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Lu J, Chen K, Cen Z, Huang Y, Li Y, Chen L, Wu W. α7nAChR on B cells directs T cell differentiation to prevent viral myocarditis. JCI Insight 2025; 10:e189323. [PMID: 40337863 DOI: 10.1172/jci.insight.189323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 03/21/2025] [Indexed: 05/09/2025] Open
Abstract
Patients with viral myocarditis (VMC) exhibit evident autonomic nervous system imbalance, and adverse cardiac remodeling is involved in impaired cholinergic function. The α7 nicotinic acetylcholine receptor (α7nAChR), which is a neurotransmitter receptor, exerts immunoregulatory effects. Recent advances have illuminated the evolution and functions of peripheral and cardiac B cells in heart disease. However, the role of α7nAChR expressed by B cells in the progression of VMC has not been established. We revealed the neuroimmune communication landscape in the heart and found that the phenotypes of cardiac and splenic B cells and their α7nAChR expression changed dynamically during the progression of VMC to dilated cardiomyopathy. α7nAChR on B cells serves as a negative regulator by inhibiting their proinflammatory functions and signaling pathways. B cell-specific α7nAChR deficiency exacerbated myocardial inflammation, fibrosis, and cardiac dysfunction. However, these effects were abrogated in non-B cells from mice with IL-17A knockdown. Enhanced degradation of acetylcholine leads to an imbalance in cholinergic signaling, resulting in impaired neurotransmission. The acetylcholinesterase inhibitor pyridostigmine bromide could improve cardiac remodeling and prevent the progression of VMC to the chronic phase, which was partly dependent on the α7nAChR on B cells. Our findings provide notable insights into cardiac-neural-immune communication during myocardial injury.
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Affiliation(s)
- Jing Lu
- Department of Cardiology, and
| | | | | | | | - Yong Li
- Emergency Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
| | | | - Weifeng Wu
- Department of Cardiology, and
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co. constructed by the Province and Ministry, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
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Dehara M, Nguyen NV, Arkema EV. Smoking and the risk of sarcoidosis: a systematic review and meta-analysis. Respir Med 2025; 241:108089. [PMID: 40194637 DOI: 10.1016/j.rmed.2025.108089] [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: 03/28/2024] [Revised: 04/02/2025] [Accepted: 04/03/2025] [Indexed: 04/09/2025]
Abstract
BACKGROUND A decreased sarcoidosis risk associated with smoking has been observed in several studies but results are conflicting, and not all of them have observed a protective effect. We aimed to assess the relationship between smoking and sarcoidosis. METHODS Medline, Embase, and Web of Science databases were used to conduct the search. Two investigators independently selected studies and extracted data, and a third investigator resolved discrepancies. Heterogeneity was assessed by estimating the Q statistic, I2, τ2 and the prediction interval (PI). The risk of bias in non-randomised studies of exposures (ROBINS-E) tool was used to assess the risk of bias. Pooled relative risks (RR) were estimated using random-effects models. The review was registered with PROSPERO (CRD42023425901). RESULTS Thirty studies were included in the systematic review and 27 in the meta-analysis. Compared with never smoking, current smoking was associated with a 39 % lower sarcoidosis risk (RR 0.61, 95 %CI 0.45-0.83; τ2 = 0.38, I2 = 92.5 %, p < 0.001, PI 0.16-2.34), and ever smoking with a 13 % lower risk (RR 0.87, 95 %CI 0.70-1.08; τ2 = 0.12, I2 = 93.7 %, p < 0.001, PI 0.39-1.95). For the risk of sarcoidosis associated with former smoking versus never smoking, the pooled RR was 1.09 (95 %CI 0.83-1.43; τ2 = 0.15, I2 = 86.4 %, p < 0.001, PI 0.42-2.85). The majority of the studies were considered to have a high risk of bias. CONCLUSION Cigarette smoking, especially current smoking, was associated with a decreased sarcoidosis risk when compared with never smoking, however, the studies were heterogeneous and many had low quality.
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Affiliation(s)
- Marina Dehara
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
| | - Ngoc V Nguyen
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Elizabeth V Arkema
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
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Hernandez K, Jones N, Ortega SB. The efficacy of an allosteric modulator of the alpha 7 nicotinic acetylcholine receptor in a murine model of stroke. Front Neurosci 2025; 19:1525975. [PMID: 40012683 PMCID: PMC11860958 DOI: 10.3389/fnins.2025.1525975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 01/24/2025] [Indexed: 02/28/2025] Open
Abstract
Introduction Ischemic strokes contribute significantly to cardiovascular-related deaths in the U.S., with current interventions limited to thrombolytic agents. However, these agents present challenges such as a limited therapeutic window, incomplete reperfusion rates, risk of transformation, reperfusion-induced inflammation, and a lack of promoting neuroprotection. We investigated an additional strategy in which prior studies indicated a neuroprotective role. Using a murine transient middle cerebral artery occlusion (tMCAO) model, we sought to evaluate the neurotherapeutic efficacy of a positive allosteric modulator of the alpha7 nicotinic acetylcholine receptor (α7-nAChR), PNU-120596 (PNU), specifically examining whether PNU would modulate stroke-induced neurological dysfunction and neuropathology, with modulation of neuroinflammation as a possible mechanism. Methods Young male C57BL/6J mice received a subcutaneous injection of 20mg/kg of vehicle (DMSO) or PNU-120596 immediately after reperfusion, and infarct area and Bederson score were analyzed 24 hours post-stroke. In the 72-hour post-stroke study, the animals were injected with 20mg/kg of PNU or vehicle subcutaneously immediately after reperfusion, followed by two additional doses of 10mg/kg of PNU or vehicle at 24 and 48 hours post-tMCAO. Seventy-two hours later, behavior function and infarct area were assessed. Results In contrast to previous rat studies that demonstrated improvements in clinical outcomes, a single administration of PNU following stroke induction led to a reduction in acute neuropathology but did not produce a significant improvement in motor outcomes. Prolonged treatment showed no significant changes in acute neuropathology or sensorimotor function. Additionally, an assessment of neuroinflammation revealed no changes in CD4 T-cell cellularity or phenotype. Discussion These findings, alongside prior studies, suggest that the therapeutic efficacy of PNU may be contingent upon the timing of administration, dosage, and pharmacokinetics.
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Affiliation(s)
| | | | - Sterling B. Ortega
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX, United States
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Orlinick BL, Farhadian SF. HIV, smoking, and the brain: a convergence of neurotoxicities. AIDS Res Ther 2025; 22:13. [PMID: 39915881 PMCID: PMC11804093 DOI: 10.1186/s12981-025-00714-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 01/31/2025] [Indexed: 02/09/2025] Open
Abstract
PURPOSE OF REVIEW The purpose of this review is to characterize the combined effects of tobacco smoking and human immunodeficiency virus (HIV) infection in people with HIV (PWH) and identify possible therapeutic targets through shared mechanisms for neurotoxicity. RECENT FINDINGS HIV and tobacco smoke can exert neurotoxicity through shared mechanisms such as brain volume changes, microglial dysregulation, and dysregulation of the cholinergic anti-inflammatory pathway (CAP) through the alpha7-nicotinic acetylcholine receptor (nAChR). Evidence also suggests the potential for synergistic effects of HIV and tobacco smoking on neurotoxicity. People with HIV (PWH) are disproportionately affected by both neurocognitive impairment (NCI) and tobacco smoking compared to the general population. Both HIV and tobacco smoking are known to have neurotoxic effects and have the potential for clinically significant impacts on brain health and cognitive functioning. Less, however, is known about how PWH may be uniquely affected by the interactive neurotoxic effects of both HIV and tobacco smoking. Evidence suggests that smoking and HIV can have synergistic effects on neurotoxicity and NCI in PWH. Some mechanisms for neurotoxicity include increased oxidative stress from microglial activation and dysfunction in the alpha7- nAChR cholinergic anti-inflammatory pathway leading to increased neuroinflammation and neuronal apoptosis. Mechanisms may vary by cell type and brain region, however, and there is a need for more human-facing, longitudinal studies on smoking in PWH.
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Affiliation(s)
| | - Shelli F Farhadian
- Yale School of Medicine, Section of Infectious Diseases, New Haven, CT, USA.
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Tanitame M, Inoue M, Yamaji T, Iwasaki M, Tsugane S, Sawada N. Cigarette Smoking, Alcohol Consumption, and the Risk of Thyroid Cancer in Japan: The Japan Public Health Center-Based Prospective Study. Cancer Epidemiol Biomarkers Prev 2025; 34:317-323. [PMID: 39665552 DOI: 10.1158/1055-9965.epi-24-0975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 09/10/2024] [Accepted: 12/06/2024] [Indexed: 12/13/2024] Open
Abstract
BACKGROUND Although cigarette smoking and alcohol consumption are established causes of cancer, most cohort studies and meta-analyses have reported inverse associations with thyroid cancer risk. However, epidemiologic evidence for this possibility is limited in Asia, where thyroid cancer histologic type differs from the West. In this study, we examined the association between cigarette smoking or alcohol consumption and the risk of thyroid cancer in Japanese. METHODS We analyzed data of 101,849 Japanese included in the Japan Public Health Center-Based Prospective Study. Cigarette smoking and alcohol consumption were assessed at baseline using a self-administered questionnaire. Cox proportional hazards regression models were used to estimate the HRs and 95% confidence intervals (CI). RESULTS During a mean 18.7 years of follow-up, we identified 232 incident cases of thyroid cancer. The multivariable-adjusted HRs (95% CIs) for current cigarette smoking with ≥20 pack-years compared with never-smoking were 0.65 (0.39-1.06) and 0.45 (0.23-0.88), respectively, combined for both sexes. After detailed adjustment for cigarette smoking, compared with no current alcohol consumption, HRs (95% CIs) were 0.90 (0.61-1.33) for any current consumption and 0.81 (0.33-1.97) for ≥300 g ethanol/week consumption combined for both sexes. CONCLUSIONS We observed an inverse association between cigarette smoking and thyroid cancer in Japan. Although an inverse association between alcohol consumption and thyroid cancer is suggested, the CI was wide and included 1. IMPACT Cigarette smoking was shown to be potentially inversely associated with thyroid cancer in Japanese, providing insights into risk factors in Asians. Further studies with larger sample sizes are needed to verify these findings.
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Affiliation(s)
- Marina Tanitame
- Division of Prevention, National Cancer Center Institute for Cancer Control, Tokyo, Japan
- Division of Social Medicine, Department of Cancer Epidemiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Manami Inoue
- Division of Prevention, National Cancer Center Institute for Cancer Control, Tokyo, Japan
- Division of Social Medicine, Department of Cancer Epidemiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Taiki Yamaji
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan
| | - Motoki Iwasaki
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan
| | - Shoichiro Tsugane
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan
- International University of Health and Welfare Graduate School of Public Health, Tokyo, Japan
| | - Norie Sawada
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan
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Liu S, Cho MY, Huang YN, Park T, Chaudhuri S, Rosewood TJ, Bice PJ, Chung D, Bennett DA, Ertekin-Taner N, Saykin AJ, Nho K. Multi-Omics Analysis for Identifying Cell-Type-Specific Druggable Targets in Alzheimer's Disease. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.01.08.25320199. [PMID: 39830273 PMCID: PMC11741481 DOI: 10.1101/2025.01.08.25320199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Background Analyzing disease-linked genetic variants via expression quantitative trait loci (eQTLs) is important for identifying potential disease-causing genes. Previous research prioritized genes by integrating Genome-Wide Association Study (GWAS) results with tissue-level eQTLs. Recent studies have explored brain cell type-specific eQTLs, but they lack a systematic analysis across various Alzheimer's disease (AD) GWAS datasets, nor did they compare effects between tissue and cell type levels or across different cell type-specific eQTL datasets. In this study, we integrated brain cell type-specific eQTL datasets with AD GWAS datasets to identify potential causal genes at the cell type level. Methods To prioritize disease-causing genes, we used Summary Data-Based Mendelian Randomization (SMR) and Bayesian Colocalization (COLOC) to integrate AD GWAS summary statistics with cell-type-specific eQTLs. Combining data from five AD GWAS, three single-cell eQTL datasets, and one bulk tissue eQTL meta-analysis, we identified and confirmed both novel and known candidate causal genes. We investigated gene regulation through enhancer activity using H3K27ac and ATAC-seq data, performed protein-protein interaction and pathway enrichment analyses, and conducted a drug/compound enrichment analysis with the Drug Signatures Database (DSigDB) to support drug repurposing for AD. Results We identified 27 candidate causal genes for AD using cell type-specific eQTL datasets, with the highest numbers in microglia, followed by excitatory neurons, astrocytes, inhibitory neurons, oligodendrocytes, and oligodendrocyte precursor cells (OPCs). PABPC1 emerged as a novel astrocyte-specific gene. Our analysis revealed protein-protein interaction (PPI) networks for these causal genes in microglia and astrocytes. We found the "regulation of aspartic-type peptidase activity" pathway being the most enriched among all the causal genes. AD-risk variants associated with candidate causal gene PABPC1 is located near or within enhancers only active in astrocytes. We classified the genes into three drug tiers and identified druggable interactions, with imatinib mesylate emerging as a key candidate. A drug-target gene network was created to explore potential drug targets for AD. Conclusions We systematically prioritized AD candidate causal genes based on cell type-specific molecular evidence. The integrative approach enhances our understanding of molecular mechanisms of AD-related genetic variants and facilitates the interpretation of AD GWAS results.
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Affiliation(s)
- Shiwei Liu
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 550 N. University Blvd. Indianapolis, IN, 46202, USA
- Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, 355 W. 16th Street, Goodman Hall, Suite 4100, Indianapolis, IN, 46202, USA
| | - Min Young Cho
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 550 N. University Blvd. Indianapolis, IN, 46202, USA
- Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, 355 W. 16th Street, Goodman Hall, Suite 4100, Indianapolis, IN, 46202, USA
- Sungkyunkwan University, Seoul, Republic of Korea
| | - Yen-Ning Huang
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 550 N. University Blvd. Indianapolis, IN, 46202, USA
- Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, 355 W. 16th Street, Goodman Hall, Suite 4100, Indianapolis, IN, 46202, USA
| | - Tamina Park
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 550 N. University Blvd. Indianapolis, IN, 46202, USA
- Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, 355 W. 16th Street, Goodman Hall, Suite 4100, Indianapolis, IN, 46202, USA
| | - Soumilee Chaudhuri
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 550 N. University Blvd. Indianapolis, IN, 46202, USA
- Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, 355 W. 16th Street, Goodman Hall, Suite 4100, Indianapolis, IN, 46202, USA
| | - Thea Jacobson Rosewood
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 550 N. University Blvd. Indianapolis, IN, 46202, USA
- Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, 355 W. 16th Street, Goodman Hall, Suite 4100, Indianapolis, IN, 46202, USA
| | - Paula J Bice
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 550 N. University Blvd. Indianapolis, IN, 46202, USA
- Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, 355 W. 16th Street, Goodman Hall, Suite 4100, Indianapolis, IN, 46202, USA
| | - Dongjun Chung
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, OH, 43210, USA
| | - David A. Bennett
- Department of Neurological Science, Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, 60612, USA
| | - Nilüfer Ertekin-Taner
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA
- Department of Neurology, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Andrew J Saykin
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 550 N. University Blvd. Indianapolis, IN, 46202, USA
- Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, 355 W. 16th Street, Goodman Hall, Suite 4100, Indianapolis, IN, 46202, USA
| | - Kwangsik Nho
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 550 N. University Blvd. Indianapolis, IN, 46202, USA
- Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, 355 W. 16th Street, Goodman Hall, Suite 4100, Indianapolis, IN, 46202, USA
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, 340 West 10th Street, Fairbanks Hall, Suite 6200 Indianapolis, Indiana, 46202, USA
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Obi ON, Saketkoo LA, Maier LA, Baughman RP. Developmental drugs for sarcoidosis. J Autoimmun 2024; 149:103179. [PMID: 38548579 DOI: 10.1016/j.jaut.2024.103179] [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: 09/10/2023] [Revised: 12/04/2023] [Accepted: 02/08/2024] [Indexed: 12/15/2024]
Abstract
Sarcoidosis is a multi-organ granulomatous inflammatory disease of unknown etiology. Over 50% of patients will require treatment at some point in their disease and 10%-30% will develop a chronic progressive disease with pulmonary fibrosis leading to significant morbidity and mortality. Recently published guidelines recommend immunosuppressive therapy for sarcoidosis patients at risk of increased disease-related morbidity and mortality, and in whom disease has negatively impacted quality of life. Prednisone the currently recommended first line therapy is associated with significant toxicity however none of the other guideline recommended steroid sparing therapy is approved by regulatory agencies for use in sarcoidosis, and data in support of their use is weak. For patients with severe refractory disease requiring prolonged therapy, treatment options are limited. The need for expanding treatment options in sarcoidosis has been emphasized. Well conducted large, randomized trials evaluating currently available therapeutic options as well as novel pathways for targeting disease are necessary to better guide treatment decisions. These trials will not be without significant challenges. Sarcoidosis is a rare disease with heterogenous presentation and variable progression and clinical outcome. There are no universally agreed upon biomarkers of disease activity and measurement of outcomes is confounded by the need to balance patient centric measures and objective measures of disease activity. Our paper provides an update on developmental drugs in sarcoidosis and outlines several novel pathways that may be targeted for future drug development. Currently available trials are highlighted and ongoing challenges to drug development and clinical trial design are briefly discussed.
