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Chauhan R, Mohan M, Mannan A, Devi S, Singh TG. Unravelling the role of Interleukin-12 in Neuroinflammatory mechanisms: Pathogenic pathways linking Neuroinflammation to neuropsychiatric disorders. Int Immunopharmacol 2025; 156:114654. [PMID: 40294470 DOI: 10.1016/j.intimp.2025.114654] [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: 12/12/2024] [Revised: 04/08/2025] [Accepted: 04/08/2025] [Indexed: 04/30/2025]
Abstract
Neuropsychiatric disorders are clinically characterized conditions involving both neurology and psychiatry, arising from dysfunctioning of cerebral function, or indirect effects of extra cerebral disease. Neuropsychiatric disorders tend to influence emotions, mood, and brain functioning. Growing evidence indicates that the etiology of these disorders is not confined to neuronal abnormalities but extends to include inflammation. While the underlying mechanism of these disorders is still in its infancy, recent data highlights the significant role of neuroinflammation in their pathophysiology. Neuroinflammation concerns the inflammation within the neural tissue characterized by alteration in astrocytes, cytokines, microglia, and chemokines within the central nervous system. The cytokines include IFN-γ, IL-1β, IL-2, IL4, IL-6, IL-8, IL-10, and IL-12. This review focuses on interleukin-12 (IL-12), a key mediator of neuroinflammation, and its potential involvement in neuropsychiatric disorders. IL-12 promotes neuroinflammation and influences neurotransmitter systems. Additionally, it also affects the HPA axis, impairs neuroplasticity, and activates microglia by interacting with TLR, JAK-STAT, PI3K/Akt, GSK-3, NMDA, MAPK, PKC, VEGFR, ROCK, and Wnt signaling pathways and elicit its role in ND. In this review, we dwell on the current evidence supporting IL-12's pathogenic role and explore the possible mechanisms by which it contributes to the development and progression of these conditions. This review aims to provide insights that may aid in future therapeutic strategies by illuminating the interplay between neuroinflammation and neuropsychiatric disorders.
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Affiliation(s)
- Rupali Chauhan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Maneesh Mohan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Sushma Devi
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
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Choudhary D, Nasiruddin Khan MD, Khan Z, Mehan S, Gupta GD, Narula AS, Samant R. Navigating the complexities of neuronal signaling and targets in neurological disorders: From pathology to therapeutics. Eur J Pharmacol 2025; 995:177417. [PMID: 40010482 DOI: 10.1016/j.ejphar.2025.177417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 02/19/2025] [Accepted: 02/19/2025] [Indexed: 02/28/2025]
Abstract
Neurological disorders arising from structural and functional disruptions in the nervous system present major global health challenges. This review examines the intricacies of various cellular signaling pathways, including Nrf2/Keap1/HO-1, SIRT-1, JAK/STAT3/mTOR, and BACE-1/gamma-secretase/MAPT, which play pivotal roles in neuronal health and pathology. The Nrf2-Keap1 pathway, a key antioxidant response mechanism, mitigates oxidative stress, while SIRT-1 contributes to mitochondrial integrity and inflammation control. Dysregulation of these pathways has been identified in neurodegenerative and neuropsychiatric disorders, including Alzheimer's and Parkinson's diseases, characterized by inflammation, protein aggregation, and mitochondrial dysfunction. Additionally, the JAK/STAT3 signaling pathway emphasizes the connection between cytokine responses and neuroinflammation, further compounding disease progression. This review explores the crosstalk among these signaling networks, elucidating how their disruption leads to neuronal decline. It also addresses the dual roles of these pathways, presenting challenges in targeting them for therapeutic purposes. Despite the potential benefits of activating neuroprotective pathways, excessive stimulation may cause deleterious effects, including tumorigenesis. Future research should focus on designing multi-targeted therapies that enhance the effectiveness and safety of treatments, considering individual variabilities and the obstacles posed by the blood-brain barrier to drug delivery. Understanding these complex signaling interactions is crucial for developing innovative and effective neuroprotective strategies that could significantly improve the management of neurological disorders.
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Affiliation(s)
- Divya Choudhary
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - M D Nasiruddin Khan
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Zuber Khan
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Sidharth Mehan
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India.
| | | | - Acharan S Narula
- Narula Research, LLC, 107 Boulder Bluff, Chapel Hill, NC, 27516, USA
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Azouz AA, Tohamy MA, Ali FEM, Mahmoud HM. Enhanced eNOS/nitric oxide production by nebivolol interferes with TGF-β1/Smad3 signaling and collagen I deposition in the kidney after prolonged tacrolimus administration. Life Sci 2024; 355:122995. [PMID: 39159720 DOI: 10.1016/j.lfs.2024.122995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 08/13/2024] [Accepted: 08/15/2024] [Indexed: 08/21/2024]
Abstract
AIMS Tacrolimus is an effective immunosuppressant commonly used post-transplantation and in certain autoimmune diseases. However, its long-term administration is associated with renal fibrosis through transforming growth factor-beta/suppressor of mother against decapentaplegic (TGF-β/Smad) signaling that could be partly attributed to endothelial dysfunction alongside decreased nitric oxide (NO) release. Our study aimed to investigate the prospective renal anti-fibrotic effect of enhanced NO production by nebivolol against tacrolimus-stimulated TGF-β1/Smad3 signaling. MATERIALS AND METHODS To illustrate the proposed mechanism of nebivolol, Nω-nitro-L-arginine methyl ester (L-NAME); nitric oxide synthase inhibitor; was co-administered with nebivolol. Rats were treated for 30 days as control, tacrolimus, tacrolimus/nebivolol, tacrolimus/L-NAME, and tacrolimus/nebivolol/L-NAME groups. KEY FINDINGS Our results revealed that renal NO content was reduced in tacrolimus-treated rats, while treatment with tacrolimus/nebivolol enhanced NO content via up-regulated endothelial nitric oxide synthase (eNOS), but down-regulated inducible nitric oxide synthase (iNOS) expression. That participated in the inhibition of TGF-β1/Smad3 signaling induced by tacrolimus, where the addition of L-NAME abolished the defensive effects of nebivolol. Subsequently, the deposition of collagen I and alpha-smooth muscle actin (α-SMA) was retarded by nebivolol, emphasized by reduced Masson's trichrome staining. In accordance, there was a strong negative correlation between eNOS and both TGF-β1 and collagen I protein expression. The protective effects of nebivolol were further confirmed by the improvement in kidney function biomarkers and histological features. SIGNIFICANCE It can be suggested that treatment with nebivolol along with tacrolimus could effectively suppress renal TGF-β1/Smad3 fibrotic signaling via the enhancement of endothelial NO production, thus curbing renal fibrosis development.
