scholarly journals A novel definition and treatment of hyperinflammation in COVID-19 based on purinergic signalling

2021 ◽  
Author(s):  
Djo Hasan ◽  
Atsuko Shono ◽  
Coenraad K. van Kalken ◽  
Peter J. van der Spek ◽  
Eric P. Krenning ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Immune Cells ◽  
Purinergic Receptors ◽  
Atp Release ◽  
The Body ◽  
Purinergic Signalling ◽  
Cytokine Storm ◽  
Secondary Infections ◽  
Half Maximal Effective Concentration ◽  
Anti Inflammatory

AbstractHyperinflammation plays an important role in severe and critical COVID-19. Using inconsistent criteria, many researchers define hyperinflammation as a form of very severe inflammation with cytokine storm. Therefore, COVID-19 patients are treated with anti-inflammatory drugs. These drugs appear to be less efficacious than expected and are sometimes accompanied by serious adverse effects. SARS-CoV-2 promotes cellular ATP release. Increased levels of extracellular ATP activate the purinergic receptors of the immune cells initiating the physiologic pro-inflammatory immune response. Persisting viral infection drives the ATP release even further leading to the activation of the P2X7 purinergic receptors (P2X7Rs) and a severe yet physiologic inflammation. Disease progression promotes prolonged vigorous activation of the P2X7R causing cell death and uncontrolled ATP release leading to cytokine storm and desensitisation of all other purinergic receptors of the immune cells. This results in immune paralysis with co-infections or secondary infections. We refer to this pathologic condition as hyperinflammation. The readily available and affordable P2X7R antagonist lidocaine can abrogate hyperinflammation and restore the normal immune function. The issue is that the half-maximal effective concentration for P2X7R inhibition of lidocaine is much higher than the maximal tolerable plasma concentration where adverse effects start to develop. To overcome this, we selectively inhibit the P2X7Rs of the immune cells of the lymphatic system inducing clonal expansion of Tregs in local lymph nodes. Subsequently, these Tregs migrate throughout the body exerting anti-inflammatory activities suppressing systemic and (distant) local hyperinflammation. We illustrate this with six critically ill COVID-19 patients treated with lidocaine.

scholarly journals Emerging concepts regarding pannexin 1 in the vasculature

2015 ◽  
Vol 43 (3) ◽  
pp. 495-501 ◽  
Author(s):  
Miranda E. Good ◽  
Daniela Begandt ◽  
Leon J. DeLalio ◽  
Alexander S. Keller ◽  
Marie Billaud ◽  
...  
Keyword(s):  
Vascular Function ◽  
Atp Release ◽  
The Body ◽  
Purinergic Signalling ◽  
Molecular Tools ◽  
Cellular Functions ◽  
Post Translational Modifications ◽  
Pannexin 1 ◽  
Knockout Animals

Pannexin channels are newly discovered ATP release channels expressed throughout the body. Pannexin 1 (Panx1) channels have become of great interest as they appear to participate in a multitude of signalling cascades, including regulation of vascular function. Although numerous Panx1 pharmacological inhibitors have been discovered, these inhibitors are not specific for Panx1 and have additional effects on other proteins. Therefore, molecular tools, such as RNA interference and knockout animals, are needed to demonstrate the role of pannexins in various cellular functions. This review focuses on the known roles of Panx1 related to purinergic signalling in the vasculature focusing on post-translational modifications and channel gating mechanisms that may participate in the regulated release of ATP.

