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Pellegrino R, Gravina AG. Irritable bowel syndrome remains a complex disorder of gut-brain interaction: Too many actors on stage. World J Gastroenterol 2025; 31:101357. [DOI: 10.3748/wjg.v31.i8.101357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 12/29/2024] [Accepted: 01/06/2025] [Indexed: 01/23/2025] Open
Abstract
The recent study published in the World Journal of Gastroenterology examines the interplay among the neuroendocrine axis, gut microbiota, inflammatory markers, and gastrointestinal symptoms in irritable bowel syndrome (IBS). By integrating all these factors into a single study, this approach reflects the modern concept of functional gastrointestinal disorders as disorders of the gut-brain interaction to be approached in a multiparametric manner, also incorporating non-gastroenterological elements and extending evaluations to parameters related to the neuroendocrine axis. This invited letter to the editor summarizes the main results of the aforementioned study and highlights its multiparametric approach, including variables not strictly gastroenterological, in the study of IBS, and discusses its strengths and limitations.
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Affiliation(s)
- Raffaele Pellegrino
- Division of Hepatogastroenterology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Antonietta Gerarda Gravina
- Division of Hepatogastroenterology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples 80138, Italy
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Orandi AH, Mansour A, Bagheri N, Majedi H, Emami Meibodi SA, Pestehei SK, Saberian P. The comparison of the efficacy of intramuscular tetracosactide and subacromial triamcinolone injection in rotator cuff tendinitis: a randomized trial. Rheumatol Adv Pract 2024; 9:rkae150. [PMID: 39764362 PMCID: PMC11703363 DOI: 10.1093/rap/rkae150] [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: 10/09/2024] [Accepted: 11/28/2024] [Indexed: 02/16/2025] Open
Abstract
Objectives Rotator cuff tendinitis (RCT) is a tendon inflammation often following subacromial impingement syndrome. One of the non-surgical management modalities for RCT is subacromial injection of corticosteroids. Some studies have claimed a correlation between ACTH (Adrenocorticotropic Hormone) deficiency and rotator cuff lesions; hence, intramuscular ACTH analogue injection has been recommended as an option. This research aimed to compare the effectiveness of these two treatment methods. Methods We conducted a study with 86 patients suffering from RCT. The patients were randomly divided into two groups of 43; one group received a subacromial injection of 40 mg of triamcinolone acetonide, while the other group received 1 mg of intramuscular tetracosactide injection. We recorded the Constant-Murley (CM) and visual analogue scale (VAS) scores for each patient before and 4 weeks after injections to measure pain acuity and joint functionality. Later, we compared and analysed the two scores in each group. Results Based on the statistical analysis, the mean ages of the participants in the triamcinolone and tetracosactide groups were 53.21 ± 11.37 and 54.56 ± 11.98, respectively. Both groups demonstrated an improvement in VAS for pain and CM scores (P < 0.05). However, the VAS for pain score decreased, and the CM score increased more significantly in the triamcinolone group than in the tetracosactide group (P < 0.05). Conclusion Although both treatment methods exhibit promise for pain relief, subacromial injection of triamcinolone appears more efficacious than intramuscular injection of tetracosactide in patients with RCT, based on a 4-week follow-up. Trial registration Iranian Registry of Clinical Trials, https://irct.behdasht.gov.ir, IRCT20240110060673N1.
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Affiliation(s)
- Amir Hossein Orandi
- Department of Anesthesiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirpasha Mansour
- Department of Anesthesiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Bagheri
- Joint Reconstruction Research Center, Department of Orthopedics, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Majedi
- Pain Research Center, Neuroscience Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
- Department of Anesthesiology, Critical Care and Pain Medicine, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Ali Emami Meibodi
- Pain Research Center, Neuroscience Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
- Department of Anesthesiology, Critical Care and Pain Medicine, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Khalil Pestehei
- Department of Anesthesiology, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Peyman Saberian
- Department of Anesthesiology, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
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Fernandez AP, Gallop J, Polly S, Khanna U. Efficacy and safety of repository corticotropin injection for refractory cutaneous dermatomyositis: a prospective, open-label study. Rheumatology (Oxford) 2024; 63:3370-3379. [PMID: 37941470 DOI: 10.1093/rheumatology/kead595] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 09/19/2023] [Accepted: 10/19/2023] [Indexed: 11/10/2023] Open
Abstract
OBJECTIVES Cutaneous dermatomyositis (DM) is often refractory to multiple medications. Repository corticotropin injection (RCI) is FDA-approved for DM, but little is known about its efficacy and safety for treating cutaneous DM. We conducted a prospective, open-label trial assessing efficacy and safety of RCI for treating refractory cutaneous DM. METHODS DM patients with moderate-to-severe cutaneous activity [Cutaneous Dermatomyositis Disease Area and Severity Index activity (CDASI-A)] >14 despite prior treatment with ≥2 systemic agents were enrolled. Patients were initiated on 80 u RCI twice weekly for 6 months. Primary outcomes included significant decreases in CDASI-A and Physician's Global Assessment (PGA) scores at 6 months. RESULTS Of 19 patients enrolled, 15 patients (11 females, four males) with DM (seven classic, eight amyopathic) completed 6 months of RCI treatment. Patients were treated with a median 3.0 systemic medications prior to enrolment and were taking a median of 2.0 systemic medications at enrolment. Median baseline CDASI-A score was 19.0 and median PGA activity score was 2.5/10. For patient-reported outcomes, baseline median patient global skin score (PtGSS) was 3.0/10 and median dermatology life quality index (DLQI) score was 7.0/10. At 6 months, there were statistically significant improvements in CDASI-A scores (median = 10.0), PGA scores (median = 0.8/10), PtGSS scores (median = 7.0) and DLQI scores (median = 2.0), among others. Adverse effects were mild. CONCLUSIONS RCI treatment resulted in statistically significant and clinically meaningful improvement in cutaneous DM activity and quality of life. Our results suggest RCI is an effective, safe and well-tolerated treatment for patients with refractory cutaneous dermatomyositis. CLINICAL TRIAL REGISTRATION This clinical trial was registered with ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT01906372).
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Affiliation(s)
- Anthony P Fernandez
- Departments of Dermatology and Pathology, Cleveland Clinic, Cleveland, OH, USA
| | - Josh Gallop
- Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA
| | - Samantha Polly
- Department of Dermatology, Duke University, Durham, NC, USA
| | - Urmi Khanna
- Division of Dermatology, Montefiore Medical Center, Albert Einstein College of Medicine, New York, NY, USA
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He L, Li A, Yu P, Qin S, Tan HY, Zou D, Wu H, Wang S. Therapeutic peptides in the treatment of digestive inflammation: Current advances and future prospects. Pharmacol Res 2024; 209:107461. [PMID: 39423954 DOI: 10.1016/j.phrs.2024.107461] [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: 07/10/2024] [Revised: 10/06/2024] [Accepted: 10/10/2024] [Indexed: 10/21/2024]
Abstract
Digestive inflammation is a widespread global issue that significantly impacts quality of life. Recent advances have highlighted the unique potential of therapeutic peptides for treating this condition, owing to their specific bioactivity and high specificity. By specifically targeting key proteins involved in the pathological process and modulating biomolecular functions, therapeutic peptides offer a novel and promising approach to managing digestive inflammation. This review explores the development history, pharmacological characteristics, clinical applications, and regulatory mechanisms of therapeutic peptides in treating digestive inflammation. Additionally, the review addresses pharmacokinetics and quality control methods of therapeutic peptides, focusing on challenges such as low bioavailability, poor stability, and difficulties in delivery. The role of modern biotechnologies and nanotechnologies in overcoming these challenges is also examined. Finally, future directions for therapeutic peptides and their potential impact on clinical applications are discussed, with emphasis placed on their significant role in advancing medical and therapeutic practices.
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Affiliation(s)
- Liangliang He
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research and Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou, China
| | - Aijing Li
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research and Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou, China
| | - Ping Yu
- Department of Pharmacy, Xixi Hospital of Hangzhou, Hangzhou, China
| | - Shumin Qin
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Hor-Yue Tan
- Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong SAR
| | - Denglang Zou
- Hubei Shizhen Laboratory, Hubei University of Chinese Medicine, Wuhan, China.
| | - Haomeng Wu
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.
| | - Shuai Wang
- Chinese Medicine Guangdong Laboratory, Hengqin, China; School of Pharmaceutical Sciences, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.
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Lawrence S, Scofield RH. Post traumatic stress disorder associated hypothalamic-pituitary-adrenal axis dysregulation and physical illness. Brain Behav Immun Health 2024; 41:100849. [PMID: 39280087 PMCID: PMC11401111 DOI: 10.1016/j.bbih.2024.100849] [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: 12/27/2023] [Revised: 08/11/2024] [Accepted: 08/17/2024] [Indexed: 09/18/2024] Open
Abstract
Conventional human stress responses are mediated by the sympathetic adrenal medullar (SAM) axis and the hypothalamic pituitary adrenal (HPA) axis. The SAM axis mediates the immediate response to stress through norepinephrine and epinephrine while the HPA axis mediates the slow response through corticosteroids, primarily cortisol, to effect systemic changes. Post Traumatic Stress Disorder (PTSD), a psychiatric disorder that develops in a small subset of people exposed to a traumatic event, may dysregulate these systems and result in increased risk of various clinical conditions. These conditions include but are not limited to cardiovascular disease, metabolic conditions, autoimmune diseases, neurocognitive disorders, and women's health complications such as preterm birth, polycystic ovarian syndrome, and endometriosis to name a few. This review focuses on how PTSD dysregulates the HPA axis, and further, how these alterations affect the immune system and physical health outcomes.
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Affiliation(s)
- Stephanie Lawrence
- Department of Veterans Affairs Medical Center, Oklahoma City, OK, 73104, USA
- University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
- Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - R Hal Scofield
- Department of Veterans Affairs Medical Center, Oklahoma City, OK, 73104, USA
- University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
- Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
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Siemiradzka W, Kędzierska K, Rynk W, Dolińska B. Study of the Effect of Phosvitin as a Potential Carrier on the Permeation Process of Somatotropin (STH) and Corticotropin (ACTH) from Biodegradable Polymers Used as Vehicles for STH and ACTH in Semi-Solid Formulations for Skin Application. Polymers (Basel) 2024; 16:2640. [PMID: 39339104 PMCID: PMC11436162 DOI: 10.3390/polym16182640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 09/06/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
Phosvitin shows chelating abilities, an affinity for ACTH (corticotropin), growth factors, antioxidant properties, and acidic nature. An attempt was made to use this protein in hydrogels as a transporter of other protein substances: somatotropin (STH) and (ACTH). The aim of the study was to evaluate the effect of phosvitin on the permeation of ACTH and STH from semi-solid forms of the drug applied to the skin. Four hydrogel substrates were prepared using natural polymers: sodium alginate, methylcellulose, and starch. Based on the evaluation of physicochemical parameters, the hydrogel with the most favorable properties was selected and loaded with the active substances STH and ACTH, followed by the addition of phosvitin. A study of the permeation of STH and ACTH through the artificial cellulose membrane and through porcine skin was carried out without and with the addition of phosvitin. The effect of protein substances on rheological and textural parameters was studied. The evaluation of physicochemical parameters showed a favorable effect of STH and Phosvitin on the stability of the hydrogel with 4% methylcellulose and no effect of ACTH. All prepared formulations showed a reaction close to the natural pH of human skin. In the porcine skin permeation study, the addition of Phosvitin to the hydrogel with STH caused a slight increase in the amount of STH permeated and an increase in the time for STH to permeate porcine skin by 30 min. Phosvitin caused an increase in the amount of ACTH permeated through porcine skin almost twofold. Phosvitin may prove to be a promising permeation promoter for model protein-peptide substances when applied to the skin surface.
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Affiliation(s)
- Wioletta Siemiradzka
- Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Kasztanowa 3, 41-200 Sosnowiec, Poland
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Wang F, Ma W, Fan D, Hu J, An X, Wang Z. The biochemistry of melanogenesis: an insight into the function and mechanism of melanogenesis-related proteins. Front Mol Biosci 2024; 11:1440187. [PMID: 39228912 PMCID: PMC11368874 DOI: 10.3389/fmolb.2024.1440187] [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: 05/29/2024] [Accepted: 07/22/2024] [Indexed: 09/05/2024] Open
Abstract
Melanin is an amino acid derivative produced by melanocyte through a series of enzymatic reactions using tyrosinase as substrate. Human skin and hair color is also closely related to melanin, so understanding the mechanisms and proteins that produce melanin is very important. There are many proteins involved in the process of melanin expression, For example, proteins involved in melanin formation such as p53, HNF-1α (Hepatocyte nuclear factor 1α), SOX10 (Sry-related HMg-Box gene 10) and pax3 (paired box gene 3), MC1R(Melanocortin 1 Receptor), MITF (Microphthalmia-associated transcription factor), TYR (tyrosinase), TYRP1 (tyrosinase-related protein-1), TYRP2 (tyrosinase-related protein-2), and can be regulated by changing their content to control the production rate of melanin. Others, such as OA1 (ocular albinism type 1), Par-2 (protease-activated receptor 2) and Mlph (Melanophilin), have been found to control the transfer rate of melanosomes from melanocytes to keratinocytes, and regulate the amount of human epidermal melanin to control the depth of human skin color. In addition to the above proteins, there are other protein families also involved in the process of melanin expression, such as BLOC, Rab and Rho. This article reviews the origin of melanocytes, the related proteins affecting melanin and the basic causes of related gene mutations. In addition, we also summarized the active ingredients of 5 popular whitening cosmetics and their mechanisms of action.