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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.
| | - Lesley Ann Saketkoo
- New Orleans Scleroderma and Sarcoidosis Patient Care and Research Center, New Orleans, USA; University Medical Center - Comprehensive Pulmonary Hypertension Center and Interstitial Lung Disease Clinic Programs, New Orleans, USA; Louisiana State University School of Medicine, Section of Pulmonary Medicine, New Orleans, LA, USA; Tulane University School of Medicine, Undergraduate Honors Department, New Orleans, LA, USA
| | - Lisa A Maier
- Division of Environmental and Occupational Health Sciences, Department of Medicine, National Jewish Health, Denver, CO, USA; Division of Pulmonary and Critical Care Sciences, Department of Medicine, University of Colorado School of Medicine, Denver, CO, USA
| | - Robert P Baughman
- Emeritus Professor of Medicine, Department of Medicine, University of Cincinnati, Cincinnati, OH, USA
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Keane AM, Swartz TH. The impacts of tobacco and nicotine on HIV-1 infection, inflammation, and the blood-brain barrier in the central nervous system. Front Pharmacol 2024; 15:1477845. [PMID: 39529883 PMCID: PMC11550980 DOI: 10.3389/fphar.2024.1477845] [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: 08/08/2024] [Accepted: 10/17/2024] [Indexed: 11/16/2024] Open
Abstract
Human immunodeficiency virus (HIV-1) remains a persistent global health crisis. Even while successfully virologically suppressed, people with HIV (PWH) experience a higher risk for inflammatory disorders such as HIV-associated neurocognitive disorder (HAND). Tobacco use puts PWH at higher risk for neurocognitive symptoms resulting from HIV-associated neuroinflammation. The NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome has been implicated as a driver of HIV-associated inflammation, including HAND. Nicotine, the psychoactive component of tobacco smoke, has also been shown to signal through the NLRP3 inflammasome and modulate inflammatory signaling in the CNS. Here, we explore the impacts of nicotine and tobacco on the complex neurobiology of HAND, including effects on cognition, inflammation, viral latency, and blood-brain barrier integrity. We outline nicotine's role in the establishment of active and latent infection in the brain and posit the NLRP3 inflammasome as a common pathway by which HIV-1 and nicotine promote neuroinflammation in PWH.
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Affiliation(s)
- Aislinn M. Keane
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Talia H. Swartz
- Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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El Hasbani G, Madi M, Zoghbi MASE, Srour L, Uthman I, Jawad ASM. The Impact of Tobacco Smoking on Systemic Sclerosis, Idiopathic Inflammatory Myositis, and Systemic Lupus Erythematosus. CLINICAL MEDICINE INSIGHTS. ARTHRITIS AND MUSCULOSKELETAL DISORDERS 2024; 17:11795441241290522. [PMID: 39430769 PMCID: PMC11490952 DOI: 10.1177/11795441241290522] [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: 01/06/2024] [Accepted: 09/23/2024] [Indexed: 10/22/2024]
Abstract
This narrative review aims specifically to explore the relationship between tobacco exposure and systemic sclerosis (SSc), idiopathic inflammatory myositis (IIM), and systemic lupus erythematosus (SLE). Relevant articles were obtained by searching key terms such as "tobacco," "smoking," "scleroderma," "myositis," "lupus," and "Sjögren's" in PubMed and Google Scholar databases. The selected articles ranged from the years 2010 to 2023. Inclusion criteria were based on the relevance and contribution to the field of study. Systemic sclerosis is a complex condition involving multiple immune cell lines that can be influenced by tobacco. However, the existing literature does not provide sufficient evidence to support an increased risk of SSc in smokers or the impact on treatment options. Cigarette smoking does increase the risk of skin ulcerations in SSc patients. In addition, cigarette smoking has been associated with IIM through genetic and molecular mechanisms. Smokers with dermatomyositis or polymyositis are at an elevated risk of atherosclerosis and interstitial lung disease. Similarly, smoking in patients with SLE increases the risk of organ damage, thrombosis, and disease severity compared with non-smokers. Smokers with SLE also have more difficulty in controlling disease flares compared with non-smokers. Tobacco exposure can lead to secondary complications in patients with IIM and SLE, although the course of treatment may not differ significantly. No definitive conclusions can be drawn to the clear relationship between tobacco smoking and Sjögren's's syndrome.
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Affiliation(s)
- Georges El Hasbani
- Department of Medicine, Hartford Healthcare St. Vincent’s Medical Center, Bridgeport, CT, USA
| | - Mikel Madi
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | | | - Lara Srour
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Imad Uthman
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Ali SM Jawad
- Department of Rheumatology, The Royal London Hospital, London, UK
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Körtési T, Nagy-Grócz G, Vécsei L. The role of kynurenines in migraine-related neuroimmune pathways. J Headache Pain 2024; 25:129. [PMID: 39107712 PMCID: PMC11304619 DOI: 10.1186/s10194-024-01833-z] [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: 05/22/2024] [Accepted: 07/24/2024] [Indexed: 08/10/2024] Open
Abstract
Migraine, a primary headache disorder whose mechanism remains incompletely understood, appears to involve the activation of the trigeminovascular system (TS) during attacks. Research suggests that inflammatory processes mediated by the immune system may play a role in migraine pathophysiology. Neuroinflammation is often associated with migraine attacks, with cytokines serving as crucial mediators in the process. Elevated levels of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), have been observed in the blood and cerebrospinal fluid of individuals experiencing migraine attacks. These cytokines have the capacity to sensitize pain pathways in the brain, thereby increasing sensitivity to pain stimuli. This phenomenon, known as central sensitization, is believed to contribute to the intensity and persistence of migraine pain. Kynurenines, endogenous mediators of glutamatergic mechanisms, can significantly influence the pathophysiology of primary headache disorders. The kynurenine system is collectively known as the kynurenine pathway (KP), which can act on multiple receptors, such as glutamate receptors, aryl hydrocarbon receptors (AhRs), G protein-coupled receptors 35 (GPR35), and α-7 nicotinic acetylcholine (α7 nACh) receptors. These receptors are also found on various cells of the immune system, so the role of the KP in the pathomechanism of primary headaches may also be mediated through them. In this review, our goal is to show a possible link between the receptors of the KP and immune system in the context of inflammation and migraine. Migraine research in recent years has focused on neuropeptides, such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as potential pathogenic factors and possible therapeutic approaches. These peptides share many similarities in their characteristics and roles. For instance, they exhibit potent vasodilation, occur in both the peripheral and central nervous systems, and play a role in transmitting nociception and neurogenic inflammation. The investigation of potential connections between the aforementioned neuropeptides and the kynurenine pathway could play a significant role in uncovering the pathomechanism of migraine and identifying new drug candidates.
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Affiliation(s)
- Tamás Körtési
- Department of Theoretical Health Sciences and Health Management, Faculty of Health Sciences and Social Studies, University of Szeged, Temesvári krt. 31, Szeged, H-6726, Hungary
- HUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, Danube Neuroscience Research Laboratory, University of Szeged (HUN-REN-SZTE), Tisza Lajos krt. 113, Szeged, H- 6725, Hungary
- Preventive Health Sciences Research Group, Incubation Competence Centre of the Centre of Excellence for Interdisciplinary Research, Development and Innovation of the University of Szeged, Szeged, H-6720, Hungary
| | - Gábor Nagy-Grócz
- Department of Theoretical Health Sciences and Health Management, Faculty of Health Sciences and Social Studies, University of Szeged, Temesvári krt. 31, Szeged, H-6726, Hungary
- Preventive Health Sciences Research Group, Incubation Competence Centre of the Centre of Excellence for Interdisciplinary Research, Development and Innovation of the University of Szeged, Szeged, H-6720, Hungary
| | - László Vécsei
- HUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, Danube Neuroscience Research Laboratory, University of Szeged (HUN-REN-SZTE), Tisza Lajos krt. 113, Szeged, H- 6725, Hungary.
- Department of Neurology, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis u. 6, Szeged, H-6725, Hungary.
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Natarajan C, Le LHD, Gunasekaran M, Tracey KJ, Chernoff D, Levine YA. Electrical stimulation of the vagus nerve ameliorates inflammation and disease activity in a rat EAE model of multiple sclerosis. Proc Natl Acad Sci U S A 2024; 121:e2322577121. [PMID: 38968104 PMCID: PMC11252997 DOI: 10.1073/pnas.2322577121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 05/31/2024] [Indexed: 07/07/2024] Open
Abstract
Multiple sclerosis (MS) is a demyelinating central nervous system (CNS) disorder that is associated with functional impairment and accruing disability. There are multiple U.S. Food and Drug Administration (FDA)-approved drugs that effectively dampen inflammation and slow disability progression. However, these agents do not work well for all patients and are associated with side effects that may limit their use. The vagus nerve (VN) provides a direct communication conduit between the CNS and the periphery, and modulation of the inflammatory reflex via electrical stimulation of the VN (VNS) shows efficacy in ameliorating pathology in several CNS and autoimmune disorders. We therefore investigated the impact of VNS in a rat experimental autoimmune encephalomyelitis (EAE) model of MS. In this study, VNS-mediated neuroimmune modulation is demonstrated to effectively decrease EAE disease severity and duration, infiltration of neutrophils and pathogenic lymphocytes, myelin damage, blood-brain barrier disruption, fibrinogen deposition, and proinflammatory microglial activation. VNS modulates expression of genes that are implicated in MS pathogenesis, as well as those encoding myelin proteins and transcription factors regulating new myelin synthesis. Together, these data indicate that neuroimmune modulation via VNS may be a promising approach to treat MS, that not only ameliorates symptoms but potentially also promotes myelin repair (remyelination).
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Affiliation(s)
| | | | | | - Kevin J. Tracey
- Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY11030
- Department of Neurosurgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY11549
- Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY11549
| | | | - Yaakov A. Levine
- SetPoint Medical, Valencia, CA91355
- Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY11549
- Division of Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm171 76, Sweden
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12
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Alexandrova Y, Yero A, Olivenstein R, Orlova M, Schurr E, Estaquier J, Costiniuk CT, Jenabian MA. Dynamics of pulmonary mucosal cytotoxic CD8 T-cells in people living with HIV under suppressive antiretroviral therapy. Respir Res 2024; 25:240. [PMID: 38867225 PMCID: PMC11170847 DOI: 10.1186/s12931-024-02859-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 05/29/2024] [Indexed: 06/14/2024] Open
Abstract
BACKGROUND Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) suffer from a high burden of pulmonary diseases, even after accounting for their smoking status. Cytotoxic CD8 T-cells are likely implicated in this phenomenon and may act as a double-edged sword. While being essential in viral infection control, their hyperactivation can also contribute to lung mucosal tissue damage. The effects of HIV and smoking on pulmonary mucosal CD8 T-cell dynamics has been a neglected area of research, which we address herein. METHODS Bronchoalveolar lavage (BAL) fluid were obtained from ART-treated PLWH (median duration of supressed viral load: 9 years; smokers: n = 14; non-smokers: n = 21) and HIV-uninfected controls (smokers: n = 11; non-smokers: n = 20) without any respiratory symptoms or active infection. Lymphocytes were isolated and CD8 T-cell subsets and homing markers were characterized by multiparametric flow cytometry. RESULTS Both smoking and HIV infection were independently associated with a significant increase in frequencies of total pulmonary mucosal CD8 T-cell. BAL CD8 T-cells were primarily CD69 + expressing CD103 and/or CD49a, at least one of the two granzymes (GzmA/GzmB), and little Perforin. Higher expression levels of CD103, CD69, and GzmB were observed in smokers versus non-smokers. The ex vivo phenotype of GzmA + and GzmB + cells revealed increased expression of CD103 and CXCR6 in smokers, while PLWH displayed elevated levels of CX3CR1 compared to controls. CONCLUSION Smoking and HIV could promote cytotoxic CD8 T-cell retention in small airways through different mechanisms. Smoking likely increases recruitment and retention of GzmB + CD8 Trm via CXCR6 and CD103. Heightened CX3CR1 expression could be associated with CD8 non-Trm recruitment from the periphery in PLWH.
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Affiliation(s)
- Yulia Alexandrova
- Department of Biological Sciences, Université du Québec à Montréal (UQAM), 141, Avenue President Kennedy, Montreal, QC, H2X 1Y4, Canada
- Infectious Diseases and Immunity in Global Health Program, Research Institute of McGill University Health Centre, Montreal, QC, Canada
| | - Alexis Yero
- Department of Biological Sciences, Université du Québec à Montréal (UQAM), 141, Avenue President Kennedy, Montreal, QC, H2X 1Y4, Canada
| | - Ronald Olivenstein
- Division of Respirology, Department of Medicine, McGill University, Montreal, QC, Canada
| | - Marianna Orlova
- Infectious Diseases and Immunity in Global Health Program, Research Institute of McGill University Health Centre, Montreal, QC, Canada
| | - Erwin Schurr
- Infectious Diseases and Immunity in Global Health Program, Research Institute of McGill University Health Centre, Montreal, QC, Canada
- Departments of Human Genetics and Medicine, McGill University, Montreal, QC, Canada
| | - Jerome Estaquier
- Centre de recherche de CHU de Québec - Université Laval Research Center, Québec City, Québec, Canada
| | - Cecilia T Costiniuk
- Infectious Diseases and Immunity in Global Health Program, Research Institute of McGill University Health Centre, Montreal, QC, Canada
- Division of Infectious Diseases and Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada
| | - Mohammad-Ali Jenabian
- Department of Biological Sciences, Université du Québec à Montréal (UQAM), 141, Avenue President Kennedy, Montreal, QC, H2X 1Y4, Canada.
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13
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Kawashima K, Mashimo M, Nomura A, Fujii T. Contributions of Non-Neuronal Cholinergic Systems to the Regulation of Immune Cell Function, Highlighting the Role of α7 Nicotinic Acetylcholine Receptors. Int J Mol Sci 2024; 25:4564. [PMID: 38674149 PMCID: PMC11050324 DOI: 10.3390/ijms25084564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 04/13/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024] Open
Abstract
Loewi's discovery of acetylcholine (ACh) release from the frog vagus nerve and the discovery by Dale and Dudley of ACh in ox spleen led to the demonstration of chemical transmission of nerve impulses. ACh is now well-known to function as a neurotransmitter. However, advances in the techniques for ACh detection have led to its discovery in many lifeforms lacking a nervous system, including eubacteria, archaea, fungi, and plants. Notably, mRNAs encoding choline acetyltransferase and muscarinic and nicotinic ACh receptors (nAChRs) have been found in uninnervated mammalian cells, including immune cells, keratinocytes, vascular endothelial cells, cardiac myocytes, respiratory, and digestive epithelial cells. It thus appears that non-neuronal cholinergic systems are expressed in a variety of mammalian cells, and that ACh should now be recognized not only as a neurotransmitter, but also as a local regulator of non-neuronal cholinergic systems. Here, we discuss the role of non-neuronal cholinergic systems, with a focus on immune cells. A current focus of much research on non-neuronal cholinergic systems in immune cells is α7 nAChRs, as these receptors expressed on macrophages and T cells are involved in regulating inflammatory and immune responses. This makes α7 nAChRs an attractive potential therapeutic target.