The War Against SARS-CoV-2: The Immune Giant Collapsing Under Its Own Rampaging Cytokine Storm

2021 ◽  
Author(s):  
Xanya Sofra
Keyword(s):  
Skeletal Muscle ◽  
Immune Response ◽  
Immune Cells ◽  
Preventive Intervention ◽  
Inflammatory Marker ◽  
The Body ◽  
Alternative Methods ◽  
Cytokine Storm ◽  
Protective Function ◽  
Age Related

We examined SARS-CoV-2 (Covid-19) available treatments and prophylactic methods that included interventions associated with inhibiting the ‘type II transmembrane serine protease’ (TMPRSS2) to limit the fusion between the Covid-19 Spike proteins and ACE2 receptors, or newly developed therapeutics like Remdesivir that interferes with the viral RNA replication. We explored the dilemma of ACE2 receptors that have a protective function against high blood pressure associated disorders, yet, they serve as the viral points of entry, elevating the probability of infection. Human tissues’ analysis reveals a higher ACE2 expression in adipose tissue, placing obesity-related conditions in the eye of the pandemic storm. It primarily exposes males due to the surge of ACE2 receptors in the testes along with other tissues. Males manifest a relatively higher positive ACE2 correlation with certain immune cells in the lungs, thyroid, adrenals, liver and colon, while females evidence higher ACE2 correlations with immune cells in the heart. The remaining tissues’ ACE2/immunity expressions are equivalent in both sexes, indicating that despite its preference for males, the threat of Covid-19 can easily target females. Recent reports indicate that Covid-19 is empowered by hindering the critical process of viral recognition during the adaptive immune response leading to the “cytokine storm,” the aggravated immune response that indiscriminately perseveres, rampaging the host’s vital organs. Sedentary lifestyle, age-related hormonal imbalance, and adiposity induced inflammation predispose the body to the immune collapse following Covid-19 invasion, spotlighting the detrimental aftermath of metabolic dysfunction, and excess food consumption, provoked by elevated cortisol and dysregulated appetite hormones. ACE2 expression is suppressed in the skeletal muscle, rendering fitness and weight management an effective Covid-19 preventive intervention, along with social distancing, hygiene, and facial coverings. Physical activity, or exercise alternative methods have recently demonstrated statistically significant reductions of the inflammatory marker C-Reactive Protein (CRP), triglycerides, visceral fat, cortisol and the orexigenic hormone ghrelin, juxtaposed by optimal increases of IGF-1, skeletal muscle mass, Free T3, HDL, and the anorexic hormone leptin.

scholarly journals Chronic Sulfasalazine Treatment in Mice Induces System xc− - Independent Adverse Effects

2021 ◽  
Vol 12 ◽  
Author(s):  
Lise Verbruggen ◽  
Lindsay Sprimont ◽  
Eduard Bentea ◽  
Pauline Janssen ◽  
Azzedine Gharib ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Therapeutic Potential ◽  
Negative Impact ◽  
Chronic Administration ◽  
Systemic Circulation ◽  
The Body ◽  
Ample Evidence ◽  
Anti Inflammatory ◽  
First Time

Despite ample evidence for the therapeutic potential of inhibition of the cystine/glutamate antiporter system xc− in neurological disorders and in cancer, none of the proposed inhibitors is selective. In this context, a lot of research has been performed using the EMA- and FDA-approved drug sulfasalazine (SAS). Even though this molecule is already on the market for decades as an anti-inflammatory drug, serious side effects due to its use have been reported. Whereas for the treatment of the main indications, SAS needs to be cleaved in the intestine into the anti-inflammatory compound mesalazine, it needs to reach the systemic circulation in its intact form to allow inhibition of system xc−. The higher plasma levels of intact SAS (or its metabolites) might induce adverse effects, independent of its action on system xc−. Some of these effects have however been attributed to system xc− inhibition, calling into question the safety of targeting system xc−. In this study we chronically treated system xc− - deficient mice and their wildtype littermates with two different doses of SAS (160 mg/kg twice daily or 320 mg/kg once daily, i.p.) and studied some of the adverse effects that were previously reported. SAS had a negative impact on the survival rate, the body weight, the thermoregulation and/or stress reaction of mice of both genotypes, and thus independent of its inhibitory action on system xc−. While SAS decreased the total distance travelled in the open-field test the first time the mice encountered the test, it did not influence this parameter on the long-term and it did not induce other behavioral changes such as anxiety- or depressive-like behavior. Finally, no major histological abnormalities were observed in the spinal cord. To conclude, we were unable to identify any undesirable system xc−-dependent effect of chronic administration of SAS.

