive oxygen species (ROS) production. ROS may regulate many genes whose expression affects cell-cycle regulation, cell proliferation, and apoptosis. The cAMP-responsive element modulator-τ (CREMτ) gene expression in the testis is essential for normal germ cell differentiation. The present study was aimed at investigating the effect of sesamol, a powerful antioxidant, on testicular ischemia-reperfusion injury and related mechanisms in an experimental testicular torsion-detorsion rat model. The type of our study was a randomized controlled trial. Sixty rats were randomly divided into the following 3 groups: (1) sham-operated control group (n = 20), (2) testicular ischemia-reperfusion group (n = 20), and (3) testicular ischemia-reperfusion+sesamol-treated group (n = 20). Testicular ischemia-reperfusion was induced by left testicular torsion (720° rotation in a counterclockwise direction) for 2 hours, followed by detorsion. Orchiectomy was performed at 4 hours or 3 months after detorsion. The testis was obtained for the analysis of the following parameters, including malondialdehyde level (a sensitive indicator of ROS), CREMτ expression, and spermatogenesis. In the testicular ischemia-reperfusion group, the malondialdehyde level was significantly increased with a concomitant significant decrease in CREMτ expression and spermatogenesis in ipsilateral testis. These results suggest that overproduction of ROS after testicular ischemia-reperfusion may downregulate CREMτ expression, which causes spermatogenic injury. Sesamol treatment resulted in a significant reduction in the malondialdehyde level and significant increase in CREMτ expression and spermatogenesis in ipsilateral testis. These data support the above suggestion. Our study shows that sesamol can attenuate testicular ischemia-reperfusion injury through scavenging ROS and upregulating CREMτ expression.
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Affiliation(s)
- Si-Ming Wei
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou City, Zhejiang Province 310015, China
- School of Nursing, Zhejiang Chinese Medical University, Hangzhou City, Zhejiang Province 310053, China
| | - Rong-Yun Wang
- School of Nursing, Zhejiang Chinese Medical University, Hangzhou City, Zhejiang Province 310053, China
| | - Yan-Song Chen
- Department of Orthopedics, Zhejiang Xiaoshan Hospital, Hangzhou City, Zhejiang Province 311200, China
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang Chinese Medical University (Xinhua Hospital of Zhejiang Province), Hangzhou City, Zhejiang Province 310005, China
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NDP-MSH binding melanocortin-1 receptor ameliorates neuroinflammation and BBB disruption through CREB/Nr4a1/NF-κB pathway after intracerebral hemorrhage in mice. J Neuroinflammation 2019; 16:192. [PMID: 31660977 PMCID: PMC6816206 DOI: 10.1186/s12974-019-1591-4] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 09/20/2019] [Indexed: 12/22/2022] Open
Abstract
Background Neuroinflammation and blood-brain barrier (BBB) disruption are two vital mechanisms of secondary brain injury following intracerebral hemorrhage (ICH). Recently, melanocortin-1 receptor (Mc1r) activation by Nle4-D-Phe7-α-MSH (NDP-MSH) was shown to play a neuroprotective role in an experimental autoimmune encephalomyelitis (EAE) mouse model. This study aimed to investigate whether NDP-MSH could alleviate neuroinflammation and BBB disruption after experimental ICH, as well as the potential mechanisms of its neuroprotective roles. Methods Two hundred and eighteen male C57BL/6 mice were subjected to autologous blood-injection ICH model. NDP-MSH, an agonist of Mc1r, was administered intraperitoneally injected at 1 h after ICH insult. To further explore the related protective mechanisms, Mc1r small interfering RNA (Mc1r siRNA) and nuclear receptor subfamily 4 group A member 1 (Nr4a1) siRNA were administered via intracerebroventricular (i.c.v) injection before ICH induction. Neurological test, BBB permeability, brain water content, immunofluorescence staining, and Western blot analysis were implemented. Results The Expression of Mc1r was significantly increased after ICH. Mc1r was mainly expressed in microglia, astrocytes, and endothelial cells following ICH. Treatment with NDP-MSH remarkably improved neurological function and reduced BBB disruption, brain water content, and the number of microglia in the peri-hematoma tissue after ICH. Meanwhile, the administration of NDP-MSH significantly reduced the expression of p-NF-κB p65, IL-1β, TNF-α, and MMP-9 and increased the expression of p-CREB, Nr4a1, ZO-1, occludin, and Lama5. Inversely, the knockdown of Mc1r or Nr4a1 abolished the neuroprotective effects of NDP-MSH. Conclusions Taken together, NDP-MSH binding Mc1r attenuated neuroinflammation and BBB disruption and improved neurological deficits, at least in part through CREB/Nr4a1/NF-κB pathway after ICH.
