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1.
Transpl Int ; 35: 10269, 2022.
Article in English | MEDLINE | ID: covidwho-1938660

ABSTRACT

Kidney transplant recipients (KTRs) are at increased risk of severe COVID-19 disease compared to the general population. This is partly driven by their use of immunosuppressive therapy, which influences inflammatory responses and viral loads. Current guidelines suggest to withdraw mycophenolate while calcineurin inhibitors are often continued during a COVID-19 infection. However, clinical signs of calcineurin toxicity have been described in multiple COVID-19 positive KTRs. In this report we describe the course of tacrolimus exposure prior to, during, and post COVID-19 in observations from three clinical cases as well as four KTRs from a controlled trial population. We postulate inflammation driven downregulation of the CYP3A metabolism as a potential mechanism for higher tacrolimus exposure. To mitigate the risk of tacrolimus overexposure and toxicity therapeutic drug monitoring is recommended in KTRs with COVID-19 both in the in-, out-patient and home monitoring setting.


Subject(s)
COVID-19 , Kidney Transplantation , Down-Regulation , Humans , Inflammation/etiology , Kidney Transplantation/adverse effects , Tacrolimus/adverse effects
2.
Lancet Respir Med ; 9(5): 533-544, 2021 05.
Article in English | MEDLINE | ID: covidwho-1931217

ABSTRACT

Cough is one of the most common presenting symptoms of COVID-19, along with fever and loss of taste and smell. Cough can persist for weeks or months after SARS-CoV-2 infection, often accompanied by chronic fatigue, cognitive impairment, dyspnoea, or pain-a collection of long-term effects referred to as the post-COVID syndrome or long COVID. We hypothesise that the pathways of neurotropism, neuroinflammation, and neuroimmunomodulation through the vagal sensory nerves, which are implicated in SARS-CoV-2 infection, lead to a cough hypersensitivity state. The post-COVID syndrome might also result from neuroinflammatory events in the brain. We highlight gaps in understanding of the mechanisms of acute and chronic COVID-19-associated cough and post-COVID syndrome, consider potential ways to reduce the effect of COVID-19 by controlling cough, and suggest future directions for research and clinical practice. Although neuromodulators such as gabapentin or opioids might be considered for acute and chronic COVID-19 cough, we discuss the possible mechanisms of COVID-19-associated cough and the promise of new anti-inflammatories or neuromodulators that might successfully target both the cough of COVID-19 and the post-COVID syndrome.


Subject(s)
COVID-19/complications , COVID-19/physiopathology , Cough/etiology , Inflammation/etiology , Nervous System Diseases/etiology , Neuroimmunomodulation , Cough/physiopathology , Humans , Inflammation/physiopathology , Nervous System Diseases/physiopathology , SARS-CoV-2 , Syndrome
3.
Int J Mol Sci ; 23(13)2022 Jun 22.
Article in English | MEDLINE | ID: covidwho-1911403

ABSTRACT

Myocarditis in response to COVID-19 vaccination has been reported since early 2021. In particular, young male individuals have been identified to exhibit an increased risk of myocardial inflammation following the administration of mRNA-based vaccines. Even though the first epidemiological analyses and numerous case reports investigated potential relationships, endomyocardial biopsy (EMB)-proven cases are limited. Here, we present a comprehensive histopathological analysis of EMBs from 15 patients with reduced ejection fraction (LVEF = 30 (14-39)%) and the clinical suspicion of myocarditis following vaccination with Comirnaty® (Pfizer-BioNTech) (n = 11), Vaxzevria® (AstraZenica) (n = 2) and Janssen® (Johnson & Johnson) (n = 2). Immunohistochemical EMB analyses reveal myocardial inflammation in 14 of 15 patients, with the histopathological diagnosis of active myocarditis according the Dallas criteria (n = 2), severe giant cell myocarditis (n = 2) and inflammatory cardiomyopathy (n = 10). Importantly, infectious causes have been excluded in all patients. The SARS-CoV-2 spike protein has been detected sparsely on cardiomyocytes of nine patients, and differential analysis of inflammatory markers such as CD4+ and CD8+ T cells suggests that the inflammatory response triggered by the vaccine may be of autoimmunological origin. Although a definitive causal relationship between COVID-19 vaccination and the occurrence of myocardial inflammation cannot be demonstrated in this study, data suggest a temporal connection. The expression of SARS-CoV-2 spike protein within the heart and the dominance of CD4+ lymphocytic infiltrates indicate an autoimmunological response to the vaccination.