scholarly journals GILZ as a Regulator of Cell Fate and Inflammation

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 122
Author(s):  
Stefano Bruscoli ◽  
Carlo Riccardi ◽  
Simona Ronchetti
Keyword(s):  
Adverse Effects ◽  
Cell Fate ◽  
Immune Cells ◽  
Leucine Zipper ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Therapeutic Outcomes ◽  
Proliferation And Differentiation ◽  
Adrenal Response ◽  
Anti Inflammatory

One of the human body’s initial responses to stress is the adrenal response, involving the release of mediators that include adrenaline and glucocorticoids (GC). GC are involved in controlling the inflammatory and immune response mechanisms. Of these, the molecular mechanisms that contribute to anti-inflammatory effects warrant more investigation. Previously, we found that GC induced GILZ (glucocorticoid-induced leucine zipper) quickly and widely in thymocytes, T lymphocytes, and other leukocytes. GILZ regulates the activation of cells and is an essential mediator of endogenous GC and the majority of GC anti-inflammatory effects. Further research in this regard could lead to the development of an anti-inflammatory treatment that yields the therapeutic outcomes of GC but without their characteristic adverse effects. Here, we examine the mechanisms of GILZ in the context of GC. Specifically, we review its role in the proliferation and differentiation of cells and in apoptosis. We also examine its involvement in immune cells (macrophages, neutrophils, dendritic cells, T and B lymphocytes), and in non-immune cells, including cancer cells. In conclusion, GILZ is an anti-inflammatory molecule that could mediate the immunomodulatory activities of GC, with less adverse effects, and could be a target molecule for designing new therapies to treat inflammatory diseases.

Principles of Pharmacology

2013 ◽  
Author(s):  
Graham Brack ◽  
Penny Franklin ◽  
Jill Caldwell
Keyword(s):  
Patient Safety ◽  
Adverse Effects ◽  
Renal Impairment ◽  
Drug Interactions ◽  
Point Of View ◽  
The Body ◽  
Detailed Knowledge ◽  
Inflammatory Drug ◽  
Anti Inflammatory ◽  
Compromised Patients

From the previous chapters you will see that understanding the pharmacological aspects of the drugs you are administering is vital to keeping your patients safe. Nurses need to understand the pharmacodynamics of a medicine, or how it actually works within the body, since this will need to be explained to patients and carers. For example, how will you ensure that a patient understands the importance of taking their treatment for hypertension (especially if they are experiencing no symptoms) if you are unable to explain how the medicine will be working? Similarly, your understanding of the pharmacokinetics (the absorption, distribution, metabolism, and excretion) of individual medicines is vital to ensure compromised patients are not administered inappropriate medicines. For example, you would question the prescribing of a non-steroidal anti-inflammatory drug (NSAID) to a patient with significant renal impairment, because the kidney is essential to the elimination of NSAIDs so the drug could accumulate if the kidneys are not functioning properly. From the point of view of ensuring patient safety, you will need to understand the principles of drug interactions so that you can understand how two medicines (or food and medicine) could interact and be alert to signs that this may be happening. There are several good textbooks dealing with the uses and actions of individual medicines, including interactions. However, these will not be discussed here because at this stage of your career you are not expected to have a detailed knowledge of particular medicines, but rather an understanding of the key principles. As nurses, we are concerned with how the body handles medicines (pharmacokinetics) so that we can see how this may be affected by age, genetics, or illness, and how the actions of medicines may conflict with one another or produce toxicity because their effects are additive. Equally, we need to look at occasions in which two medicines produce the same response by two different routes; such interactions can be beneficial to the patient and avoid having to give large doses of a single medicine because the same result can be achieved with smaller doses of two medicines, thereby reducing the risk of adverse effects.

scholarly journals SARS-CoV-2-the Unforeseen Peril of David Winning Against Goliath: the Immune Giant Collapsing Under Its Own Rampaging Cytokine Storm