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Affiliation(s)
- Feifei Wang
- Yunnan Characteristic Plant Extraction Laboratory, Yunnan Yunke Characteristic Plant Extraction Laboratory Co., Ltd., Kunming, China
- Yunnan Botanee Bio-Technology Group Co., Ltd., Kunming, China
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
- Shanghai Jiyan Bio-Pharmaceutical Co., Ltd., Shanghai, China
| | - Wenjing Ma
- Yunnan Characteristic Plant Extraction Laboratory, Yunnan Yunke Characteristic Plant Extraction Laboratory Co., Ltd., Kunming, China
- Shanghai Jiyan Bio-Pharmaceutical Co., Ltd., Shanghai, China
| | - Dongjie Fan
- Yunnan Characteristic Plant Extraction Laboratory, Yunnan Yunke Characteristic Plant Extraction Laboratory Co., Ltd., Kunming, China
- Shanghai Jiyan Bio-Pharmaceutical Co., Ltd., Shanghai, China
| | - Jing Hu
- Yunnan Characteristic Plant Extraction Laboratory, Yunnan Yunke Characteristic Plant Extraction Laboratory Co., Ltd., Kunming, China
- Shanghai Jiyan Bio-Pharmaceutical Co., Ltd., Shanghai, China
| | - Xiaohong An
- Yunnan Characteristic Plant Extraction Laboratory, Yunnan Yunke Characteristic Plant Extraction Laboratory Co., Ltd., Kunming, China
- Yunnan Botanee Bio-Technology Group Co., Ltd., Kunming, China
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
- Shanghai Jiyan Bio-Pharmaceutical Co., Ltd., Shanghai, China
| | - Zuding Wang
- Yunnan Characteristic Plant Extraction Laboratory, Yunnan Yunke Characteristic Plant Extraction Laboratory Co., Ltd., Kunming, China
- Yunnan Botanee Bio-Technology Group Co., Ltd., Kunming, China
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Chauhan K, Tyagi M. Update on non-infectious uveitis treatment: anti-TNF-alpha and beyond. FRONTIERS IN OPHTHALMOLOGY 2024; 4:1412930. [PMID: 39157460 PMCID: PMC11327136 DOI: 10.3389/fopht.2024.1412930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 07/16/2024] [Indexed: 08/20/2024]
Abstract
Non-infectious uveitis (NIU) encompasses a range of conditions marked by inflammation within various layers of the eye. NIU is a significant contributor to irreversible vision loss among the working-age population in developed countries. The aim of treating uveitis is to manage inflammation, prevent its recurrences and to restore or salvage vision. Presently, the standard treatment protocol for NIU involves initiating corticosteroids as the primary therapeutic agents, although more aggressive approaches and steroid sparing agent may be necessary in certain cases. These advanced treatments option include synthetic immunosuppressants like antimetabolites, calcineurin inhibitors and alkylating agents. For patients who exhibit an intolerance or resistance to corticosteroids and conventional immunosuppressive therapies, biologic agents have emerged as a promising alternative. Notably, among the biologic treatments evaluated, TNF-α inhibitors, anti-CD20 therapy and alkylating agents have shown considerable efficacy. In this review, we delve into the latest evidence surrounding the effectiveness of biologic therapy and introduce novel therapeutic strategies targeting immune components as potential avenues for advancing treatment of NIU.
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Affiliation(s)
- Khushboo Chauhan
- Saroja A Rao Centre for Uveitis, L V Prasad Eye Institute, Hyderabad, India
- Smt. Kanuri Santhamma Centre for Vitreo-Retinal Diseases, L V Prasad Eye Institute, Hyderabad, India
| | - Mudit Tyagi
- Saroja A Rao Centre for Uveitis, L V Prasad Eye Institute, Hyderabad, India
- Smt. Kanuri Santhamma Centre for Vitreo-Retinal Diseases, L V Prasad Eye Institute, Hyderabad, India
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Wang X, Wen X, Yuan S, Zhang J. Gut-brain axis in the pathogenesis of sepsis-associated encephalopathy. Neurobiol Dis 2024; 195:106499. [PMID: 38588753 DOI: 10.1016/j.nbd.2024.106499] [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: 03/04/2024] [Revised: 03/31/2024] [Accepted: 04/04/2024] [Indexed: 04/10/2024] Open
Abstract
The gut-brain axis is a bidirectional communication network linking the gut and the brain, overseeing digestive functions, emotional responses, body immunity, brain development, and overall health. Substantial research highlights a connection between disruptions of the gut-brain axis and various psychiatric and neurological conditions, including depression and Alzheimer's disease. Given the impact of the gut-brain axis on behavior, cognition, and brain diseases, some studies have started to pay attention to the role of the axis in sepsis-associated encephalopathy (SAE), where cognitive impairment is the primary manifestation. SAE emerges as the primary and earliest form of organ dysfunction following sepsis, potentially leading to acute cognitive impairment and long-term cognitive decline in patients. Notably, the neuronal damage in SAE does not stem directly from the central nervous system (CNS) infection but rather from an infection occurring outside the brain. The gut-brain axis is posited as a pivotal factor in this process. This review will delve into the gut-brain axis, exploring four crucial pathways through which inflammatory signals are transmitted and elevate the incidence of SAE. These pathways encompass the vagus nerve pathway, the neuroendocrine pathway involving the hypothalamic-pituitary-adrenal (HPA) axis and serotonin (5-HT) regulation, the neuroimmune pathway, and the microbial regulation. These pathways can operate independently or collaboratively on the CNS to modulate brain activity. Understanding how the gut affects and regulates the CNS could offer the potential to identify novel targets for preventing and treating this condition, ultimately enhancing the prognosis for individuals with SAE.
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Affiliation(s)
- Xin Wang
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Xiaoyue Wen
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Shiying Yuan
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China.
| | - Jiancheng Zhang
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China.
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Gravina AG, Panarese I, Trotta MC, D'Amico M, Pellegrino R, Ferraraccio F, Galdiero M, Alfano R, Grieco P, Federico A. Melanocortin 3,5 receptors immunohistochemical expression in colonic mucosa of inflammatory bowel disease patients: A matter of disease activity? World J Gastroenterol 2024; 30:1132-1142. [PMID: 38577176 PMCID: PMC10989484 DOI: 10.3748/wjg.v30.i9.1132] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/15/2024] [Accepted: 02/08/2024] [Indexed: 03/06/2024] Open
Abstract
BACKGROUND Melanocortin 3 and 5 receptors (i.e., MC3R and MC5R) belong to the melanocortin family. However, data regarding their role in inflammatory bowel diseases (IBD) are currently unavailable. AIM This study aims to ascertain their expression profiles in the colonic mucosa of Crohn's disease (CD) and ulcerative colitis (UC), aligning them with IBD disease endoscopic and histologic activity. METHODS Colonic mucosal biopsies from CD/UC patients were sampled, and immunohistochemical analyses were conducted to evaluate the expression of MC3R and MC5R. Colonic sampling was performed on both traits with endoscopic scores (Mayo endoscopic score and CD endoscopic index of severity) consistent with inflamed mucosa and not consistent with disease activity (i.e., normal appearing mucosa). RESULTS In both CD and UC inflamed mucosa, MC3R (CD: + 7.7 fold vs normal mucosa, P < 0.01; UC: + 12 fold vs normal mucosa, P < 0.01) and MC5R (CD: + 5.5 fold vs normal mucosa, P < 0.01; UC: + 8.1 fold vs normal mucosa, P < 0.01) were significantly more expressed compared to normal mucosa. CONCLUSION MC3R and MC5R are expressed in the colon of IBD patients. Furthermore, expression may differ according to disease endoscopic activity, with a higher degree of expression in the traits affected by disease activity in both CD and UC, suggesting a potential use of these receptors in IBD pharmacology.
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Affiliation(s)
- Antonietta Gerarda Gravina
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Iacopo Panarese
- Pathology Division, Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Maria Consiglia Trotta
- Department of Experimental Medicine, Division of Pharmacology, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Michele D'Amico
- Department of Experimental Medicine, Division of Pharmacology, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Raffaele Pellegrino
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Franca Ferraraccio
- Pathology Division, Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Marilena Galdiero
- Department of Experimental Medicine, Division of Pharmacology, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Roberto Alfano
- Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Paolo Grieco
- Department of Pharmacy, University of Naples Federico II, Naples 80131, Italy
| | - Alessandro Federico
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples 80138, Italy
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Obi ON. Anti-inflammatory Therapy for Sarcoidosis. Clin Chest Med 2024; 45:131-157. [PMID: 38245362 DOI: 10.1016/j.ccm.2023.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2024]
Abstract
Over 50% of patients with sarcoidosis will require anti-inflammatory therapy at some point in their disease course. Indications for therapy are to improve health-related quality of life, prevent or arrest organ dysfunction (or organ failure) or avoid death. Recently published treatment guidelines recommended a stepwise approach to therapy however there are some patients for whom up front combination or more intense therapy maybe reasonable. The last decade has seen an explosion of studies and trials evaluating novel therapeutic agents and treatment strategies. Currently available anti-inflammatory therapies and several novel therapies are discussed here.
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Affiliation(s)
- Ogugua Ndili Obi
- Department of Internal Medicine, Division of Pulmonary Critical Care and Sleep Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
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Sævik ÅB, Ueland G, Åkerman AK, Methlie P, Quinkler M, Jørgensen AP, Höybye C, Debowska AWJ, Nedrebø BG, Dahle AL, Carlsen S, Tomkowicz A, Sollid ST, Nermoen I, Grønning K, Dahlqvist P, Grimnes G, Skov J, Finnes T, Valland SF, Wahlberg J, Holte SE, Kämpe O, Bensing S, Husebye ES, Øksnes M. Altered biomarkers for cardiovascular disease and inflammation in autoimmune Addison's disease - a cross-sectional study. Eur J Endocrinol 2023; 189:438-447. [PMID: 37807083 DOI: 10.1093/ejendo/lvad136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 08/01/2023] [Accepted: 09/25/2023] [Indexed: 10/10/2023]
Abstract
OBJECTIVE Increased prevalence of cardiovascular disease has been reported in autoimmune Addison's disease (AAD), but pathomechanisms are poorly understood. DESIGN Cross-sectional study. METHODS We compared serum levels of 177 cardiovascular and inflammatory biomarkers in 43 patients with AAD at >18-h glucocorticoid withdrawal and 43 matched controls, overall and stratified for sex. Biomarker levels were correlated with the frequency of adrenal crises and quality of life (QoL) by AddiQoL-30. Finally, we investigated changes in biomarker levels following 250 µg tetracosactide injection in patients without residual adrenocortical function (RAF) to explore glucocorticoid-independent effects of high ACTH. RESULTS Nineteen biomarkers significantly differed between patients with AAD and controls; all but 1 (ST1A1) were higher in AAD. Eight biomarkers were significantly higher in female patients compared with controls (IL6, MCP1, GAL9, SPON2, DR4, RAGE, TNFRSF9, and PGF), but none differed between male patients and controls. Levels of RAGE correlated with the frequency of adrenal crises (r = 0.415, P = .006) and AddiQoL-30 scores (r = -0.347, P = .028) but not after correction for multiple testing. PDL2 and leptin significantly declined 60 min after injection of ACTH in AAD without RAF (-0.15 normalized protein expression [NPX], P = .0001, and -0.25 NPX, P = .0003, respectively). CONCLUSIONS We show that cardiovascular and inflammatory biomarkers are altered in AAD compared with controls, particularly in women. RAGE might be a marker of disease severity in AAD, associated with more adrenal crises and reduced QoL. High ACTH reduced PDL2 and leptin levels in a glucocorticoid-independent manner but the overall effect on biomarker profiles was small.