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Hu Y, Xu Y. Relationship between interleukin‐6 and brain ischemia. IBRAIN 2019. [DOI: 10.1002/j.2769-2795.2019.tb00039.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
- Yue Hu
- Department of AnesthesiologyThe First People's Hospital of Shuangliu DistrictChengduSichuanChina
| | - Yang Xu
- Institute of Neurological Disease, Translational Neuroscience Center, West China Hospital, Sichuan UniversityChengduChina
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Szokol M, Priksz D, Bombicz M, Varga B, Kovacs A, Fulop GA, Csipo T, Posa A, Toth A, Papp Z, Szilvassy Z, Juhasz B. Long Term Osmotic Mini Pump Treatment with Alpha-MSH Improves Myocardial Function in Zucker Diabetic Fatty Rats. Molecules 2017; 22:molecules22101702. [PMID: 29023410 PMCID: PMC6151765 DOI: 10.3390/molecules22101702] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Accepted: 10/03/2017] [Indexed: 01/20/2023] Open
Abstract
The present investigation evaluates the cardiovascular effects of the anorexigenic mediator alpha-melanocyte stimulating hormone (MSH), in a rat model of type 2 diabetes. Osmotic mini pumps delivering MSH or vehicle, for 6 weeks, were surgically implanted in Zucker Diabetic Fatty (ZDF) rats. Serum parameters, blood pressure, and weight gain were monitored along with oral glucose tolerance (OGTT). Echocardiography was conducted and, following sacrifice, the effects of treatment on ischemia/reperfusion cardiac injury were assessed using the isolated working heart method. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was measured to evaluate levels of oxidative stress, and force measurements were performed on isolated cardiomyocytes to determine calcium sensitivity, active tension and myofilament co-operation. Vascular status was also evaluated on isolated arterioles using a contractile force measurement setup. The echocardiographic parameters ejection fraction (EF), fractional shortening (FS), isovolumetric relaxation time (IVRT), mitral annular plane systolic excursion (MAPSE), and Tei-index were significantly better in the MSH-treated group compared to ZDF controls. Isolated working heart aortic and coronary flow was increased in treated rats, and higher Hill coefficient indicated better myofilament co-operation in the MSH-treated group. We conclude that MSH improves global heart functions in ZDF rats, but these effects are not related to the vascular status.
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Affiliation(s)
- Miklos Szokol
- Department of Cardiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
| | - Daniel Priksz
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
| | - Mariann Bombicz
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
| | - Balazs Varga
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
| | - Arpad Kovacs
- Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
| | - Gabor Aron Fulop
- Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
| | - Tamas Csipo
- Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
| | - Aniko Posa
- Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, H-6720 Szeged, Hungary.