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Grants
- 19-31: TF; 20-25: TF. Individual Research Grants from the Doshisha Women's College of Liberal Arts
- 24590120, K.K., T.F., K.H.; 22K06638, T.F., A.N., 15K18871, M.M.; 15K07979, T.F., 15K07969-m, K.K.; 18K06903, T.F. The Ministry of Education, Science, Sports and Culture of Japan
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Affiliation(s)
- Koichiro Kawashima
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Minato-ku, Tokyo 108-8641, Japan
| | - Masato Mashimo
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kyotanabe 610-0395, Japan; (M.M.); (A.N.)
| | - Atsuo Nomura
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kyotanabe 610-0395, Japan; (M.M.); (A.N.)
| | - Takeshi Fujii
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kyotanabe 610-0395, Japan; (M.M.); (A.N.)
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14
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Lauten TH, Natour T, Case AJ. Innate and adaptive immune system consequences of post-traumatic stress disorder. Auton Neurosci 2024; 252:103159. [PMID: 38428324 PMCID: PMC11494466 DOI: 10.1016/j.autneu.2024.103159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 01/06/2024] [Accepted: 02/21/2024] [Indexed: 03/03/2024]
Abstract
In the field of psychiatry, biological markers are rarely, if ever, used in the diagnosis of mental health disorders. Clinicians rely primarily on patient histories and behavioral symptoms to identify specific psychopathologies, which makes diagnosis highly subjective. Moreover, therapies for mental health disorders are aimed specifically at attenuating behavioral manifestations, which overlooks the pathophysiological indices of the disease. This is highly evident in posttraumatic stress disorder (PTSD) where inflammation and immune system perturbations are becoming increasingly described. Further, patients with PTSD possess significantly elevated risks of developing comorbid inflammatory diseases such as autoimmune and cardiovascular diseases, which are likely linked (though not fully proven) to the apparent dysregulation of the immune system after psychological trauma. To date, there is little to no evidence that demonstrates current PTSD therapies are able to reverse the increased risk for psychological trauma-induced inflammatory diseases, which suggests the behavioral and somatic consequences of PTSD may not be tightly coupled. This observation provides an opportunity to explore unique mechanisms outside of the brain that contribute to the long-term pathology of PTSD. Herein, we provide an overview of neuroimmune mechanisms, describe what is known regarding innate and adaptive immunity in PTSD, and suggest new directions that are needed to advance the understanding, diagnosis, and treatment of PTSD moving forward.
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Affiliation(s)
- Tatlock H Lauten
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, United States; Department of Medical Physiology, Texas A&M University, Bryan, TX, United States
| | - Tamara Natour
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, United States; Department of Medical Physiology, Texas A&M University, Bryan, TX, United States
| | - Adam J Case
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, United States; Department of Medical Physiology, Texas A&M University, Bryan, TX, United States.
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15
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Kjerulff B, Dowsett J, Jacobsen RL, Gladov J, Larsen MH, Lundgaard AT, Banasik K, Westergaard D, Mikkelsen S, Dinh KM, Hindhede L, Kaspersen KA, Schwinn M, Juul A, Poulsen B, Lindegaard B, Pedersen CB, Sabel CE, Bundgaard H, Nielsen HS, Møller JA, Boldsen JK, Burgdorf KS, Kessing LV, Handgaard LJ, Thørner LW, Didriksen M, Nyegaard M, Grarup N, Ødum N, Johansson PI, Jennum P, Frikke-Schmidt R, Berger SS, Brunak S, Jacobsen S, Hansen TF, Lundquist TK, Hansen T, Sørensen TL, Sigsgaard T, Nielsen KR, Bruun MT, Hjalgrim H, Ullum H, Rostgaard K, Sørensen E, Pedersen OB, Ostrowski SR, Erikstrup C. Lifestyle and demographic associations with 47 inflammatory and vascular stress biomarkers in 9876 blood donors. COMMUNICATIONS MEDICINE 2024; 4:50. [PMID: 38493237 PMCID: PMC10944541 DOI: 10.1038/s43856-024-00474-2] [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: 03/31/2023] [Accepted: 03/04/2024] [Indexed: 03/18/2024] Open
Abstract
BACKGROUND The emerging use of biomarkers in research and tailored care introduces a need for information about the association between biomarkers and basic demographics and lifestyle factors revealing expectable concentrations in healthy individuals while considering general demographic differences. METHODS A selection of 47 biomarkers, including markers of inflammation and vascular stress, were measured in plasma samples from 9876 Danish Blood Donor Study participants. Using regression models, we examined the association between biomarkers and sex, age, Body Mass Index (BMI), and smoking. RESULTS Here we show that concentrations of inflammation and vascular stress biomarkers generally increase with higher age, BMI, and smoking. Sex-specific effects are observed for multiple biomarkers. CONCLUSION This study provides comprehensive information on concentrations of 47 plasma biomarkers in healthy individuals. The study emphasizes that knowledge about biomarker concentrations in healthy individuals is critical for improved understanding of disease pathology and for tailored care and decision support tools.
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Affiliation(s)
- Bertram Kjerulff
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
- BERTHA Big Data Centre for Environment and Health, Aarhus University, Aarhus, Denmark.
| | - Joseph Dowsett
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Rikke Louise Jacobsen
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Josephine Gladov
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- BERTHA Big Data Centre for Environment and Health, Aarhus University, Aarhus, Denmark
| | - Margit Hørup Larsen
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Agnete Troen Lundgaard
- Translational Disease Systems Biology, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Karina Banasik
- Translational Disease Systems Biology, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - David Westergaard
- Translational Disease Systems Biology, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Susan Mikkelsen
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
| | - Khoa Manh Dinh
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
| | - Lotte Hindhede
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
| | - Kathrine Agergård Kaspersen
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
- BERTHA Big Data Centre for Environment and Health, Aarhus University, Aarhus, Denmark
| | - Michael Schwinn
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Anders Juul
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Betina Poulsen
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Birgitte Lindegaard
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Pulmonary and Infectious Diseases, Copenhagen University Hospital-North Zealand, Hillerød, Denmark
| | - Carsten Bøcker Pedersen
- BERTHA Big Data Centre for Environment and Health, Aarhus University, Aarhus, Denmark
- National Centre for Register-based Research, Aarhus BSS, Aarhus University, Aarhus, Denmark
| | - Clive Eric Sabel
- BERTHA Big Data Centre for Environment and Health, Aarhus University, Aarhus, Denmark
- Department of Public Health, Aarhus University, DK-8000, Aarhus, Denmark
- School of Geography, Earth and Environmental Sciences, University of Plymouth, Plymouth, PL4 8AA, UK
| | - Henning Bundgaard
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- The Heart Center, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Henriette Svarre Nielsen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Recurrent Pregnancy Loss Unit, Capital Region, Copenhagen University Hospitals, Hvidovre and Rigshospitalet, Copenhagen, Denmark
- Department of Obstetrics and Gynecology, Copenhagen University Hospital, Hvidovre, Denmark
| | - Janne Amstrup Møller
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Jens Kjærgaard Boldsen
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
- BERTHA Big Data Centre for Environment and Health, Aarhus University, Aarhus, Denmark
| | - Kristoffer Sølvsten Burgdorf
- Translational Disease Systems Biology, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lars Vedel Kessing
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Copenhagen Affective Disorder Research Center (CADIC), Psychiatric Center Copenhagen, Copenhagen, Denmark
| | - Linda Jenny Handgaard
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Lise Wegner Thørner
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Maria Didriksen
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Mette Nyegaard
- Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Niels Grarup
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Niels Ødum
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Pär I Johansson
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- Department of Obstetrics and Gynecology, Copenhagen University Hospital, Hvidovre, Denmark
| | - Poul Jennum
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, Rigshospitalet, Copenhagen, Denmark
| | - Ruth Frikke-Schmidt
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark
| | - Sanne Schou Berger
- Centre for Diagnostics, DTU Health Technology, Technical University of Denmark, 2800, Kgs. Lyngby, Denmark
| | - Søren Brunak
- Translational Disease Systems Biology, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Søren Jacobsen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Copenhagen Lupus and Vasculitis Clinic, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen, Denmark
| | - Thomas Folkmann Hansen
- Translational Disease Systems Biology, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Danish Headache Center and Danish Multiple Sclerosis Center, Copenhagen University Hospital, Rigshospitalet Glostrup, Glostrup, Denmark
| | - Tine Kirkeskov Lundquist
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Torben Lykke Sørensen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Eye Research Division, Department of Ophthalmology, Zealand University, Hospital, Roskilde, Denmark
| | - Torben Sigsgaard
- BERTHA Big Data Centre for Environment and Health, Aarhus University, Aarhus, Denmark
- Department of Public Health, Aarhus University, DK-8000, Aarhus, Denmark
| | - Kaspar René Nielsen
- Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark
| | - Mie Topholm Bruun
- Department of Clinical Immunology, Odense University Hospital, Odense, Denmark
| | - Henrik Hjalgrim
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
- Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark
- Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark
| | | | - Klaus Rostgaard
- Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
- Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark
| | - Erik Sørensen
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Ole Birger Pedersen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark
| | - Sisse Rye Ostrowski
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Christian Erikstrup
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- BERTHA Big Data Centre for Environment and Health, Aarhus University, Aarhus, Denmark
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16
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Li L, Huang RW, Liu XN, Xiang XY, Zhou YT, Feng XX, Tao LY, Yu J, Qin Yi, Wang YC, Liu XM. Modulation of plasmacytoid dendritic cell and CD4 + T cell differentiation accompanied by upregulation of the cholinergic anti-inflammatory pathway induced by enterovirus 71. Arch Virol 2024; 169:73. [PMID: 38472498 DOI: 10.1007/s00705-024-05974-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 12/12/2023] [Indexed: 03/14/2024]
Abstract
Enterovirus 71 (EV71) is a neurotropic enterovirus associated with hand, foot, and mouth disease (HFMD) fatalities. In this study, we investigated the impact of EV71 on plasmacytoid dendritic cells (pDCs) and CD4+ T cells. The results showed that pDCs were promptly activated, secreting interferon (IFN)-α and inducing CD4+ T cell proliferation and differentiation during early EV71 infection. This initiated adaptive immune responses and promoted proinflammatory cytokine production by CD4+ T cells. Over time, viral nucleic acids and proteins were synthesized in pDCs and CD4+ T cells. Concurrently, the cholinergic anti-inflammatory pathway (CAP) was activated, exhibiting an anti-inflammatory role. With constant viral stimulation, pDCs and CD4+ T cells showed reduced differentiation and cytokine secretion. Defects in pDCs were identified as a key factor in CD4+ T cell tolerance. CAP had a more significant regulatory effect on CD4+ T cells than on pDCs and was capable of inhibiting inflammation in these cells.
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Affiliation(s)
- Li Li
- Yunnan Medical Center for Pediatric Diseases, Yunnan Institute of Pediatrics, Kunming Children's Hospital, Kunming, 650228, Yunnan, China
- Kunming Key Laboratory of Children Infection and Immunity, Yunnan Key Laboratory of Children's Major Disease Research, Yunnan Province Clinical Research Center for Children's Health and Disease, Kunming, 650228, Yunnan, China
| | - Rong-Wei Huang
- Kunming Key Laboratory of Children Infection and Immunity, Yunnan Key Laboratory of Children's Major Disease Research, Yunnan Province Clinical Research Center for Children's Health and Disease, Kunming, 650228, Yunnan, China
| | - Xiao-Ning Liu
- Department of Pharmacy, Kunming Children's Hospital, Kunming, 650228, Yunnan, China
| | - Xiao-Yi Xiang
- Kunming Key Laboratory of Children Infection and Immunity, Yunnan Key Laboratory of Children's Major Disease Research, Yunnan Province Clinical Research Center for Children's Health and Disease, Kunming, 650228, Yunnan, China
| | - Yuan-Tao Zhou
- Kunming Key Laboratory of Children Infection and Immunity, Yunnan Key Laboratory of Children's Major Disease Research, Yunnan Province Clinical Research Center for Children's Health and Disease, Kunming, 650228, Yunnan, China
| | - Xing-Xing Feng
- Department of Clinical Laboratory, Kunming Children's Hospital, Kunming, 650228, Yunnan, China
| | - Lv-Yuan Tao
- Yunnan Medical Center for Pediatric Diseases, Yunnan Institute of Pediatrics, Kunming Children's Hospital, Kunming, 650228, Yunnan, China
- Kunming Key Laboratory of Children Infection and Immunity, Yunnan Key Laboratory of Children's Major Disease Research, Yunnan Province Clinical Research Center for Children's Health and Disease, Kunming, 650228, Yunnan, China
| | - Jia Yu
- Yunnan Medical Center for Pediatric Diseases, Yunnan Institute of Pediatrics, Kunming Children's Hospital, Kunming, 650228, Yunnan, China
| | - Qin Yi
- Department of Clinical Laboratory, Zouping People's Hospital, Binzhou, 256200, Shandong, China
| | - Yan-Chun Wang
- Department of 2nd Infection, Kunming Children's Hospital, Zouping People's Hospital, Kunming, 650228, Yunnan, China
| | - Xiao-Mei Liu
- Kunming Key Laboratory of Children Infection and Immunity, Yunnan Key Laboratory of Children's Major Disease Research, Yunnan Province Clinical Research Center for Children's Health and Disease, Kunming, 650228, Yunnan, China.
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17
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Zißler J, Rothhammer V, Linnerbauer M. Gut-Brain Interactions and Their Impact on Astrocytes in the Context of Multiple Sclerosis and Beyond. Cells 2024; 13:497. [PMID: 38534341 PMCID: PMC10968834 DOI: 10.3390/cells13060497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 03/04/2024] [Accepted: 03/12/2024] [Indexed: 03/28/2024] Open
Abstract
Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS) that leads to physical and cognitive impairment in young adults. The increasing prevalence of MS underscores the critical need for innovative therapeutic approaches. Recent advances in neuroimmunology have highlighted the significant role of the gut microbiome in MS pathology, unveiling distinct alterations in patients' gut microbiota. Dysbiosis not only impacts gut-intrinsic processes but also influences the production of bacterial metabolites and hormones, which can regulate processes in remote tissues, such as the CNS. Central to this paradigm is the gut-brain axis, a bidirectional communication network linking the gastrointestinal tract to the brain and spinal cord. Via specific routes, bacterial metabolites and hormones can influence CNS-resident cells and processes both directly and indirectly. Exploiting this axis, novel therapeutic interventions, including pro- and prebiotic treatments, have emerged as promising avenues with the aim of mitigating the severity of MS. This review delves into the complex interplay between the gut microbiome and the brain in the context of MS, summarizing current knowledge on the key signals of cross-organ crosstalk, routes of communication, and potential therapeutic relevance of the gut microbiome. Moreover, this review places particular emphasis on elucidating the influence of these interactions on astrocyte functions within the CNS, offering insights into their role in MS pathophysiology and potential therapeutic interventions.
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Affiliation(s)
| | - Veit Rothhammer
- Department of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany
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18
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Miller G, Pareek O, Penman SL, Thanos PK. The Effects of Nicotine and Cannabinoids on Cytokines. Curr Pharm Des 2024; 30:2468-2484. [PMID: 38859790 DOI: 10.2174/0113816128293077240529111824] [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: 01/11/2024] [Revised: 03/11/2024] [Accepted: 04/04/2024] [Indexed: 06/12/2024]
Abstract
BACKGROUND The usage of nicotine and cannabinoids has rapidly grown in popularity, leading to increased research into how they can affect people's health, both positively and negatively. Nicotine, Cannabidiol (CBD), and Δ9-tetrahydrocannabinol (THC) have been shown to have significant effects on cytokine function and inflammatory response. OBJECTIVE This study aimed to review and summarize the current literature on the effects of nicotine and cannabinoids on cytokines, including interleukins, TNF, IFN, and TGF-β. METHODS Literature search was conducted on Medline/PubMed electronic databases utilizing the search terms "nicotine" OR "cannabis" OR "cannabinoids" AND "cytokine" AND "inflammation" AND "stress" AND "immune" from 11/1973 to 02/2024. RESULTS THC and CBD usage have been associated with conflicting impacts on immune response, and observed to both exacerbate and inhibit inflammation. Nicotine has been shown to be generally proinflammatory with regards to cytokines. These responses have been reported to have significant effects on bodily response to inflammation-related diseases. Nicotine usage is associated with worsened outcomes for some conditions, like chronic pain, but improved outcomes for others, like arthritis. The impacts of cannabinoid usage tend to be more positive, exerting anti-inflammatory effects across a wide range of diseases. Given the widespread usage of these substances, it is important to understand the nature of their consequences on immune functions and the underlying mechanisms by which they act. CONCLUSION This review has covered how cannabinoids and nicotine affect inflammation directly and how these effects can be attributed to the treatment of inflammatory diseases. In summary, the existing research studying the effects of cannabinoids and nicotine supports the major relationship between nicotine and cannabis use and inflammatory diseases.