Subject(s)
COVID-19 , Myocarditis , Biopsy , CD8-Positive T-Lymphocytes , COVID-19 Vaccines/adverse effects , Humans , Inflammation/etiology , Male , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Vaccination/adverse effects
4.
Int J Environ Res Public Health ; 19(11)2022 06 05.
Article in English | MEDLINE | ID: covidwho-1892887

ABSTRACT

Childhood obesity is a leading public health problem worldwide, as it is increasingly prevalent and therefore responsible for serious obesity-related comorbidities, not only in childhood but also in adulthood. In addition to cardio-metabolic obesity-related disorders, recent evidence suggests that excess adipose tissue in turn is associated with immune cell infiltration, increased adipokine release, and the development of low-grade systemic inflammation obesity. Exercise is considered a non-pharmacological intervention that can delay obesity-related comorbidities, improving cardiovascular fitness and modulating the inflammatory processes. It has been reported that the anti-inflammatory effect of regular exercise may be mediated by a reduction in visceral fat mass, with a subsequent decrease in the release of adipokines from adipose tissue (AT) and/or by the induction of an anti-inflammatory environment. In this narrative review, we discuss the role of AT as an endocrine organ associated with chronic inflammation and its role in obesity-related complications, focusing on the effect of exercise in reducing inflammation in children and adolescents with obesity. Regular physical exercise must be considered as a natural part of a healthy lifestyle, and promoting physical activity starting from childhood is useful to limit the negative effects of obesity on health. The crucial role of the immune system in the development of obesity-induced inflammatory processes and the efficacy of exercise as an anti-inflammatory, non-pharmacological intervention may provide possible targets for the development of new treatments and early preventive strategies.


Subject(s)
Pediatric Obesity , Adipokines , Adipose Tissue , Adolescent , Child , Exercise , Humans , Inflammation/etiology , Pediatric Obesity/complications , Pediatric Obesity/prevention & control
5.
J Cosmet Dermatol ; 21(8): 3181-3187, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1868673

ABSTRACT

BACKGROUND: Adverse events (AE) after COVID-19 vaccines, particularly, but not solely, with those messenger RNA (mRNA)-based vaccines, have rarely been reported in patients previously treated with dermal fillers (DF). OBJECTIVE: To evaluate the morphology, clinical characteristics, the timing of presentation, and outcomes of inflammatory AE appeared in patients injected with DF, after anti-COVID-19 vaccination. METHODS: Descriptive study of a case series of 20 consecutive patients collected after the occurrence of AE in previously filled areas post COVID-19 vaccination. RESULTS: From January 2021 to July 2021, we analyzed 20 AE reactions triggered by COVID-19 vaccines in the previously mentioned cohort. They were vaccinated with Pfizer/Biontech (11; 55%), Moderna (5; 25%), Astra-Zeneca (3; 15%), and Sputnik (1; 5%). The most common manifestations were oedema/swelling, angioedema, erythema, skin induration, and granuloma. Less common reactions included myalgia and lymphadenopathy. In 13/20 (65%) cases, the AE appeared after the first dose of vaccine. These inflammatory AE appeared more rapidly after the second dose than after the first one. In 13/20 (65%) cases, the symptomatology subsided with anti-inflammatory/antihistaminic drugs, while spontaneously in 3/20 (15%). The manifestations are ongoing.in the remaining four cases (20%). CONCLUSION: Although probably rare, both RNA-based and adenovirus-based anti-COVID-19 vaccines can cause inflammatory bouts in patients previously treated with DF. In these cases, caution should be paid on subsequent vaccine doses, considering a tailored risk/benefit for any case before next vaccination.