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Affiliation(s)
- Amany A Azouz
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
| | - Mohamed A Tohamy
- Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
| | - Fares E M Ali
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt; Michael Sayegh, Faculty of Pharmacy, Aqaba University of Technology, Aqaba 77110, Jordan
| | - Heba M Mahmoud
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
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Lin Y, Yan GJ, Liu MY, Cao Y, Zhang K, Wang N, Long FL, Mao DW. Review of the potential value of serum interleukin levels as prognostic biomarkers of liver failure. World J Clin Cases 2024; 12:6045-6056. [PMID: 39328855 PMCID: PMC11326103 DOI: 10.12998/wjcc.v12.i27.6045] [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: 03/28/2024] [Revised: 07/03/2024] [Accepted: 07/10/2024] [Indexed: 07/29/2024] Open
Abstract
Liver failure (LF) is prevalent in China and is characterized by complex pathogenesis, challenging clinical management, poor prognosis, and rising incidence and mortality rates. The immune status is an important factor affecting LF prognosis. Interleukins (Ils) are a type of cytokine that act and interact with multiple cells, including immune cells. These signaling molecules play important roles in intercellular information transmission, including the regulation of immune cells; mediation of the activation, proliferation, and differentiation of T and B cells; and orchestration of the inflammatory response. To date, many studies have explored the correlation between IL expression and liver disease prognosis, but few studies have evaluated Ils as the prognostic biomarkers of LF. This article reviews the potential use of Ils as the prognostic biomarkers of LF. Particularly, it evaluates the predictive values of IL-21, IL-22, and IL-31, the three often overlooked yet promising prognostic biomarkers, in predicting susceptibility to LF. Harnessing biomarkers for early prognostic insights can facilitate tailored treatment strategies and enhance patient survival. Thus, this article focuses on the identification of IL-21, IL-22, and IL-33 as biomarkers in preclinical and clinical studies on LF and reviews their role as biomarkers in the pathogenesis and diagnosis of LF.
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Affiliation(s)
- Yong Lin
- Graduate School, Guangxi University of Chinese Medicine, Nanning 530200, Guangxi Zhuang Autonomous Region, China
| | - Geng-Jie Yan
- Graduate School, Guangxi University of Chinese Medicine, Nanning 530200, Guangxi Zhuang Autonomous Region, China
| | - Mei-Yan Liu
- Graduate School, Guangxi University of Chinese Medicine, Nanning 530200, Guangxi Zhuang Autonomous Region, China
| | - Yin Cao
- Guangxi School of Chinese Medicine, Guangxi University of Traditional Chinese Medicine, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - Kan Zhang
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
| | - Na Wang
- Department of Administration, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
| | - Fu-Li Long
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
| | - De-Wen Mao
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
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He X, Liu J, Gong Y, Lu W, Sha X, Cao C, Li Y, Wang J. Amygdalin ameliorates alopecia areata on C3H/HeJ mice by inhibiting inflammation through JAK2/STAT3 pathway. JOURNAL OF ETHNOPHARMACOLOGY 2024; 331:118317. [PMID: 38723918 DOI: 10.1016/j.jep.2024.118317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 04/30/2024] [Accepted: 05/07/2024] [Indexed: 05/16/2024]
Abstract
BACKGROUND Evidence has demonstrated that Chinese medicine formula Xuefu Zhuyu decoction can markedly promote the formation of new hair in patients and mice with alopecia areata (AA). Amygdalin is one of the active components of Xuefu Zhuyu decoction, but its therapeutic effects and the underlying mechanisms on AA remains largely unrevealed. PURPOSE Therefore, this study aims to investigate the therapeutic effects and to probe its molecular mechanisms of inflammation and immune regulation on AA model of C3H/HeJ mice. STUDY DESIGN The C3H/HeJ female mice were divided into control, AA, rusolitinib (60 mg/kg), and amygdalin groups (60, 90, and 120 mg/kg, 0.2 ml/10 g, i.g.). METHODS The optical microscope was used to observe the feature of the local skin, and the number of lanugo and terminal hair. H&E staining was performed to determine the degree of pathological damage to the skin. ELISA was performed to detect levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in mice serum. Flow cytometry was carried out to analyze the CD4+CD25+FOXP3+, CD4+ and CD8+ of skin tissue. And the levels of CD4+ and CD8+, p-JAK/JAK2, p-STAT3/STAT, and SOCS3 were detected by immunohistochemistry. Western blot and qRT-PCR were employed to examine the expression levels of IL-6, TNF-α, IFN-γ, JAK2, p-JAK, STAT, p-STAT3 and SOCS3 proteins and genes in skin tissues. RESULTS Compared with AA group, amygdalin immensely increased the number of vellus hairs and decreased the number of terminal hairs determined by skin microscopy and H&E staining. ELISA, Western blot and qRT-PCR data showed that the levels of IL-6, TNF-α and IFN-γ in serum and skin tissues of AA mice were significantly increased, while amygdalin administration dramatically restrained the contents of the three pro-inflammatory factors. Flow cytometry and immunohistochemistry hinted that amygdalin observably enhanced the number of CD4+CD25+FOXP3+ and CD4+ cells, while inhibited the number of CD8+ positive cells in mice with AA. Moreover, amygdalin signally reduced JAK2/STAT3 pathway-related protein and gene levels in AA mice. CONCLUSION Amygdalin could inhibit inflammatory response and improve immune function in the treatment of AA. The underlying molecular mechanism may be related to inhibition of JAK2/STAT3 pathway.
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Affiliation(s)
- Xun He
- Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610071, China.
| | - Jingsong Liu
- Neurosurgery, Institute of Sichuan Cancer Hospital, Chengdu, 610041, China
| | - Yugang Gong
- Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610071, China
| | - Wei Lu
- Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610071, China
| | - Xiaowei Sha
- Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610071, China
| | - Chang Cao
- Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610071, China
| | - Yanqun Li
- Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610071, China
| | - Jiawei Wang
- Department of Dermatology, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
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Fan L, Zeng X, Jiang Y, Zheng D, Wang H, Qin Q, Li M, Wang H, Liu H, Liang S, Pang X, Shi S, Wu L, Liang S. Yigansan ameliorates maternal immune activation-induced autism-like behaviours by regulating the IL-17A/TRAF6/MMP9 pathway: Network analysis and experimental validation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 128:155386. [PMID: 38522317 DOI: 10.1016/j.phymed.2024.155386] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 01/04/2024] [Accepted: 01/23/2024] [Indexed: 03/26/2024]
Abstract
BACKGROUND Maternal immune activation (MIA) is a significant factor inducing to autism spectrum disorder (ASD) in offspring. The fundamental principle underlying MIA is that inflammation during pregnancy impedes fetal brain development and triggers behavioural alterations in offspring. The intricate pathogenesis of ASD renders drug treatment effects unsatisfactory. Traditional Chinese medicine has strong potential due to its multiple therapeutic targets. Yigansan, composed of seven herbs, is one of the few that has been proven to be effective in treating neuro-psychiatric disorders among numerous traditional Chinese medicine compounds, but its therapeutic effect on ASD remains unknown. HYPOTHESIS Yigansan improves MIA-induced ASD-like behaviours in offspring by regulating the IL-17 signalling pathway. METHODS Pregnant C57BL/6J mice were intraperitoneally injected with poly(I:C) to construct MIA models and offspring ASD models. Network analysis identified that the IL-17A/TRAF6/MMP9 pathway is a crucial pathway, and molecular docking confirmed the binding affinity between the monomer of Yigansan and target proteins. qRT-PCR and Western blot were used to detect the expression levels of inflammatory factors and pathway proteins, immunofluorescence was used to detect the distribution of IL-17A, and behavioural tests were used to evaluate the ASD-like behaviours of offspring. RESULTS We demonstrated that Yigansan can effectively alleviate MIA-induced neuroinflammation of adult offspring by regulating the IL-17A/TRAF6/MMP9 pathway, and the expression of IL-17A was reduced in the prefrontal cortex. Importantly, ASD-like behaviours have been significantly improved. Moreover, we identified that quercetin is the effective monomer for Yigansan to exert therapeutic effects. CONCLUSION Overall, this study was firstly to corroborate the positive therapeutic effect of Yigansan in the treatment of ASD. We elucidated the relevant molecular mechanism and regulatory pathway involved, determined the optimal therapeutic dose and effective monomer, providing new solutions for the challenges of drug therapy for ASD.