| | - Attila Toth
- Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
| | - Zoltan Papp
- Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
| | - Zoltan Szilvassy
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
| | - Bela Juhasz
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
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Vaos G, Zavras N. Antioxidants in experimental ischemia-reperfusion injury of the testis: Where are we heading towards? World J Methodol 2017; 7:37-45. [PMID: 28706858 PMCID: PMC5489422 DOI: 10.5662/wjm.v7.i2.37] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 04/07/2017] [Accepted: 05/15/2017] [Indexed: 02/06/2023] Open
Abstract
Testicular torsion (TT) is a medical emergency that primary affects newborns and young adolescents. It causes testicular injury due to the torsion of the spermatic cord and its components, initially in the venous blood flow and finally in the arterial blood flow. Prompt diagnosis and early surgical management are necessary in managing this urgent situation. The process of the pathophysiological events in ischemia-reperfusion is multifactorial and deals with the perception of the oxidative stress responsible for the consequences of ischemia/reperfusion (I/R) stress following TT. Duration and severity of torsion also play a significant role in the oxidative stress. A detrimental result of the defense system of the testes takes place resulting finally in testicular atrophy and impaired function. Antioxidant factors have been experimentally studied in an effort to front this state. They have been classified as endogenous or exogenous antioxidants. Endogenous antioxidants comprise a structure of enzymic enzymatic and non-enzymic enzymatic particles presented within cytoplasm and numerous other subunits in the cells. Exogenous antioxidants include a variety of natural and pharmaceutical agents that may prevent or ameliorate the harmful effects of I/R injury. In this study we review those factors and their ability to enhance the oxidative status of the testis. A feature insight into where we are heading is attempted.
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Arena S, Iacona R, Antonuccio P, Russo T, Salvo V, Gitto E, Impellizzeri P, Romeo C. Medical perspective in testicular ischemia-reperfusion injury. Exp Ther Med 2017; 13:2115-2122. [PMID: 28565817 DOI: 10.3892/etm.2017.4289] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 01/06/2017] [Indexed: 01/01/2023] Open
Abstract
Testicular torsion or torsion of the spermatic cord is one of the most serious urological conditions. It causes testicular injury, which potentially leads to male subfertility. The turning of the spermatic cord and spermatic structures around themselves results in biochemical and histological changes; however, following testicular detorsion, tissues undergo reperfusion that causes more severe damage than that induced by ischemia. Since the primary causes of testicular damage are reactive oxygen species production, an increase in intra-mitochondrial calcium concentration and an increased rate of cellular apoptosis, different medications may potentially be effective. It seems that several medications, experimentally and sometimes clinically, serve an adjuvant role in the cellular damage that occurs following ischemia-reperfusion. Antioxidants, calcium channel blockers, phytotherapeutical medicinals, anaesthetics, hormones and platelet inhibitors may potentially create a solid basis for an adjuvant restoring therapy and ameliorate testicular function following torsion. The current study aimed to review the relevant literature and discuss the actions of a number of molecules that may protect the testes during ischemia/reperfusion injury.
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Affiliation(s)
- Salvatore Arena
- Department of Human Pathology in Adult and Developmental Age 'Gaetano Barresi', Unit of Paediatric Surgery, University of Messina, I-98125 Messina, Italy
| | - Roberta Iacona
- Department of Paediatric Surgery, John Radcliffe Hospital, Oxford University Hospital, Oxford OX3 9DU, UK
| | - Pietro Antonuccio
- Department of Human Pathology in Adult and Developmental Age 'Gaetano Barresi', Unit of Paediatric Surgery, University of Messina, I-98125 Messina, Italy
| | - Tiziana Russo