Subject(s)
COVID-19 Vaccines , COVID-19 , Dermal Fillers , Inflammation , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Dermal Fillers/adverse effects , Humans , Inflammation/etiology , Injections/adverse effects , Vaccines
6.
Am J Ophthalmol ; 238: 66-74, 2022 06.
Article in English | MEDLINE | ID: covidwho-1859251

ABSTRACT

PURPOSE: To compare the intraocular inflammation after 2 surgical approaches for late in-the-bag intraocular lens (IOL) dislocation. DESIGN: Prospective, randomized, parallel-group clinical trial. METHODS: We randomly assigned 100 patients (100 eyes) referred to Oslo University Hospital (tertiary referral center) with late in-the-bag IOL dislocation into IOL repositioning by scleral suturing (n=49) or IOL exchange with retropupillary fixation of an iris-claw lens (n=51). Patients were examined before surgery and 2 weeks, 6 weeks, and 6 months after surgery. The main outcome measure was anterior chamber laser flare, measured with a laser flare meter as photon counts per millisecond (pc/ms). RESULTS: Two weeks following surgery, median flare values were 28.9 pc/ms (range, 7.9-140) in the repositioning group and 31.6 pc/ms (range, 9.8-92.3) in the exchange group (P = .83). Flare levels were still elevated after 6 weeks with no difference between the groups (P = .93), whereas it decreased to baseline levels after 6 months. Six weeks following surgery, the central retinal thickness was similar (P = .97); cystoid macular edema (CME) was found in 4 and 5 patients, respectively (P = .85); and the mean best corrected visual acuity was 0.17 (95% CI 0.09, 0.25) and 0.21 (95% CI 0.09, 0.32) logarithm of the minimum angle of resolution, respectively (P = .61). CONCLUSIONS: This study revealed similar levels of intraocular inflammation following IOL repositioning and IOL exchange. There was no significant difference regarding risk of CME and visual outcome. The prolonged elevation in postoperative flare indicates a possible requirement for an extended anti-inflammatory treatment period after these operations.


Subject(s)
Lens Subluxation , Lenses, Intraocular , Humans , Inflammation/etiology , Lens Subluxation/surgery , Postoperative Complications , Prospective Studies , Retrospective Studies , Visual Acuity
7.
Zool Res ; 43(3): 457-468, 2022 May 18.
Article in English | MEDLINE | ID: covidwho-1836354

ABSTRACT

COVID-19 is an immune-mediated inflammatory disease caused by SARS-CoV-2 infection, the combination of anti-inflammatory and antiviral therapy is predicted to provide clinical benefits. We recently demonstrated that mast cells (MCs) are an essential mediator of SARS-CoV-2-initiated hyperinflammation. We also showed that spike protein-induced MC degranulation initiates alveolar epithelial inflammation for barrier disruption and suggested an off-label use of antihistamines as MC stabilizers to block degranulation and consequently suppress inflammation and prevent lung injury. In this study, we emphasized the essential role of MCs in SARS-CoV-2-induced lung lesions in vivo, and demonstrated the benefits of co-administration of antihistamines and antiviral drug remdesivir in SARS-CoV-2-infected mice. Specifically, SARS-CoV-2 spike protein-induced MC degranulation resulted in alveolar-capillary injury, while pretreatment of pulmonary microvascular endothelial cells with antihistamines prevented adhesion junction disruption; predictably, the combination of antiviral drug remdesivir with the antihistamine loratadine, a histamine receptor 1 (HR1) antagonist, dampened viral replication and inflammation, thereby greatly reducing lung injury. Our findings emphasize the crucial role of MCs in SARS-CoV-2-induced inflammation and lung injury and provide a feasible combination antiviral and anti-inflammatory therapy for COVID-19 treatment.


Subject(s)
COVID-19 , Lung Injury , Rodent Diseases , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/veterinary , Endothelial Cells , Histamine Antagonists/therapeutic use , Inflammation/drug therapy , Inflammation/etiology , Inflammation/veterinary , Lung Injury/drug therapy , Lung Injury/veterinary , Mice , Rodent Diseases/drug therapy , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
10.
Int J Environ Res Public Health ; 17(12)2020 06 22.
Article in English | MEDLINE | ID: covidwho-1725662

ABSTRACT

Sars-cov-2 virus (Covid-19) is a member of the coronavirus family and is responsible for the pandemic recently declared by the World Health Organization. A positive correlation has been observed between the spread of the virus and air pollution, one of the greatest challenges of our millennium. Covid-19 could have an air transmission and atmospheric particulate matter (PM) could create a suitable environment for transporting the virus at greater distances than those considered for close contact. Moreover, PM induces inflammation in lung cells and exposure to PM could increase the susceptibility and severity of the Covid-19 patient symptoms. The new coronavirus has been shown to trigger an inflammatory storm that would be sustained in the case of pre-exposure to polluting agents. In this review, we highlight the potential role of PM in the spread of Covid-19, focusing on Italian cities whose PM daily concentrations were found to be higher than the annual average allowed during the months preceding the epidemic. Furthermore, we analyze the positive correlation between the virus spread, PM, and angiotensin-converting enzyme 2 (ACE2), a receptor involved in the entry of the virus into pulmonary cells and inflammation.