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Affiliation(s)
- Linlin Fan
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China
| | - Xin Zeng
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China
| | - Yutong Jiang
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China
| | - Danyang Zheng
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China
| | - Han Wang
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China
| | - Qian Qin
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China
| | - Mengyue Li
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China
| | - Hui Wang
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China
| | - Hao Liu
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China
| | - Shengjun Liang
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China
| | - Xiuming Pang
- Outpatient Department, The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin 150001, China
| | - Shanyi Shi
- Traditional Chinese Medicine Prevention and Treatment Center, The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin 150001, China
| | - Lijie Wu
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China.
| | - Shuang Liang
- Department of Child and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150081, China.
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Li X, Fu Q, Zhong M, Long Y, Zhao F, Huang Y, Zhang Z, Wen M, Chen K, Chen R, Ma X. Quantitative proteomics of the miR-301a/SOCS3/STAT3 axis reveals underlying autism and anxiety-like behavior. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102136. [PMID: 38439911 PMCID: PMC10909786 DOI: 10.1016/j.omtn.2024.102136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 01/30/2024] [Indexed: 03/06/2024]
Abstract
Autism is a widespread neurodevelopmental disorder. Although the research on autism spectrum disorders has been increasing in the past decade, there is still no specific answer to its mechanism of action and treatment. As a pro-inflammatory microRNA, miR-301a is abnormally expressed in various psychiatric diseases including autism. Here, we show that miR-301a deletion and inhibition exhibited two distinct abnormal behavioral phenotypes in mice. We observed that miR-301a deletion in mice impaired learning/memory, and enhanced anxiety. On the contrary, miR-301a inhibition effectively reduced the maternal immune activation (MIA)-induced autism-like behaviors in mice. We further demonstrated that miR-301a bound to the 3'UTR region of the SOCS3, and that inhibition of miR-301a led to the upregulation of SOCS3 in hippocampus. The last result in the reduction of the inflammatory response by inhibiting phosphorylation of AKT and STAT3, and the expression level of IL-17A in poly(I:C)-induced autism-like features in mice. The obtained data revealed the miR-301a as a critical participant in partial behavior phenotypes, which may exhibit a divergent role between gene knockout and knockdown. Our findings ascertain that miR-301a negatively regulates SOCS3 in MIA-induced autism in mice and could present a new therapeutic target for ameliorating the behavioral abnormalities of autism.
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Affiliation(s)
- Xun Li
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Science, China Three Gorges University, Yichang 443002, China
| | - Qi Fu
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
| | - Mingtian Zhong
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
| | - Yihao Long
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
| | - Fengyun Zhao
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
| | - Yanni Huang
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
| | - Zizhu Zhang
- Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Min Wen
- Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Kaizhao Chen
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
| | - Rongqing Chen
- Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Xiaodong Ma
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
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Zhang X, Hu Q, Jiang B, Xie F, Zhang Z, Hafezi-Moghadam A, Sun D. Role of Interleukin-21 in retinal ischemia-reperfusion injury: Unveiling the impact on retinal ganglion cell apoptosis. Int Immunopharmacol 2024; 128:111480. [PMID: 38194747 DOI: 10.1016/j.intimp.2023.111480] [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: 10/23/2023] [Revised: 12/22/2023] [Accepted: 12/30/2023] [Indexed: 01/11/2024]
Abstract
BACKGROUND Retinal ischemia-reperfusion (I/R) serves as a significant contributor to ocular diseases, triggering a cascade of pathological processes. The interplay between neuroinflammation and the apoptosis of retinal ganglion cell (RGC) is a well-explored aspect of retinal I/R-induced tissue damage. Within this intricate landscape, the inflammatory cytokine Interleukin-21 (IL21) emerges as a potent mediator of neuroinflammation with known detrimental effects on neuronal integrity. However, its specific impact on RGC apoptosis in the context of retinal I/R has remains to be uncovered. This study aims to unravel the potential anti-apoptotic effects of IL21 siRNA on RGC, shedding light on the neuroprotection of retinal I/R. METHODS Sprague-Dawley (SD) rats underwent a controlled elevation of intraocular pressure (IOP) to 110 mmHg for 60 min to simulate retinal I/R conditions. To explore the influence of IL21 on RGC apoptosis and its underlying molecular mechanisms, a comprehensive array of techniques such immunohistochemistry, immunofluorescence, TUNEL, Hematoxylin-eosin (H&E), immunoblotting, and qRT-PCR were carried out. RESULTS The landscape of retinal I/R injury revealed an increase in the expression of IL21, reaching its peak at 72 h. Notably, IL21 markedly induced RGC apoptosis within the retinal I/R milieu. The introduction of IL21 siRNA showed promising outcomes, manifesting as an amelioration of neurological function deficits, a reduction in RGC loss, and an increase in the thickness of the inner retinal layer at the 72-hour reperfusion. Additionally, IL21 siRNA demonstrated its ability to hinder the release of proteins associated with apoptosis via the JAK/STAT signaling pathway. In the in vitro setting, IL21 siRNA efficiently reduced R28 cell apoptosis by suppressing the production of proteins associated with apoptosis by regulating the JAK/STAT signaling pathway. CONCLUSIONS This study provides evidence for the pathogenic role of IL21 in retinal I/R. The findings underscore IL21 siRNA as a promising therapeutic target for ischemic retinal injury. Its efficacy lies in its ability to mitigate RGC apoptosis by suppressing the JAK/STAT signaling pathway. These findings not only enhance our comprehension of retinal I/R pathology but also suggests IL21 siRNA as a potential transformative factor in the development of targeted therapies for ischemic retinal injuries.