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Affiliation(s)
- Åse Bjorvatn Sævik
- Department of Clinical Science, University of Bergen, Bergen 5021, Norway
- K.G. Jebsen Center for Autoimmune Disorders, University of Bergen, Bergen 5021, Norway
| | - Grethe Ueland
- Department of Clinical Science, University of Bergen, Bergen 5021, Norway
- K.G. Jebsen Center for Autoimmune Disorders, University of Bergen, Bergen 5021, Norway
- Department of Medicine, Haukeland University Hospital, Bergen 5021, Norway
| | - Anna-Karin Åkerman
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 171 77, Sweden
- Department of Medicine, Örebro University Hospital, Örebro 702 17, Sweden
| | - Paal Methlie
- Department of Clinical Science, University of Bergen, Bergen 5021, Norway
- K.G. Jebsen Center for Autoimmune Disorders, University of Bergen, Bergen 5021, Norway
- Department of Medicine, Haukeland University Hospital, Bergen 5021, Norway
| | - Marcus Quinkler
- Practice for Endocrinology and Nephrology, Endocrinology in Charlottenburg, Berlin 10627, Germany
| | | | - Charlotte Höybye
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 171 77, Sweden
- Department of Endocrinology, Karolinska University Hospital, Stockholm 171 77, Sweden
| | | | | | - Anne Lise Dahle
- Department of Internal Medicine, Haugesund Hospital, Haugesund 5528, Norway
| | - Siri Carlsen
- Department of Endocrinology, Stavanger University Hospital, Stavanger 4019, Norway
| | - Aneta Tomkowicz
- Department of Medicine, Sørlandet Hospital, Kristiansand 4604, Norway
| | - Stina Therese Sollid
- Department of Medicine, Drammen Hospital, Vestre Viken Health Trust, Drammen 3004, Norway
| | - Ingrid Nermoen
- Department of Endocrinology, Akershus University Hospital, Lørenskog 1478, Norway
| | - Kaja Grønning
- Department of Endocrinology, Akershus University Hospital, Lørenskog 1478, Norway
| | - Per Dahlqvist
- Department of Public Health and Clinical Medicine, Umeå University, Umeå 907 37, Sweden
| | - Guri Grimnes
- Division of Internal Medicine, University Hospital of North Norway, Tromsø 9019, Norway
- Tromsø Endocrine Research Group, Department of Clinical Medicine, UiT the Arctic University of Norway, Tromsø 9019, Norway
| | - Jakob Skov
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 171 77, Sweden
| | - Trine Finnes
- Section of Endocrinology, Innlandet Hospital Trust, Hamar 2318, Norway
| | - Susanna F Valland
- Section of Endocrinology, Innlandet Hospital Trust, Hamar 2318, Norway
| | - Jeanette Wahlberg
- Department of Endocrinology, Linköping University, Linköping 581 85, Sweden
- Department of Health, Medicine and Caring Sciences, Linköping University, Linköping 581 85, Sweden
| | | | - Olle Kämpe
- K.G. Jebsen Center for Autoimmune Disorders, University of Bergen, Bergen 5021, Norway
- Department of Endocrinology, Karolinska University Hospital, Stockholm 171 77, Sweden
- Department of Medicine (Solna), Karolinska University Hospital, Karolinska Institutet, Stockholm 171 77, Sweden
| | - Sophie Bensing
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 171 77, Sweden
- Department of Endocrinology, Karolinska University Hospital, Stockholm 171 77, Sweden
| | - Eystein Sverre Husebye
- Department of Clinical Science, University of Bergen, Bergen 5021, Norway
- K.G. Jebsen Center for Autoimmune Disorders, University of Bergen, Bergen 5021, Norway
- Department of Medicine, Haukeland University Hospital, Bergen 5021, Norway
- Department of Medicine (Solna), Karolinska University Hospital, Karolinska Institutet, Stockholm 171 77, Sweden
| | - Marianne Øksnes
- Department of Clinical Science, University of Bergen, Bergen 5021, Norway
- K.G. Jebsen Center for Autoimmune Disorders, University of Bergen, Bergen 5021, Norway
- Department of Medicine, Haukeland University Hospital, Bergen 5021, Norway
- Department of Medicine (Solna), Karolinska University Hospital, Karolinska Institutet, Stockholm 171 77, Sweden
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Gebrie A. The melanocortin receptor signaling system and its role in neuroprotection against neurodegeneration: Therapeutic insights. Ann N Y Acad Sci 2023; 1527:30-41. [PMID: 37526975 DOI: 10.1111/nyas.15048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/02/2023]
Abstract
The melanocortin signaling system consists of the melanocortin peptides, their distinctive receptors, accessory proteins, and endogenous antagonists. Melanocortin peptides are small peptide hormones that have been studied in a variety of physiological and pathological conditions. There are five types of melanocortin receptors, and they are distributed within the central nervous system and in several tissues of the periphery. The G protein-coupled melanocortin receptors typically signal through adenylyl cyclase and other downstream signaling pathways. Depending on the ligand, surface expression of melanocortin receptor, receptor occupancy period, related proteins, the type of cell, and other parameters, the signaling pathways are complicated and pleiotropic. While it is known that all five melanocortin receptors are coupled to Gs, they can also occasionally couple to Gq or Gi. Both direct and indirect neuroprotection are induced by the melanocortin signaling system. Targeting several of the components of the melanocortin signaling system (ligands, receptors, accessory proteins, signaling effectors, and regulators) may provide therapeutic opportunities. Activation of the melanocortin system improves different functional traits in neurodegenerative diseases. There is a potential for additional melanocortin system interventions by interfering with dimerization or dissociation. This review aims to discuss the melanocortin receptor signaling system and its role in neuroprotection, as well as its therapeutic potential.
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Affiliation(s)
- Alemu Gebrie
- Department of Biomedical Sciences, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
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Gravina AG, Pellegrino R, Durante T, Palladino G, Imperio G, D'Amico G, Trotta MC, Dallio M, Romeo M, D'Amico M, Federico A. The Melanocortin System in Inflammatory Bowel Diseases: Insights into Its Mechanisms and Therapeutic Potentials. Cells 2023; 12:1889. [PMID: 37508552 PMCID: PMC10378568 DOI: 10.3390/cells12141889] [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: 06/24/2023] [Revised: 07/08/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
The melanocortin system is a complex set of molecular mediators and receptors involved in many physiological and homeostatic processes. These include the regulation of melanogenesis, steroidogenesis, neuromodulation and the modulation of inflammatory processes. In the latter context, the system has assumed importance in conditions of chronic digestive inflammation, such as inflammatory bowel diseases (IBD), in which numerous experiences have been accumulated in mouse models of colitis. Indeed, information on how such a system can counteract colitis inflammation and intervene in the complex cytokine imbalance in the intestinal microenvironment affected by chronic inflammatory damage has emerged. This review summarises the evidence acquired so far and highlights that molecules interfering with the melanocortin system could represent new drugs for treating IBD.
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Affiliation(s)
- Antonietta Gerarda Gravina
- Hepatogastroenterology Unit, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Raffaele Pellegrino
- Hepatogastroenterology Unit, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Tommaso Durante
- Mental Health Department, S. Pio Hospital, Via dell'Angelo, 82100 Benevento, Italy
| | - Giovanna Palladino
- Hepatogastroenterology Unit, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Giuseppe Imperio
- Hepatogastroenterology Unit, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | | | - Maria Consiglia Trotta
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Marcello Dallio
- Hepatogastroenterology Unit, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Mario Romeo
- Hepatogastroenterology Unit, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Michele D'Amico
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Alessandro Federico
- Hepatogastroenterology Unit, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
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15
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Wu CLS, Cioanca AV, Gelmi MC, Wen L, Di Girolamo N, Zhu L, Natoli R, Conway RM, Petsoglou C, Jager MJ, McCluskey PJ, Madigan MC. The multifunctional human ocular melanocortin system. Prog Retin Eye Res 2023; 95:101187. [PMID: 37217094 DOI: 10.1016/j.preteyeres.2023.101187] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 05/12/2023] [Accepted: 05/12/2023] [Indexed: 05/24/2023]
Abstract
Immune privilege in the eye involves physical barriers, immune regulation and secreted proteins that together limit the damaging effects of intraocular immune responses and inflammation. The neuropeptide alpha-melanocyte stimulating hormone (α-MSH) normally circulates in the aqueous humour of the anterior chamber and the vitreous fluid, secreted by iris and ciliary epithelium, and retinal pigment epithelium (RPE). α-MSH plays an important role in maintaining ocular immune privilege by helping the development of suppressor immune cells and by activating regulatory T-cells. α-MSH functions by binding to and activating melanocortin receptors (MC1R to MC5R) and receptor accessory proteins (MRAPs) that work in concert with antagonists, otherwise known as the melanocortin system. As well as controlling immune responses and inflammation, a broad range of biological functions is increasingly recognised to be orchestrated by the melanocortin system within ocular tissues. This includes maintaining corneal transparency and immune privilege by limiting corneal (lymph)angiogenesis, sustaining corneal epithelial integrity, protecting corneal endothelium and potentially enhancing corneal graft survival, regulating aqueous tear secretion with implications for dry eye disease, facilitating retinal homeostasis via maintaining blood-retinal barriers, providing neuroprotection in the retina, and controlling abnormal new vessel growth in the choroid and retina. The role of melanocortin signalling in uveal melanocyte melanogenesis however remains unclear compared to its established role in skin melanogenesis. The early application of a melanocortin agonist to downregulate systemic inflammation used adrenocorticotropic hormone (ACTH)-based repository cortisone injection (RCI), but adverse side effects including hypertension, edema, and weight gain, related to increased adrenal gland corticosteroid production, impacted clinical uptake. Compared to ACTH, melanocortin peptides that target MC1R, MC3R, MC4R and/or MC5R, but not adrenal gland MC2R, induce minimal corticosteroid production with fewer adverse systemic effects. Pharmacological advances in synthesising MCR-specific targeted peptides provide further opportunities for treating ocular (and systemic) inflammatory diseases. Following from these observations and a renewed clinical and pharmacological interest in the diverse biological roles of the melanocortin system, this review highlights the physiological and disease-related involvement of this system within human eye tissues. We also review the emerging benefits and versatility of melanocortin receptor targeted peptides as non-steroidal alternatives for inflammatory eye diseases such as non-infectious uveitis and dry eye disease, and translational applications in promoting ocular homeostasis, for example, in corneal transplantation and diabetic retinopathy.
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Affiliation(s)
- Chieh-Lin Stanley Wu
- School of Optometry and Vision Science, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia; Save Sight Institute and Ophthalmology, The Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Department of Optometry, Asia University, Taichung, Taiwan
| | - Adrian V Cioanca
- Save Sight Institute and Ophthalmology, The Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; John Curtin School of Medical Research, The Australian National University, ACT, Australia; ANU Medical School, The Australian National University, ACT, Australia
| | - Maria C Gelmi
- Department of Ophthalmology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Li Wen
- New South Wales Organ and Tissue Donation Service, Sydney Hospital and Sydney Eye Hospital, NSW, 2000, Australia
| | - Nick Di Girolamo
- School of Biomedical Sciences, Mechanisms of Disease and Translational Research, University of New South Wales, Sydney, Australia
| | - Ling Zhu
- Save Sight Institute and Ophthalmology, The Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Riccardo Natoli
- Save Sight Institute and Ophthalmology, The Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; John Curtin School of Medical Research, The Australian National University, ACT, Australia; ANU Medical School, The Australian National University, ACT, Australia
| | - R Max Conway
- Save Sight Institute and Ophthalmology, The Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Constantinos Petsoglou
- Save Sight Institute and Ophthalmology, The Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; New South Wales Organ and Tissue Donation Service, Sydney Hospital and Sydney Eye Hospital, NSW, 2000, Australia
| | - Martine J Jager
- Department of Ophthalmology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Peter J McCluskey
- Save Sight Institute and Ophthalmology, The Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Michele C Madigan
- School of Optometry and Vision Science, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia; Save Sight Institute and Ophthalmology, The Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
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16
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Khodeneva N, Sugimoto MA, Davan-Wetton CSA, Montero-Melendez T. Melanocortin therapies to resolve fibroblast-mediated diseases. Front Immunol 2023; 13:1084394. [PMID: 36793548 PMCID: PMC9922712 DOI: 10.3389/fimmu.2022.1084394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 11/28/2022] [Indexed: 02/01/2023] Open
Abstract
Stromal cells have emerged as central drivers in multiple and diverse diseases, and consequently, as potential new cellular targets for the development of novel therapeutic strategies. In this review we revise the main roles of fibroblasts, not only as structural cells but also as players and regulators of immune responses. Important aspects like fibroblast heterogeneity, functional specialization and cellular plasticity are also discussed as well as the implications that these aspects may have in disease and in the design of novel therapeutics. An extensive revision of the actions of fibroblasts on different conditions uncovers the existence of numerous diseases in which this cell type plays a pathogenic role, either due to an exacerbation of their 'structural' side, or a dysregulation of their 'immune side'. In both cases, opportunities for the development of innovative therapeutic approaches exist. In this regard, here we revise the existing evidence pointing at the melanocortin pathway as a potential new strategy for the treatment and management of diseases mediated by aberrantly activated fibroblasts, including scleroderma or rheumatoid arthritis. This evidence derives from studies involving models of in vitro primary fibroblasts, in vivo models of disease as well as ongoing human clinical trials. Melanocortin drugs, which are pro-resolving mediators, have shown ability to reduce collagen deposition, activation of myofibroblasts, reduction of pro-inflammatory mediators and reduced scar formation. Here we also discuss existing challenges, both in approaching fibroblasts as therapeutic targets, and in the development of novel melanocortin drug candidates, that may help advance the field and deliver new medicines for the management of diseases with high medical needs.