Subject(s)
Air Pollution/adverse effects , Betacoronavirus , Coronavirus Infections/transmission , Particulate Matter , Pneumonia, Viral/transmission , Aerosols , Angiotensin-Converting Enzyme 2 , COVID-19 , Cities , Coronavirus Infections/mortality , Coronavirus Infections/virology , Humans , Inflammation/etiology , Italy/epidemiology , Morbidity , Oxidative Stress , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , SARS-CoV-2
11.
Purinergic Signal ; 18(1): 13-59, 2022 03.
Article in English | MEDLINE | ID: covidwho-1694363

ABSTRACT

Hyperinflammation 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.


Subject(s)
Adenosine Triphosphate/metabolism , COVID-19/immunology , Cytokine Release Syndrome/etiology , Inflammation/etiology , Lidocaine/therapeutic use , Purinergic P2X Receptor Antagonists/therapeutic use , Receptors, Purinergic/physiology , Anti-Inflammatory Agents/therapeutic use , Critical Care , Cytokine Release Syndrome/drug therapy , Humans , Inflammation/drug therapy , Infusions, Subcutaneous , Lidocaine/administration & dosage , Lidocaine/pharmacology , Lymph Nodes/immunology , Lymphatic System/immunology , Male , Maximum Tolerated Dose , Middle Aged , Models, Immunological , Purinergic P2X Receptor Antagonists/administration & dosage , Purinergic P2X Receptor Antagonists/pharmacology , Receptors, Purinergic/drug effects , Receptors, Purinergic P1/drug effects , Receptors, Purinergic P1/physiology , Receptors, Purinergic P2X7/physiology , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/etiology , Signal Transduction , T-Lymphocytes, Regulatory/immunology
12.
J Cosmet Dermatol ; 21(4): 1361-1368, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1685366

ABSTRACT

INTRODUCTION: Soft tissue fillers are used for cosmetic and reconstructive purposes, and soft tissue filler procedures are among the most common nonsurgical procedures in the USA. Although soft tissue filler procedures are relatively quick and safe, adverse events such as late inflammatory reactions have been reported with every filler product. Infections and vaccinations have been proposed as potential triggers for late inflammatory reactions (LIRs), and it is therefore not surprising that these adverse events have been reported after SARS-CoV-2 infection and vaccination. Therefore, this review aims to give a detailed overview of these cases. MATERIALS AND METHODS: A literature search was undertaken on LIRs in patients with a history of soft tissue filler use after SARS-CoV-2 infection or vaccination. This systematic review was reported according to the PRISMA guidelines. We searched the electronic database PubMed from January 2020 to August 2021. Data on patient characteristics, filler characteristics, clinical findings, and treatment options were included. RESULTS: This review included 7 articles with a total of 19 patients with LIRs after SARS-CoV-2 infection or vaccination. Three patients with postinfection LIRs and 16 patients with postvaccination LIRs were reported. These LIRS mainly occurred in females who had HA injections for cosmetic purposes. Three patients with postinfection LIRs had symptoms of facial swelling and/or lip angioedema in a matter of weeks. Sixteen patients reported reactions after SARS-CoV-2 vaccination (13 following Moderna vaccination and 3 after Pfizer vaccination, after both the first and second doses) from 13 hours up to three weeks. These patients presented with similar clinical symptoms as patients with postinfection LIRs. All patients were treated in a conservative manner. DISCUSSION: This review shows a relationship between LIRs and SARS-CoV-2 infection and vaccination. In the case of vaccination, these adverse events have been reported only after Moderna and Pfizer vaccinations. The reported adverse events are generally minor and self-limiting, and we encourage patients with soft tissue fillers to participate in vaccination programs.