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Affiliation(s)
- Grace Miller
- Department of Pharmacology Toxicology, University at Buffalo, State University of New York, Buffalo, NY 14068, United States
| | - Ojas Pareek
- Department of Pharmacology Toxicology, University at Buffalo, State University of New York, Buffalo, NY 14068, United States
| | - Samantha L Penman
- Department of Pharmacology Toxicology, University at Buffalo, State University of New York, Buffalo, NY 14068, United States
| | - Panayotis K Thanos
- Department of Pharmacology Toxicology, University at Buffalo, State University of New York, Buffalo, NY 14068, United States
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19
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Boiangiu RS, Brinza I, Honceriu I, Mihasan M, Hritcu L. Insights into Pharmacological Activities of Nicotine and 6-Hydroxy-L-nicotine, a Bacterial Nicotine Derivative: A Systematic Review. Biomolecules 2023; 14:23. [PMID: 38254623 PMCID: PMC10813004 DOI: 10.3390/biom14010023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/13/2023] [Accepted: 12/20/2023] [Indexed: 01/24/2024] Open
Abstract
The purported cognitive benefits associated with nicotine and its metabolites in the brain are a matter of debate. In this review, the impact of the pharmacologically active metabolite of a nicotine derivative produced by bacteria named 6-hydroxy-L-nicotine (6HLN) on memory, oxidative stress, and the activity of the cholinergic system in the brain was examined. A search in the PubMed, Science Direct, Web of Science, and Google Scholar databases, limiting entries to those published between 1992 and 2023, was conducted. The search focused specifically on articles about nicotine metabolites, memory, oxidative stress, and cholinergic system activity, as well as enzymes or pathways related to nicotine degradation in bacteria. The preliminary search resulted in 696 articles, and following the application of exclusion criteria, 212 articles were deemed eligible for inclusion. This review focuses on experimental studies supporting nicotine catabolism in bacteria, and the chemical and pharmacological activities of nicotine and its metabolite 6HLN.
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Affiliation(s)
| | | | | | - Marius Mihasan
- BioActive Research Group, Department of Biology, Faculty of Biology, Alexandru Ioan Cuza University of Iasi, 700506 Iasi, Romania; (R.S.B.); (I.B.); (I.H.)
| | - Lucian Hritcu
- BioActive Research Group, Department of Biology, Faculty of Biology, Alexandru Ioan Cuza University of Iasi, 700506 Iasi, Romania; (R.S.B.); (I.B.); (I.H.)
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20
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Fares MB, Alijevic O, Johne S, Overk C, Hashimoto M, Kondylis A, Adame A, Dulize R, Peric D, Nury C, Battey J, Guedj E, Sierro N, Mc Hugh D, Rockenstein E, Kim C, Rissman RA, Hoeng J, Peitsch MC, Masliah E, Mathis C. Nicotine-mediated effects in neuronal and mouse models of synucleinopathy. Front Neurosci 2023; 17:1239009. [PMID: 37719154 PMCID: PMC10501483 DOI: 10.3389/fnins.2023.1239009] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 08/08/2023] [Indexed: 09/19/2023] Open
Abstract
Introduction Alpha-synuclein (α-Syn) aggregation, transmission, and contribution to neurotoxicity represent central mechanisms underlying Parkinson's disease. The plant alkaloid "nicotine" was reported to attenuate α-Syn aggregation in different models, but its precise mode of action remains unclear. Methods In this study, we investigated the effect of 2-week chronic nicotine treatment on α-Syn aggregation, neuroinflammation, neurodegeneration, and motor deficits in D-line α-Syn transgenic mice. We also established a novel humanized neuronal model of α-Syn aggregation and toxicity based on treatment of dopaminergic neurons derived from human induced pluripotent stem cells (iPSC) with α-Syn preformed fibrils (PFF) and applied this model to investigate the effects of nicotine and other compounds and their modes of action. Results and discussion Overall, our results showed that nicotine attenuated α-Syn-provoked neuropathology in both models. Moreover, when investigating the role of nicotinic acetylcholine receptor (nAChR) signaling in nicotine's neuroprotective effects in iPSC-derived dopaminergic neurons, we observed that while α4-specific antagonists reduced the nicotine-induced calcium response, α4 agonists (e.g., AZD1446 and anatabine) mediated similar neuroprotective responses against α-Syn PFF-provoked neurodegeneration. Our results show that nicotine attenuates α-Syn-provoked neuropathology in vivo and in a humanized neuronal model of synucleinopathy and that activation of α4β2 nicotinic receptors might mediate these neuroprotective effects.
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Affiliation(s)
| | - Omar Alijevic
- PMI R&D, Philip Morris Products S.A., Neuchâtel, Switzerland
| | - Stephanie Johne
- PMI R&D, Philip Morris Products S.A., Neuchâtel, Switzerland
| | - Cassia Overk
- Department of Neurosciences, University of California, San Diego, San Diego, CA, United States
| | - Makoto Hashimoto
- Department of Neurosciences, University of California, San Diego, San Diego, CA, United States
| | | | - Anthony Adame
- Department of Neurosciences, University of California, San Diego, San Diego, CA, United States
| | - Remi Dulize
- PMI R&D, Philip Morris Products S.A., Neuchâtel, Switzerland
| | - Dariusz Peric
- PMI R&D, Philip Morris Products S.A., Neuchâtel, Switzerland
| | - Catherine Nury
- PMI R&D, Philip Morris Products S.A., Neuchâtel, Switzerland
| | - James Battey
- PMI R&D, Philip Morris Products S.A., Neuchâtel, Switzerland
| | - Emmanuel Guedj
- PMI R&D, Philip Morris Products S.A., Neuchâtel, Switzerland
| | - Nicolas Sierro
- PMI R&D, Philip Morris Products S.A., Neuchâtel, Switzerland
| | - Damian Mc Hugh
- PMI R&D, Philip Morris Products S.A., Neuchâtel, Switzerland
| | - Edward Rockenstein
- Department of Neurosciences, University of California, San Diego, San Diego, CA, United States
| | - Changyoun Kim
- Department of Neurosciences, University of California, San Diego, San Diego, CA, United States
| | - Robert A. Rissman
- Department of Neurosciences, University of California, San Diego, San Diego, CA, United States
| | - Julia Hoeng
- PMI R&D, Philip Morris Products S.A., Neuchâtel, Switzerland
| | | | - Eliezer Masliah
- Department of Neurosciences, University of California, San Diego, San Diego, CA, United States
| | - Carole Mathis
- PMI R&D, Philip Morris Products S.A., Neuchâtel, Switzerland
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21
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Wu J, Olsson T, Hillert J, Alfredsson L, Hedström AK. Influence of oral tobacco versus smoking on multiple sclerosis disease activity and progression. J Neurol Neurosurg Psychiatry 2023; 94:589-596. [PMID: 37001984 PMCID: PMC10359558 DOI: 10.1136/jnnp-2022-330848] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 02/13/2023] [Indexed: 06/19/2023]
Abstract
We aimed to study the influence of smoking habits, exposure to passive smoking and snuff use on disease progression, cognitive performance and quality of life in patients with multiple sclerosis (MS). METHOD Patients from two population-based case-control studies were categorised based on tobacco exposure at diagnosis and were followed up to 15 years post diagnosis through the Swedish MS registry (n=9089) regarding changes in Expanded Disability Status Scale (EDSS), Multiple Sclerosis Impact Scale 29 and Symbol Digit Modalities Test. We used linear mixed models to analyse long-term changes, and Cox regression models with 95% CI using 24-week confirmed disability worsening, reaching EDSS 3 and EDSS 4, respectively, physical and psychological worsening and cognitive disability worsening as end points. The influence of smoking cessation post diagnosis was also investigated. RESULTS Compared with non-smokers, current smokers had a faster EDSS progression (βcurrent smoking×time=0.03, 95% CI 0.02 to 0.04). A faster EDSS progression was also associated with passive smoking (βcurrent passive smoking×time=0.04, 95% CI 0.03 to 0.06). Smoke exposure negatively impacted all secondary outcomes. Those who continued smoking had worse outcomes than those who stopped smoking post diagnosis. Snuff users had a more favourable EDSS progression, compared with never users. CONCLUSIONS Our findings indicate that both smoking and passive smoking have a negative influence on MS and that smoking cessation post diagnosis may be an important secondary preventive measure. Snuff use was associated with slower disease progression, suggesting that nicotine replacement therapy could be an attractive way to increase the chance of quitting smoking among patients with MS.
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Affiliation(s)
- Jing Wu
- Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Stockholm, Sweden
| | - Tomas Olsson
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Jan Hillert
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Lars Alfredsson
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Centre for Occupational and Environmental Medicine, Region Stockholm, Stockholm, Sweden
| | - Anna Karin Hedström
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
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22
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Mashimo M, Fujii T, Ono S, Moriwaki Y, Misawa H, Azami T, Kasahara T, Kawashima K. GTS-21 Enhances Regulatory T Cell Development from T Cell Receptor-Activated Human CD4 + T Cells Exhibiting Varied Levels of CHRNA7 and CHRFAM7A Expression. Int J Mol Sci 2023; 24:12257. [PMID: 37569633 PMCID: PMC10418795 DOI: 10.3390/ijms241512257] [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: 06/13/2023] [Revised: 07/22/2023] [Accepted: 07/28/2023] [Indexed: 08/13/2023] Open
Abstract
Immune cells such as T cells and macrophages express α7 nicotinic acetylcholine receptors (α7 nAChRs), which contribute to the regulation of immune and inflammatory responses. Earlier findings suggest α7 nAChR activation promotes the development of regulatory T cells (Tregs) in mice. Using human CD4+ T cells, we investigated the mRNA expression of the α7 subunit and the human-specific dupα7 nAChR subunit, which functions as a dominant-negative regulator of ion channel function, under resting conditions and T cell receptor (TCR)-activation. We then explored the effects of the selective α7 nAChR agonist GTS-21 on proliferation of TCR-activated T cells and Treg development. Varied levels of mRNA for both the α7 and dupα7 nAChR subunits were detected in resting human CD4+ T cells. mRNA expression of the α7 nAChR subunit was profoundly suppressed on days 4 and 7 of TCR-activation as compared to day 1, whereas mRNA expression of the dupα7 nAChR subunit remained nearly constant. GTS-21 did not alter CD4+ T cell proliferation but significantly promoted Treg development. These results suggest the potential ex vivo utility of GTS-21 for preparing Tregs for adoptive immunotherapy, even with high expression of the dupα7 subunit.
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Affiliation(s)
- Masato Mashimo
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kyotanabe 610-0395, Japan; (M.M.); (T.F.)
| | - Takeshi Fujii
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kyotanabe 610-0395, Japan; (M.M.); (T.F.)
| | - Shiro Ono
- Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi 584-8540, Japan;
| | - Yasuhiro Moriwaki
- Department of Pharmacology, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo 105-8512, Japan; (Y.M.); (H.M.)
| | - Hidemi Misawa
- Department of Pharmacology, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo 105-8512, Japan; (Y.M.); (H.M.)
| | - Tetsushi Azami
- Division of Gastroenterology, Department of Internal Medicine, Showa University Fujigaoka Hospital, Yokohama 227-8502, Japan;
| | - Tadashi Kasahara
- Division of Inflammation Research, Jichi Medical University, Shimotsukeshi 324-0498, Japan;
| | - Koichiro Kawashima
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Minato-ku, Tokyo 108-8641, Japan
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23
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Zouali M. Pharmacological and Electroceutical Targeting of the Cholinergic Anti-Inflammatory Pathway in Autoimmune Diseases. Pharmaceuticals (Basel) 2023; 16:1089. [PMID: 37631004 PMCID: PMC10459025 DOI: 10.3390/ph16081089] [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: 07/02/2023] [Revised: 07/23/2023] [Accepted: 07/25/2023] [Indexed: 08/27/2023] Open
Abstract
Continuous dialogue between the immune system and the brain plays a key homeostatic role in various immune responses to environmental cues. Several functions are under the control of the vagus nerve-based inflammatory reflex, a physiological mechanism through which nerve signals regulate immune functions. In the cholinergic anti-inflammatory pathway, the vagus nerve, its pivotal neurotransmitter acetylcholine, together with the corresponding receptors play a key role in modulating the immune response of mammals. Through communications of peripheral nerves with immune cells, it modulates proliferation and differentiation activities of various immune cell subsets. As a result, this pathway represents a potential target for treating autoimmune diseases characterized by overt inflammation and a decrease in vagal tone. Consistently, converging observations made in both animal models and clinical trials revealed that targeting the cholinergic anti-inflammatory pathway using pharmacologic approaches can provide beneficial effects. In parallel, bioelectronic medicine has recently emerged as an alternative approach to managing systemic inflammation. In several studies, nerve electrostimulation was reported to be clinically relevant in reducing chronic inflammation in autoimmune diseases, including rheumatoid arthritis and diabetes. In the future, these new approaches could represent a major therapeutic strategy for autoimmune and inflammatory diseases.
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Affiliation(s)
- Moncef Zouali
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan
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24
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Yun Y, Wang X, Xu J, Chen J, Wang X, Yang P, Qin L. Optogenetic stimulation of basal forebrain cholinergic neurons prevents neuroinflammation and neuropsychiatric manifestations in pristane induced lupus mice. BEHAVIORAL AND BRAIN FUNCTIONS : BBF 2023; 19:11. [PMID: 37322485 DOI: 10.1186/s12993-023-00213-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 06/07/2023] [Indexed: 06/17/2023]
Abstract
BACKGROUND Neuroinflammation has been identified as one of the primary pathogenic factors of neuropsychiatric systemic lupus erythematosus (NPSLE). However, there are no dedicated treatments available in clinics to alleviate neuroinflammation in NPSLE. It has been proposed that stimulating basal forebrain (BF) cholinergic neurons may provide potent anti-inflammatory effects in several inflammatory diseases, but its potential role in NPSLE remains unexplored. This study aims to investigate whether and how stimulating BF cholinergic neurons has a protective effect on NPSLE. RESULTS Optogenetic stimulation of BF cholinergic neurons significantly ameliorated olfactory dysfunction and anxiety- and depression-like phenotype in pristane induced lupus (PIL) mice. The increased expression of adhesion molecules (P-selectin and vascular cell adhesion molecule-1 (VCAM-1)), leukocyte recruitment, blood-brain barrier (BBB) leakage were significantly decreased. Notably, the brain histopathological changes, including the elevated levels of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β), IgG deposition in the choroid plexus and lateral ventricle wall and lipofuscin accumulation in the cortical and hippocampal neurons, were also significantly attenuated. Furthermore, we confirmed the colocalization between the BF cholinergic projections and the cerebral vessels, and the expression of α7-nicotinic acetylcholine receptor (α7nAChR) on the cerebral vessels. CONCLUSION Our data indicate that stimulation of BF cholinergic neurons could play a neuroprotective role in the brain through its cholinergic anti-inflammatory effects on cerebral vessels. Therefore, this may be a promising preventive target for NPSLE.
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Affiliation(s)
- Yang Yun
- Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xuejiao Wang
- Department of Physiology, China Medical University, Shenyang, China
| | - Jingyi Xu
- Department of Rheumatology and Immunology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jingyu Chen
- Department of Physiology, China Medical University, Shenyang, China
| | - Xueru Wang
- Department of Physiology, China Medical University, Shenyang, China
| | - Pingting Yang
- Department of Rheumatology and Immunology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Ling Qin
- Department of Physiology, China Medical University, Shenyang, China.