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Perretti M, Dalli J. Resolution Pharmacology: Focus on Pro-Resolving Annexin A1 and Lipid Mediators for Therapeutic Innovation in Inflammation. Annu Rev Pharmacol Toxicol 2023; 63:449-469. [PMID: 36151051 DOI: 10.1146/annurev-pharmtox-051821-042743] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Chronic diseases that affect our society are made more complex by comorbidities and are poorly managed by the current pharmacology. While all present inflammatory etiopathogeneses, there is an unmet need for better clinical management of these diseases and their multiple symptoms. We discuss here an innovative approach based on the biology of the resolution of inflammation. Studying endogenous pro-resolving peptide and lipid mediators, how they are formed, and which target they interact with, can offer innovative options through augmenting the expression or function of pro-resolving pathways or mimicking their actions with novel targeted molecules. In all cases, resolution offers innovation for the treatment of the primary cause of a given disease and/or for the management of its comorbidities, ultimately improving patient quality of life. By implementing resolution pharmacology, we harness the whole physiology of inflammation, with the potential to bring a marked change in the management of inflammatory conditions.
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Affiliation(s)
- Mauro Perretti
- The William Harvey Research Institute, Faculty of Medicine and Dentistry, and Centre for Inflammation and Therapeutic Innovation, Queen Mary University of London, London, United Kingdom; ,
| | - Jesmond Dalli
- The William Harvey Research Institute, Faculty of Medicine and Dentistry, and Centre for Inflammation and Therapeutic Innovation, Queen Mary University of London, London, United Kingdom; ,
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18
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Rivera PA, Gupta A, Kombo N. Treatment of non-infectious retinal vasculitis. Ther Adv Ophthalmol 2023; 15:25158414231152761. [PMID: 37077655 PMCID: PMC10107051 DOI: 10.1177/25158414231152761] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 01/05/2023] [Indexed: 02/16/2023] Open
Abstract
Retinal vasculitis (RV) refers to an entity in which the retinal vasculature is inflamed, frequently with indications of inflammation elsewhere in the eye. Non-infectious RV can be idiopathic or associated with systemic disease, ocular conditions, and malignancy. It can also be classified based on the vessel affected: artery, vein, or both. Due to the lack of strong evidence-based treatment trials and algorithms for RV, physicians must often rely on their experience, which creates great variability in treating this entity. This article provides an overview of various treatment modalities used in the management of non-infectious RV, with a focus on immunomodulatory therapies. We outline a potential stepwise approach of starting with steroids to control the acute inflammation and subsequently changing to immunomodulatory therapy (IMT) for long-term treatment.
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Affiliation(s)
- Paola A. Rivera
- Department of Ophthalmology and Visual Science, School of Medicine, Yale University, New Haven, CT, USA
| | - Akash Gupta
- Department of Medicine, School of Medicine, Yale University, New Haven, CT 06510, USA
| | - Ninani Kombo
- Department of Ophthalmology and Visual Science, School of Medicine, Yale University, New Haven, CT, USA
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Perretti M, Subramanian M. Resolution pharmacology - A fresh approach to the clinical management of human inflammatory diseases. Semin Immunol 2023; 65:101669. [PMID: 36565567 DOI: 10.1016/j.smim.2022.101669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Mauro Perretti
- The William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom.
| | - Manikandan Subramanian
- The William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom.
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Iliopoulos G, Daoussis D. FDA-APPROVED INDICATIONS OF ADRENOCORTICOTROPIC HORMONE (ACTH) AS A DRUG: DOES IT HAVE A PLACE IN DISEASE MANAGEMENT TODAY? CENTRAL ASIAN JOURNAL OF MEDICAL HYPOTHESES AND ETHICS 2022. [DOI: 10.47316/cajmhe.2022.3.4.01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2023] Open
Abstract
ACTH is a pituitary hormone important for proper function of adrenal glands, cortisol production as well as human physiology in general. It is involved in the pathogenesis of several endocrine disorders like Cushing syndrome and can be a useful diagnostic tool for diseases like primary adrenal insufficiency. Although popular as a hormone in endocrine system physiology and testing, ACTH has been used as a drug since the 1950s. Except for steroid-releasing properties, its mechanism of action involves a steroid-independent anti-inflammatory and possible immune-modulatory effect. Pharmaceutic ACTH has a wide range of indications approved by FDA and usually comes in the form of subcutaneous injections. In this narrative review, we accumulated what we considered as important data from reviews, cases and trials involving the most basic FDA-approved ACTH indications. A special emphasis was given on rheumatologic indications of ACTH. More large data studies need to be performed to assess ACTH usefulness, efficacy, safety and cost-effectiveness as a drug.
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Garrido-Mesa J, Thomas BL, Dodd J, Spana C, Perretti M, Montero-Melendez T. Pro-resolving and anti-arthritic properties of the MC 1 selective agonist PL8177. Front Immunol 2022; 13:1078678. [PMID: 36505403 PMCID: PMC9730523 DOI: 10.3389/fimmu.2022.1078678] [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: 10/24/2022] [Accepted: 11/07/2022] [Indexed: 11/25/2022] Open
Abstract
Background Melanocortins are peptides endowed with anti-inflammatory and pro-resolving activities. Many of these effects are mediated by the Melanocortin receptor 1 (MC1) as reported in several experimental settings. As such, MC1 can be a viable target for the development of new therapies that mimic endogenous pro-resolving mediators. The aim of this study was to assess the immunopharmacology of a selective MC1 agonist (PL8177) in vitro and in a mouse model of inflammatory arthritis. Methods PL8177 and the natural agonist αMSH were tested for activation of mouse and human Melanocortin receptors (MC1,3,4,5), monitoring cAMP accumulation and ERK1/2 phosphorylation, using transiently transfected HEK293A cells. The anti-inflammatory and pro-resolving effects of PL8177 and αMSH were evaluated using mouse peritoneal Macrophages. Finally, a model of K/BxN serum transfer induced arthritis was used to determine the in vivo potential of PL8177. Results PL8177 activates mouse and human MC1 with apparent EC50 values of 0.01 and 1.49 nM, respectively, using the cAMP accumulation assay. Similar profiles were observed for the induction of ERK phosphorylation (EC50: 0.05 and 1.39 nM). PL8177 displays pro-resolving activity (enhanced Macrophage efferocytosis) and counteracts the inflammatory profile of zymosan-stimulated macrophages, reducing the release of IL-1β, IL-6, TNF-α and CCL-2. In the context of joint inflammation, PL8177 (3mg/kg i.p.) reduces clinical score, paw swelling and incidence of severe disease as well as the recruitment of immune cells into the arthritic joint. Conclusion These results demonstrate that the MC1 agonism with PL8177 affords therapeutic effects in inflammatory conditions including arthritis. Significance Drugs targeting the Melanocortin system have emerged as promising therapeutics for several conditions including inflammation or obesity. Multiple candidates are under clinical development, and some have already reached approval. Here we present the characterization of a novel drug candidate, PL8177, selective for the Melanocortin 1 receptor (MC1), demonstrating its selectivity profile on cAMP and ERK1/2 phosphorylation signaling pathways, of relevance as selective drugs will translate into lesser off-target effect. PL8177 also demonstrated, not only anti-inflammatory activity, but pro-resolving actions due to its ability to enhance efferocytosis (i.e. the phagocytosis of apoptotic cells), endowing this molecule with therapeutic advantages compared to classical anti-inflammatory drugs. Using a mouse model of inflammatory arthritis, the compound demonstrated in vivo efficacy by reducing clinical score, paw swelling and overall disease severity. Taken together, these results present Melanocortin-based therapies, and specifically targeting MC1 receptor, as a promising strategy to manage chronic inflammatory diseases.
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Affiliation(s)
- Jose Garrido-Mesa
- The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Bethan Lynne Thomas
- The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - John Dodd
- Palatin Technologies, Inc., Cranbury, NJ, United States
| | - Carl Spana
- Palatin Technologies, Inc., Cranbury, NJ, United States
| | - Mauro Perretti
- The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom,Centre for inflammation and Therapeutic Innovation, Queen Mary University of London, London, United Kingdom
| | - Trinidad Montero-Melendez
- The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom,Centre for inflammation and Therapeutic Innovation, Queen Mary University of London, London, United Kingdom,*Correspondence: Trinidad Montero-Melendez,
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22
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Yuan XC, Tao YX. Ligands for Melanocortin Receptors: Beyond Melanocyte-Stimulating Hormones and Adrenocorticotropin. Biomolecules 2022; 12:biom12101407. [PMID: 36291616 PMCID: PMC9599618 DOI: 10.3390/biom12101407] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/25/2022] [Accepted: 09/28/2022] [Indexed: 11/16/2022] Open
Abstract
The discovery of melanocortins in 1916 has resulted in more than 100 years of research focused on these peptides. Extensive studies have elucidated well-established functions of melanocortins mediated by cell surface receptors, including MSHR (melanocyte-stimulating hormone receptor) and ACTHR (adrenocorticotropin receptor). Subsequently, three additional melanocortin receptors (MCRs) were identified. Among these five MCRs, MC3R and MC4R are expressed primarily in the central nervous system, and are therefore referred to as the neural MCRs. Since the central melanocortin system plays important roles in regulating energy homeostasis, targeting neural MCRs is emerging as a therapeutic approach for treating metabolic conditions such as obesity and cachexia. Early efforts modifying endogenous ligands resulted in the development of many potent and selective ligands. This review focuses on the ligands for neural MCRs, including classical ligands (MSH and agouti-related peptide), nonclassical ligands (lipocalin 2, β-defensin, small molecules, and pharmacoperones), and clinically approved ligands (ACTH, setmelanotide, bremelanotide, and several repurposed drugs).
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Affiliation(s)
- Xiao-Chen Yuan
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230061, China
| | - Ya-Xiong Tao
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
- Correspondence:
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Wu F, Liu Z, Zhou L, Ye D, Zhu Y, Huang K, Weng Y, Xiong X, Zhan R, Shen J. Systemic immune responses after ischemic stroke: From the center to the periphery. Front Immunol 2022; 13:911661. [PMID: 36211352 PMCID: PMC9533176 DOI: 10.3389/fimmu.2022.911661] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 07/18/2022] [Indexed: 12/01/2022] Open
Abstract
Ischemic stroke is a leading cause of disability and death. It imposes a heavy economic burden on individuals, families and society. The mortality rate of ischemic stroke has decreased with the help of thrombolytic drug therapy and intravascular intervention. However, the nerve damage caused by ischemia-reperfusion is long-lasting and followed by multiple organ dysfunction. In this process, the immune responses manifested by systemic inflammatory responses play an important role. It begins with neuroinflammation following ischemic stroke. The large number of inflammatory cells released after activation of immune cells in the lesion area, along with the deactivated neuroendocrine and autonomic nervous systems, link the center with the periphery. With the activation of systemic immunity and the emergence of immunosuppression, peripheral organs become the second “battlefield” of the immune response after ischemic stroke and gradually become dysfunctional and lead to an adverse prognosis. The purpose of this review was to describe the systemic immune responses after ischemic stroke. We hope to provide new ideas for future research and clinical treatments to improve patient outcomes and quality of life.