Subject(s)
COVID-19 , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Female , Humans , Inflammation/etiology , SARS-CoV-2 , Vaccination/adverse effects
13.
Pharmacol Res Perspect ; 10(1): e00917, 2022 02.
Article in English | MEDLINE | ID: covidwho-1664438

ABSTRACT

SARS-CoV-2 interacting with its receptor, angiotensin-converting enzyme 2 (ACE2), turns the host response to viral infection into a dysregulated uncontrolled inflammatory response. This is because ACE2 limits the production of the peptide angiotensin II (Ang II) and SARS-CoV-2, through the destruction of ACE2, allows the uncontrolled production of Ang II. Recovery from trauma requires activation of both a tissue response to injury and activation of a whole-body response to maintain tissue perfusion. Tissue and circulating renin-angiotensin systems (RASs) play an essential role in the host response to infection and injury because of the actions of Ang II, mediated via its AT1 receptor. Both tissue and circulating arms of the renin angiotensin aldosterone system's (RAAS) response to injury need to be regulated. The effects of Ang II and the steroid hormone, aldosterone, on fluid and electrolyte homeostasis and on the circulation are controlled by elaborate feedback networks that respond to alterations in the composition and volume of fluids within the circulatory system. The role of Ang II in the tissue response to injury is however, controlled mainly by its metabolism and conversion to Ang-(1-7) by the enzyme ACE2. Ang-(1-7) has effects that are contrary to Ang II-AT1 R mediated effects. Thus, destruction of ACE2 by SARS-CoV-2 results in loss of control of the pro-inflammatory actions of Ang II and tissue destruction. Therefore, it is the response of the host to SARS-CoV-2 that is responsible for the pathogenesis of COVID-19.


Subject(s)
COVID-19/etiology , Renin-Angiotensin System/physiology , SARS-CoV-2/physiology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2/physiology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19/drug therapy , Drug Repositioning , Humans , Inflammation/etiology , Renin/antagonists & inhibitors
14.
Viruses ; 14(2)2022 01 24.
Article in English | MEDLINE | ID: covidwho-1648620

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as COVID-19, is currently developing into a rapidly disseminating and an overwhelming worldwide pandemic. In severe COVID-19 cases, hypercoagulability and inflammation are two crucial complications responsible for poor prognosis and mortality. In addition, coagulation system activation and inflammation overlap and produce life-threatening complications, including coagulopathy and cytokine storm, which are associated with overproduction of cytokines and activation of the immune system; they might be a lead cause of organ damage. However, patients with severe COVID-19 who received anticoagulant therapy had lower mortality, especially with elevated D-dimer or fibrin degradation products (FDP). In this regard, the discovery of natural products with anticoagulant potential may help mitigate the numerous side effects of the available synthetic drugs. This review sheds light on blood coagulation and its impact on the complication associated with COVID-19. Furthermore, the sources of natural anticoagulants, the role of nanoparticle formulation in this outbreak, and the prevalence of thrombosis with thrombocytopenia syndrome (TTS) after COVID-19 vaccines are also reviewed. These combined data provide many research ideas related to the possibility of using these anticoagulant agents as a treatment to relieve acute symptoms of COVID-19 infection.


Subject(s)
Anticoagulants/therapeutic use , Blood Coagulation Disorders/etiology , COVID-19 Vaccines/chemistry , COVID-19/complications , COVID-19/prevention & control , Nanoparticles/therapeutic use , Anticoagulants/administration & dosage , Anticoagulants/isolation & purification , Blood Coagulation , Blood Coagulation Disorders/classification , Blood Coagulation Disorders/prevention & control , Blood Coagulation Disorders/virology , COVID-19 Vaccines/administration & dosage , Cytokine Release Syndrome/prevention & control , Cytokine Release Syndrome/virology , Humans , Inflammation/etiology , Inflammation/prevention & control , Nanoparticles/chemistry , SARS-CoV-2/pathogenicity , Thrombophilia/etiology
15.
Molecules ; 27(3)2022 Jan 20.
Article in English | MEDLINE | ID: covidwho-1648332