- Department of Human Pathology in Adult and Developmental Age 'Gaetano Barresi', Unit of Paediatric Surgery, University of Messina, I-98125 Messina, Italy
| | - Vincenzo Salvo
- Department of Human Pathology in Adult and Developmental Age 'Gaetano Barresi', Neonatal and Intensive Care Unit, University of Messina, I-98125 Messina, Italy
| | - Eloisa Gitto
- Department of Human Pathology in Adult and Developmental Age 'Gaetano Barresi', Neonatal and Intensive Care Unit, University of Messina, I-98125 Messina, Italy
| | - Pietro Impellizzeri
- Department of Human Pathology in Adult and Developmental Age 'Gaetano Barresi', Unit of Paediatric Surgery, University of Messina, I-98125 Messina, Italy
| | - Carmelo Romeo
- Department of Human Pathology in Adult and Developmental Age 'Gaetano Barresi', Unit of Paediatric Surgery, University of Messina, I-98125 Messina, Italy
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Ginkgo Biloba Ameliorates Subfertility Induced by Testicular Ischemia/Reperfusion Injury in Adult Wistar Rats: A Possible New Mitochondrial Mechanism. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:6959274. [PMID: 28101298 PMCID: PMC5215564 DOI: 10.1155/2016/6959274] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 10/19/2016] [Indexed: 12/19/2022]
Abstract
Testicular torsion, a surgical emergency, could affect the endocrine and exocrine testicular functions. This study demonstrates histopathological and physiological effects of testicular ischemia/perfusion (I/R) injury and the possible protective effects of Ginkgo biloba treatment. Fifty adult male Wistar rats, 180–200 gm, were randomly divided into sham-operated, Gingko biloba supplemented, ischemia only, I/R, and Gingko biloba treated I/R groups. Overnight fasted rats were anaesthetized by Pentobarbital; I/R was performed by left testis 720° rotation in I/R and treated I/R groups. Orchiectomy was performed for histopathological studies and detection of mitochondrial NAD+. Determination of free testosterone, FSH, TNF-α, and IL1-β in plasma was performed. Plasma-free testosterone was significantly decreased, while plasma FSH, TNF-α, IL-1β, and testicular mitochondrial NAD+ were significantly increased in I/R group compared to control group. These parameters were reversed in Gingko biloba treated I/R group compared to I/R group. I/R caused marked testicular damage and increased APAF-1 in the apoptotic cells which were reversed by Ginkgo biloba treatment. It could be concluded that I/R caused subfertility induced by apoptosis and oxidative stress manifested by the elevated testicular mitochondrial NAD+, which is considered a new possible mechanism. Also, testicular injury could be reduced by Gingko biloba administration alone.
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Multiple beneficial effects of melanocortin MC 4 receptor agonists in experimental neurodegenerative disorders: Therapeutic perspectives. Prog Neurobiol 2016; 148:40-56. [PMID: 27916623 DOI: 10.1016/j.pneurobio.2016.11.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 11/22/2016] [Accepted: 11/28/2016] [Indexed: 12/13/2022]
Abstract
Melanocortin peptides induce neuroprotection in acute and chronic experimental neurodegenerative conditions. Melanocortins likewise counteract systemic responses to brain injuries. Furthermore, they promote neurogenesis by activating critical signaling pathways. Melanocortin-induced long-lasting improvement in synaptic activity and neurological performance, including learning and memory, sensory-motor orientation and coordinated limb use, has been consistently observed in experimental models of acute and chronic neurodegeneration. Evidence indicates that the neuroprotective and neurogenic effects of melanocortins, as well as the protection against systemic responses to a brain injury, are mediated by brain melanocortin 4 (MC4) receptors, through an involvement of the vagus nerve. Here we discuss the targets and mechanisms underlying the multiple beneficial effects recently observed in animal models of neurodegeneration. We comment on the potential clinical usefulness of melanocortin MC4 receptor agonists as neuroprotective and neuroregenerative agents in ischemic stroke, subarachnoid hemorrhage, traumatic brain injury, spinal cord injury, and Alzheimer's disease.