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Affiliation(s)
- Xue Zhang
- Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin 150086, China; Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Qiang Hu
- Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin 150086, China; Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Bo Jiang
- Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Fang Xie
- Department of Ophthalmology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Zhongyu Zhang
- Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Ali Hafezi-Moghadam
- Molecular Biomarkers Nano-Imaging Laboratory (MBNI), Brigham & Women's Hospital, Boston, MA 02115, USA
| | - Dawei Sun
- Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin 150086, China; Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China.
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Pedini G, Chen CL, Achsel T, Bagni C. Cancer drug repurposing in autism spectrum disorder. Trends Pharmacol Sci 2023; 44:963-977. [PMID: 37940430 DOI: 10.1016/j.tips.2023.09.008] [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: 08/24/2023] [Revised: 09/20/2023] [Accepted: 09/20/2023] [Indexed: 11/10/2023]
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with uncertain origins. Understanding of the mechanisms underlying ASD remains limited, and treatments are lacking. Genetic diversity complicates drug development. Given the complexity and severity of ASD symptoms and the rising number of diagnoses, exploring novel therapeutic strategies is essential. Here, we focus on shared molecular pathways between ASD and cancer and highlight recent progress on the repurposing of cancer drugs for ASD treatment, such as mTOR inhibitors, histone deacetylase inhibitors, and anti-inflammatory agents. We discuss how to improve trial design considering drug dose and patient age. Lastly, the discussion explores the critical aspects of side effects, commercial factors, and the efficiency of drug-screening pipelines; all of which are essential considerations in the pursuit of repurposing cancer drugs for addressing core features of ASD.
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Affiliation(s)
- Giorgia Pedini
- University of Rome Tor Vergata, Department of Biomedicine and Prevention, Via Montpellier 1, 00133, Rome, Italy
| | - Chin-Lin Chen
- University of Lausanne, Department of Fundamental Neurosciences, Rue du Bugnon 9, 1005, Lausanne, Switzerland
| | - Tilmann Achsel
- University of Lausanne, Department of Fundamental Neurosciences, Rue du Bugnon 9, 1005, Lausanne, Switzerland
| | - Claudia Bagni
- University of Rome Tor Vergata, Department of Biomedicine and Prevention, Via Montpellier 1, 00133, Rome, Italy; University of Lausanne, Department of Fundamental Neurosciences, Rue du Bugnon 9, 1005, Lausanne, Switzerland.
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10
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Assiri MA, Albekairi TH, Ansari MA, Nadeem A, Attia SM, Bakheet SA, Shahid M, Aldossari AA, Almutairi MM, Almanaa TN, Alwetaid MY, Ahmad SF. The Exposure to Lead (Pb) Exacerbates Immunological Abnormalities in BTBR T + Itpr 3tf/J Mice through the Regulation of Signaling Pathways Relevant to T Cells. Int J Mol Sci 2023; 24:16218. [PMID: 38003408 PMCID: PMC10671427 DOI: 10.3390/ijms242216218] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 11/07/2023] [Accepted: 11/09/2023] [Indexed: 11/26/2023] Open
Abstract
Autism spectrum disorder (ASD) is a common neurodevelopmental illness characterized by abnormal social interactions, communication difficulties, and repetitive and limited behaviors or interests. The BTBR T+ Itpr3tf/J (BTBR) mice have been used extensively to research the ASD-like phenotype. Lead (Pb) is a hazardous chemical linked to organ damage in the human body. It is regarded as one of the most common metal exposure sources and has been connected to the development of neurological abnormalities. We used flow cytometry to investigate the molecular mechanism behind the effect of Pb exposure on subsets of CD4+ T cells in the spleen expressing IFN-γ, T-bet, STAT1, STAT4, IL-9, IRF4, IL-22, AhR, IL-10, and Foxp3. Furthermore, using RT-PCR, we studied the effect of Pb on the expression of numerous genes in brain tissue, including IFN-γ, T-bet, STAT1, STAT4, IL-9, IRF4, IL-22, AhR, IL-10, and Foxp3. Pb exposure increased the population of CD4+IFN-γ+, CD4+T-bet+, CD4+STAT1+, CD4+STAT4+, CD4+IL-9+, CD4+IRF4+, CD4+IL-22+, and CD4+AhR+ cells in BTBR mice. In contrast, CD4+IL-10+ and CD4+Foxp3+ cells were downregulated in the spleen cells of Pb-exposed BTBR mice compared to those treated with vehicle. Furthermore, Pb exposure led to a significant increase in IFN-γ, T-bet, STAT1, STAT4, IL-9, IRF4, IL-22, and AhR mRNA expression in BTBR mice. In contrast, IL-10 and Foxp3 mRNA expression was significantly lower in those treated with the vehicle. Our data suggest that Pb exposure exacerbates immunological dysfunctions associated with ASD. These data imply that Pb exposure may increase the risk of ASD.
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Affiliation(s)
- Mohammed A. Assiri
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia (S.A.B.)
| | - Thamer H. Albekairi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia (S.A.B.)
| | - Mushtaq A. Ansari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia (S.A.B.)
| | - Ahmed Nadeem
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia (S.A.B.)
| | - Sabry M. Attia
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia (S.A.B.)
| | - Saleh A. Bakheet
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia (S.A.B.)
| | - Mudassar Shahid
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Abdullah A. Aldossari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia (S.A.B.)
| | - Mohammed M. Almutairi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia (S.A.B.)
| | - Taghreed N. Almanaa
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia (M.Y.A.)
| | - Mohammad Y. Alwetaid
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia (M.Y.A.)
| | - Sheikh F. Ahmad
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia (S.A.B.)
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11
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Alwetaid MY, Almanaa TN, Bakheet SA, Ansari MA, Nadeem A, Attia SM, Hussein MH, Ahmad SF. Aflatoxin B 1 Exposure Aggravates Neurobehavioral Deficits and Immune Dysfunctions of Th1, Th9, Th17, Th22, and T Regulatory Cell-Related Transcription Factor Signaling in the BTBR T +Itpr3 tf/J Mouse Model of Autism. Brain Sci 2023; 13:1519. [PMID: 38002479 PMCID: PMC10669727 DOI: 10.3390/brainsci13111519] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/22/2023] [Accepted: 10/26/2023] [Indexed: 11/26/2023] Open
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by impaired communication, reciprocal social interactions, restricted sociability deficits, and stereotyped behavioral patterns. Environmental factors and genetic susceptibility have been implicated in an increased risk of ASD. Aflatoxin B1 (AFB1) is a typical contaminant of food and feed that causes severe immune dysfunction in humans and animals. Nevertheless, the impact of ASD on behavioral and immunological responses has not been thoroughly examined. To investigate this phenomenon, we subjected BTBR T+Itpr3tf/J (BTBR) mice to AFB1 and evaluated their marble-burying and self-grooming behaviors and their sociability. The exposure to AFB1 resulted in a notable escalation in marble-burying and self-grooming activities while concurrently leading to a decline in social contacts. In addition, we investigated the potential molecular mechanisms that underlie the impact of AFB1 on the production of Th1 (IFN-γ, STAT1, and T-bet), Th9 (IL-9 and IRF4), Th17 (IL-17A, IL-21, RORγT, and STAT3), Th22 (IL-22, AhR, and TNF-α), and T regulatory (Treg) (IL-10, TGF-β1, and FoxP3) cells in the spleen. This was achieved using RT-PCR and Western blot analyses to assess mRNA and protein expression in brain tissue. The exposure to AFB1 resulted in a significant upregulation of various immune-related factors, including IFN-γ, STAT1, T-bet, IL-9, IRF4, IL-17A, IL-21, RORγ, STAT3, IL-22, AhR, and TNF-α in BTBR mice. Conversely, the production of IL-10, TGF-β1, and FoxP3 by CD4+ T cells was observed to be downregulated. Exposure to AFB1 demonstrated a notable rise in Th1/Th9/Th22/Th17 levels and a decrease in mRNA and protein expression of Treg. The results above underscore the significance of AFB1 exposure in intensifying neurobehavioral and immunological abnormalities in BTBR mice, hence indicating the necessity for a more comprehensive investigation into the contribution of AFB1 to the development of ASD.