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25
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Salehi Z, Motlagh Ghoochani BFN, Hasani Nourian Y, Jamalkandi SA, Ghanei M. The controversial effect of smoking and nicotine in SARS-CoV-2 infection. ALLERGY, ASTHMA, AND CLINICAL IMMUNOLOGY : OFFICIAL JOURNAL OF THE CANADIAN SOCIETY OF ALLERGY AND CLINICAL IMMUNOLOGY 2023; 19:49. [PMID: 37264452 PMCID: PMC10234254 DOI: 10.1186/s13223-023-00797-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 04/18/2023] [Indexed: 06/03/2023]
Abstract
The effects of nicotine and cigarette smoke in many diseases, notably COVID-19 infection, are being debated more frequently. The current basic data for COVID-19 is increasing and indicating the higher risk of COVID-19 infections in smokers due to the overexpression of corresponding host receptors to viral entry. However, current multi-national epidemiological reports indicate a lower incidence of COVID-19 disease in smokers. Current data indicates that smokers are more susceptible to some diseases and more protective of some other. Interestingly, nicotine is also reported to play a dual role, being both inflammatory and anti-inflammatory. In the present study, we tried to investigate the effect of pure nicotine on various cells involved in COVID-19 infection. We followed an organ-based systematic approach to decipher the effect of nicotine in damaged organs corresponding to COVID-19 pathogenesis (12 related diseases). Considering that the effects of nicotine and cigarette smoke are different from each other, it is necessary to be careful in generalizing the effects of nicotine and cigarette to each other in the conducted researches. The generalization and the undifferentiation of nicotine from smoke is a significant bias. Moreover, different doses of nicotine stimulate different effects (dose-dependent response). In addition to further assessing the role of nicotine in COVID-19 infection and any other cases, a clever assessment of underlying diseases should also be considered to achieve a guideline for health providers and a personalized approach to treatment.
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Affiliation(s)
- Zahra Salehi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | | | - Yazdan Hasani Nourian
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Sadegh Azimzadeh Jamalkandi
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Mostafa Ghanei
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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26
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O'Brien BCV, Weber L, Hueffer K, Weltzin MM. SARS-CoV-2 spike ectodomain targets α7 nicotinic acetylcholine receptors. J Biol Chem 2023; 299:104707. [PMID: 37061001 PMCID: PMC10101490 DOI: 10.1016/j.jbc.2023.104707] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 03/13/2023] [Accepted: 04/10/2023] [Indexed: 04/17/2023] Open
Abstract
Virus entry into animal cells is initiated by attachment to target macromolecules located on host cells. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) trimeric spike glycoprotein targets host angiotensin converting enzyme 2 to gain cellular access. The SARS-CoV-2 glycoprotein contains a neurotoxin-like region that has sequence similarities to the rabies virus and the HIV glycoproteins, as well as to snake neurotoxins, which interact with nicotinic acetylcholine receptor (nAChR) subtypes via this region. Using a peptide of the neurotoxin-like region of SARS-CoV-2 (SARS-CoV-2 glycoprotein peptide [SCoV2P]), we identified that this area moderately inhibits α3β2, α3β4, and α4β2 subtypes, while potentiating and inhibiting α7 nAChRs. These nAChR subtypes are found in target tissues including the nose, lung, central nervous system, and immune cells. Importantly, SCoV2P potentiates and inhibits ACh-induced α7 nAChR responses by an allosteric mechanism, with nicotine enhancing these effects. Live-cell confocal microscopy was used to confirm that SCoV2P interacts with α7 nAChRs in transfected neuronal-like N2a and human embryonic kidney 293 cells. The SARS-CoV-2 ectodomain functionally potentiates and inhibits the α7 subtype with nanomolar potency. Our functional findings identify that the α7 nAChR is a target for the SARS-CoV-2 glycoprotein, providing a new aspect to our understanding of SARS-CoV-2 and host cell interactions, in addition to disease pathogenesis.
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Affiliation(s)
- Brittany C V O'Brien
- Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, Alaska, USA
| | - Lahra Weber
- Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, Alaska, USA
| | - Karsten Hueffer
- Department of Veterinary Medicine, University of Alaska Fairbanks, Fairbanks, Alaska, USA
| | - Maegan M Weltzin
- Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, Alaska, USA.
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27
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Shelukhina I, Siniavin A, Kasheverov I, Ojomoko L, Tsetlin V, Utkin Y. α7- and α9-Containing Nicotinic Acetylcholine Receptors in the Functioning of Immune System and in Pain. Int J Mol Sci 2023; 24:ijms24076524. [PMID: 37047495 PMCID: PMC10095066 DOI: 10.3390/ijms24076524] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/26/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
Nicotinic acetylcholine receptors (nAChRs) present as many different subtypes in the nervous and immune systems, muscles and on the cells of other organs. In the immune system, inflammation is regulated via the vagus nerve through the activation of the non-neuronal α7 nAChR subtype, affecting the production of cytokines. The analgesic properties of α7 nAChR-selective compounds are mostly based on the activation of the cholinergic anti-inflammatory pathway. The molecular mechanism of neuropathic pain relief mediated by the inhibition of α9-containing nAChRs is not fully understood yet, but the role of immune factors in this process is becoming evident. To obtain appropriate drugs, a search of selective agonists, antagonists and modulators of α7- and α9-containing nAChRs is underway. The naturally occurring three-finger snake α-neurotoxins and mammalian Ly6/uPAR proteins, as well as neurotoxic peptides α-conotoxins, are not only sophisticated tools in research on nAChRs but are also considered as potential medicines. In particular, the inhibition of the α9-containing nAChRs by α-conotoxins may be a pathway to alleviate neuropathic pain. nAChRs are involved in the inflammation processes during AIDS and other viral infections; thus they can also be means used in drug design. In this review, we discuss the role of α7- and α9-containing nAChRs in the immune processes and in pain.
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Affiliation(s)
| | | | | | | | | | - Yuri Utkin
- Correspondence: or ; Tel.: +7-495-3366522
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28
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Chen J, Li S, Feng L, Wang H, Huang X, Feng H. Nomogram for the acute exacerbation of acetylcholine receptor antibody-positive generalized myasthenia gravis. Neurol Sci 2023; 44:1049-1057. [PMID: 36369308 DOI: 10.1007/s10072-022-06493-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 11/02/2022] [Indexed: 11/13/2022]
Abstract
BACKGROUND AND OBJECTIVE An acute exacerbation of myasthenia gravis (MG) can lead to the life-threatening myasthenia crisis which can increase the in-hospital mortality. This study aimed to clarify the correlative factor of the severity and activity of MG and the predictors of its exacerbation. METHODS A prospective study was conducted to compare the clinical characteristics of acetylcholine receptor antibody (AChR-Ab)-positive generalized MG during acute exacerbation (AE) and in a stable state (SS). Logistic regression was used to determine risk factors, and a nomogram was developed. RESULTS A total of 97 AChR-Ab MG patients were enrolled, of whom 44 had AE and 53 were in SS. The concentrations of AChR-Ab were 35.24 (23.26, 42.52) nmol/L and 19.51 (8.30, 36.93) nmol/L in the AE and SS groups (P = 0.005), respectively. The receiver operating characteristic curve showed that a single AChR-Ab predicted severity and acute exacerbation, with an area under the curve (AUC) of 0.679. Logistic regression analysis showed that, in addition to AChR-Ab (P = 0.018), bulbar symptoms (P = 0.001), interleukin (IL)-6 (P = 0.025), CD4+/CD8+ T cell ratio (P = 0.031), and CD19+ B cell proportion (P = 0.019) were independent risk factors for acute exacerbation of MG. The developed nomogram had an AUC of 0.878. The Hosmer and Lemeshow chi-square test was 4.37 (P = 0.929). CONCLUSION AChR-Ab concentration was positively correlated with the severity and activity of MG. AChR-Ab concentration, alongside bulbar symptoms, IL-6 concentration, CD4+/CD8+ T cell ratio, and CD19+ B cell proportion can predict the acute exacerbation of MG.
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Affiliation(s)
- Jiaxin Chen
- Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China
| | - Shiyin Li
- Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China
| | - Li Feng
- Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China
| | - Haiyan Wang
- Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China
| | - Xin Huang
- Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China. .,Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China.
| | - Huiyu Feng
- Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China. .,Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China.
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Trushenko NV, Suvorova OA, Pershina ES, Nekludova GV, Chikina SY, Levina IA, Chernyaev AL, Samsonova MV, Tyurin IE, Mustafina MK, Yaroshetskiy AI, Nadtochiy NB, Merzhoeva ZM, Proshkina AA, Avdeev SN. Predictors of Progression and Mortality in Patients with Chronic Hypersensitivity Pneumonitis: Retrospective Analysis of Registry of Fibrosing Interstitial Lung Diseases. Life (Basel) 2023; 13:life13020467. [PMID: 36836825 PMCID: PMC9965638 DOI: 10.3390/life13020467] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 01/28/2023] [Accepted: 02/03/2023] [Indexed: 02/11/2023] Open
Abstract
Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) resulting from an immune-mediated response in susceptible and sensitized individuals to a large variety of inhaled antigens. Chronic HP with a fibrotic phenotype is characterized by disease progression and a dismal prognosis. The aim of this study was to identify predictors of progression and mortality in patients with chronic HP in real clinical practice. MATERIALS AND METHODS This retrospective, multicenter, observational study used data from a registry of 1355 patients with fibrosing ILDs. The study included 292 patients diagnosed with chronic HP based on the conclusion of a multidisciplinary discussion (MDD). RESULTS The patients were divided into groups with progressive (92 (30.3%) patients) and nonprogressive pulmonary fibrosis (200 (69.7%) patients). The most significant predictors of adverse outcomes were a DLco < 50% predicted, an SpO2 at the end of a six-minute walk test (6-MWT) < 85%, and a GAP score ≥ 4 points. CONCLUSION Pulmonary fibrosis and a progressive fibrotic phenotype are common in patients with chronic HP. Early detection of the predictors of an adverse prognosis of chronic HP is necessary for the timely initiation of antifibrotic therapy.
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Affiliation(s)
- Natalia V. Trushenko
- Pulmonology Department, Sechenov First Moscow State Medical University (Sechenov University), Healthcare Ministry of Russia, Trubetskaya St. 8, Build. 2, 119991 Moscow, Russia
- Pulmonology Scientific Research Institute, Federal Medical and Biological Agency of Russian Federation, Orekhovyy Boulevard 28, 115682 Moscow, Russia
- Correspondence: (N.V.T.); (O.A.S.)
| | - Olga A. Suvorova
- Pulmonology Department, Sechenov First Moscow State Medical University (Sechenov University), Healthcare Ministry of Russia, Trubetskaya St. 8, Build. 2, 119991 Moscow, Russia
- Correspondence: (N.V.T.); (O.A.S.)
| | - Ekaterina S. Pershina
- Pulmonology Department, Sechenov First Moscow State Medical University (Sechenov University), Healthcare Ministry of Russia, Trubetskaya St. 8, Build. 2, 119991 Moscow, Russia
- Pirogov City Clinical Hospital No. 1, Moscow Healthcare Department, Leninsky Avenue 8, 117049 Moscow, Russia
| | - Galina V. Nekludova
- Pulmonology Department, Sechenov First Moscow State Medical University (Sechenov University), Healthcare Ministry of Russia, Trubetskaya St. 8, Build. 2, 119991 Moscow, Russia
- Pulmonology Scientific Research Institute, Federal Medical and Biological Agency of Russian Federation, Orekhovyy Boulevard 28, 115682 Moscow, Russia
| | - Svetlana Yu. Chikina
- Pulmonology Department, Sechenov First Moscow State Medical University (Sechenov University), Healthcare Ministry of Russia, Trubetskaya St. 8, Build. 2, 119991 Moscow, Russia
| | - Iuliia A. Levina
- Pulmonology Department, Sechenov First Moscow State Medical University (Sechenov University), Healthcare Ministry of Russia, Trubetskaya St. 8, Build. 2, 119991 Moscow, Russia
| | - Andrey L. Chernyaev
- Pulmonology Scientific Research Institute, Federal Medical and Biological Agency of Russian Federation, Orekhovyy Boulevard 28, 115682 Moscow, Russia
- Morphology Department, Pirogov Federal Russian National Research Medical University, Healthcare Ministry of Russia, Ostrovityanova St. 1, 117997 Moscow, Russia
- Federal Research Institute of Human Morphology, Tsyurupy St. 3, 117418 Moscow, Russia
| | - Maria V. Samsonova
- Pulmonology Scientific Research Institute, Federal Medical and Biological Agency of Russian Federation, Orekhovyy Boulevard 28, 115682 Moscow, Russia
- Moscow Clinical Scientific Center, Enthusiasts Highway 84/1, 111123 Moscow, Russia
| | - Igor E. Tyurin
- Russian Federal Academy of Continued Medical Education, Healthcare Ministry of Russia, Barrikadnaya St. 2/1, Build. 1, 123995 Moscow, Russia
| | - Malika Kh. Mustafina
- Pulmonology Department, Sechenov First Moscow State Medical University (Sechenov University), Healthcare Ministry of Russia, Trubetskaya St. 8, Build. 2, 119991 Moscow, Russia
- Pulmonology Scientific Research Institute, Federal Medical and Biological Agency of Russian Federation, Orekhovyy Boulevard 28, 115682 Moscow, Russia
| | - Andrey I. Yaroshetskiy
- Pulmonology Department, Sechenov First Moscow State Medical University (Sechenov University), Healthcare Ministry of Russia, Trubetskaya St. 8, Build. 2, 119991 Moscow, Russia
- Morphology Department, Pirogov Federal Russian National Research Medical University, Healthcare Ministry of Russia, Ostrovityanova St. 1, 117997 Moscow, Russia
| | - Nikita B. Nadtochiy
- Chelyabinsk Regional Clinical Hospital, Vorovskogo St. 70, 454076 Chelyabinsk, Russia
- Radiology Department, South-Ural State Medical University, Healthcare Ministry of Russia, Vorovskogo St. 64, 454092 Chelyabinsk, Russia
| | - Zamira M. Merzhoeva
- Pulmonology Department, Sechenov First Moscow State Medical University (Sechenov University), Healthcare Ministry of Russia, Trubetskaya St. 8, Build. 2, 119991 Moscow, Russia
- Pulmonology Scientific Research Institute, Federal Medical and Biological Agency of Russian Federation, Orekhovyy Boulevard 28, 115682 Moscow, Russia
| | - Anna A. Proshkina
- Pulmonology Department, Sechenov First Moscow State Medical University (Sechenov University), Healthcare Ministry of Russia, Trubetskaya St. 8, Build. 2, 119991 Moscow, Russia
| | - Sergey N. Avdeev
- Pulmonology Department, Sechenov First Moscow State Medical University (Sechenov University), Healthcare Ministry of Russia, Trubetskaya St. 8, Build. 2, 119991 Moscow, Russia
- Pulmonology Scientific Research Institute, Federal Medical and Biological Agency of Russian Federation, Orekhovyy Boulevard 28, 115682 Moscow, Russia
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Mahmoudzadeh L, Abtahi Froushani SM, Ajami M, Mahmoudzadeh M. Effect of Nicotine on Immune System Function. Adv Pharm Bull 2023; 13:69-78. [PMID: 36721811 PMCID: PMC9871277 DOI: 10.34172/apb.2023.008] [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: 02/22/2021] [Revised: 09/30/2021] [Accepted: 12/31/2021] [Indexed: 02/03/2023] Open
Abstract
As a parasympathetic alkaloid and the main substance in cigarette smoke, nicotine modulates the immune system, inhibits innate and acquired immunity and is used in treating many autoimmune diseases. It often stimulates the α7 receptor and causes an anti-inflammatory state in the body. This study is designed to evaluate the role of nicotine treatment on immune system. The results showed that nicotine affects many cells in immune system, alters the downstream intracellular mechanisms and changes lymphocytes polarization. This substance alters TLRs and STATs gene expression and thus changes in the innate immune system. All these events inhibit the secretion of pro-inflammatory cytokines and chemokines which increase angiogenesis and metastasis and exacerbates tumors due to increasing survival and cell growth. Nicotine can aggravate tumors in cancer patients, with many positive effects observed in the treating autoimmune disease, Nicotine treatment function in different conditions depends on factors such as concentration, how it is employed, treatment duration and other conditions such as body conditions affecting the immune system, hence, further studies and review of all conditions are required.