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Affiliation(s)
- Fan Wu
- Department of Neurosurgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zongchi Liu
- Department of Neurosurgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lihui Zhou
- Department of Neurosurgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Di Ye
- Department of Neurosurgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yu Zhu
- Department of Neurosurgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Kaiyuan Huang
- Department of Neurosurgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yuxiang Weng
- Department of Neurosurgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoxing Xiong
- Department of Clinical Laboratory, Renmin Hospital, Faculty of Medical Sciences, Wuhan University, Wuhan, China
| | - Renya Zhan
- Department of Neurosurgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Jian Shen, ; Renya Zhan,
| | - Jian Shen
- Department of Neurosurgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Jian Shen, ; Renya Zhan,
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24
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Zhao J, Wei K, Jiang P, Chang C, Xu L, Xu L, Shi Y, Guo S, He D. G-Protein-Coupled Receptors in Rheumatoid Arthritis: Recent Insights into Mechanisms and Functional Roles. Front Immunol 2022; 13:907733. [PMID: 35874704 PMCID: PMC9304905 DOI: 10.3389/fimmu.2022.907733] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 06/20/2022] [Indexed: 12/24/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joint damage and even disability. Although there are various clinical therapies for RA, some patients still have poor or no response. Thus, the development of new drug targets remains a high priority. In this review, we discuss the role of G-protein-coupled receptors (GPCRs), including chemokine receptors, melanocortin receptors, lipid metabolism-related receptors, adenosine receptors, and other inflammation-related receptors, on mechanisms of RA, such as inflammation, lipid metabolism, angiogenesis, and bone destruction. Additionally, we summarize the latest clinical trials on GPCR targeting to provide a theoretical basis and guidance for the development of innovative GPCR-based clinical drugs for RA.
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Affiliation(s)
- Jianan Zhao
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Kai Wei
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Ping Jiang
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Cen Chang
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Lingxia Xu
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Linshuai Xu
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Yiming Shi
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Shicheng Guo
- Computation and Informatics in Biology and Medicine, University of Wisconsin-Madison, Madison, WI, United States
- Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
- *Correspondence: Shicheng Guo, ; Dongyi He,
| | - Dongyi He
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
- Arthritis Institute of Integrated Traditional and Western Medicine, Shanghai Chinese Medicine Research Institute, Shanghai, China
- *Correspondence: Shicheng Guo, ; Dongyi He,
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25
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Webber T, Ronacher K, Conradie-Smit M, Kleynhans L. Interplay Between the Immune and Endocrine Systems in the Lung: Implications for TB Susceptibility. Front Immunol 2022; 13:829355. [PMID: 35273609 PMCID: PMC8901994 DOI: 10.3389/fimmu.2022.829355] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 02/02/2022] [Indexed: 12/25/2022] Open
Abstract
The role of the endocrine system on the immune response, especially in the lung, remains poorly understood. Hormones play a crucial role in the development, homeostasis, metabolism, and response to the environment of cells and tissues. Major infectious and metabolic diseases, such as tuberculosis and diabetes, continue to converge, necessitating the development of a clearer understanding of the immune and endocrine interactions that occur in the lung. Research in bacterial respiratory infections is at a critical point, where the limitations in identifying and developing antibiotics is becoming more profound. Hormone receptors on alveolar and immune cells may provide a plethora of targets for host-directed therapy. This review discusses the interactions between the immune and endocrine systems in the lung. We describe hormone receptors currently identified in the lungs, focusing on the effect hormones have on the pulmonary immune response. Altered endocrine responses in the lung affect the balance between pro- and anti-inflammatory immune responses and play a role in the response to infection in the lung. While some hormones, such as leptin, resistin and lipocalin-2 promote pro-inflammatory responses and immune cell infiltration, others including adiponectin and ghrelin reduce inflammation and promote anti-inflammatory cell responses. Furthermore, type 2 diabetes as a major endocrine disease presents with altered immune responses leading to susceptibility to lung infections, such as tuberculosis. A better understanding of these interactions will expand our knowledge of the mechanisms at play in susceptibility to infectious diseases and may reveal opportunities for the development of host-directed therapies.
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Affiliation(s)
- Tariq Webber
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Katharina Ronacher
- Translational Research Institute, Mater Research Institute - The University of Queensland, Brisbane, QLD, Australia
| | - Marli Conradie-Smit
- Division of Endocrinology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Léanie Kleynhans
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
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26
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Busch H, Wan GJ, Niewoehner J, Houston P, Su Y, Clinton C, Panaccio MP. Real-world treatment patterns for repository corticotropin injection in patients with rheumatoid arthritis. Drugs Context 2022; 11:dic-2021-10-4. [PMID: 35382109 PMCID: PMC8966709 DOI: 10.7573/dic.2021-10-4] [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: 10/11/2021] [Accepted: 02/11/2022] [Indexed: 11/21/2022] Open
Abstract
Introduction Repository corticotropin injection (RCI, Acthar® Gel) is a naturally sourced mixture of adrenocorticotropic hormone analogues and other pituitary peptides with anti-inflammatory and immunomodulatory effects. In a recent clinical trial, RCI was safe and effective for the treatment of refractory rheumatoid arthritis (RA). This study aims to describe real-world use and outcomes of patients with RA who were prescribed RCI in clinical practice through retrospective analysis of an electronic medical record database. Methods Patients with RA who were prescribed RCI were identified through the ColumbusTM electronic medical record repository, representing approximately 100 rheumatology practices. Demographics, medications, comorbidities, disease histories, laboratory evaluations, clinical outcomes and patient-reported outcomes were evaluated from 12 months pre-RCI to 12 months post-RCI initiation. Results The RCI cohort (n=63) comprised predominantly white women, aged 54 years on average, at 6 years from RA diagnosis, with high disease activity at baseline according to Clinical Disease Activity Index (CDAI) and Routine Assessment of Patient Index Data 3 (RAPID3) scores. Within the 12 months pre-RCI initiation, 87% of patients were prescribed disease-modifying antirheumatic drugs and 67% were prescribed glucocorticoids. Twelve months post-RCI initiation, glucocorticoid, opioid and non-steroidal anti-inflammatory drug prescriptions decreased; disease-modifying antirheumatic drug prescriptions remained stable. Reductions in CDAI, RAPID3, physician global assessment, tender joint count, swollen joint count, and pain visual analogue scale scores were observed 12 months post-RCI initiation. Few discontinuations were due to side effects. Study limitations included small sample size and incomplete electronic medical record data. Conclusion These findings support the safety and effectiveness of RCI for short-term adjunctive treatment of refractory RA and provide patient-management insights from routine clinical practice.
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Affiliation(s)
- Howard Busch
- American Arthritis and Rheumatology Associates LLC, Loxahatchee, FL, USA
| | | | | | | | - Yujie Su
- University of Alabama at Birmingham, Birmingham, AL, USA
| | - Cassie Clinton
- University of Alabama at Birmingham, Birmingham, AL, USA
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27
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Lan J, Wang M, Qin K, Liu X, Shi X, Sun G, Liu X, Chen Y, He Z. Functional characterization of cAMP signaling of variant porcine MC1R alleles in PK15 cells. Anim Genet 2022; 53:317-326. [PMID: 35292981 DOI: 10.1111/age.13189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 01/21/2022] [Accepted: 03/01/2022] [Indexed: 11/28/2022]
Abstract
The melanocortin 1 receptor (MC1R), encoded by the classical extension (E) coat color locus, is expressed on the surface of melanocytes and plays a critical role in switching melanin synthesis from pheomelanin (red/yellow) to eumelanin (black/brown). Different MC1R alleles associated with various coat color patterns in pigs have been identified over the past decades. However, functional analysis of variant porcine MC1R alleles has not yet been performed. Therefore, in this study, we examined the subcellular localization and cyclic adenosine monophosphate (cAMP) signaling capability of MC1R variants in porcine kidney epithelial cells (PK15) overexpressing different MC1R alleles. Transcriptional slippage may partially restore the reading frame of the EP allele, possibly accounting for the observed spot phenotype. The A243T substitution in the e allele severely disrupted the membrane localization of the MC1R receptor, resulting in a severely impaired cAMP signaling capability. Both the V95M and L102P substitutions in the ED1 allele may contribute to the constitutively active function of MC1R, thus accounting for the dominant black phenotype. The D124N substitution in the ED2 allele severely attenuated the cAMP signaling capability of MC1R; however, whether this mutation contributes to the distinct phenotype of Hampshire pigs requires further investigation. Thus, our results provide new insights into the functional characteristics of MC1R variants and their roles in porcine coat color formation.
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Affiliation(s)
- Jin Lan
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Min Wang
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Ke Qin
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Xiaofeng Liu
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Xuan Shi
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Guanjie Sun
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Xiaohong Liu
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Yaosheng Chen
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Zuyong He
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China
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28
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Sun J, Sun J. How neuroactive factors mediates immune responses during pregnancy: An interdisciplinary view. Neuropeptides 2022; 91:102213. [PMID: 34839164 DOI: 10.1016/j.npep.2021.102213] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 10/25/2021] [Accepted: 11/18/2021] [Indexed: 11/25/2022]
Abstract
Pregnancy, from insemination to parturition, is a highly complex but well-orchestrated process that requires various organs and systems to participate. Immune system and neuroendocrine system are important regulators in healthy pregnancy. Dozens of neuroactive factors have been detected in human placenta, whether they are locally secreted or circulated. Among them, some are vividly studied such as corticotropin-releasing hormone (CRH), human chorionic gonadotropin (hCG), transforming growth factor-β (TGF-β), progesterone and estrogens, while others are relatively lack of research. Though the neuroendocrine-immune interactions are demonstrated in some diseases for decades, the roles of neuroactive factors in immune system and lymphocytes during pregnancy are not fully elucidated. This review aims to provide an interdisciplinary view on how the neuroendocrine system mediate immune system during pregnancy process.
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Affiliation(s)
- Jiani Sun
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Jing Sun
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
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29
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Sharon Y, Anesi SD, Martinez CE, Huang AJW, Foster CS, Chu DS. Repository Corticotropin Injection as an Alternative Treatment for Refractory Ocular Mucous Membrane Pemphigoid. Cornea 2022; 41:45-51. [PMID: 34050065 DOI: 10.1097/ico.0000000000002771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 04/03/2021] [Indexed: 11/26/2022]
Abstract
PURPOSE The purpose of this study was to report the clinical course and outcome of patients with refractory ocular mucous membrane pemphigoid (MMP) treated by repository corticotropin injection (RCI). METHODS Patients with biopsy-proven ocular MMP treated with RCI from 3 tertiary medical centers were evaluated. Medical records between January 2013 and January 2021 were reviewed and deidentified to retrieve relevant disease-related data. Primary outcome measures included conjunctival inflammatory activity, change in Foster clinical conjunctival scarring staging after RCI treatment, and the development of ocular and systemic complications. RESULTS Included were 15 patients (10 women and 5 men; 36-95 yrs of age) with a mean follow-up of 4.5 years. Most of the patients (80%) had Foster stage 3 at presentation, and all patients had active MMP. Each patient had failed to respond to at least 1 immunomodulatory drug during the follow-up, and 9 (60%) patients had treatment failure of at least 2 other agents before the use of RCI. The mean duration of RCI treatment was 21 months (range, 3-54 mo). Foster stage did not change in any of the 15 patients at the last follow-up. Nine patients continued RCI therapy at the last follow-up, and in all of them, the disease activity of MMP was well controlled. No serious adverse events because of RCI were documented during the follow-up in any treated patient. CONCLUSIONS RCI may serve as an alternative or an adjunctive treatment in patients with severe and refractory ocular MMP. Treatment with RCI seems to be safe and well-tolerated.
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Affiliation(s)
- Yael Sharon
- Department of Ophthalmology, Rabin Medical Center, Petah-Tikva, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Metropolitan Eye Research and Surgery Institute, Palisades Park, NJ
| | - Stephen D Anesi
- Massachusetts Eye Research and Surgery Institution (MERSI), Waltham, MA
- Ocular Immunology and Uveitis Foundation (OIUF), Waltham, MA
| | - Christine E Martinez
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO
- Department of Ophthalmology and Visual Sciences, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Andrew J W Huang
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO
| | - Charles Stephen Foster
- Massachusetts Eye Research and Surgery Institution (MERSI), Waltham, MA
- Ocular Immunology and Uveitis Foundation (OIUF), Waltham, MA
- Department of Ophthalmology, Harvard Medical School, Boston, MA; and
| | - David S Chu
- Metropolitan Eye Research and Surgery Institute, Palisades Park, NJ
- Institute of Ophthalmology and Visual Science, New Jersey Medical School, Rutgers University, Newark, NJ
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Translational advances of melanocortin drugs: Integrating biology, chemistry and genetics. Semin Immunol 2022; 59:101603. [PMID: 35341670 DOI: 10.1016/j.smim.2022.101603] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 03/10/2022] [Accepted: 03/15/2022] [Indexed: 01/15/2023]
Abstract
Melanocortin receptors have emerged as important targets with a very unusual versatility, as their widespread distribution on multiple tissues (e.g. skin, adrenal glands, brain, immune cells, exocrine glands) together with the variety of physiological processes they control (pigmentation, cortisol release, satiety mechanism, inflammation, secretions), place this family of receptors as genuine therapeutic targets for many disorders. This review focuses in the journey of the development of melanocortin receptors as therapeutic targets from the discovery of their existence in the early 1990 s to the approval of the first few drugs of this class. Two major areas of development characterise the current state of melanocortin drug development: their role in obesity, recently culminated with the approval of setmelanotide, and their potential for the treatment of chronic inflammatory and autoimmune diseases like rheumatoid arthritis, multiple sclerosis or fibrosis. The pro-resolving nature of these drugs offers the advantage of acting by mimicking the way our body naturally resolves inflammation, expecting fewer side effects and a more balanced (i.e. non-immunosuppressive) response from them. Here we also review the approaches followed for the design and development of novel compounds, the importance of the GPCR nature of these receptors in the process of drug development, therapeutic value, current challenges and successes, and the potential for the implementation of precision medicine approaches through the incorporation of genetics advances.
