Phenylmethimazole is a candidate drug for the treatment of severe forms of coronavirus disease 2019 (COVID-19) as well as other virus-induced “cytokines storm”

Giuliani, Cesidio; Bucci, Ines; Napolitano, Giorgio

doi:10.1016/j.mehy.2020.110473

Cited by 6 publications

(7 citation statements)

References 17 publications

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“…We believe that the use of tocilizumab, an anti-IL‐6R antibody ( 78 ), is a promising strategy for treating severe hCoV-induced CRS ( 79 ), as it showed promising results in clinical trials ( 80 ). However, the focus on anti-cytokine therapy might have led to the opportunity to explore other potential therapies that target the host’s immune system, such as stem cell therapy, transfusion of convalescent plasma, targeting of the microRNA network, and immune-supportive therapy ( 53 , 81 – 84 ). It is therefore recommended to combine immunotherapy with antiviral treatment.…”

Section: Discussionmentioning

confidence: 99%

Profile of Circulatory Cytokines and Chemokines in Human Coronaviruses: A Systematic Review and Meta-Analysis

et al. 2021

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BackgroundSARS, MERS, and COVID-19 share similar characteristics. For instance, the genetic homology of SARS-CoV-2 compared to SARS-CoV and MERS-CoV is 80% and 50%, respectively, which may cause similar clinical features. Moreover, uncontrolled release of proinflammatory mediators (also called a cytokine storm) by activated immune cells in SARS, MERS, and COVID-19 patients leads to severe phenotype development.AimThis systematic review and meta-analysis aimed to evaluate the inflammatory cytokine profile associated with three strains of severe human coronavirus diseases (MERS-CoV, SARS-CoV, and SARS-CoV-2).MethodThe PubMed, Embase, and Cochrane Library databases were searched for studies published until July 2020. Randomized and observational studies reporting the inflammatory cytokines associated with severe and non-severe human coronavirus diseases, including MERS-CoV, SARS-CoV, and SARS-CoV-2, were included. Two reviewers independently screened articles, extracted data, and assessed the quality of the included studies. Meta-analysis was performed using a random-effects model with a 95% confidence interval to estimate the pooled mean of inflammatory biomarkers.ResultsA high level of circulating IL-6 could be associated with the severity of infection of the three coronavirus strains. TNF, IL-10, and IL-8 are associated with the severity of COVID-19. Increased circulating levels of CXCL10/IP10 and CCL2/MCP-1 might also be related to the severity of MERS.ConclusionThis study suggests that the immune response and immunopathology in the three severe human coronavirus strains are somewhat similar. The findings highlight that nearly all studies reporting severe cases of SARS, MERS, and COVID-19 have been associated with elevated levels of IL-6. This could be used as a potential therapeutic target to improve patients’ outcomes in severe cases.Systematic Review RegistrationPROSPERO registration 94 number: CRD42020209931.

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Section: Discussionmentioning

confidence: 99%

Profile of Circulatory Cytokines and Chemokines in Human Coronaviruses: A Systematic Review and Meta-Analysis

et al. 2021

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“…MMI is a drug widely used to treat hyperthyroidism that, beside an antithyroid effect, also has anti-inflammatory and immunosuppressive effects (42)(43)(44). C10, a phenyl derivative of MMI (17), is a more potent anti-inflammatory agent both in vitro and in vivo (17,45). Thymosin-a1 is a drug used to stimulate the immune response (46) and one of its mechanisms of action is the increase of MHC class I expression (20,47).…”

Section: Discussionmentioning

confidence: 99%

“…For this reason, we and other groups have studied MMI derivatives characterized by a high anti-inflammatory and immunosuppressive potency and a low or no effect on thyroid function (17,45,53,54). C10 is one of these derivatives and several studies suggest its potential use in severe inflammatory diseases (45). On the other hand, the information obtained on the mechanism of action of thymosin-a1 are important for its use in cancer immunotherapy and to stimulate the research of new drugs with the same mechanism of action, considering that the loss of MHC class I expression is a feature of several tumors including papillary thyroid cancer (55)(56)(57)(58)(59).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, we speculate that the effectiveness of MMI in the treatment of autoimmune thyroid diseases is not only due to its antithyroid effect but also to its ability to suppress the inflammatory and immune processes. For this reason, we and other groups have studied MMI derivatives characterized by a high anti-inflammatory and immunosuppressive potency and a low or no effect on thyroid function ( 17 , 45 , 53 , 54 ). C10 is one of these derivatives and several studies suggest its potential use in severe inflammatory diseases ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