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Affiliation(s)
- leila Mahmoudzadeh
- Division of Immunology, Department of Microbiology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | | | - Marjan Ajami
- Department of Food and Nutrition Policy and Planning Research, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Mahmoudzadeh
- Nutrition Research Center and Department of Food Science and Technology, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran.,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Corresponding Author: Maryam Mahmoudzadeh, Fax:+98 41 33363231,
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Zhan X, Du Y, Luo J, Que Y, Hu C, Xu L, Wang Z, Wu Y, Jin M, Zheng C, Gao Y, Chang C, Li H, Tong Z, Xu G. Features of transbronchial lung cryobiopsy-diagnosed fibrotic hypersensitivity pneumonitis. THE CLINICAL RESPIRATORY JOURNAL 2022; 17:50-58. [PMID: 36397265 PMCID: PMC9829620 DOI: 10.1111/crj.13561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 08/22/2022] [Accepted: 11/07/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Hypersensitivity pneumonitis (HP) is a common type among all the interstitial lung diseases, and transbronchial lung cryobiopsy is an alternative diagnostic technique for interstitial lung diseases. In this study, we describe the clinical and pathological features of fibrotic hypersensitivity pneumonitis diagnosed with transbronchial lung cryobiopsy (TBLC). METHODS A total of 46 diffused parenchyma lung disease (DPLD) patients received TBLC were included in this study. Medical records including medical history spirometry examinations, 6-min walk test (6MWT) results, high resolution computed tomographic (HRCT) scans, BAL, and histopathology were collected. Results of HRCT and histopathology were compared and classified, especially. RESULTS Sixteen patients were diagnosed with fibrotic HP, the mean age of whom was 56.3 ± 12.1 years, and 62.5% of them were male. Three of the 16 patients had been misdiagnosed as tuberculosis and received antituberculosis medications, five patients had been diagnosed as unclassifiable pulmonary fibrosis, and five patients had been diagnosed as idiopathic pulmonary fibrosis (IPF). Thirteen (81.3%) patients had a normal lymphocyte count in BAL. The pathological features of usual interstitial pneumonia (UIP) were detected in 11 (68.8%) of the cases, poor defined granulomatous was detected in nine (56.3%) of the cases, and bronchiolocentric fibrosis was detected in two (12.5%) of the 16 cases. CONCLUSIONS Fibrotic hypersensitivity pneumonitis should be included in differential diagnosis of pulmonary fibrosis. Pathological characteristics of fibrotic hypersensitivity pneumonitis could be demonstrated from cryobiopsy lung tissue. TBLC is recommended as an alternative diagnostic technique, which may improve the specificity of hypersensitivity pneumonia detection, and UIP is the most frequent pathological finding.
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Affiliation(s)
- Xi Zhan
- Department of Respiratory Medicine and Critical Care, Institute of Respiratory Medicine Beijing, Chaoyang HospitalCapital Medical UniversityBeijingChina
| | - Yingzhen Du
- Department of Respiratory and Critical Care Medicine, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General HospitalMedical School of Chinese PLABeijingChina
| | - Jiang Luo
- The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General HospitalMedical School of Chinese PLABeijingChina
| | - Yifan Que
- Department of Respiratory and Critical Care Medicine, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General HospitalMedical School of Chinese PLABeijingChina
| | - Chao Hu
- The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General HospitalMedical School of Chinese PLABeijingChina
| | - Lili Xu
- Department of Respiratory Medicine and Critical Care, Institute of Respiratory Medicine Beijing, Chaoyang HospitalCapital Medical UniversityBeijingChina
| | - Zhen Wang
- Department of Respiratory Medicine and Critical Care, Institute of Respiratory Medicine Beijing, Chaoyang HospitalCapital Medical UniversityBeijingChina
| | - Yanbing Wu
- Department of Respiratory Medicine and Critical Care, Institute of Respiratory Medicine Beijing, Chaoyang HospitalCapital Medical UniversityBeijingChina
| | - Mulan Jin
- Department of Pathology, Chaoyang HospitalCapital Medical UniversityBeijingChina
| | - Chunming Zheng
- Medical Research Center, Chaoyang HospitalCapital Medical UniversityBeijingChina
| | - Yanhong Gao
- Department of Respiratory and Critical Care Medicine, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General HospitalMedical School of Chinese PLABeijingChina
| | - Christopher Chang
- Division of Pediatric Immunology, Allergy and RheumatologyJoe DiMaggio Children's HospitalHollywoodFloridaUSA,Division of Rheumatology, Allergy and Clinical ImmunologyUniversity of California, DavisDavisCaliforniaUSA
| | - Hongxia Li
- Department of Respiratory and Critical Care Medicine, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General HospitalMedical School of Chinese PLABeijingChina
| | - Zhaohui Tong
- Department of Respiratory Medicine and Critical Care, Institute of Respiratory Medicine Beijing, Chaoyang HospitalCapital Medical UniversityBeijingChina
| | - Guogang Xu
- The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General HospitalMedical School of Chinese PLABeijingChina
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Obi ON, Saketkoo LA, Russell AM, Baughman RP. Sarcoidosis: Updates on therapeutic drug trials and novel treatment approaches. Front Med (Lausanne) 2022; 9:991783. [PMID: 36314034 PMCID: PMC9596775 DOI: 10.3389/fmed.2022.991783] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 08/17/2022] [Indexed: 12/04/2022] Open
Abstract
Sarcoidosis is a systemic granulomatous inflammatory disease of unknown etiology. It affects the lungs in over 90% of patients yet extra-pulmonary and multi-organ involvement is common. Spontaneous remission of disease occurs commonly, nonetheless, over 50% of patients will require treatment and up to 30% of patients will develop a chronic progressive non-remitting disease with marked pulmonary fibrosis leading to significant morbidity and death. Guidelines outlining an immunosuppressive treatment approach to sarcoidosis were recently published, however, the strength of evidence behind many of the guideline recommended drugs is weak. None of the drugs currently used for the treatment of sarcoidosis have been rigorously studied and prescription of these drugs is often based on off-label” indications informed by experience with other diseases. Indeed, only two medications [prednisone and repository corticotropin (RCI) injection] currently used in the treatment of sarcoidosis are approved by the United States Food and Drug Administration. This situation results in significant reimbursement challenges especially for the more advanced (and often more effective) drugs that are favored for severe and refractory forms of disease causing an over-reliance on corticosteroids known to be associated with significant dose and duration dependent toxicities. This past decade has seen a renewed interest in developing new drugs and exploring novel therapeutic pathways for the treatment of sarcoidosis. Several of these trials are active randomized controlled trials (RCTs) designed to recruit relatively large numbers of patients with a goal to determine the safety, efficacy, and tolerability of these new molecules and therapeutic approaches. While it is an exciting time, it is also necessary to exercise caution. Resources including research dollars and most importantly, patient populations available for trials are limited and thus necessitate that several of the challenges facing drug trials and drug development in sarcoidosis are addressed. This will ensure that currently available resources are judiciously utilized. Our paper reviews the ongoing and anticipated drug trials in sarcoidosis and addresses the challenges facing these and future trials. We also review several recently completed trials and draw lessons that should be applied in future.
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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, United States,*Correspondence: Ogugua Ndili Obi,
| | - Lesley Ann Saketkoo
- New Orleans Scleroderma and Sarcoidosis Patient Care and Research Center, New Orleans, LA, United States,University Medical Center—Comprehensive Pulmonary Hypertension Center and Interstitial Lung Disease Clinic Programs, New Orleans, LA, United States,Section of Pulmonary Medicine, Louisiana State University School of Medicine, New Orleans, LA, United States,Department of Undergraduate Honors, Tulane University School of Medicine, New Orleans, LA, United States
| | - Anne-Marie Russell
- Exeter Respiratory Institute University of Exeter, Exeter, United Kingdom,Royal Devon and Exeter NHS Foundation Trust, Devon, United Kingdom,Faculty of Medicine, Imperial College and Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Robert P. Baughman
- Department of Medicine, University of Cincinnati, Cincinnati, OH, United States
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Kelly MJ, Breathnach C, Tracey KJ, Donnelly SC. Manipulation of the inflammatory reflex as a therapeutic strategy. Cell Rep Med 2022; 3:100696. [PMID: 35858588 PMCID: PMC9381415 DOI: 10.1016/j.xcrm.2022.100696] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 06/20/2021] [Accepted: 06/23/2022] [Indexed: 02/07/2023]
Abstract
The cholinergic anti-inflammatory pathway is the efferent arm of the inflammatory reflex, a neural circuit through which the CNS can modulate peripheral immune responses. Signals communicated via the vagus and splenic nerves use acetylcholine, produced by Choline acetyltransferase (ChAT)+ T cells, to downregulate the inflammatory actions of macrophages expressing α7 nicotinic receptors. Pre-clinical studies using transgenic animals, cholinergic agonists, vagotomy, and vagus nerve stimulation have demonstrated this pathway's role and therapeutic potential in numerous inflammatory diseases. In this review, we summarize what is understood about the inflammatory reflex. We also demonstrate how pre-clinical findings are being translated into promising clinical trials, and we draw particular attention to innovative bioelectronic methods of harnessing the cholinergic anti-inflammatory pathway for clinical use.
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Affiliation(s)
- Mark J Kelly
- Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland; Tallaght University Hospital, Dublin, Ireland
| | | | - Kevin J Tracey
- Center for Biomedical Science and Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY 11030, USA
| | - Seamas C Donnelly
- Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland; Tallaght University Hospital, Dublin, Ireland.
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Abstract
Background: Urticaria is a common skin disease characterized by episodes of wheals, and it has a negative effect on patients’ quality of life. Large-scale population-based epidemiological studies of urticaria are scarce in China. The aim of this survey was to determine the prevalence, clinical forms, and risk factors of urticaria in the Chinese population. Methods: This survey was conducted in 35 cities from 31 provinces, autonomous regions, and municipalities of China. Two to three communities in each city were selected in this investigation. Participants completed questionnaires and received dermatological examinations. We analyzed the prevalence, clinical forms, and risk factors of urticaria. Results: In total, 44,875 questionnaires were distributed and 41,041 valid questionnaires were collected (17,563 male and 23,478 female participants). The lifetime prevalence of urticaria was 7.30%, with 8.26% in female and 6.34% in male individuals (P < 0.05). The point prevalence of urticaria was 0.75%, with 0.79% in female and 0.71% in male individuals (P < 0.05). Concomitant angioedema was found in 6.16% of patients. Adults had a higher prevalence of urticaria than adolescents and children. Living in urban areas, exposure to pollutants, an anxious or depressed psychological status, a personal and family history of allergy, thyroid diseases, and Helicobacter pylori infection were associated with a higher prevalence of urticaria. Smoking was correlated with a reduced risk of urticaria. Conclusion: This study demonstrated that the lifetime prevalence of urticaria was 7.30% and the point prevalence was 0.75% in the Chinese population; women had a higher prevalence of urticaria than men. Various factors were correlated with urticaria.
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Su Y, Zhang W, Zhang R, Yuan Q, Wu R, Liu X, Wuri J, Li R, Yan T. Activation of Cholinergic Anti-Inflammatory Pathway Ameliorates Cerebral and Cardiac Dysfunction After Intracerebral Hemorrhage Through Autophagy. Front Immunol 2022; 13:870174. [PMID: 35812436 PMCID: PMC9260497 DOI: 10.3389/fimmu.2022.870174] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 05/23/2022] [Indexed: 12/12/2022] Open
Abstract
Background Intracerebral hemorrhage (ICH) is the devastating subtype of stroke with cardiovascular complications, resulting in high rates of mortality and morbidity with the release of inflammatory factors. Previous studies have demonstrated that activation of α7nAChR can reduce immune and inflammation-related diseases by triggering the cholinergic anti-inflammatory pathway (CAIP). α7nAChR mediates protection from nervous system inflammation through AMPK-mTOR-p70S6K-associated autophagy. Therefore, the purpose of this study is to explore whether the activation of α7nAChR improves cerebral and cardiac dysfunction after ICH through autophagy. Methods Male C57BL/6 mice were randomly divided into five groups (1): Control + saline (2), ICH+ saline (3), ICH + PNU-282987 (4), ICH+ PNU-282987 + MLA (5), ICH + PNU-282987 + 3-MA. The neurological function was evaluated at multiple time points. Brain water content was measured at 3 days after ICH to assess the severity of brain edema. PCR, immunofluorescence staining, and Western Blot were performed at 7 days after ICH to detect inflammation and autophagy. Picro-Sirius Red staining was measured at 30 days after ICH to evaluate myocardial fibrosis, echocardiography was performed at 3 and 30 days to measure cardiac function. Results Our results indicated that the PNU-282987 reduced inflammatory factors (MCP-1, IL-1β, MMP-9, TNF-α, HMGB1, TLR2), promoted the polarization of macrophage/microglia into anti-inflammatory subtypes(CD206), repaired blood-brain barrier injury (ZO-1, Claudin-5, Occludin), alleviated acute brain edema and then recovered neurological dysfunction. Echocardiography and PSR indicated that activation of α7nAChR ameliorated cardiac dysfunction. Western Blot showed that activation of α7nAChR increased autophagy protein (LC3, Beclin) and decreased P62. It demonstrated that the activation of α7nAChR promotes autophagy and then recovers brain and heart function after ICH. Conclusions In conclusion, PNU-282987 promoted the cerebral and cardiac functional outcomes after ICH in mice through activated α7nAChR, which may be attributable to promoting autophagy and then reducing inflammatory reactions after ICH.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Tao Yan
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma, Neurorepair, and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, China
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Zhi YK, Li J, Yi L, Zhu RL, Luo JF, Shi QP, Bai SS, Li YW, Du Q, Cai JZ, Liu L, Wang PX, Zhou H, Dong Y. Sinomenine inhibits macrophage M1 polarization by downregulating α7nAChR via a feedback pathway of α7nAChR/ERK/Egr-1. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 100:154050. [PMID: 35397284 DOI: 10.1016/j.phymed.2022.154050] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 03/08/2022] [Accepted: 03/11/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND Sinomenine (SIN) is an anti-inflammatory drug that has been used for decades in China to treat arthritis. In a previous study, SIN acted on α7 nicotinic acetylcholine receptor (α7nAChR) to inhibit inflammatory responses in macrophages, which indicates a new anti-inflammatory mechanism of SIN. However, the level of α7nAChR was increased in the inflammatory responses and was downregulated by SIN in vitro, so the underlying mechanisms of SIN acting on α7nAChR remain unclear. PURPOSE To analyze the role of α7nAChR in inflammation and the effect and mechanism of SIN regulation of α7nAChR. METHODS The effects of SIN on α7nAChR in endotoxemic mice and LPS-stimulated macrophages were observed. Nicotine (Nic) was used as a positive control, and berberine (Ber) was used as a negative control targeting α7nAChR. The antagonists of α7nAChR, α-bungarotoxin (BTX) and mecamylamine (Me), were used to block α7nAChR. In RAW264.7 macrophage cells in vitro, α7nAChR short hairpin RNA (shRNA) was used to knock down α7nAChR. Macrophage polarization was analyzed by the detection of TNF-α, IL-6, iNOS, IL-10, Arg-1, and Fizz1. U0126 was used to block ERK phosphorylation. The cytokines α7nAChR, ERK1/2, p-ERK1/2 and Egr-1 were detected. RESULTS SIN decreased the levels of TNF-α, IL-6 and the expression of α7nAChR increased by LPS in endotoxemic mice. The above effects of SIN were attenuated by BTX. In the α7nAChR shRNA transfected RAW264.7 cells, compared with the control, α7nAChR was knocked down, and M1 phenotype markers (including TNF-α, IL-6, and iNOS) were significantly downregulated, whereas M2 phenotype markers (including IL-10, Arg-1, and Fizz1) were significantly upregulated when stimulated by LPS. SIN inhibited the expression of p-ERK1/2 and the transcription factor Egr-1 induced by LPS in RAW264.7 cells, and the above effects of SIN were attenuated by BTX. The expression of α7nAChR was suppressed by U0126, which lessened the expression of p-ERK1/2 and Egr-1. CONCLUSIONS SIN acts on α7nAChR to inhibit inflammatory responses and downregulates high expression of α7nAChR in vivo and in vitro. The increase of α7nAChR expression is correlated with inflammatory responses and participates in macrophage M1 polarization. SIN downregulates α7nAChR via a feedback pathway of α7nAChR/ERK/Egr-1, which contributes to inhibiting macrophage M1 polarization and inflammatory responses.
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Affiliation(s)
- Ying-Kun Zhi
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, P.R. China
| | - Jing Li
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, P.R. China
| | - Lang Yi
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, P.R. China
| | - Rui-Li Zhu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, P.R. China
| | - Jin-Fang Luo
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, P.R. China
| | - Qing-Ping Shi
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, P.R. China
| | - Sha-Sha Bai
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, P.R. China
| | - Yan-Wu Li
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, P.R. China
| | - Qun Du
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, P.R. China
| | - Jia-Zhong Cai
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, P.R. China
| | - Liang Liu
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, P.R. China
| | - Pei-Xun Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, P.R. China
| | - Hua Zhou
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, P.R. China.
| | - Yan Dong
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, P.R. China.