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Affiliation(s)
- Mohammad Y. Alwetaid
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Taghreed N. Almanaa
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Saleh A. Bakheet
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mushtaq A. Ansari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Ahmed Nadeem
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Sabry M. Attia
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Marwa H. Hussein
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Sheikh F. Ahmad
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
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12
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Zhou Y, Zhang Y, Yu W, Qin Y, He H, Dai F, Wang Y, Zhu F, Zhou G. Immunomodulatory role of spleen tyrosine kinase in chronic inflammatory and autoimmune diseases. Immun Inflamm Dis 2023; 11:e934. [PMID: 37506139 PMCID: PMC10373573 DOI: 10.1002/iid3.934] [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: 01/26/2023] [Revised: 06/18/2023] [Accepted: 06/19/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND The high prevalence of chronic inflammatory diseases or autoimmune reactions is a major source of concern and affects the quality of life of patients. Chronic inflammatory or autoimmune diseases are associated with many diseases in humans, including asthma, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and cancer. Splenic tyrosine kinase (SYK) is a non-receptor tyrosine kinase that plays an important role in immune receptor signalling in immune and inflammatory responses. METHODS This is a review article in which we searched for keywords "splenic tyrosine kinase", "inflammation" and "autoimmune diseases" in published literature such as Pubmed and Web of Science to collect relevant information and then conducted a study focusing on the latest findings on the involvement of SYK in chronic inflammatory or autoimmune diseases. RESULTS This paper reviews the regulation of Fcγ, NF-κB, B cell and T cell-related signalling pathways by SYK, which contributes to disease progression in chronic inflammatory and autoimmune diseases such as airway fibrosis, inflammatory skin disease and inflammatory bowel disease. CONCLUSION This paper shows that SYK plays an important role in chronic inflammatory and autoimmune diseases. syk targets hematological, autoimmune and other inflammatory diseases and therefore, inhibition of SYK expression or blocking its related pathways may provide new ideas for clinical prevention and treatment of inflammatory or autoimmune diseases.
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Affiliation(s)
- Yaqi Zhou
- Department of Clinical Medicine, Jining Medical University, Jining, Shandong, China
| | - Yaowen Zhang
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China
| | - Wei Yu
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China
| | - Yufen Qin
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China
| | - Heng He
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China
| | - Fengxian Dai
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China
| | - Yibo Wang
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China
| | - Fengqin Zhu
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China
| | - Guangxi Zhou
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China
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13
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Alanazi MM, Ansari MA, Nadeem A, Attia SM, Bakheet SA, Al-Mazroua HA, Aldossari AA, Almutairi MM, Albekairi TH, Hussein MH, Al-Hamamah MA, Ahmad SF. Cadmium Exposure Is Associated with Behavioral Deficits and Neuroimmune Dysfunction in BTBR T+ Itpr3tf/J Mice. Int J Mol Sci 2023; 24:ijms24076575. [PMID: 37047547 PMCID: PMC10095149 DOI: 10.3390/ijms24076575] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 03/28/2023] [Accepted: 03/31/2023] [Indexed: 04/05/2023] Open
Abstract
Autism spectrum disorders (ASD) are neurobehavioral disabilities characterized by impaired social interactions, poor communication skills, and restrictive/repetitive behaviors. Cadmium is a common heavy metal implicated in ASD. In this study, we investigated the effects of Cd exposure on BTBR T+ Itpr3tf/J (BTBR) mice, an ASD model. We looked for changes in repetitive behaviors and sociability through experiments. We also explored the molecular mechanisms underlying the effects of Cd exposure, focusing on proinflammatory cytokines and pathways. Flow cytometry measured IL-17A-, IL-17F-, IL-21-, TNF-α-, STAT3-, and RORγt-expressing CD4+ T cells from the spleens of experimental mice. We then used RT-PCR to analyze IL-17A, IL-17F, IL-21, TNF-α, STAT3, and RORγ mRNA expression in the brain. The results of behavioral experiments showed that Cd exposure significantly increased self-grooming and marble-burying in BTBR mice while decreasing social interactions. Cd exposure also significantly increased the number of CD4+IL-17A+, CD4+IL-17F+, CD4+IL-21+, CD4+TNF-α+, CD4+STAT3+, and CD4+RORγt+ cells, while upregulating the mRNA expression of the six molecules in the brain. Overall, our results suggest that oral exposure to Cd aggravates behavioral and immune abnormalities in an ASD animal model. These findings have important implications for ASD etiology and provide further evidence of heavy metals contributing to neurodevelopmental disorders through proinflammatory effects.
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Affiliation(s)
- Mohammed M. Alanazi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mushtaq A. Ansari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Ahmed Nadeem
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Sabry M. Attia
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Saleh A. Bakheet
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Haneen A. Al-Mazroua
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Abdullah A. Aldossari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammed M. Almutairi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Thamer H. Albekairi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Marwa H. Hussein
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammed A. Al-Hamamah
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Sheikh F. Ahmad
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
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14
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Kumar S, Mehan S, Narula AS. Therapeutic modulation of JAK-STAT, mTOR, and PPAR-γ signaling in neurological dysfunctions. J Mol Med (Berl) 2023; 101:9-49. [PMID: 36478124 DOI: 10.1007/s00109-022-02272-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 10/10/2022] [Accepted: 11/11/2022] [Indexed: 12/12/2022]
Abstract
The cytokine-activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) cascade is a pleiotropic pathway that involves receptor subunit multimerization. The mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine-threonine kinase that perceives and integrates a variety of intracellular and environmental stimuli to regulate essential activities such as cell development and metabolism. Peroxisome proliferator-activated receptor-gamma (PPARγ) is a prototypical metabolic nuclear receptor involved in neural differentiation and axon polarity. The JAK-STAT, mTOR, and PPARγ signaling pathways serve as a highly conserved signaling hub that coordinates neuronal activity and brain development. Additionally, overactivation of JAK/STAT, mTOR, and inhibition of PPARγ signaling have been linked to various neurocomplications, including neuroinflammation, apoptosis, and oxidative stress. Emerging research suggests that even minor disruptions in these cellular and molecular processes can have significant consequences manifested as neurological and neuropsychiatric diseases. Of interest, target modulators have been proven to alleviate neuronal complications associated with acute and chronic neurological deficits. This research-based review explores the therapeutic role of JAK-STAT, mTOR, and PPARγ signaling modulators in preventing neuronal dysfunctions in preclinical and clinical investigations.