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Zeng R, Glaubitz S, Schmidt J. Inflammatory myopathies: shedding light on promising agents and combination therapies in clinical trials. Expert Opin Investig Drugs 2021; 30:1125-1140. [PMID: 34779311 DOI: 10.1080/13543784.2021.2003776] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Due to new insights into the pathogenesis of inflammatory myopathies - in short myositis - and the urgent need for new treatment options in patients who are refractory to standard therapy, multiple novel drugs have been developed and studied in clinical trials. In light of this exciting development, a critical evaluation of the present data is necessary in order to identify the best pathway to future treatment of inflammatory myopathies. AREAS COVERED This review focuses on the current evidence from clinical trials in myositis and encompasses dermatomyositis, polymyositis, necrotizing myopathy, antisynthetase-syndrome, overlap myositis, and inclusion body myositis. The results of studies on new therapeutic agents are summarized, in particular larger cohort studies and randomized trials from recent years. When such data were not available, earlier and smaller representative studies were included instead. EXPERT OPINION Current studies in most myositis subtypes have shown positive effects of novel biologicals such as abatacept, sifalimumab, JAK-Inhibitors as well as known agents such as rituximab, but further studies are needed to confirm these observations. In inclusion body myositis, the eagerly awaited recent therapeutic trials have missed their primary endpoints, except for the phase 2 study with rapamycin, which has demonstrated significant improvements in secondary endpoints. Future trials will also need to focus on combination therapies of multiple immunomodulatory agents.
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Affiliation(s)
- Rachel Zeng
- Muscle Immunobiology Group, Department of Neurology, Neuromuscular Center, University Medical Center Göttingen, Göttingen, Germany
| | - Stefanie Glaubitz
- Muscle Immunobiology Group, Department of Neurology, Neuromuscular Center, University Medical Center Göttingen, Göttingen, Germany
| | - Jens Schmidt
- Muscle Immunobiology Group, Department of Neurology, Neuromuscular Center, University Medical Center Göttingen, Göttingen, Germany.,Department of Neurology and Pain Treatment, University Hospital of the Medical School Brandenburg, Immanuel Klinik Rüdersdorf, Rüdersdorf bei Berlin, Germany.,Faculty of Health Sciences Brandenburg, Brandenburg Medical School Theodor Fontane, Rüdersdorf bei Berlin, Germany
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32
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Gandhi F, Jhaveri S, Avanthika C, Singh A, Jain N, Gulraiz A, Shah P, Nasir F. Impact of Vitamin D Supplementation on Multiple Sclerosis. Cureus 2021; 13:e18487. [PMID: 34754649 PMCID: PMC8567111 DOI: 10.7759/cureus.18487] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/04/2021] [Indexed: 12/14/2022] Open
Abstract
Multiple sclerosis (MS) is an autoimmune disease affecting a large number of people every year. The exact causal factor for this disease is unclear, but it commonly affects middle-aged women, with known triggers like stress, childbirth, infections, poor diet, lack of sleep, etc. Many epidemiological studies have indicated that various genetic abnormalities are also critical drivers of the onset of MS. The major risk factors of MS identified include hypovitaminosis D while environmental protective factors include allele HLA DRB1 1501, obesity, Epstein-Barr virus infection, sexual hormones, and smoking. Our article explores the correlation between the deficiency of vitamin D and the onset and progression of MS. The study uses a systematic review methodology by researching and reviewing scholarly articles exploring the topic. We conducted online searches of literature on Google Scholar and PubMed using the keywords "vitamin D deficiency" and "multiple sclerosis" and accessed the relevant secondary literature sources for review. The variables under study included vitamin D insufficiency as the dependent variable while MS was the independent variable. Causal variables included environmental, genetic, and protective factors. We hypothesized that there is indeed a correlation between vitamin D deficiency and MS. The findings from our review indicate a strong correlation between the insufficiency of vitamin D and the onset and progression of MS. These results are essential in devising interventions to accomplish primary and secondary prevention of MS, as well as integrating vitamin D supplementation in current treatment protocols for MS.
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Affiliation(s)
- Fenil Gandhi
- Internal Medicine, Shree Krishna Hospital, Anand, IND
| | - Sharan Jhaveri
- Internal Medicine, Nathiba Hargovandas Lakhmichand Municipal Medical College, Ahmedabad, IND
| | - Chaithanya Avanthika
- Medicine and Surgery, Karnataka Institute of Medical Sciences, Hubli, IND.,Pediatrics, Karnataka Institute of Medical Sciences, Hubli, IND
| | - Abhishek Singh
- Internal Medicine, Mount Sinai Morningside, New York City, USA
| | - Nidhi Jain
- Internal Medicine, Sir Ganga Ram Hospital, New Delhi, IND
| | - Azouba Gulraiz
- Medicine, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA
| | | | - Fareeha Nasir
- Internal Medicine, Harlem Hospital Center, New York City, USA
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Modelling and Control of Corticotropin Permeation from Hydrogels across a Natural Membrane in the Presence of Albumin. Processes (Basel) 2021. [DOI: 10.3390/pr9091674] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
(1) Background: Skin is a difficult barrier to overcome, especially for molecules with masses greater than 500 Da. It has been suggested that albumin may contribute to more effective penetration of many therapeutic substances. In this study, an attempt was made to use albumin in semi-solid formulations to increase the skin penetration of another peptide—corticotropin (ACTH). (2) Methods: Hydrogels were prepared at two concentrations: 15 mg/g and 20 mg/g corticotropin, then albumin was added to them in different stoichiometric ratios. The degree of ACTH release from hydrogels, both with and without albumin addition, was investigated. For selected hydrogels the process of corticotropin permeation through a model membrane, i.e., pig skin, was examined. (3) Results: The study of corticotropin release showed that the addition of albumin, depending on its amount, may delay or increase the release process. Similarly, a study of ACTH permeation through porcine skin showed that albumin can delay or increase and accelerate ACTH permeation. (4) Conclusions: Hydrogel, applicated on the skin surface, may prove to be a beneficial and convenient solution for patients. It is an innovative way of application ACTH that bypasses the gastrointestinal tract and may result in increased availability of the peptide and its efficacy.
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Ashwal S, Siebold L, Krueger AC, Wilson CG. Post-traumatic Neuroinflammation: Relevance to Pediatrics. Pediatr Neurol 2021; 122:50-58. [PMID: 34304972 DOI: 10.1016/j.pediatrneurol.2021.04.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 04/19/2021] [Accepted: 04/20/2021] [Indexed: 10/21/2022]
Abstract
Both detrimental and beneficial effects of post-traumatic neuroinflammation have become a major research focus as they offer the potential for immediate as well as delayed targeted reparative therapies. Understanding the complex interactions of central and peripheral immunocompetent cells as well as their mediators on brain injury and recovery is complicated by the temporal, regional, and developmental differences in their response to injuries. Microglia, the brain-resident macrophages, have become central in these investigations as they serve a major surveillance function, have the ability to react swiftly to injury, recruit various cellular and chemical mediators, and monitor the reparative/degenerative processes. In this review we describe selected aspects of this burgeoning literature, describing the critical role of cytokines and chemokines, microglia, advances in neuroimaging, genetics and fractal morphology analysis, our research efforts in this area, and selected aspects of pediatric post-traumatic neuroinflammation.
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Affiliation(s)
- Stephen Ashwal
- Department of Pediatrics, Loma Linda University, School of Medicine, Loma Linda, California.
| | - Lorraine Siebold
- Department of Pediatrics, Loma Linda University, School of Medicine, Loma Linda, California
| | - A Camille Krueger
- Department of Pediatrics, Loma Linda University, School of Medicine, Loma Linda, California
| | - Christopher G Wilson
- Department of Pediatrics, Loma Linda University, School of Medicine, Loma Linda, California
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Vago JP, Amaral FA, van de Loo FAJ. Resolving inflammation by TAM receptor activation. Pharmacol Ther 2021; 227:107893. [PMID: 33992683 DOI: 10.1016/j.pharmthera.2021.107893] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/06/2021] [Accepted: 05/10/2021] [Indexed: 12/12/2022]
Abstract
The control of inflammation is strictly regulated to ensure the adequate intensity and duration of an inflammatory response, enabling the removal of the trigger factors and the restoration of the integrity of the tissues and their functions. This process is coordinated by anti-inflammatory and pro-resolving mediators that regulate the cellular and molecular events necessary to restore homeostasis, and defects in this control are associated with the development of chronic and autoimmune diseases. The TAM family of receptor tyrosine kinases-Tyro3, Axl, and MerTK-plays an essential role in efferocytosis, a key process for the resolution of inflammation. However, new studies have demonstrated that TAM receptor activation not only reduces the synthesis of pro-inflammatory mediators by different cell types in response to some stimuli but also stimulates the production of anti-inflammatory and pro-resolving molecules that control the inflammation. This review provides a comprehensive view of TAM receptor family members as important players in controlling inflammatory responses through anti-inflammatory and pro-resolving actions.
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Affiliation(s)
- Juliana P Vago
- Experimental Rheumatology, Department of Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, the Netherlands
| | - Flávio A Amaral
- Experimental Rheumatology, Department of Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, the Netherlands; Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Fons A J van de Loo
- Experimental Rheumatology, Department of Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, the Netherlands.
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Modulating skin colour: role of the thioredoxin and glutathione systems in regulating melanogenesis. Biosci Rep 2021; 41:228417. [PMID: 33871027 PMCID: PMC8112849 DOI: 10.1042/bsr20210427] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/09/2021] [Accepted: 04/19/2021] [Indexed: 01/23/2023] Open
Abstract
Different skin colour among individuals is determined by the varying amount and types of melanin pigment. Melanin is produced in melanocytes, a type of dendritic cell located in the basal layer of the epidermis, through the process of melanogenesis. Melanogenesis consists of a series of biochemical and enzymatic reactions catalysed by tyrosinase and other tyrosinase-related proteins, leading to the formation of two types of melanin, eumelanin and pheomelanin. Melanogenesis can be regulated intrinsically by several signalling pathways, including the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA), stem cell factor (SCF)/c-kit and wingless-related integration site (Wnt)/β-catenin signalling pathways. Ultraviolet radiation (UVR) is the major extrinsic factor in the regulation of melanogenesis, through the generation of reactive oxygen species (ROS). Antioxidants or antioxidant systems, with the ability to scavenge ROS, may decrease melanogenesis. This review focuses on the two main cellular antioxidant systems, the thioredoxin (Trx) and glutathione (GSH) systems, and discusses their roles in melanogenesis. In the Trx system, high levels/activities of thioredoxin reductase (TrxR) are correlated with melanin formation. The GSH system is linked with regulating pheomelanin formation. Exogenous addition of GSH has been shown to act as a depigmenting agent, suggesting that other antioxidants may also have the potential to act as depigmenting agents for the treatment of human hyperpigmentation disorders.
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Anesi SD, Chang PY, Maleki A, Stephenson A, Montieth A, Filipowicz A, Syeda S, Asgari S, Walsh M, Metzinger JL, Foster CS. Treatment of Noninfectious Retinal Vasculitis Using Subcutaneous Repository Corticotropin Injection. J Ophthalmic Vis Res 2021; 16:219-233. [PMID: 34055260 PMCID: PMC8126741 DOI: 10.18502/jovr.v16i2.9086] [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: 03/15/2019] [Accepted: 02/01/2021] [Indexed: 11/24/2022] Open
Abstract
PURPOSE To show whether subcutaneous repository corticotropin injection (RCI, Acthar® Gel, a repository corticotropin injection, can be an effective potential therapeutic agent for noninfectious retinal vasculitis. METHODS Patients with active retinal vasculitis were followed with serial ultra-wide-field fluorescein angiograms and treated with 80 units of subcutaneous repository corticotropin injection twice weekly. RESULTS Primary outcome of ≥ 50% improvement in response level (RL) for retinal vasculitis and percent improvement in retinal vasculitis severity scoring (RVSS) by more than one quartile ( ≥ 25%) at week 12 was met in 15 and 16 of the 30 total eyes, respectively, including 1 eye with severe retinal vasculitis in each group. Complete resolution of retinal vasculitis was seen in seven eyes with a mean time of 17.1 weeks. Intraocular pressure elevation requiring therapy and cataract progression were noted in two and three eyes, respectively. One patient stopped medication due to side effects (injection site reaction). CONCLUSION Repository corticotropin injection was well-tolerated overall. Repository corticotropin injection may be an effective therapeutic agent in the treatment of noninfectious retinal vasculitis.