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Kim DH, Lee JY, Cho SI, Jo SJ. Risks of Comorbidities in Patients With Palmoplantar Pustulosis vs Patients With Psoriasis Vulgaris or Pompholyx in Korea. JAMA Dermatol 2022; 158:650-660. [PMID: 35476054 PMCID: PMC9047771 DOI: 10.1001/jamadermatol.2022.1081] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Importance Palmoplantar pustulosis (PPP) has been reported to be accompanied by systemic conditions. However, the risks of comorbidities in patients with PPP have rarely been evaluated. Objective To assess the risks of comorbidities in patients with PPP compared with patients with psoriasis vulgaris or pompholyx. Design, Setting, and Participants This nationwide population-based cross-sectional study used data from the Korean National Health Insurance database and the National Health Screening Program collected from January 1, 2010, to December 31, 2019. Data were analyzed from July 1, 2020, to October 31, 2021. Korean patients diagnosed with PPP, psoriasis vulgaris, or pompholyx who visited a dermatologist between January 1, 2010, and December 31, 2019, were enrolled. Exposures Presence of PPP. Main Outcomes and Measures The risks of comorbidities among patients with PPP vs patients with psoriasis vulgaris or pompholyx were evaluated using a multivariable logistic regression model. Results A total of 37 399 patients with PPP (mean [SD] age, 48.98 [17.20] years; 51.7% female), 332 279 patients with psoriasis vulgaris (mean [SD] age, 47.29 [18.34] years; 58.7% male), and 365 415 patients with pompholyx (mean [SD] age, 40.92 [17.63] years; 57.4% female) were included in the analyses. Compared with patients with pompholyx, those with PPP had significantly higher risks of developing psoriasis vulgaris (adjusted odds ratio [aOR], 72.96; 95% CI, 68.19-78.05; P < .001), psoriatic arthritis (aOR, 8.06; 95% CI, 6.55-9.92; P < .001), ankylosing spondylitis (aOR, 1.91; 95% CI, 1.61-2.27; P < .001), type 1 diabetes (aOR, 1.33; 95% CI, 1.16-1.52; P < .001), type 2 diabetes (aOR, 1.33; 95% CI, 1.29-1.38; P < .001), Graves disease (aOR, 1.25; 95% CI, 1.11-1.42; P < .001), Crohn disease (aOR, 1.63; 95% CI, 1.11-2.40; P = .01), and vitiligo (aOR, 1.87; 95% CI, 1.65-2.12; P < .001) after adjusting for demographic covariates. The risks of ankylosing spondylitis (aOR, 1.37; 95% CI, 1.16-1.62; P < .001) and Graves disease (aOR, 1.40; 95% CI, 1.23-1.58; P < .001) were significantly higher among patients with PPP vs psoriasis vulgaris. However, the risks of psoriatic arthritis (aOR, 0.54; 95% CI, 0.47-0.63; P < .001), systemic lupus erythematosus (aOR, 0.67; 95% CI, 0.46-0.97; P = .04), Sjögren syndrome (aOR, 0.70; 95% CI, 0.50-0.96; P = .03), systemic sclerosis (aOR, 0.29; 95% CI, 0.11-0.77; P = .01), vitiligo (aOR, 0.53; 95% CI, 0.47-0.60; P < .001), and alopecia areata (aOR, 0.88; 95% CI, 0.81-0.95; P = .001) were significantly lower among those with PPP vs psoriasis vulgaris. Conclusions and Relevance The results of this cross-sectional study suggest that patients with PPP have an overlapping comorbidity profile with patients with psoriasis vulgaris but not patients with pompholyx. However, the risks of comorbidities among patients with PPP may be substantially different from those among patients with psoriasis vulgaris.
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Affiliation(s)
- Dong Hyo Kim
- Department of Dermatology, Seoul National University College of Medicine, Seoul, South Korea.,Department of Dermatology, Seoul National University Hospital, Seoul, South Korea
| | - Jin Yong Lee
- Public Healthcare Center, Seoul National University Hospital, Seoul, South Korea.,Department of Health Policy and Management, Seoul National University College of Medicine, Seoul, South Korea
| | - Soo Ick Cho
- Department of Dermatology, Seoul National University College of Medicine, Seoul, South Korea.,Department of Dermatology, Seoul National University Hospital, Seoul, South Korea
| | - Seong Jin Jo
- Department of Dermatology, Seoul National University College of Medicine, Seoul, South Korea.,Department of Dermatology, Seoul National University Hospital, Seoul, South Korea
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Rudzki S. Is PTSD an Evolutionary Survival Adaptation Initiated by Unrestrained Cytokine Signaling and Maintained by Epigenetic Change? Mil Med 2022; 188:usac095. [PMID: 35446412 DOI: 10.1093/milmed/usac095] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 03/01/2022] [Accepted: 03/24/2022] [Indexed: 12/22/2022] Open
Abstract
INTRODUCTION Treatment outcomes for PTSD with current psychological therapies are poor, with very few patients achieving sustained symptom remission. A number of authors have identified physiological and immune disturbances in Post Traumatic Stress Disorder (PTSD) patients, but there is no unifying hypothesis that explains the myriad features of the disorder. MATERIALS AND METHODS The medical literature was reviewed over a 6-year period primarily using the medical database PUBMED. RESULTS The literature contains numerous papers that have identified a range of physiological and immune dysfunction in association with PTSD. This paper proposes that unrestrained cytokine signaling induces epigenetic changes that promote an evolutionary survival adaptation, which maintains a defensive PTSD phenotype. The brain can associate immune signaling with past threat and initiate a defensive behavioral response. The sympathetic nervous system is pro-inflammatory, while the parasympathetic nervous system is anti-inflammatory. Prolonged cholinergic withdrawal will promote a chronic inflammatory state. The innate immune cytokine IL-1β has pleiotropic properties and can regulate autonomic, glucocorticoid, and glutamate receptor functions, sleep, memory, and epigenetic enzymes. Changes in epigenetic enzyme activity can potentially alter phenotype and induce an adaptation. Levels of IL-1β correlate with severity and duration of PTSD and PTSD can be prevented by bolus administration of hydrocortisone in acute sepsis, consistent with unrestrained inflammation being a risk factor for PTSD. The nervous and immune systems engage in crosstalk, governed by common receptors. The benefits of currently used psychiatric medication may arise from immune, as well as synaptic, modulation. The psychedelic drugs (3,4-Methylenedioxymethamphetamine (MDMA), psilocybin, and ketamine) have potent immunosuppressive and anti-inflammatory effects on the adaptive immune system, which may contribute to their reported benefit in PTSD. There may be distinct PTSD phenotypes induced by innate and adaptive cytokine signaling. CONCLUSION In order for an organism to survive, it must adapt to its environment. Cytokines signal danger to the brain and can induce epigenetic changes that result in a persistent defensive phenotype. PTSD may be the price individuals pay for the genomic flexibility that promotes adaptation and survival.
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Affiliation(s)
- Stephan Rudzki
- Canberra Sports Medicine, Deakin, Australian Capital Territory 2600, Australia
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Ho J, Koshibu K, Xia W, Luettich K, Kondylis A, Garcia L, Phillips B, Peitsch M, Hoeng J. Effects of cigarette smoke exposure on a mouse model of multiple sclerosis. Toxicol Rep 2022; 9:597-610. [PMID: 35392156 PMCID: PMC8980708 DOI: 10.1016/j.toxrep.2022.03.032] [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: 07/18/2021] [Revised: 02/06/2022] [Accepted: 03/26/2022] [Indexed: 10/31/2022] Open
Abstract
Multiple sclerosis (MS) is an inflammatory autoimmune disease associated with genetic and environmental factors. Cigarette smoking is harmful to health and may be one of the risk factors for MS. However, there have been no systematic investigations under controlled experimental conditions linking cigarette smoke (CS) and MS. The present study is the first inhalation study to correlate the pre-clinical and pathological manifestations affected by different doses of CS exposure in a mouse experimental autoimmune encephalomyelitis (EAE) model. Female C57BL/6 mice were whole-body exposed to either fresh air (sham) or three concentrations of CS from a reference cigarette (3R4F) for 2 weeks before and 4 weeks after EAE induction. The effects of exposure on body weight, clinical symptoms, spinal cord pathology, and serum biochemicals were then assessed. Exposure to low and medium concentrations of CS exacerbated the severity of symptoms and spinal cord pathology, while the high concentration had no effect relative to sham exposure in mice with EAE. Interestingly, the clinical chemistry parameters for metabolic profile as well as liver and renal function (e.g. triglycerides and creatinine levels, alkaline phosphatase activity) were lower in these mice than in naïve controls. Although the mouse EAE model does not fully recapitulate the pathology or symptoms of MS in humans, these findings largely corroborate previous epidemiological findings that exposure to CS can worsen the symptoms and pathology of MS. Furthermore, the study newly highlights the possible correlation of clinical chemistry findings such as metabolism and liver and renal function between MS patients and EAE mice.
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Key Words
- AAALAC, Assessment and Accreditation of Laboratory Animal Care
- BBB, Blood-brain barrier
- CFA, Freund’s complete adjuvant
- CNS, Central nervous system
- CO, Carbon monoxide
- CS, Cigarette smoke
- Cigarette smoke
- Clinical chemistry
- DAPI, 4′,6-diamidino-2-phenylindole
- EAE, Experimental autoimmune encephalomyelitis
- Experimental autoimmune encephalomyelitis
- GAM, generalized additive model
- IACUC, Institutional Animal Care and Use Committee
- ISO, International Organization for Standardization
- Inhalation
- MOG, Myelin oligodendrocyte glycoprotein
- MS, Multiple sclerosis
- Multiple sclerosis
- OCT, Optimal cutting temperature
- PFA, Paraformaldehyde
- PMI, Philip Morris International
- PTX, Pertussis toxin
- QC, Quality control
- STAT3, signal transducer and activator of transcription 3
- TPM, Total particulate matter
- US, United States
- eGFR, estimated glomerular filtration rate
- nAChR, nicotinic acetylcholine receptors
- s.c., Subcutaneous
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Affiliation(s)
- Jenny Ho
- PMI R&D, Philip Morris International Research Laboratories Pte. Ltd., Science Park II, 117406, Singapore
| | - Kyoko Koshibu
- PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland
| | - Wenhao Xia
- PMI R&D, Philip Morris International Research Laboratories Pte. Ltd., Science Park II, 117406, Singapore
| | - Karsta Luettich
- PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland
| | - Athanasios Kondylis
- PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland
| | - Llenalia Garcia
- PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland
| | - Blaine Phillips
- PMI R&D, Philip Morris International Research Laboratories Pte. Ltd., Science Park II, 117406, Singapore
| | - Manuel Peitsch
- PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland
| | - Julia Hoeng
- PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland
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Safety and Feasibility of Lung Cancer Surgery under the COVID-19 Circumstance. Cancers (Basel) 2022; 14:cancers14051334. [PMID: 35267642 PMCID: PMC8909353 DOI: 10.3390/cancers14051334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 02/25/2022] [Indexed: 11/29/2022] Open
Abstract
Simple Summary The global coronavirus disease 2019 (COVID-19) pandemic has drastically changed the current practice of medicine worldwide. As more clinical data is collected and processed, we are beginning to have an understanding of which patients are more at risk for severe complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Preliminary data has shown that patients with lung cancer are disproportionally affected by the current COVID-19 pandemic. Furthermore, studies have shown that lung cancer patients are also significantly more likely to be admitted to the ICU and need mechanical ventilation. A specific subset of patients that are even more at risk for severe COVID-19 are those that require lung cancer surgery. To minimize the risk of SARS-CoV-2 infections in patients undergoing surgery, new treatment guidelines and preventive measures are necessary. In this review, we summarize the latest evidence regarding recommendations for patients undergoing lung cancer surgery in the COVID-19 era. Abstract The current coronavirus disease 2019 (COVID-19) pandemic has forced healthcare providers worldwide to adapt their practices. Our understanding of the effects of COVID-19 has increased exponentially since the beginning of the pandemic. Data from large-scale, international registries has provided more insight regarding risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and has allowed us to delineate specific subgroups of patients that have higher risks for severe complications. One particular subset of patients that have significantly higher risks of SARS-CoV-2 infection with higher morbidity and mortality rates are those that require surgical treatment for lung cancer. Earlier studies have shown that COVID-19 infections in patients that underwent lung cancer surgery is associated with higher rates of respiratory failure and mortality. However, deferral of cancer treatments is associated with increased mortality as well. This creates difficult situations in which healthcare providers are forced to weigh the benefits of surgical treatment against the possibility of SARS-CoV-2 infections. A number of oncological and surgical organizations have proposed treatment guidelines and recommendations for patients planned for lung cancer surgery. In this review, we summarize the latest data and recommendations for patients undergoing lung cancer surgery in the COVID-19 circumstance.
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Pan S, Wu YJ, Zhang SS, Cheng XP, Olatunji OJ, Yin Q, Zuo J. The Effect of α7nAChR Signaling on T Cells and Macrophages and Their Clinical Implication in the Treatment of Rheumatic Diseases. Neurochem Res 2022; 47:531-544. [PMID: 34783974 DOI: 10.1007/s11064-021-03480-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 11/02/2021] [Accepted: 11/05/2021] [Indexed: 10/19/2022]
Abstract
Rheumatoid arthritis (RA) is one of the most common autoimmune disease and until now, the etiology and pathogenesis of RA is not fully understood, although dysregulation of immune cells is one of the leading cause of RA-related pathological changes. Based on current understanding, the priority of anti-rheumatic treatments is to restore immune homeostasis. There are several anti-rheumatic drugs with immunomodulatory effects available nowadays, but most of them have obvious safety or efficacy shortcomings. Therefore, the development of novel anti-rheumatic drugs is still in urgently needed. Cholinergic anti-inflammatory pathway (CAP) has been identified as an important aspect of the so-called neuro-immune regulation feedback, and the interaction between acetylcholine and alpha 7 nicotinic acetylcholine receptor (α7nAChR) serves as the foundation for this signaling. Consistent to its immunomodulatory functions, α7nAChR is extensively expressed by immune cells. Accordingly, CAP activation greatly affects the differentiation and function of α7nAChR-expressing immune cells. As a result, targeting α7nAChR will bring profound therapeutic impacts on the treatment of inflammatory diseases like RA. RA is widely recognized as a CD4+ T cells-driven disease. As a major component of innate immunity, macrophages also significantly contribute to RA-related immune abnormalities. Theoretically, manipulation of CAP in immune cells is a feasible way to treat RA. In this review, we summarized the roles of different T cells and macrophages subsets in the occurrence and progression of RA, and highlighted the immune consequences of CAP activation in these cells under RA circumstances. The in-depth discussion is supposed to inspire the development of novel cell-specific CAP-targeting anti-rheumatic regimens.
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Affiliation(s)
- Shu Pan
- Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, China
- School of Pharmacy, Wannan Medical College, Wuhu, 241000, China
- Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, China
| | - Yi-Jin Wu
- Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, China
- School of Pharmacy, Wannan Medical College, Wuhu, 241000, China
- Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, China
| | - Sa-Sa Zhang
- Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, China
- School of Pharmacy, Wannan Medical College, Wuhu, 241000, China
- Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, China
| | - Xiu-Ping Cheng
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, China
| | - Opeyemi Joshua Olatunji
- Faculty of Traditional Thai Medicine, Prince of Songkla University, Hat Yai, 90110, Thailand
| | - Qin Yin
- Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, China.
- School of Pharmacy, Wannan Medical College, Wuhu, 241000, China.
| | - Jian Zuo
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, China.
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241000, China.