2021 ◽  
Vol 2 (1) ◽  
pp. 26
Author(s):  
Xanya Sofra
Keyword(s):  
Skeletal Muscle ◽  
Immune Response ◽  
Immune Cells ◽  
Preventive Intervention ◽  
Inflammatory Marker ◽  
The Body ◽  
Alternative Methods ◽  
Cytokine Storm ◽  
Protective Function ◽  
Age Related

We examined SARS-CoV-2 (Covid-19) available treatments and prophylactic methods that included interventions associated with inhibiting the “type II transmembrane serine protease” (TMPRSS2) to limit the fusion between the Covid-19 Spike proteins and ACE2 receptors, or newly developed therapeutics like Remdesivir that interferes with the viral RNA replication. We explored the dilemma of ACE2 receptors that have a protective function against high blood pressure associated disorders, yet,they serve as the viral points of entry, elevating the probability of infection. Human tissues’ analysis reveals a higher ACE2 expression in adipose tissue, placing obesity-related conditions in the eye of the pandemic storm. It primarily exposes males due to the surge of ACE2 receptors in the testes along with other tissues. Males manifest a relatively higher positive ACE2 orrelations with certain immune cells in the lungs,thyroid, adrenals, liver and colon, while females evidence higher ACE2 correlations with immune cells in the heart. The remaining tissues’ ACE2/immunity expressions are equivalent in both sexes, indicating that despite its preference for males, the threat of Covid-19 can easily target females.Recent reports indicate that Covid-19 is empowered by hindering the critical process of viral recognition during the adaptive immune response leading to the “cytokine storm”, the aggravated immune response that indiscriminately perseveres, rampaging the host’s vital organs. Sedentary lifestyle, age-related hormonal imbalance, and adiposity induced inflammation predispose the body to the immune collapse following Covid-19 invasion, spotlighting the detrimental aftermath of metabolic dysfunction,and excess food consumption provoked by elevated cortisol and dysregulated appetite hormones. ACE 2 expression is suppressed in the skeletal muscle, rendering fitness and weight management an effective Covid-19 preventive intervention, along with social distancing, hygiene, and facial coverings. Physical activity, or exercise alternative methods have recently demonstrated statistically significant reductions of the inflammatory marker C-Reactive Protein (CRP), triglycerides, visceral fat, cortisol and the orexigenic hormone ghrelin, juxtaposed by optimal increases of IGF-1, skeletal muscle mass, Free T3, HDL, and the anorexic hormone leptin.

scholarly journals Combination of oxymatrine and diammonium glycyrrhizinate significantly mitigates mice allergic contact dermatitis induced by dinitrofluorobenzene

2019 ◽  
Vol 244 (13) ◽  
pp. 1111-1119
Author(s):  
Hui-juan Shi ◽  
Hong-bin Song ◽  
Qiong Gao ◽  
Jia-wei Si ◽  
Qian Zou
Keyword(s):  
Contact Dermatitis ◽  
Adverse Effects ◽  
Allergic Contact Dermatitis ◽  
The Body ◽  
Plasma Sodium ◽  
Serum Ige ◽  
Body Weights ◽  
Anti Inflammatory ◽  
Allergic Contact ◽  
Inflammatory Infiltrates