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Al-Maghrebi M, Renno WM. Altered expression profile of glycolytic enzymes during testicular ischemia reperfusion injury is associated with the p53/TIGAR pathway: effect of fructose 1,6-diphosphate. PeerJ 2016; 4:e2195. [PMID: 27441124 PMCID: PMC4941766 DOI: 10.7717/peerj.2195] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Accepted: 06/08/2016] [Indexed: 12/21/2022] Open
Abstract
Background. Testicular ischemia reperfusion injury (tIRI) is considered the mechanism underlying the pathology of testicular torsion and detorsion. Left untreated, tIRI can induce testis dysfunction, damage to spermatogenesis and possible infertility. In this study, we aimed to assess the activities and expression of glycolytic enzymes (GEs) in the testis and their possible modulation during tIRI. The effect of fructose 1,6-diphosphate (FDP), a glycolytic intermediate, on tIRI was also investigated. Methods. Male Sprague-Dawley rats were divided into three groups: sham, unilateral tIRI, and tIRI + FDP (2 mg/kg). tIRI was induced by occlusion of the testicular artery for 1 h followed by 4 h of reperfusion. FDP was injected peritoneally 30 min prior to reperfusion. Histological and biochemical analyses were used to assess damage to spermatogenesis, activities of major GEs, and energy and oxidative stress markers. The relative mRNA expression of GEs was evaluated by real-time PCR. ELISA and immunohistochemistry were used to evaluate the expression of p53 and TP53-induced glycolysis and apoptosis regulator (TIGAR). Results. Histological analysis revealed tIRI-induced spermatogenic damage as represented by a significant decrease in the Johnsen biopsy score. In addition, tIRI reduced the activities of hexokinase 1, phosphofructokinase-1, glyceraldehyde 3-phosphate dehydrogenase, and lactate dehydrogenase C. However, mRNA expression downregulation was detected only for hexokinase 1, phosphoglycerate kinase 2, and lactate dehydrogenase C. ATP and NADPH depletion was also induced by tIRI and was accompanied by an increased Malondialdehyde concentration, reduced glutathione level, and reduced superoxide dismutase and catalase enzyme activities. The immunoexpression of p53 and TIGAR was markedly increased after tIRI. The above tIRI-induced alterations were attenuated by FDP treatment. Discussion. Our findings indicate that tIRI-induced spermatogenic damage is associated with dysregulation of GE activity and gene expression, which were associated with activation of the TIGAR/p53 pathway. FDP treatment had a beneficial effect on alleviating the damaging effects of tIRI. This study further emphasizes the importance of metabolic regulation for proper spermatogenesis.
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Affiliation(s)
- May Al-Maghrebi
- Faculty of Medicine—Department of Biochemistry, Kuwait University, Jabriyah, Kuwait
| | - Waleed M. Renno
- Faculty of Medicine—Department of Anatomy, Kuwait University, Jabriyah, Kuwait
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Xu M, Alwahsh SM, Ramadori G, Kollmar O, Slotta JE. Upregulation of hepatic melanocortin 4 receptor during rat liver regeneration. J Surg Res 2016; 203:222-30. [DOI: 10.1016/j.jss.2013.12.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Revised: 11/10/2013] [Accepted: 12/20/2013] [Indexed: 12/19/2022]
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14
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Melanocortin-4 receptor agonists alleviate intestinal dysfunction in secondary intra-abdominal hypertension rat model. J Surg Res 2015; 195:263-70. [PMID: 25659615 DOI: 10.1016/j.jss.2015.01.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/11/2014] [Accepted: 01/08/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Intra-abdominal hypertension (IAH) is a potentially life-threatening disease. Melanocortin-4 (MC4) receptor activation exhibits life-saving properties. The aim of the present study was to examine whether treatment with the MC4 receptor agonist RO27-3225 ameliorates intestinal injury in IAH rats. METHODS A total of 72 male Sprague-Dawley rats were randomized into six groups. Group 1 was the sham group. Group 2, the sham + RO group, received RO27-3225 (180 μg/kg, intraperitoneally). IAH was induced in group 3, the IAH group, by blood draw (mean arterial pressure = 30 mm Hg for 90 min) followed by shed blood and/or Ringer solution reinfusion. Intra-abdominal pressure was increased to 20 mm Hg by injecting air into the peritoneal cavity. Group 4, the RO group, was administered RO27-3225 at 5 min after blood draw. Groups 5 and 6 were the chlorisondamine (Chl) and HS024 groups, in which the rats were pretreated with the nicotinic acetylcholine receptor antagonist Chl or selective MC4 receptor antagonist (HS024), respectively, at 2 min before RO27-3225 was administered. RESULTS RO27-3225 restored mean arterial pressure, reduced tumor necrosis factor-α, and interleukin-1β messenger RNA expression increased by IAH, alleviated histologic damage, and improved superoxide dismutase activity in the intestine. Compared with the IAH group, the levels of intestinal fatty acid-binding protein, intestinal edema and intestinal permeability were lower in the RO group. Furthermore, the RO27-3225 treatment increased the expression of Rho-associated coiled-coil-containing protein kinase 1 and phosphorylated myosin light chain. Chl and HS024 abrogated the protective effects of RO27-3225. CONCLUSIONS These data indicate that the MC4 receptor agonist counteracts the intestinal inflammatory response, ameliorating intestinal injury in experimental secondary IAH by MC4 receptor-triggered activation of the cholinergic anti-inflammatory pathway. It may represent a promising strategy for the treatment of IAH in the future.