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Levite M, Goldberg H. Autoimmune Epilepsy - Novel Multidisciplinary Analysis, Discoveries and Insights. Front Immunol 2022; 12:762743. [PMID: 35095841 PMCID: PMC8790247 DOI: 10.3389/fimmu.2021.762743] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 10/18/2021] [Indexed: 11/13/2022] Open
Abstract
Epilepsy affects ~50 million people. In ~30% of patients the etiology is unknown, and ~30% are unresponsive to anti-epileptic drugs. Intractable epilepsy often leads to multiple seizures daily or weekly, lasting for years, and accompanied by cognitive, behavioral, and psychiatric problems. This multidisciplinary scientific (not clinical) 'Perspective' article discusses Autoimmune Epilepsy from immunological, neurological and basic-science angles. The article includes summaries and novel discoveries, ideas, insights and recommendations. We summarize the characteristic features of the respective antigens, and the pathological activity in vitro and in animal models of autoimmune antibodies to: Glutamate/AMPA-GluR3, Glutamate/NMDA-NR1, Glutamate/NMDA-NR2, GAD-65, GABA-R, GLY-R, VGKC, LGI1, CASPR2, and β2 GP1, found in subpopulations of epilepsy patients. Glutamate receptor antibodies: AMPA-GluR3B peptide antibodies, seem so far as the most exclusive and pathogenic autoimmune antibodies in Autoimmune Epilepsy. They kill neural cells by three mechanisms: excitotoxicity, Reactive-Oxygen-Species, and complement-fixation, and induce and/or facilitate brain damage, seizures, and behavioral impairments. In this article we raise and discuss many more topics and new insights related to Autoimmune Epilepsy. 1. Few autoimmune antibodies tilt the balance between excitatory Glutamate and inhibitory GABA, thereby promoting neuropathology and epilepsy; 2. Many autoantigens are synaptic, and have extracellular domains. These features increase the likelihood of autoimmunity against them, and the ease with which autoimmune antibodies can reach and harm these self-proteins. 3. Several autoantigens have 'frenetic character'- undergoing dynamic changes that can increase their antigenicity; 4. The mRNAs of the autoantigens are widely expressed in multiple organs outside the brain. If translated by default to proteins, broad spectrum detrimental autoimmunity is expected; 5. The autoimmunity can precede seizures, cause them, and be detrimental whether primary or epiphenomenon; 6. Some autoimmune antibodies induce, and associate with, cognitive, behavioral and psychiatric impairments; 7. There are evidences for epitope spreading in Autoimmune Epilepsy; 8. T cells have different 'faces' in the brain, and in Autoimmune Epilepsy: Normal T cells are needed for the healthy brain. Normal T cells are damaged by autoimmune antibodies to Glutamate/AMPA GluR3, which they express, and maybe by additional autoantibodies to: Dopamine-R, GABA-R, Ach-R, Serotonin-R, and Adrenergic-R, present in various neurological diseases (summarized herein), since T cells express all these Neurotransmitter receptors. However, autoimmune and/or cytotoxic T cells damage the brain; 9. The HLA molecules are important for normal brain function. The HLA haplotype can confer susceptibility or protection from Autoimmune Epilepsy; 10. There are several therapeutic strategies for Autoimmune Epilepsy.
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Affiliation(s)
- Mia Levite
- Faculty of Medicine, The Hebrew University, Jerusalem, Israel
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Hadassa Goldberg
- Epilepsy Center, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Nienhuis WA, Grutters JC. Potential therapeutic targets to prevent organ damage in chronic pulmonary sarcoidosis. Expert Opin Ther Targets 2021; 26:41-55. [PMID: 34949145 DOI: 10.1080/14728222.2022.2022123] [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: 11/04/2022]
Abstract
INTRODUCTION Sarcoidosis is a granulomatous inflammatory disease with high chances of reduced quality of life, irreversible organ damage, and reduced life expectancy when vital organs are involved. Any organ system can be affected, and the lungs are most often affected. There is no preventive strategy as the exact etiology is unknown, and complex immunogenetic and environmental factors determine disease susceptibility and phenotype. Present-day treatment options originated from clinical practice and are effective in many patients. However, a substantial percentage of patients suffer from unacceptable side effects or still develop refractory, threatening pulmonary or extrapulmonary disease. AREAS COVERED As non-caseating granulomas, the pathological hallmark of disease, are assigned to divergent activation and regulation of the immune system, targets in relation to the possible triggers of granuloma formation and their sequelae were searched and reviewed. EXPERT OPINION :The immunopathogenesis underlying sarcoidosis has been a dynamic field of study. Several recent new insights give way to promising new therapeutic targets, such as certain antigenic triggers (e.g. from Aspergillus nidulans), mTOR, JAK-STAT and PPARγ pathways, the NRP2 receptor and MMP-12, which await further exploration. Clinical and trigger related phenotyping, and molecular endotyping in sarcoidosis will likely hold the key for precision medicine in the future.
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Affiliation(s)
- W A Nienhuis
- ILD Center of Excellence, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands
| | - J C Grutters
- ILD Center of Excellence, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands.,Division of Hearth and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands
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The Mechanisms Mediated by α7 Acetylcholine Nicotinic Receptors May Contribute to Peripheral Nerve Regeneration. Molecules 2021; 26:molecules26247668. [PMID: 34946750 PMCID: PMC8709212 DOI: 10.3390/molecules26247668] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/15/2021] [Accepted: 12/17/2021] [Indexed: 01/25/2023] Open
Abstract
Due to the microenvironment created by Schwann cell (SC) activity, peripheral nerve fibers are able to regenerate. Inflammation is the first response to nerve damage and the removal of cellular and myelin debris is essential in preventing the persistence of the local inflammation that may negatively affect nerve regeneration. Acetylcholine (ACh) is one of the neurotransmitters involved in the modulation of inflammation through the activity of its receptors, belonging to both the muscarinic and nicotinic classes. In this report, we evaluated the expression of α7 nicotinic acetylcholine receptors (nAChRs) in rat sciatic nerve, particularly in SCs, after peripheral nerve injury. α7 nAChRs are absent in sciatic nerve immediately after dissection, but their expression is significantly enhanced in SCs after 24 h in cultured sciatic nerve segments or in the presence of the proinflammatory neuropeptide Bradykinin (BK). Moreover, we found that activation of α7 nAChRs with the selective partial agonist ICH3 causes a decreased expression of c-Jun and an upregulation of uPA, MMP2 and MMP9 activity. In addition, ICH3 treatment inhibits IL-6 transcript level expression as well as the cytokine release. These results suggest that ACh, probably released from regenerating axons or by SC themselves, may actively promote through α7 nAChRs activation an anti-inflammatory microenvironment that contributes to better improving the peripheral nerve regeneration.
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Neuroinflammation Modulation via α7 Nicotinic Acetylcholine Receptor and Its Chaperone, RIC-3. Molecules 2021; 26:molecules26206139. [PMID: 34684720 PMCID: PMC8539643 DOI: 10.3390/molecules26206139] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/07/2021] [Accepted: 10/08/2021] [Indexed: 12/14/2022] Open
Abstract
Nicotinic acetylcholine receptors (nAChRs) are widely expressed in or on various cell types and have diverse functions. In immune cells nAChRs regulate proliferation, differentiation and cytokine release. Specifically, activation of the α7 nAChR reduces inflammation as part of the cholinergic anti-inflammatory pathway. Here we review numerous effects of α7 nAChR activation on immune cell function and differentiation. Further, we also describe evidence implicating this receptor and its chaperone RIC-3 in diseases of the central nervous system and in neuroinflammation, focusing on multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Deregulated neuroinflammation due to dysfunction of α7 nAChR provides one explanation for involvement of this receptor and of RIC-3 in neurodegenerative diseases. In this review, we also provide evidence implicating α7 nAChRs and RIC-3 in neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) involving neuroinflammation. Besides, we will describe the therapeutic implications of activating the cholinergic anti-inflammatory pathway for diseases involving neuroinflammation.
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Dobric A, De Luca SN, Spencer SJ, Bozinovski S, Saling MM, McDonald CF, Vlahos R. Novel pharmacological strategies to treat cognitive dysfunction in chronic obstructive pulmonary disease. Pharmacol Ther 2021; 233:108017. [PMID: 34626675 DOI: 10.1016/j.pharmthera.2021.108017] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/19/2021] [Accepted: 10/04/2021] [Indexed: 12/12/2022]
Abstract
Chronic obstructive pulmonary disease (COPD) is a major incurable global health burden and currently the 3rd largest cause of death in the world, with approximately 3.23 million deaths per year. Globally, the financial burden of COPD is approximately €82 billion per year and causes substantial morbidity and mortality. Importantly, much of the disease burden and health care utilisation in COPD is associated with the management of its comorbidities and viral and bacterial-induced acute exacerbations (AECOPD). Recent clinical studies have shown that cognitive dysfunction is present in up to 60% of people with COPD, with impairments in executive function, memory, and attention, impacting on important outcomes such as quality of life, hospitalisation and survival. The high prevalence of cognitive dysfunction in COPD may also help explain the insufficient adherence to therapeutic plans and strategies, thus worsening disease progression in people with COPD. However, the mechanisms underlying the impaired neuropathology and cognition in COPD remain largely unknown. In this review, we propose that the observed pulmonary oxidative burden and inflammatory response of people with COPD 'spills over' into the systemic circulation, resulting in damage to the brain and leading to cognitive dysfunction. As such, drugs targeting the lungs and comorbidities concurrently represent an exciting and unique therapeutic opportunity to treat COPD and cognitive impairments, which may lead to the production of novel targets to prevent and reverse the debilitating and life-threatening effects of cognitive dysfunction in COPD.
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Affiliation(s)
- Aleksandar Dobric
- School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia
| | - Simone N De Luca
- School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia
| | - Sarah J Spencer
- School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia; ARC Centre of Excellence for Nanoscale Biophotonics, RMIT University, Melbourne, VIC, Australia
| | - Steven Bozinovski
- School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia
| | - Michael M Saling
- Clinical Neuropsychology, The University of Melbourne and Austin Health, VIC, Australia
| | - Christine F McDonald
- Institute for Breathing and Sleep, Austin Health, Melbourne, VIC, Australia; Department of Respiratory & Sleep Medicine, The University of Melbourne and Austin Health, Melbourne, VIC, Australia
| | - Ross Vlahos
- School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia.
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Bhargava M, Mroz MM, Maier LA. Smoke Signals: Promise of Nicotine as a Treatment for Pulmonary Sarcoidosis. Chest 2021; 160:1169-1170. [PMID: 34625164 DOI: 10.1016/j.chest.2021.06.051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 06/29/2021] [Indexed: 11/25/2022] Open
Affiliation(s)
- Maneesh Bhargava
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep, University of Minnesota, Minneapolis, MN
| | - Margaret M Mroz
- Division of Environmental and Occupational Health Sciences, National Jewish Health, Denver, CO
| | - Lisa A Maier
- Division of Environmental and Occupational Health Sciences, National Jewish Health, Denver, CO; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO; Department of Environmental and Occupational Health, Colorado School of Public Health, Aurora, CO.
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Johnson SD, Olwenyi OA, Bhyravbhatla N, Thurman M, Pandey K, Klug EA, Johnston M, Dyavar SR, Acharya A, Podany AT, Fletcher CV, Mohan M, Singh K, Byrareddy SN. Therapeutic implications of SARS-CoV-2 dysregulation of the gut-brain-lung axis. World J Gastroenterol 2021; 27:4763-4783. [PMID: 34447225 PMCID: PMC8371510 DOI: 10.3748/wjg.v27.i29.4763] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/10/2021] [Accepted: 07/20/2021] [Indexed: 02/06/2023] Open
Abstract
The emergence and rapid spread of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over 180 million confirmed cases resulting in over 4 million deaths worldwide with no clear end in sight for the coronavirus disease 19 (COVID-19) pandemic. Most SARS-CoV-2 exposed individuals experience mild to moderate symptoms, including fever, cough, fatigue, and loss of smell and taste. However, many individuals develop pneumonia, acute respiratory distress syndrome, septic shock, and multiorgan dysfunction. In addition to these primarily respiratory symptoms, SARS-CoV-2 can also infiltrate the central nervous system, which may damage the blood-brain barrier and the neuron's synapses. Resultant inflammation and neurodegeneration in the brain stem can further prevent efferent signaling to cranial nerves, leading to the loss of anti-inflammatory signaling and normal respiratory and gastrointestinal functions. Additionally, SARS-CoV-2 can infect enterocytes resulting in gut damage followed by microbial dysbiosis and translocation of bacteria and their byproducts across the damaged epithelial barrier. As a result, this exacerbates pro-inflammatory responses both locally and systemically, resulting in impaired clinical outcomes. Recent evidence has highlighted the complex interactions that mutually modulate respiratory, neurological, and gastrointestinal function. In this review, we discuss the ways SARS-CoV-2 potentially disrupts the gut-brain-lung axis. We further highlight targeting specific responses to SARS-CoV-2 for the development of novel, urgently needed therapeutic interventions. Finally, we propose a prospective related to the individuals from Low- and Middle-Income countries. Here, the underlying propensity for heightened gut damage/microbial translocation is likely to result in worse clinical outcomes during this COVID-19 pandemic.
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Affiliation(s)
- Samuel D Johnson
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Omalla A Olwenyi
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Namita Bhyravbhatla
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Michellie Thurman
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kabita Pandey
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Elizabeth A Klug
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Morgan Johnston
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Shetty Ravi Dyavar
- Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, Omaha, NE 68198, United States
| | - Arpan Acharya
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Anthony T Podany
- Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, Omaha, NE 68198, United States
| | - Courtney V Fletcher
- Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, Omaha, NE 68198, United States
| | - Mahesh Mohan
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78227, United States
| | - Kamal Singh
- Department of Molecular Microbiology and Immunology and Bond Life Sciences Center, University of Missouri, Columbia, MO 65212, United States
| | - Siddappa N Byrareddy
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, United States
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Baron JA, Nichols HB, Anderson C, Safe S. Cigarette Smoking and Estrogen-Related Cancer. Cancer Epidemiol Biomarkers Prev 2021; 30:1462-1471. [PMID: 33990391 PMCID: PMC8338753 DOI: 10.1158/1055-9965.epi-20-1803] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 03/13/2021] [Accepted: 05/10/2021] [Indexed: 12/23/2022] Open
Abstract
Cigarette smoking is a known cause of many cancers, yet epidemiologic studies have found protective associations with the risk of four "estrogen-related" malignancies: endometrial cancer, endometrioid and clear cell ovarian cancers, and thyroid cancer. This review considers epidemiologic and biological aspects of these associations, focusing particularly on estrogen signaling, and contrasts them with those for breast cancer, another estrogen-related malignancy. The observational findings regarding the inverse associations are consistent and remain after adjustment for possible confounding factors. In general, women who smoke do not have lower circulating estrogen levels than nonsmokers, eliminating one possible explanation for reduced risks of these malignancies. For endometrial and endometrioid ovarian cancer, the negative associations could plausibly be explained by interference with signaling through the estrogen receptor α. However, this is unlikely to explain the lower risks of thyroid and clear cell ovarian cancers. For thyroid cancer, an anti-inflammatory effect of nicotine and reduced TSH levels from smoking have been proposed explanations for the inverse association, but both lack convincing evidence. While the overall impact of cigarette smoking is overwhelmingly negative, protective associations such as those discussed here can provide potential clues to disease etiology, treatment, and prevention.
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Affiliation(s)
- John A Baron
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
| | - Hazel B Nichols
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina
| | - Chelsea Anderson
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina
| | - Stephen Safe
- Department of Veterinary Physiology & Pharmacology, Texas A&M University, College Station, Texas
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Role of Lung Ultrasound in Predicting Clinical Severity and Fatality in COVID-19 Pneumonia. J Pers Med 2021; 11:jpm11080757. [PMID: 34442401 PMCID: PMC8399683 DOI: 10.3390/jpm11080757] [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: 06/03/2021] [Revised: 07/24/2021] [Accepted: 07/29/2021] [Indexed: 02/08/2023] Open
Abstract
Background: Lung ultrasound (LUS) is a useful imaging method for identifying COVID-19 pneumonia. The aim of this study was to explore the role of LUS in predicting the severity of the disease and fatality in patients with COVID-19. Methods: This was a single-center, follow-up study, conducted from 1 November 2020, to 22 March 2021. The LUS protocol was based on the assessment of 14 lung zones with a total score up to 42, which was compared to the disease severity and fatality. Results: A total of 133 patients with COVID-19 pneumonia confirmed by RT-PCR were enrolled, with a median time from hospital admission to lung ultrasound of one day. The LUS score was correlated with clinical severity at hospital admission (Spearman’s rho 0.40, 95% CI 0.24 to 0.53, p < 0.001). Patients with higher LUS scores were experiencing greater disease severity; a high flow nasal cannula had an odds ratio of 1.43 (5% CI 1.17–1.74) in patients with LUS score > 29; the same score also predicted the need for mechanical ventilation (1.25, [1.07–1.48]). An LUS score > 30 (1.41 [1.18–1.68]) and age over 68 (1.26 [1.11–1.43]) were significant predictors of fatality. Conclusions: LUS at hospital admission is shown to have a high predictive power of the severity and fatality of COVID-19 pneumonia.
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