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Affiliation(s)
- Stephen D. Anesi
- Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States
- The Ocular Immunology and Uveitis Foundation, Waltham, MA, United States
| | - Peter Y. Chang
- Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States
- The Ocular Immunology and Uveitis Foundation, Waltham, MA, United States
| | - Arash Maleki
- Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States
- The Ocular Immunology and Uveitis Foundation, Waltham, MA, United States
| | - Andrew Stephenson
- Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States
- The Ocular Immunology and Uveitis Foundation, Waltham, MA, United States
| | - Alyssa Montieth
- Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States
- The Ocular Immunology and Uveitis Foundation, Waltham, MA, United States
| | - Artur Filipowicz
- Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States
- The Ocular Immunology and Uveitis Foundation, Waltham, MA, United States
| | - Sarah Syeda
- Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States
- The Ocular Immunology and Uveitis Foundation, Waltham, MA, United States
| | - Soheila Asgari
- Noor Ophthalmology Research Center, Noor Eye Hospital, Tehran, Iran
| | - Marisa Walsh
- Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States
- The Ocular Immunology and Uveitis Foundation, Waltham, MA, United States
| | - Jamie Lynne Metzinger
- Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States
- The Ocular Immunology and Uveitis Foundation, Waltham, MA, United States
| | - C. Stephen Foster
- Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States
- The Ocular Immunology and Uveitis Foundation, Waltham, MA, United States
- Harvard Medical School, Department of Ophthalmology, Boston, MA, United States
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Affiliation(s)
- Mauro Perretti
- The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK. .,Centre for Inflammation and Therapeutic Innovation, Queen Mary University of London, London, UK.
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Heksch R, Bowden S, Hoffman R. Novel function of adrenocorticotropic hormone in the stimulation of vascular endothelial growth factor release in healthy children and adolescents: a proof-of-concept study. Ann Pediatr Endocrinol Metab 2021; 26:46-52. [PMID: 33541031 PMCID: PMC8026337 DOI: 10.6065/apem.2040110.055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 07/28/2020] [Accepted: 09/28/2020] [Indexed: 11/20/2022] Open
Abstract
PURPOSE To assess the effect of adrenocorticotropic hormone (ACTH) on plasma vascular endothelial growth factor (VEGF) levels in healthy children and adolescents and to inform future work on the effects of ACTH on VEGF in bone. METHODS An Institutional Review Board-approved prospective study of 10 healthy subjects, ages 9-17, was conducted to assess the effect of ACTH on plasma VEGF levels. VEGF levels were collected at baseline and every 30 minutes for 3 hours. Cosyntropin (a synthetic ACTH analogue) was administered at a low-dose (1 μg) given at t=0 minutes and a high-dose (250 μg) given at t=60 minutes. A Friedman test was performed comparing baseline to peak VEGF levels after stimulation with low-dose and high-dose cosyntropin. RESULTS Peak plasma VEGF levels significantly increased after high-dose cosyntropin compared with baseline (P=0.042). Peak plasma VEGF levels did not significantly increase after low-dose cosyntropin compared to baseline. CONCLUSION To our knowledge, this is the first study to demonstrate that ACTH administration causes a significant increase in plasma VEGF levels in humans. This finding may have important implications in the protective effects of ACTH on bone. Decreased bone mineral density and adrenal suppression are common side effects of glucocorticoid use in pediatrics. VEGF increases vascularity and may play a role in reducing glucocorticoid-induced bone disease. Animal studies have shown that ACTH stimulates release of VEGF in osteoblasts, though this effect has yet to be evaluated in humans.
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Affiliation(s)
- Ryan Heksch
- Nationwide Children's Hospital, Columbus, OH, USA
- Akron Children's Hospital, Akron, OH, USA
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Chang M, Chen B, Shaffner J, Dworkin LD, Gong R. Melanocortin System in Kidney Homeostasis and Disease: Novel Therapeutic Opportunities. Front Physiol 2021; 12:651236. [PMID: 33716796 PMCID: PMC7943476 DOI: 10.3389/fphys.2021.651236] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 02/03/2021] [Indexed: 12/30/2022] Open
Abstract
Melanocortin peptides, melanocortin receptors, melanocortin receptor accessory proteins, and endogenous antagonists of melanocortin receptors are the key components constituting the melanocortin hormone system, one of the most complex and important hormonal systems in our body. A plethora of evidence suggests that melanocortins possess a protective activity in a variety of kidney diseases in both rodent models and human patients. In particular, the steroidogenic melanocortin peptide adrenocorticotropic hormone (ACTH), has been shown to exert a beneficial effect in a number of kidney diseases, possibly via a mechanism independent of its steroidogenic activity. In patients with steroid-resistant nephrotic glomerulopathy, ACTH monotherapy is still effective in inducing proteinuria remission. This has inspired research on potential implications of the melanocortin system in glomerular diseases. However, our understanding of the role of the melanocortinergic pathway in kidney disease is very limited, and there are still huge unknowns to be explored. The most controversial among these is the identification of effector cells in the kidney as well as the melanocortin receptors responsible for conveying the renoprotective action. This review article introduces the melanocortin hormone system, summarizes the existing evidence for the expression of melanocortin receptors in the kidney, and evaluates the potential strategy of melanocortin therapy for kidney disease.
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Affiliation(s)
- Mingyang Chang
- Division of Nephrology, Department of Medicine, University of Toledo College of Medicine, Toledo, OH, United States
| | - Bohan Chen
- Division of Nephrology, Department of Medicine, University of Toledo College of Medicine, Toledo, OH, United States
| | - James Shaffner
- Division of Nephrology, Department of Medicine, University of Toledo College of Medicine, Toledo, OH, United States
| | - Lance D Dworkin
- Division of Nephrology, Department of Medicine, University of Toledo College of Medicine, Toledo, OH, United States
| | - Rujun Gong
- Division of Nephrology, Department of Medicine, University of Toledo College of Medicine, Toledo, OH, United States
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Obi ON, Lower EE, Baughman RP. Biologic and advanced immunomodulating therapeutic options for sarcoidosis: a clinical update. Expert Rev Clin Pharmacol 2021; 14:179-210. [PMID: 33487042 DOI: 10.1080/17512433.2021.1878024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: Sarcoidosis is a multi-organ disease with a wide range of clinical manifestations and outcomes. A quarter of sarcoidosis patients require long-term treatment for chronic disease. In this group, corticosteroids and cytotoxic agents be insufficient to control diseaseAreas covered: Several biologic agents have been studied for treatment of chronic pulmonary and extra-pulmonary disease. A review of the available literature was performed searching PubMed and an expert opinion regarding specific therapy was developed.Expert opinion: These agents have the potential of treating patients who have progressive disease. Many of these agents have different mechanisms of action, response rates, and toxicity profiles.
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Affiliation(s)
- Ogugua Ndili Obi
- Division of Pulmonary Critical Care and Sleep Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA
| | - Elyse E Lower
- Department of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
| | - Robert P Baughman
- Department of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
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Senescence under appraisal: hopes and challenges revisited. Cell Mol Life Sci 2021; 78:3333-3354. [PMID: 33439271 PMCID: PMC8038995 DOI: 10.1007/s00018-020-03746-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 11/20/2020] [Accepted: 12/17/2020] [Indexed: 02/06/2023]
Abstract
In recent years, cellular senescence has become the focus of attention in multiple areas of biomedical research. Typically defined as an irreversible cell cycle arrest accompanied by increased cellular growth, metabolic activity and by a characteristic messaging secretome, cellular senescence can impact on multiple physiological and pathological processes such as wound healing, fibrosis, cancer and ageing. These unjustly called 'zombie cells' are indeed a rich source of opportunities for innovative therapeutic development. In this review, we collate the current understanding of the process of cellular senescence and its two-faced nature, i.e. beneficial/detrimental, and reason this duality is linked to contextual aspects. We propose the senescence programme as an endogenous pro-resolving mechanism that may lead to sustained inflammation and damage when dysregulated or when senescent cells are not cleared efficiently. This pro-resolving model reconciles the paradoxical two faces of senescence by emphasising that it is the unsuccessful completion of the programme, and not senescence itself, what leads to pathology. Thus, pro-senescence therapies under the right context, may favour inflammation resolution. We also review the evidence for the multiple therapeutic approaches under development based on senescence, including its induction, prevention, clearance and the use of senolytic and senomorphic drugs. In particular, we highlight the importance of the immune system in the favourable outcome of senescence and the implications of an inefficient immune surveillance in completion of the senescent cycle. Finally, we identify and discuss a number of challenges and existing gaps to encourage and stimulate further research in this exciting and unravelled field, with the hope of promoting and accelerating the clinical success of senescence-based therapies.
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Lonati C, Gatti S, Catania A. Activation of Melanocortin Receptors as a Potential Strategy to Reduce Local and Systemic Reactions Induced by Respiratory Viruses. Front Endocrinol (Lausanne) 2020; 11:569241. [PMID: 33362713 PMCID: PMC7758465 DOI: 10.3389/fendo.2020.569241] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 11/10/2020] [Indexed: 12/17/2022] Open
Abstract
The clinical hallmarks of infections caused by critical respiratory viruses consist of pneumonia, which can progress to acute lung injury (ALI), and systemic manifestations including hypercoagulopathy, vascular dysfunction, and endotheliitis. The disease outcome largely depends on the immune response produced by the host. The bio-molecular mechanisms underlying certain dire consequences of the infection partly arise from an aberrant production of inflammatory molecules, an event denoted as "cytokine storm". Therefore, in addition to antiviral therapies, molecules able to prevent the injury caused by cytokine excess are under investigation. In this perspective, taking advantage of melanocortin peptides and their receptors, components of an endogenous modulatory system that exerts marked anti-inflammatory and immunomodulatory influences, could be an effective therapeutic strategy to control disease evolution. Exploiting the melanocortin system using natural or synthetic ligands can form a realistic basis to counteract certain deleterious effects of respiratory virus infections. The central and peripheral protective actions exerted following melanocortin receptor activation could allow dampening the harmful events that trigger the cytokine storm and endothelial dysfunction while sustaining the beneficial signals required to elicit repair mechanisms. The long standing evidence for melanocortin safety encourages this approach.
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Affiliation(s)
- Caterina Lonati
- Center for Preclinical Research, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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Askanase AD, Zhao E, Zhu J, Bilyk R, Furie RA. Repository Corticotropin Injection for Persistently Active Systemic Lupus Erythematosus: Results from a Phase 4, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial. Rheumatol Ther 2020; 7:893-908. [PMID: 32996096 PMCID: PMC7695765 DOI: 10.1007/s40744-020-00236-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 09/14/2020] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION We assessed the efficacy and safety of repository corticotropin injection (RCI; Acthar® Gel) for persistently active systemic lupus erythematosus (SLE) despite use of moderate-dose glucocorticoids. METHODS This multicenter, double-blind, randomized, placebo-controlled study enrolled patients ≥ 18 years with active SLE and moderate to severe rash and/or arthritis despite stable glucocorticoid doses (7.5-30 mg/day prednisone equivalent) and antimalarials for ≥ 4 weeks and/or immunosuppressants for ≥ 8 weeks before screening. Stable glucocorticoid doses were required through week 16 with optional taper from weeks 16 to 24. Patients were randomized (1:1) to 80 U RCI subcutaneously or placebo every other day to week 4, then twice weekly to week 24. Endpoints included the proportion of SLE Responder Index (SRI)-4 responders at week 16; changes from baseline to week 16 in 28 Swollen Joint Count/Tender Joint Count (28 SJC/TJC) and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI)-Activity score; and changes from baseline to week 24 in inflammatory cytokines. Safety was assessed by adverse events. RESULTS In the modified intention-to-treat population (RCI, n = 84; placebo, n = 85), the proportion of SRI-4 responders at week 16 was not significantly different between groups (RCI, 47.6%; placebo, 43.5%; OR [95% CI] 1.2 [0.6 to 2.2]; p = 0.5762). RCI treatment resulted in a reduction from baseline to week 16 in 28 SJC/TJC and CLASI-Activity score and from baseline to week 8 in a proliferation-inducing ligand cytokine. Post hoc analyses demonstrated a greater proportion of BILAG-based Combined Lupus Assessment responders for RCI than placebo at weeks 4, 12, and 20 and greater SRI-4 response in RCI-treated patients with baseline SLE Disease Activity Index-2000 ≥ 10 and CLASI-Activity ≥ 11. No new safety signals were identified. CONCLUSIONS Despite failure to achieve the primary endpoint, these results support the utility of RCI for treating persistently active SLE. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT02953821.