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Affiliation(s)
- Sumit Kumar
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Punjab, Moga, India
| | - Sidharth Mehan
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Punjab, Moga, India.
| | - Acharan S Narula
- Narula Research, LLC, 107 Boulder Bluff, Chapel Hill, NC, 27516, USA
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15
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Lim S, Lee S. Chemical Modulators for Targeting Autism Spectrum Disorders: From Bench to Clinic. Molecules 2022; 27:molecules27165088. [PMID: 36014340 PMCID: PMC9414776 DOI: 10.3390/molecules27165088] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/05/2022] [Accepted: 08/09/2022] [Indexed: 11/16/2022] Open
Abstract
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by diverse behavioral symptoms such as repetitive behaviors, social deficits, anxiety, hyperactivity, and irritability. Despite their increasing incidence, the specific pathological mechanisms of ASD are still unknown, and the degree and types of symptoms that vary from patient to patient make it difficult to develop drugs that target the core symptoms of ASD. Although various atypical antipsychotics and antidepressants have been applied to regulate ASD symptoms, these drugs can only alleviate the symptoms and do not target the major causes. Therefore, development of novel drugs targeting factors directly related to the onset of ASD is required. Among the various factors related to the onset of ASD, several chemical modulators to treat ASD, focused on serotonin (5-hydroxytryptamine, 5-HT) and glutamate receptors, microbial metabolites, and inflammatory cytokines, are explored in this study. In particular, we focus on the chemical drugs that have improved various aspects of ASD symptoms in animal models and in clinical trials for various ages of patients with ASD.
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Affiliation(s)
- Songhyun Lim
- Creative Research Center for Brain Science, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Korea
| | - Sanghee Lee
- Creative Research Center for Brain Science, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Korea
- Department of HY-KIST Bio-Convergence, Hanyang University, Seoul 04763, Korea
- Correspondence: ; Tel.: +82-2-958-5138
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16
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Gill PS, Dweep H, Rose S, Wickramasinghe PJ, Vyas KK, McCullough S, Porter-Gill PA, Frye RE. Integrated microRNA–mRNA Expression Profiling Identifies Novel Targets and Networks Associated with Autism. J Pers Med 2022; 12:jpm12060920. [PMID: 35743705 PMCID: PMC9225282 DOI: 10.3390/jpm12060920] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/23/2022] [Accepted: 05/27/2022] [Indexed: 01/27/2023] Open
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder, with mutations in hundreds of genes contributing to its risk. Herein, we studied lymphoblastoid cell lines (LCLs) from children diagnosed with autistic disorder (n = 10) and controls (n = 7) using RNA and miRNA sequencing profiles. The sequencing analysis identified 1700 genes and 102 miRNAs differentially expressed between the ASD and control LCLs (p ≤ 0.05). The top upregulated genes were GABRA4, AUTS2, and IL27, and the top upregulated miRNAs were hsa-miR-6813-3p, hsa-miR-221-5p, and hsa-miR-21-5p. The RT-qPCR analysis confirmed the sequencing results for randomly selected candidates: AUTS2, FMR1, PTEN, hsa-miR-15a-5p, hsa-miR-92a-3p, and hsa-miR-125b-5p. The functional enrichment analysis showed pathways involved in ASD control proliferation of neuronal cells, cell death of immune cells, epilepsy or neurodevelopmental disorders, WNT and PTEN signaling, apoptosis, and cancer. The integration of mRNA and miRNA sequencing profiles by miRWalk2.0 identified correlated changes in miRNAs and their targets’ expression. The integration analysis found significantly dysregulated miRNA–gene pairs in ASD. Overall, these findings suggest that mRNA and miRNA expression profiles in ASD are greatly altered in LCLs and reveal numerous miRNA–gene interactions that regulate critical pathways involved in the proliferation of neuronal cells, cell death of immune cells, and neuronal development.
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Affiliation(s)
- Pritmohinder S. Gill
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA;
- Arkansas Children′s Research Institute, Little Rock, AR 72202, USA; (K.K.V.); (S.M.); (P.A.P.-G.)
- Correspondence: ; Tel.: +1-501-364-2743
| | - Harsh Dweep
- The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104, USA; (H.D.); (P.J.W.)
| | - Shannon Rose
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA;
- Arkansas Children′s Research Institute, Little Rock, AR 72202, USA; (K.K.V.); (S.M.); (P.A.P.-G.)
| | | | - Kanan K. Vyas
- Arkansas Children′s Research Institute, Little Rock, AR 72202, USA; (K.K.V.); (S.M.); (P.A.P.-G.)
| | - Sandra McCullough
- Arkansas Children′s Research Institute, Little Rock, AR 72202, USA; (K.K.V.); (S.M.); (P.A.P.-G.)
| | - Patricia A. Porter-Gill
- Arkansas Children′s Research Institute, Little Rock, AR 72202, USA; (K.K.V.); (S.M.); (P.A.P.-G.)
| | - Richard E. Frye
- Barrow Neurological Institute at Phoenix Children′s Hospital, Phoenix, AZ 85016, USA;
- Department of Child Health, University of Arizona College of Medicine, Phoenix, AZ 85004, USA
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17
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Role of JAK-STAT and PPAR-Gamma Signalling Modulators in the Prevention of Autism and Neurological Dysfunctions. Mol Neurobiol 2022; 59:3888-3912. [PMID: 35437700 DOI: 10.1007/s12035-022-02819-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 03/23/2022] [Indexed: 01/10/2023]
Abstract
The Janus-kinase (JAK) and signal transducer activator of transcription (STAT) signalling pathways regulate gene expression and control various factors involved in normal physiological functions such as cell proliferation, neuronal development, and cell survival. JAK activation phosphorylates STAT3 in astrocytes and microglia, and this phosphorylation has been linked to mitochondrial damage, apoptosis, neuroinflammation, reactive astrogliosis, and genetic mutations. As a regulator, peroxisome proliferator-activated receptor gamma (PPAR-gamma), in relation to JAK-STAT signalling, prevents this phosphorylation and aids in the treatment of the above-mentioned neurocomplications. Changes in cellular signalling may also contribute to the onset and progression of autism. Thus, PPAR-gamma agonist upregulation may be associated with JAK-STAT signal transduction downregulation. It may also be responsible for attenuating neuropathological changes by stimulating SOCS3 or involving RXR or SMRT, thereby reducing transcription of the various cytokine proteins and genes involved in neuronal damage. Along with JAK-STAT inhibitors, PPAR-gamma agonists could be used as target therapeutic interventions for autism. This research-based review explores the potential involvement and mutual regulation of JAK-STAT and PPAR-gamma signalling in controlling multiple pathological factors associated with autism.