This study investigated the safety and effect of oxymatrine (OMT) and/or diammonium glycyrrhizinate (DG) on allergic contact dermatitis (ACD) induced by 1-fluoro-2,4-dinitrofluorobenzene (DNFB) in ICR mice. Mice were topically smeared with vehicle (control) or DNFB on their ear and skin to induce ACD. The mice were randomized and injected with saline as the model, treated intraperitoneally with dexamethasone (DEX), 45 or 90 mg·kg−1 OMT and/or DG daily beginning one day post the first smearing for two weeks. The body weights, the severity of ear and skin inflammation, the levels of serum IgE, IL-4, and IFNγ, creatinine and urea as well as plasma sodium and potassium in individual mice were measured. In comparison with the control group, the model group did not change the body weights, but developed severe skin and ear inflammation with increased ear thickness, accompanied by many inflammatory infiltrates in the lesions and high levels of serum IgE, IL-4, and IFNγ. Combination of OMT and DG prevented the OMT- or DG-altered body weights in mice. While treatment with either OMT or DG moderately reduced the skin and ear inflammation, their thickness and inflammatory infiltrates, combination of OMT and DG further significantly increased their anti-inflammatory effects in mice. A similar pattern of inhibitory effect on the levels of serum IgE, IL-4, and IFNγ was observed in the different groups of mice. Combination of OMT and DG also prevented the OMT-, DG-, or DEX-altered plasma sodium or potassium levels in mice. Therefore, combination of OMT and DG significantly increased anti-inflammatory effects on ACD induced by DNFB in mice and attenuated DG- or OMT-related adverse effects. Impact statement Diammonium glycyrrhizinate (DG) and oxymatrine (OMT) have similar anti-inflammatory, anti-allergic, anti-tumor, immunomodulatory, and other pharmacological properties. Our previous study has shown that when DG and OMT are combined, DG can attenuate both high-dose (347.44 mg·kg−1) and regular-dose (90 mg·kg−1) OMT-induced mortality and adverse effects (such as body weight loss and hyponatremia). Furthermore, OMT can similarly attenuate the adverse effects (such as body weight gain, hypernatremia, and hypokalemia) induced by regular dose (90 mg·kg−1) of DG. Accordingly, we tested whether combination of OMT and DG would increase anti-inflammatory activities and reduce their adverse effect in a mouse model of allergic contact dermatitis (ACD) induced by 1-fluoro-2,4-dinitrofluorobenzene (DNFB). Our findings indicated that combination of OMT and DG significantly increased anti-inflammatory effects on ACD induced by DNFB in ICR mice and attenuated adverse effects of DG or OMT alone.

scholarly journals The Immunomodulating Effect of Baicalin on Inflammation and Insulin Resistance in High-Fat-Diet-Induced Obese Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Ji-Won Noh ◽  
Oh-Jun Kwon ◽  
Byung-Cheol Lee
Keyword(s):  
Insulin Resistance ◽  
Immune Cells ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
Liver Weight ◽  
Tolerance Test ◽  
The Body ◽  
High Fat ◽  
Normal Chow ◽  
Anti Inflammatory

Background. Obesity is a chronic low-grade systemic inflammation state, which causes insulin resistance, diabetes, and other metabolic diseases. Baicalin is known to have anti-inflammatory and antiobesity effects. In this study, we investigated the cellular and molecular immunological effects of baicalin on obesity-induced inflammation. Methods. Male C57BL/6 mice were assigned to four groups: the normal chow, high-fat diet (HFD), BC2 (HFD + baicalin 200 mg/kg), and BC4 (HFD + baicalin 400 mg/kg) group; the three groups except normal chow were fed with a high-fat diet for 8 weeks to induce obesity followed by baicalin treatment with two doses for 8 weeks. The body weight, epididymal fat weight, liver weight, food intake, oral glucose tolerance test (OGTT), oral fat tolerance test (OFTT), and serum lipids were measured. We evaluated insulin resistance by measuring the serum insulin level and homeostatic model assessment of insulin resistance (HOMA-IR). Also, the major obesity-associated immune cells including monocytes, macrophages, T lymphocytes, and dendritic cells in the blood, fat, and liver and the inflammatory and insulin signaling-related gene expressions in the fat and liver were evaluated. Results. Baicalin significantly reduced the body weight and liver weight and improved serum fasting glucose, insulin, HOMA-IR, free fatty acid, HDL cholesterol, and the levels of glucose and triglyceride at each time point in the OGTT and OFTT. In the analysis of immune cells, baicalin significantly decreased inflammatory Ly6Chi monocytes, M1 adipose tissue macrophages (ATMs), and M1 Kupffer cells. On the contrary, baicalin increased anti-inflammatory M2 ATMs and liver CD4+ T cells and CD4/CD8 ratio. In the analysis of inflammatory and insulin signaling molecules, baicalin significantly downregulated the gene expression of tumor necrosis factor-α, F4/80, and C-C motif chemokine 2 while upregulated the insulin receptor mRNA expression. Conclusion. From these results, baicalin can be a promising treatment option for obesity and its related metabolic diseases based on its anti-inflammatory property.