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Affiliation(s)
| | - Enxu Zhao
- Mallinckrodt Pharmaceuticals, Bedminster, NJ, USA
| | - Julie Zhu
- Mallinckrodt Pharmaceuticals, Bedminster, NJ, USA
| | - Roman Bilyk
- Mallinckrodt Pharmaceuticals, Bedminster, NJ, USA
| | - Richard A Furie
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
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Saygin D, Oddis CV, Marder G, Moghadam-Kia S, Nandkumar P, Neiman N, Dzanko S, Koontz D, Aggarwal R. Follow-up results of myositis patients treated with H. P. Acthar gel. Rheumatology (Oxford) 2020; 59:2976-2981. [PMID: 32160301 DOI: 10.1093/rheumatology/keaa076] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 01/20/2020] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterized by proximal muscle weakness. H. P. Acthar gel [repository corticotropin injection (RCI)] is a formulation of adrenocorticotropic hormone and has been approved by Food and Drug Administration for use in IIM; however, literature is limited. In this study, we report longitudinal follow-up of myositis patients treated with RCI. METHODS Patients with refractory IIM who were enrolled in the prospective, open-label RCI trial were included in this study. The post-trial follow-up period was 6 months with assessments every 2 months, which included myositis core set measures including extra-muscular global, muscle and patient global disease activities, HAQ, and manual muscle testing. RESULTS Two patients were lost to follow-up after finalization of the trial, and the remaining eight patients were enrolled in the follow-up study. One patient remained on RCI after the trial. In the follow-up period, four of eight patients had flare at on average 4.1 months after the RCI trial. Among the patients who flared, three required an increase in prednisone. One patient was restarted on RCI at 5.5 months, but had minimal improvement after 3 months. Four patients who remained stable continued to satisfy criteria for the definition of improvement through the 6-month follow-up. However, none showed any further improvement in the primary or secondary efficacy outcomes after the initial RCI trial. CONCLUSION To our knowledge, this is the first study reporting the follow-up results of patients treated with standard dose and duration of Acthar. We believe that our study will provide the basis for the development of future randomized RCI trials in IIM.
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Affiliation(s)
- Didem Saygin
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Chester V Oddis
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Galina Marder
- Division of Rheumatology, Northwell Health, Formerly North Shore-Long Island Jewish Medical Center, Queens, NY, USA
| | - Siamak Moghadam-Kia
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Preeya Nandkumar
- Division of Rheumatology, Northwell Health, Formerly North Shore-Long Island Jewish Medical Center, Queens, NY, USA
| | | | - Sedin Dzanko
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Diane Koontz
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Rohit Aggarwal
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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Crane AB, Sharon Y, Chu DS. Use of Adrenocorticotropic Hormone in Ophthalmology. J Ocul Pharmacol Ther 2020; 36:661-667. [PMID: 32762596 DOI: 10.1089/jop.2020.0039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
The ability of the adrenocorticotropic hormone (ACTH) to induce steroidogenesis and upregulate anti-inflammatory processes has long been known. More recently, however, extrasteroidal mechanisms, through which ACTH exerts anti-inflammatory processes, have been described. This has renewed hope that ACTH can combat inflammatory conditions even when resistant to steroids. This review article summarizes the literature on the use of ACTH in ocular disease. Unfortunately, much of the data regarding the clinical utility of ACTH are outdated, with many studies published in the 1950s and 1960s. Many of these older studies are inconsistent or incomplete with their reporting, making it difficult to ascertain the meaning of the outcomes. Despite the limitations, 2 important trends are evident. First, when used to treat an inflammatory disease, ACTH can be effective at decreasing or eliminating ocular inflammation, even in a refractory disease resistant to multiple treatment modalities. Second, adverse effects of ACTH are rare and are most likely to be reported with relatively high doses of ACTH therapy. Taken as a whole, these studies offer initial promising data that ACTH may be a safe and effective alternative in refractory ocular inflammatory disease. However, they highlight an important lack of prospective data to more rigorously understand the true safety and efficacy of this therapy.
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Affiliation(s)
- Alexander B Crane
- Rutgers New Jersey Medical School, Institute of Ophthalmology and Visual Science, Rutgers University, Newark, New Jersey, USA
| | - Yael Sharon
- Department of Ophthalmology, Rabin Medical Center, Petah Tikva, Israel
| | - David S Chu
- Rutgers New Jersey Medical School, Institute of Ophthalmology and Visual Science, Rutgers University, Newark, New Jersey, USA.,Metropolitan Eye Research and Surgery Institute, Palisades Park, New Jersey, USA
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Recchiuti A, Patruno S, Plebani R, Romano M. The Resolution Approach to Cystic Fibrosis Inflammation. Front Pharmacol 2020; 11:1129. [PMID: 32848748 PMCID: PMC7403222 DOI: 10.3389/fphar.2020.01129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 07/10/2020] [Indexed: 01/11/2023] Open
Abstract
Despite the high expectations associated with the recent introduction of CFTR modulators, airway inflammation still remains a relevant clinical issue in cystic fibrosis (CF). The classical anti-inflammatory drugs have shown very limited efficacy, when not being harmful, raising the question of whether alternative approaches should be undertaken. Thus, a better knowledge of the mechanisms underlying the aberrant inflammation observed in CF is pivotal to develop more efficacious pharmacology. In this respect, the observation that endogenous proresolving pathways are defective in CF and that proresolving mediators, physiologically generated during an acute inflammatory reaction, do not completely suppress inflammation, but promote resolution, tissue healing and microbial clearance, without compromising immune host defense mechanisms, opens interesting therapeutic scenarios for CF. In this mini-review, we present the current knowledge and perspectives of proresolving pharmacology in CF, focusing on the specialized proresolving lipid mediators and selected peptides.
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Affiliation(s)
- Antonio Recchiuti
- Laboratory of Molecular Medicine, Center on Advanced Studies and Technology (CAST), Department of Medical, Oral e Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Sara Patruno
- Laboratory of Molecular Medicine, Center on Advanced Studies and Technology (CAST), Department of Medical, Oral e Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Roberto Plebani
- Laboratory of Molecular Medicine, Center on Advanced Studies and Technology (CAST), Department of Medical, Oral e Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Mario Romano
- Laboratory of Molecular Medicine, Center on Advanced Studies and Technology (CAST), Department of Medical, Oral e Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy
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Chopra I, Qin Y, Kranyak J, Gallagher JR, Heap K, Carroll S, Wan GJ. Repository corticotropin injection in patients with advanced symptomatic sarcoidosis: retrospective analysis of medical records. Ther Adv Respir Dis 2020; 13:1753466619888127. [PMID: 31722624 PMCID: PMC6856972 DOI: 10.1177/1753466619888127] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background: Repository corticotropin injection (RCI) has regulatory approval for many indications, including symptomatic sarcoidosis. This large case series of patients with advanced symptomatic sarcoidosis treated with RCI describes patient characteristics, RCI utilization patterns, concomitant therapies, and physicians’ assessments of treatment response. Methods: Patients ⩾18 years with symptomatic sarcoidosis, treated with RCI in the previous 36 months, who had completed a course of RCI or received RCI for ⩾6 months at the time of data collection were included. Results: The study included 302 patients (mean age, 51 years; 52%, women) with a mean 4.8 years since initial diagnosis of sarcoidosis. Most patients (76%) had extrapulmonary involvement, primarily in the skin (28%), joints (25%), heart (22%), and eyes (22%); 34% had multiple (⩾2) organ involvement. The mean duration of RCI treatment was 32.5 weeks, with 61.6% of patients continuing RCI therapy for ⩾6 months. The RCI utilization pattern indicated an individualized approach to therapy, with a higher starting dose associated with a shorter duration of therapy compared with a lower starting dose. The percentage of patients who used corticosteroids decreased from 61.3% during the 3 months before initiation of RCI to 12.9% 3 months after RCI therapy; the mean daily dose of corticosteroid decreased from 18.2 mg to 9.9 mg. The proportion of patients given <10 mg/day of prednisone increased from 21% before RCI use to 47% 3 months after RCI use. According to physicians’ assessments of change in patients’ health status after RCI therapy, overall status improved in 95% of patients, overall symptoms in 73%, lung function in 38%, and inflammation in 33%. Conclusions: The findings suggest that RCI is a viable treatment option for patients with advanced symptomatic sarcoidosis and provide insights on patient characteristics and practice patterns to help clinicians determine appropriate use. The reviews of this paper are available via the supplemental material section.
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Affiliation(s)
| | - Yimin Qin
- Mallinckrodt Pharmaceuticals, Bedminster, NJ, USA
| | - John Kranyak
- Mallinckrodt Pharmaceuticals, Bedminster, NJ, USA
| | | | - Kylee Heap
- Clarity Pharma Research LLC, Spartanburg, SC, USA
| | | | - George J Wan
- Mallinckrodt Pharmaceuticals, 1425 U.S. Route 206, Bedminster, NJ 07921, USA
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Siebold L, Krueger AC, Abdala JA, Figueroa JD, Bartnik-Olson B, Holshouser B, Wilson CG, Ashwal S. Cosyntropin Attenuates Neuroinflammation in a Mouse Model of Traumatic Brain Injury. Front Mol Neurosci 2020; 13:109. [PMID: 32670020 PMCID: PMC7332854 DOI: 10.3389/fnmol.2020.00109] [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: 02/18/2020] [Accepted: 05/22/2020] [Indexed: 12/21/2022] Open
Abstract
Aim: Traumatic brain injury (TBI) is a leading cause of mortality/morbidity and is associated with chronic neuroinflammation. Melanocortin receptor agonists including adrenocorticotropic hormone (ACTH) ameliorate inflammation and provide a novel therapeutic approach. We examined the effect of long-acting cosyntropin (CoSyn), a synthetic ACTH analog, on the early inflammatory response and functional outcome following experimental TBI. Methods: The controlled cortical impact model was used to induce TBI in mice. Mice were assigned to injury and treatment protocols resulting in four experimental groups including sham + saline, sham + CoSyn, TBI + saline, and TBI + CoSyn. Treatment was administered subcutaneously 3 h post-injury and daily injections were given for up to 7 days post-injury. The early inflammatory response was evaluated at 3 days post-injury through the evaluation of cytokine expression (IL1β and TNFα) and immune cell response. Quantification of immune cell response included cell counts of microglia/macrophages (Iba1+ cells) and neutrophils (MPO+ cells) in the cortex and hippocampus. Behavioral testing (n = 10–14 animals/group) included open field (OF) and novel object recognition (NOR) during the first week following injury and Morris water maze (MWM) at 10–15 days post-injury. Results: Immune cell quantification showed decreased accumulation of Iba1+ cells in the perilesional cortex and CA1 region of the hippocampus for CoSyn-treated TBI animals compared to saline-treated. Reduced numbers of MPO+ cells were also found in the perilesional cortex and hippocampus in CoSyn treated TBI mice compared to their saline-treated counterparts. Furthermore, CoSyn treatment reduced IL1β expression in the cortex of TBI mice. Behavioral testing showed a treatment effect of CoSyn for NOR with CoSyn increasing the discrimination ratio in both TBI and Sham groups, indicating increased memory performance. CoSyn also decreased latency to find platform during the early training period of the MWM when comparing CoSyn to saline-treated TBI mice suggesting moderate improvements in spatial memory following CoSyn treatment. Conclusion: Reduced microglia/macrophage accumulation and neutrophil infiltration in conjunction with moderate improvements in spatial learning in our CoSyn treated TBI mice suggests a beneficial anti-inflammatory effect of CoSyn following TBI.
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Affiliation(s)
- Lorraine Siebold
- Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, United States.,The Lawrence D. Longo MD Center for Perinatal Biology, Loma Linda University, Loma Linda, CA, United States
| | - Amy C Krueger
- Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, United States
| | - Jonathan A Abdala
- The Lawrence D. Longo MD Center for Perinatal Biology, Loma Linda University, Loma Linda, CA, United States
| | - Johnny D Figueroa
- Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, United States.,Center for Health Disparities and Molecular Medicine, School of Medicine, Loma Linda University, Loma Linda, CA, United States
| | - Brenda Bartnik-Olson
- Department of Radiology, Loma Linda University Medical Center, Loma Linda, CA, United States
| | - Barbara Holshouser
- Department of Radiology, Loma Linda University Medical Center, Loma Linda, CA, United States
| | - Christopher G Wilson
- Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, United States.,The Lawrence D. Longo MD Center for Perinatal Biology, Loma Linda University, Loma Linda, CA, United States.,Department of Pediatrics, Loma Linda University Medical Center, Loma Linda, CA, United States
| | - Stephen Ashwal
- Department of Pediatrics, Loma Linda University Medical Center, Loma Linda, CA, United States
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