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Hormonal Regulation of the MHC Class I Gene in Thyroid Cells: Role of the Promoter “Tissue-Specific” Region

et al. 2021

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In previous studies we have demonstrated that the expression of the Major Histocompatibility Complex (MHC) class I gene in thyrocytes is controlled by several hormones, growth factors, and drugs. These substances mainly act on two regions of the MHC class I promoter a “tissue-specific” region (−800 to −676 bp) and a “hormone/cytokines-sensitive” region (−500 to −68 bp). In a previous study, we have shown that the role of the “tissue-specific” region in the MHC class I gene expression is dominant compared to that of the “hormone/cytokines-sensitive” region. In the present report we further investigate the dominant role of the “tissue-specific” region evaluating the effect of thyroid stimulating hormone (TSH), methimazole (MMI), phenylmethimazole (C10), glucose and thymosin-α1. By performing experiments of electrophoretic mobility shift assays (EMSAs) we show that TSH, MMI and C10, which inhibit MHC class I expression, act on the “tissue-specific” region increasing the formation of a silencer complex. Glucose and thymosin-α1, which stimulate MHC class I expression, act decreasing the formation of this complex. We further show that the silencer complex is formed by two distinct members of the transcription factors families activator protein-1 (AP-1) and nuclear factor-kB (NF-kB), c-jun and p65, respectively. These observations are important in order to understand the regulation of MHC class I gene expression in thyroid cells and its involvement in the development of thyroid autoimmunity.

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“…Vitamin C plays an important role in immunomodulation; it can inhibit the activation of the nuclear factor kappa-B, the main pro-inflammatory transcription factor, and is also important in the overall immunity of the body. Vitamin C may also inhibit the production of IL-6 and may also act as a cytokine regulator [ 35 ].…”

Section: Cytokine Storm and Covid-19mentioning

confidence: 99%

Disorders of the Cholinergic System in COVID-19 Era—A Review of the Latest Research

Kopańska

Batoryna²,

Bartman

et al. 2022

IJMS

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The appearance of the SARS-CoV-2 virus initiated many studies on the effects of the virus on the human body. So far, its negative influence on the functioning of many morphological and physiological units, including the nervous system, has been demonstrated. Consequently, research has been conducted on the changes that SARS-CoV-2 may cause in the cholinergic system. The aim of this study is to review the latest research from the years 2020/2021 regarding disorders in the cholinergic system caused by the SARS-CoV-2 virus. As a result of the research, it was found that the presence of the COVID-19 virus disrupts the activity of the cholinergic system, for example, causing the development of myasthenia gravis or a change in acetylcholine activity. The SARS-CoV-2 spike protein has a sequence similar to neurotoxins, capable of binding nicotinic acetylcholine receptors (nAChR). This may be proof that SARS-CoV-2 can bind nAChR. Nicotine and caffeine have similar structures to antiviral drugs, capable of binding angiotensin-converting enzyme 2 (ACE 2) epitopes that are recognized by SARS-CoV-2, with the potential to inhibit the formation of the ACE 2/SARS-CoV-2 complex. The blocking is enhanced when nicotine and caffeine are used together with antiviral drugs. This is proof that nAChR agonists can be used along with antiviral drugs in COVID-19 therapy. As a result, it is possible to develop COVID-19 therapies that use these compounds to reduce cytokine production. Another promising therapy is non-invasive stimulation of the vagus nerve, which soothes the body’s cytokine storm. Research on the influence of COVID-19 on the cholinergic system is an area that should continue to be developed as there is a need for further research. It can be firmly stated that COVID-19 causes a dysregulation of the cholinergic system, which leads to a need for further research, because there are many promising therapies that will prevent the SARS-CoV-2 virus from binding to the nicotinic receptor. There is a need for further research, both in vitro and in vivo. It should be noted that in the functioning of the cholinergic system and its connection with the activity of the COVID-19 virus, there might be many promising dependencies and solutions.

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Phenylmethimazole is a candidate drug for the treatment of severe forms of coronavirus disease 2019 (COVID-19) as well as other virus-induced “cytokines storm”

Cited by 6 publications

References 17 publications

Profile of Circulatory Cytokines and Chemokines in Human Coronaviruses: A Systematic Review and Meta-Analysis

Profile of Circulatory Cytokines and Chemokines in Human Coronaviruses: A Systematic Review and Meta-Analysis

Hormonal Regulation of the MHC Class I Gene in Thyroid Cells: Role of the Promoter “Tissue-Specific” Region

Disorders of the Cholinergic System in COVID-19 Era—A Review of the Latest Research

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