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Abstract
Testicular torsion is a urological emergency most commonly seen in adolescence, involving a decrease in blood flow in the testis resulting from torsion of the spermatic cord that can result in gonad injury or even loss if not treated in time. Testicular ischaemia-reperfusion injury represents the principle pathophysiology of testicular torsion, with ischaemia caused by twisting of the spermatic cord, and reperfusion on its subsequent release. Many cellular and molecular mechanisms are involved in ischaemia-reperfusion injury following testicular torsion. Studies have investigated the use of pharmacological agents as supportive therapy to surgical repair in order to prevent the adverse effects of testicular torsion. Numerous substances have been proposed as important in the prevention of post-ischaemia-reperfusion testicular injury. A range of chemicals and drugs has been successfully tested in animal models for the purpose of mitigating the dangerous effects of ischaemia-reperfusion in testis torsion.
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Minutoli L, Irrera N, Squadrito F, Marini H, Nicotina PA, Arena S, Romeo C, Antonuccio P, Altavilla D. Effects of ischaemic post-conditioning on the early and late testicular damage after experimental testis ischaemia-reperfusion. Andrology 2013; 2:76-82. [PMID: 24282156 DOI: 10.1111/j.2047-2927.2013.00154.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2013] [Revised: 09/25/2013] [Accepted: 10/04/2013] [Indexed: 12/24/2022]
Abstract
Ischaemic post-conditioning (IPostC) might represent an innovative surgical approach to protect organs from ischaemia and reperfusion (I/R) injury. We investigated the molecular mechanisms underlying the contrasting effects of IPostC on the early and late damage induced by testicular I/R injury. Testis I/R was induced by occluding the right testicular vessels using a clip. Male rats were divided into the following groups: sham, I/R and I/R + IPostC. In the I/R group, the clip was removed after 60 min of ischaemia, and reperfusion was allowed for 30 min, 1 and 30 days. In the I/R + IPostC group, three cycles of 30-sec reperfusion and 30-sec ischaemia were performed after 60 min of ischaemia and then reperfusion followed up for 30 min, 1 and 30 days. Following 30-min reperfusion, there was an increase in mitogen-activated protein kinases (MAPKs) in I/R rats; after 1 day of reperfusion, interleukin-6, tumour necrosis factor-α and nuclear factor-κB (NF-κB) expression were significantly increased; IκB-α expression reduced; and a marked damage in both testes was observed. IPostC inhibited MAPKs, cytokines and NF-κB expression, augmented IκB-α expression and decreased histological damage in testes subjected to I/R. After 30 days of reperfusion, I/R injury activated the apoptosis machinery, caused severe histological damage and reduced spermatogenic activity. By contrast, IPostC did not modify the apoptotic markers, the histological alterations as well as spermatogenic activity following 30 days of reperfusion. Our data demonstrate that IPostC protects the testis from the early damage induced by I/R injury, but it does not protect against the late damage.