scholarly journals Sirtuins and Sepsis: Cross Talk between Redox and Epigenetic Pathways

Antioxidants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 3
Author(s):  
Anugraha Gandhirajan ◽  
Sanjoy Roychowdhury ◽  
Vidula Vachharajani
Keyword(s):  
Immune Response ◽  
Immune Cells ◽  
Compensatory Mechanism ◽  
Inflammatory Phase ◽  
Epigenetic Programming ◽  
Secondary Infections ◽  
The Us ◽  
Anti Oxidant ◽  
Anti Inflammatory ◽  
Sepsis And Septic Shock

Sepsis and septic shock are the leading causes of death among hospitalized patients in the US. The immune response in sepsis transitions from a pro-inflammatory and pro-oxidant hyper-inflammation to an anti-inflammatory and cytoprotective hypo-inflammatory phase. While 1/3rd sepsis-related deaths occur during hyper-, a vast majority of sepsis-mortality occurs during the hypo-inflammation. Hyper-inflammation is cytotoxic for the immune cells and cannot be sustained. As a compensatory mechanism, the immune cells transition from cytotoxic hyper-inflammation to a cytoprotective hypo-inflammation with anti-inflammatory/immunosuppressive phase. However, the hypo-inflammation is associated with an inability to clear invading pathogens, leaving the host susceptible to secondary infections. Thus, the maladaptive immune response leads to a marked departure from homeostasis during sepsis-phases. The transition from hyper- to hypo-inflammation occurs via epigenetic programming. Sirtuins, a highly conserved family of histone deacetylators and guardians of homeostasis, are integral to the epigenetic programming in sepsis. Through their anti-inflammatory and anti-oxidant properties, the sirtuins modulate the immune response in sepsis. We review the role of sirtuins in orchestrating the interplay between the oxidative stress and epigenetic programming during sepsis.

Invivo Activity of Polyherbal Gels Prepared Using Carbopol

2020 ◽  
Vol 10 (3) ◽  
pp. 63-66
Author(s):  
Parasakthi N ◽  
Deepika R ◽  
Sivanathan C ◽  
Abubackkar Sithiq PD ◽  
Venkateshan N
Keyword(s):  
Physiological Stress ◽  
Defense Responses ◽  
The Body ◽  
Peptic Ulcers ◽  
Onset Of Action ◽  
Standard Drug ◽  
Root Extracts ◽  
Carbopol 940 ◽  
Anti Inflammatory ◽  
Rich Countries

Pain and inflammation are the basic defense responses of the body that the result of the injury and any other damage to the body. During the years the concerns were raised towards the inflammation that is caused to the oxidative damage that is resulted in the physiological stress due to oxidation. There are a lot of drugs that are used to treat the condition effectively and the typical examples are NSAID’s and SAID’s which have a noted mechanism to show the anti-inflammatory activity. They have serious problems with the side effects like Gastrointestinal irritation, Gastric pain, Gastric perforations and peptic ulcers. Herbs have been used as better alternatives that are used to treat diseases. The significance of the medicinal plants had been emphasized significantly in tradition rich countries like India and all over the world. The research proof of those herbs for their activities and their traditional claims were proven. Poly Herbal Gels were prepared using the root extracts of the plant Corchorus olitorius. The gels were prepared using the Carbopol 940 and the prepared gels were investigated for their anti-inflammatory property and the gels showed a significantly better activity compared to the plant extract and the standard drug too. The addition of other drugs in to the gels added and advantage to the increase in the activity and faster onset of action as the gel was applied directly in the place of the inflammation.

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