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18
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Yao Y, Uddin MN, Manley K, Lawrence DA. Constitutive activation of Notch signalling and T cell activation characterize a mouse model of autism. Cell Biochem Funct 2022; 40:150-162. [PMID: 34978084 DOI: 10.1002/cbf.3684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 11/19/2021] [Accepted: 12/21/2021] [Indexed: 11/08/2022]
Abstract
Gene and protein expression of BTBR T+ Itpr3tf /J (BTBR) mice with autistic-like behaviours were compared with the C57BL/6J strain, which is considered to have normal immunity and behaviour. Notch signalling pathway was constitutively activated in the immune system and liver of BTBR T+ Itpr3tf /J (BTBR) mice. Notch ligand 4 (Dll4), Notch receptors (Notch1 Notch2 and Notch3) and recombination signal binding protein for immunoglobulin κ j region (RBPJ) were increased both at gene and protein levels in BTBR spleens and thymi. Notch downstream transcriptional factors, Tbx21, Gata3, Rorc and FoxP3 were increased in BTBR spleens, Gata3 and FoxP3 were increased in BTBR thymi and BTBR mice have a high blood CD4/CD8 T cell ratio. Reduced nucleotide excision repair ability in BTBR spleens was associated with increased 8-oxoguanine, Ogg1 inhibition, an enhanced level of apoptotic thymocytes and higher expression of GATA-3. Ogg1 inhibition and enhanced GATA-3 expression also were detected in BTBR brain. Notch signal promoted mitochondrial dynamics switching to enhanced fission with an increased number and mass of mitochondria in immune cells of BTBR mice, but not in livers and brains. Constitutive influences on mitochondria exist in this mouse model of autism spectrum disorder; similar outcomes from environmental exposures might occur perinatally in susceptible individuals to affect the development of autism.
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Affiliation(s)
- Yunyi Yao
- New York State Department of Health, Wadsworth Center, Albany, New York, USA
| | | | - Kevin Manley
- New York State Department of Health, Wadsworth Center, Albany, New York, USA
| | - David A Lawrence
- New York State Department of Health, Wadsworth Center, Albany, New York, USA.,Department of Environmental Health Sciences, School of Public Health, University at Albany, Rensselaer, New York, USA
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19
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Chu SJ, Tang SE, Pao HP, Wu SY, Liao WI. Protease-Activated Receptor-1 Antagonist Protects Against Lung Ischemia/Reperfusion Injury. Front Pharmacol 2021; 12:752507. [PMID: 34658893 PMCID: PMC8514687 DOI: 10.3389/fphar.2021.752507] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 09/20/2021] [Indexed: 01/14/2023] Open
Abstract
Protease-activated receptor (PAR)-1 is a thrombin-activated receptor that plays an essential role in ischemia/reperfusion (IR)-induced acute inflammation. PAR-1 antagonists have been shown to alleviate injuries in various IR models. However, the effect of PAR-1 antagonists on IR-induced acute lung injury (ALI) has not yet been elucidated. This study aimed to investigate whether PAR-1 inhibition could attenuate lung IR injury. Lung IR was induced in an isolated perfused rat lung model. Male rats were treated with the specific PAR-1 antagonist SCH530348 (vorapaxar) or vehicle, followed by ischemia for 40 min and reperfusion for 60 min. To examine the role of PAR-1 and the mechanism of SCH530348 in lung IR injury, western blotting and immunohistochemical analysis of lung tissue were performed. In vitro, mouse lung epithelial cells (MLE-12) were treated with SCH530348 or vehicle and subjected to hypoxia-reoxygenation (HR). We found that SCH530348 decreased lung edema and neutrophil infiltration, attenuated thrombin production, reduced inflammatory factors, including cytokine-induced neutrophil chemoattractant-1, interleukin-6 and tumor necrosis factor-α, mitigated lung cell apoptosis, and downregulated the phosphoinositide 3-kinase (PI3K), nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways in IR-injured lungs. In addition, SCH530348 prevented HR-induced NF-κB activation and inflammatory chemokine production in MLE12 cells. Our results demonstrate that SCH530348 exerts protective effects by blocking PAR-1 expression and modulating the downstream PI3K, NF-κB and MAPK pathways. These findings indicate that the PAR-1 antagonist protects against IR-induced ALI and is a potential therapeutic candidate for lung protection following IR injury.
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Affiliation(s)
- Shi-Jye Chu
- Department of Internal Medicine, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan
| | - Shih-En Tang
- Division of Pulmonary and Critical Care, Department of Internal Medicine, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan.,Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan
| | - Hsin-Ping Pao
- The Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Shu-Yu Wu
- Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan
| | - Wen-I Liao
- Department of Emergency Medicine, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan
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20
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Baranova J, Dragunas G, Botellho MCS, Ayub ALP, Bueno-Alves R, Alencar RR, Papaiz DD, Sogayar MC, Ulrich H, Correa RG. Autism Spectrum Disorder: Signaling Pathways and Prospective Therapeutic Targets. Cell Mol Neurobiol 2021; 41:619-649. [PMID: 32468442 PMCID: PMC11448616 DOI: 10.1007/s10571-020-00882-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 05/16/2020] [Indexed: 12/11/2022]
Abstract
The Autism Spectrum Disorder (ASD) consists of a prevalent and heterogeneous group of neurodevelopmental diseases representing a severe burden to affected individuals and their caretakers. Despite substantial improvement towards understanding of ASD etiology and pathogenesis, as well as increased social awareness and more intensive research, no effective drugs have been successfully developed to resolve the main and most cumbersome ASD symptoms. Hence, finding better treatments, which may act as "disease-modifying" agents, and novel biomarkers for earlier ASD diagnosis and disease stage determination are needed. Diverse mutations of core components and consequent malfunctions of several cell signaling pathways have already been found in ASD by a series of experimental platforms, including genetic associations analyses and studies utilizing pre-clinical animal models and patient samples. These signaling cascades govern a broad range of neurological features such as neuronal development, neurotransmission, metabolism, and homeostasis, as well as immune regulation and inflammation. Here, we review the current knowledge on signaling pathways which are commonly disrupted in ASD and autism-related conditions. As such, we further propose ways to translate these findings into the development of genetic and biochemical clinical tests for early autism detection. Moreover, we highlight some putative druggable targets along these pathways, which, upon further research efforts, may evolve into novel therapeutic interventions for certain ASD conditions. Lastly, we also refer to the crosstalk among these major signaling cascades as well as their putative implications in therapeutics. Based on this collective information, we believe that a timely and accurate modulation of these prominent pathways may shape the neurodevelopment and neuro-immune regulation of homeostatic patterns and, hopefully, rescue some (if not all) ASD phenotypes.