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Affiliation(s)
- L Minutoli
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
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Giuliani D, Bitto A, Galantucci M, Zaffe D, Ottani A, Irrera N, Neri L, Cavallini GM, Altavilla D, Botticelli AR, Squadrito F, Guarini S. Melanocortins protect against progression of Alzheimer's disease in triple-transgenic mice by targeting multiple pathophysiological pathways. Neurobiol Aging 2013; 35:537-47. [PMID: 24094579 DOI: 10.1016/j.neurobiolaging.2013.08.030] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Revised: 08/20/2013] [Accepted: 08/23/2013] [Indexed: 01/02/2023]
Abstract
Besides specific triggering causes, Alzheimer's disease (AD) involves pathophysiological pathways that are common to acute and chronic neurodegenerative disorders. Melanocortins induce neuroprotection in experimental acute neurodegenerative conditions, and low melanocortin levels have been found in occasional studies performed in AD-type dementia patients. Here we investigated the possible neuroprotective role of melanocortins in a chronic neurodegenerative disorder, AD, by using 12-week-old (at the start of the study) triple-transgenic (3xTg-AD) mice harboring human transgenes APPSwe, PS1M146V, and tauP301L. Treatment of 3xTg-AD mice, once daily until the end of the study (30 weeks of age), with the melanocortin analog [Nle(4),D-Phe(7)]-α-melanocyte-stimulating hormone (NDP-α-MSH) reduced cerebral cortex/hippocampus phosphorylation/level of all AD-related biomarkers investigated (mediators of amyloid/tau cascade, oxidative/nitrosative stress, inflammation, apoptosis), decreased neuronal loss, induced over-expression of the synaptic activity-dependent gene Zif268, and improved cognitive functions, relative to saline-treated 3xTg-AD mice. Pharmacological blockade of melanocortin MC4 receptors prevented all neuroprotective effects of NDP-α-MSH. Our study identifies, for the first time, a class of drugs, MC4 receptor-stimulating melanocortins, that are able to counteract the progression of experimental AD by targeting pathophysiological mechanisms up- and down-stream of β-amyloid and tau. These data could have important clinical implications.
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Affiliation(s)
- Daniela Giuliani
- Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy
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Gómez-SanMiguel AB, Martín AI, Nieto-Bona MP, Fernández-Galaz C, López-Menduiña M, Villanúa MÁ, López-Calderón A. Systemic α-melanocyte-stimulating hormone administration decreases arthritis-induced anorexia and muscle wasting. Am J Physiol Regul Integr Comp Physiol 2013; 304:R877-86. [PMID: 23515620 DOI: 10.1152/ajpregu.00447.2012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Rheumatoid cachexia is associated with rheumatoid arthritis and it increases mortality and morbidity. Adjuvant-induced arthritis is an experimental model of rheumatoid arthritis that causes anorexia and muscle wasting. α-Melanocyte-stimulating hormone (α-MSH) has anti-inflammatory actions, and it is able to decrease inflammation in several inflammatory diseases including experimental arthritis. In this study we tested whether systemic α-MSH treatment is able to ameliorate cachexia in arthritic rats. On day 8 after adjuvant injection control and arthritic rats were treated with α-MSH (50 μg/rat ip) twice a day, until day 16 when all rats were euthanized. Arthritis decreased food intake, but it increased hypothalamic expression of neuropeptide Y (NPY) and Agouti-related peptides (AgRP) as well as interleukin-1β (IL-1β) and cyclooxygenase-2 (COX-2) mRNA. In arthritic rats, α-MSH decreased the external signs of arthritis and increased food intake (P < 0.01). In addition, α-MSH decreased hypothalamic expression of IL-1β, COX-2, proopiomelanocortin, and prohormone-converting (PC) enzymes PC1/3 and PC2 mRNA in arthritic rats. In control rats, α-MSH did not modify food intake or hypothalamic expression of aforementioned mRNA. α-MSH prevented arthritis-induced increase in gastrocnemius COX-2, muscle-specific RING-finger protein-1 (MuRF1), and atrogin-1 expression, and it increased fast myofiber size. In conclusion our data show that in arthritic rats peripheral α-MSH treatment has an anti-cachectic action increasing food intake and decreasing muscle wasting.
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Rinne P, Harjunpää J, Mäkelä S, Savontaus E. Genetic and pharmacological mouse models of chronic melanocortin activation show enhanced baroreflex control of heart rate. ACTA ACUST UNITED AC 2013; 182:19-27. [DOI: 10.1016/j.regpep.2012.12.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Revised: 09/05/2012] [Accepted: 12/17/2012] [Indexed: 10/27/2022]
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Giuliani D, Minutoli L, Ottani A, Spaccapelo L, Bitto A, Galantucci M, Altavilla D, Squadrito F, Guarini S. Melanocortins as potential therapeutic agents in severe hypoxic conditions. Front Neuroendocrinol 2012; 33:179-93. [PMID: 22531139 DOI: 10.1016/j.yfrne.2012.04.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2011] [Revised: 03/26/2012] [Accepted: 04/09/2012] [Indexed: 01/14/2023]
Abstract
Melanocortin peptides with the adrenocorticotropin/melanocyte-stimulating hormone (ACTH/MSH) sequences and synthetic analogs have protective and life-saving effects in experimental conditions of circulatory shock, myocardial ischemia, ischemic stroke, traumatic brain injury, respiratory arrest, renal ischemia, intestinal ischemia and testicular ischemia, as well as in experimental heart transplantation. Moreover, melanocortins improve functional recovery and stimulate neurogenesis in experimental models of cerebral ischemia. These beneficial effects of ACTH/MSH-like peptides are mostly mediated by brain melanocortin MC(3)/MC(4) receptors, whose activation triggers protective pathways that counteract the main ischemia/reperfusion-related mechanisms of damage. Induction of signaling pathways and other molecular regulators of neural stem/progenitor cell proliferation, differentiation and integration seems to be the key mechanism of neurogenesis stimulation. Synthesis of stable and highly selective agonists at MC(3) and MC(4) receptors could provide the potential for development of a new class of drugs for a novel approach to management of severe ischemic diseases.
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Affiliation(s)
- Daniela Giuliani
- Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, 41125 Modena, Italy
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Bertolini A. Drug-induced activation of the nervous control of inflammation: a novel possibility for the treatment of hypoxic damage. Eur J Pharmacol 2012; 679:1-8. [PMID: 22293371 DOI: 10.1016/j.ejphar.2012.01.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2011] [Revised: 01/12/2012] [Accepted: 01/12/2012] [Indexed: 01/14/2023]
Abstract
Together with undernutrition and, on the opposite, overeating and obesity, sudden tissue hypoperfusion is the most important cause of mortality and disability worldwide. Tissue hypoperfusion/hypoxia rapidly triggers an unrestrained inflammatory cascade that is the main responsible for the severity of the eventual outcome. The brain plays a key role in inflammation, either through activation of the hypothalamic-pituitary-adrenal humoral response or through activation of the vagal "cholinergic anti-inflammatory pathway". Both humoral and nervous brain responses to inflammation are under the regulatory control of melanocortins, which have moreover a direct anti-inflammatory effect on inflammatory cells. Abundant experimental and clinical evidence indicates that MC(3)/MC(4) melanocortin receptor agonists and cholinergic receptor agonists (mainly at the α7-nicotinic subtype) should by now be considered as completely innovative, effective drugs for the treatment of hypoxic conditions; melanocortin agonists being practically devoid of harmful side effects.
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Affiliation(s)
- Alfio Bertolini
- Division of Clinical Pharmacology, Department of Diagnostic Services, School of Medicine, University of Modena and Reggio Emilia, Largo del Pozzo 71, 41100 Modena, Italy.
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