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Affiliation(s)
- Juliana Baranova
- Department of Biochemistry, Chemistry Institute, University of São Paulo, Avenida Professor Lineu Prestes 748, Butantã, São Paulo, SP, 05508-000, Brazil
| | - Guilherme Dragunas
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Avenida Professor Lineu Prestes 1524, Butantã, São Paulo, SP, 05508-000, Brazil
| | - Mayara C S Botellho
- Department of Biochemistry, Chemistry Institute, University of São Paulo, Avenida Professor Lineu Prestes 748, Butantã, São Paulo, SP, 05508-000, Brazil
| | - Ana Luisa P Ayub
- Department of Pharmacology, Federal University of São Paulo, Rua Pedro de Toledo 669, Vila Clementino, São Paulo, SP, 04039-032, Brazil
| | - Rebeca Bueno-Alves
- Department of Biochemistry, Chemistry Institute, University of São Paulo, Avenida Professor Lineu Prestes 748, Butantã, São Paulo, SP, 05508-000, Brazil
| | - Rebeca R Alencar
- Department of Biochemistry, Chemistry Institute, University of São Paulo, Avenida Professor Lineu Prestes 748, Butantã, São Paulo, SP, 05508-000, Brazil
| | - Debora D Papaiz
- Department of Pharmacology, Federal University of São Paulo, Rua Pedro de Toledo 669, Vila Clementino, São Paulo, SP, 04039-032, Brazil
| | - Mari C Sogayar
- Department of Biochemistry, Chemistry Institute, University of São Paulo, Avenida Professor Lineu Prestes 748, Butantã, São Paulo, SP, 05508-000, Brazil
- Cell and Molecular Therapy Center, School of Medicine, University of São Paulo, Rua Pangaré 100 (Edifício NUCEL), Butantã, São Paulo, SP, 05360-130, Brazil
| | - Henning Ulrich
- Department of Biochemistry, Chemistry Institute, University of São Paulo, Avenida Professor Lineu Prestes 748, Butantã, São Paulo, SP, 05508-000, Brazil
| | - Ricardo G Correa
- NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
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21
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Liu C, Hu Q, Chen Y, Wu L, Liu X, Liang D. Behavioral and Gene Expression Analysis of Stxbp6-Knockout Mice. Brain Sci 2021; 11:brainsci11040436. [PMID: 33805317 PMCID: PMC8066043 DOI: 10.3390/brainsci11040436] [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: 02/08/2021] [Revised: 03/21/2021] [Accepted: 03/26/2021] [Indexed: 11/16/2022] Open
Abstract
Since the first report that Stxbp6, a brain-enriched protein, regulates the assembly of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes, little has been discovered about its functions over the past two decades. To determine the effects of Stxbp6 loss on nervous-system-associated phenotypes and underlying mechanisms, we constructed a global Stxbp6-knockout mouse. We found that Stxbp6-null mice survive normally, with normal behavior, but gained less weight relative to age- and sex-matched wildtype mice. RNA-seq analysis of the cerebral cortex of Stxbp6-null mice relative to wildtype controls identified 126 differentially expressed genes. Of these, 57 were upregulated and 69 were downregulated. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the most significant enriched KEGG term was “complement and coagulation cascades”. Our results suggest some potential regulatory pathways of Stxbp6 in the central nervous system, providing a remarkable new resource for understanding Stxbp6 function at the organism level.
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22
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Uddin MN, Yao Y, Mondal T, Matala R, Manley K, Lin Q, Lawrence DA. Immunity and autoantibodies of a mouse strain with autistic-like behavior. Brain Behav Immun Health 2020; 4:100069. [PMID: 34589851 PMCID: PMC8474232 DOI: 10.1016/j.bbih.2020.100069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 04/07/2020] [Accepted: 04/08/2020] [Indexed: 12/20/2022] Open
Abstract
Female and male mice of the BTBR T + Itpr3 tf /J (BTBR) strain have behaviors that resemble autism spectrum disorder. In comparison to C57BL/6 (B6) mice, BTBR mice have elevated humoral immunity, in that they have naturally high serum IgG levels and generate high levels of IgG antibodies, including autoantibodies to brain antigens. This study focused on the specificities of autoantibodies and the immune cells and their transcription factors that might be responsible for the autoantibodies. BTBR IgG autoantibodies bind to neurons better than microglia and with highest titer to nuclear antigens. Two of the antigens identified were alpha-enolase (ENO1) and dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial (DLST). Surprisingly based on IgG levels, the blood and spleens of BTBR mice have more CD4+ and CD8+ T cells, but fewer B cells than B6 mice. The high levels of autoantibodies in BTBR relates to their splenic T follicular helper (Tfh) cell levels, which likely are responsible for the higher number of plasma cells in BTBR mice than B6 mice. BTBR mice have increased gene expression of interleukin-21 receptor (I l -21 r) and Paired Box 5 (Pax5), which are known to aid B cell differentiation to plasma cells, and an increased Lysine Demethylase 6B (Kdm6b)/DNA Methyltransferase 1 (Dnmt1) ratio, which increases gene expression. Identification of gene expression and immune activities of BTBR mice may aid understanding of mechanisms associated with autism since neuroimmune network interactions have been posited and induction of autoantibodies may drive the neuroinflammation associated with autism.
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Key Words
- ASD, autism spectrum disorder
- Ab, antibody
- Ag, antigen
- Alpha-enolase
- Autism
- Autoantibody
- BM, bone marrow
- BTBR
- Dlst, dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial
- Dnmt1
- Dnmt1, DNA Methyltransferase 1
- Eno1, alpha-enolase
- IL-21r
- IL21R, interleukin-21 receptor
- Kdm6b
- Kdm6b, Lysine Demethylase 6B
- Pax5
- Pax5, Paired Box 5
- Plasma cell
- T follicular helper cell
- Tfh, T follicular helper cell
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Affiliation(s)
- Mohammad Nizam Uddin
- Wadsworth Center/New York State Department of Health, RNA Epitranscriptomics & Proteomics Resource, SUNY at Albany, Albany, NY, USA
| | - Yunyi Yao
- Wadsworth Center/New York State Department of Health, RNA Epitranscriptomics & Proteomics Resource, SUNY at Albany, Albany, NY, USA
| | - Tapan Mondal
- Wadsworth Center/New York State Department of Health, RNA Epitranscriptomics & Proteomics Resource, SUNY at Albany, Albany, NY, USA
| | - Rosemary Matala
- University at Albany School of Public Health, Rensselaer, NY, USA
| | - Kevin Manley
- Wadsworth Center/New York State Department of Health, RNA Epitranscriptomics & Proteomics Resource, SUNY at Albany, Albany, NY, USA
| | - Qishan Lin
- RNA Epitranscriptomics & Proteomics Resource, SUNY at Albany, Albany, NY, USA
| | - David A Lawrence
- Wadsworth Center/New York State Department of Health, RNA Epitranscriptomics & Proteomics Resource, SUNY at Albany, Albany, NY, USA.,University at Albany School of Public Health, Rensselaer, NY, USA
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