ABSTRACT

In spite of advances in vaccination, control of the COVID-19 pandemic will require the use of pharmacological treatments against SARS-CoV2. Their development needs to consider the existence of two phases in the disease, namely the viral infection and the inflammatory stages. The main targets for antiviral therapeutic intervention are: (a) viral proteins, including the spike (S) protein characteristic of the viral cover and the viral proteases in charge of processing the polyprotein arising from viral genome translation; (b) host proteins, such as those involved in the processes related to viral entry into the host cell and the release of the viral genome inside the cell, the elongation factor eEF1A and importins. The use of antivirals targeted at host proteins is less developed but it has the potential advantage of not being affected by mutations in the genome of the virus and therefore being active against all its variants. Regarding drugs that address the hyperinflammatory phase of the disease triggered by the so-called cytokine storm, the following strategies are particularly relevant: (a) drugs targeting JAK kinases; (b) sphingosine kinase 2 inhibitors; (c) antibodies against interleukin 6 or its receptor; (d) use of the traditional anti-inflammatory corticosteroids.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/pathology , Chemistry, Pharmaceutical , Humans , Inflammation/drug therapy , Inflammation/etiology , SARS-CoV-2/drug effects , SARS-CoV-2/ultrastructure
16.
Int J Mol Sci ; 23(2)2022 Jan 14.
Article in English | MEDLINE | ID: covidwho-1633064

ABSTRACT

Peripheral blood mononuclear cells (PBMCs) belong to the innate and adaptive immune system and are highly sensitive and responsive to changes in their systemic environment. In this study, we focused on the time course of transcriptional changes in freshly isolated human PBMCs 4, 8, 24 and 48 h after onset of stimulation with the active vitamin D metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). Taking all four time points together, 662 target genes were identified and segregated either by time of differential gene expression into 179 primary and 483 secondary targets or by driver of expression change into 293 direct and 369 indirect targets. The latter classification revealed that more than 50% of target genes were primarily driven by the cells' response to ex vivo exposure than by the nuclear hormone and largely explained its down-regulatory effect. Functional analysis indicated vitamin D's role in the suppression of the inflammatory and adaptive immune response by down-regulating ten major histocompatibility complex class II genes, five alarmins of the S100 calcium binding protein A family and by affecting six chemokines of the C-X-C motif ligand family. Taken together, studying time-resolved responses allows to better contextualize the effects of vitamin D on the immune system.


Subject(s)
Adaptive Immunity/genetics , Gene Expression Profiling , Gene Expression Regulation , Inflammation Mediators/metabolism , Transcriptome , Vitamin D/metabolism , Computational Biology/methods , Gene Expression Profiling/methods , Gene Expression Regulation/drug effects , Humans , Inflammation/etiology , Inflammation/metabolism , Inflammation/pathology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Molecular Sequence Annotation , Vitamin D/analogs & derivatives , Vitamin D/pharmacology
17.
Cell Mol Biol Lett ; 27(1): 6, 2022 Jan 11.
Article in English | MEDLINE | ID: covidwho-1622208

ABSTRACT

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is associated with a high mortality rate. The majority of deaths in this disease are caused by ARDS (acute respiratory distress syndrome) followed by cytokine storm and coagulation complications. Although alterations in the level of the number of coagulation factors have been detected in samples from COVID-19 patients, the direct molecular mechanism which has been involved in this pathologic process has not been explored yet. The PI3K/AKT signaling pathway is an intracellular pathway which plays a central role in cell survival. Also, in recent years the association between this pathway and coagulopathies has been well clarified. Therefore, based on the evidence on over-activity of the PI3K/AKT signaling pathway in SARS-CoV-2 infection, in the current review, the probable role of this cellular pathway as a therapeutic target for the prevention of coagulation complications in patients with COVID-19 is discussed.


Subject(s)
Blood Coagulation Disorders/etiology , Blood Coagulation , COVID-19/complications , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Animals , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/metabolism , COVID-19/blood , COVID-19/metabolism , Humans , Inflammation/blood , Inflammation/etiology , Inflammation/metabolism , Molecular Targeted Therapy , SARS-CoV-2/physiology
18.
Inflamm Res ; 71(2): 183-185, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1611373

ABSTRACT

Growth Hormone-Releasing Hormone (GHRH) is a neuropeptide regulating the release of Growth Hormone (GH) from the anterior pituitary gland, and acts as a growth factor in a diverse variety of tissues. GHRH antagonists (GHRHAnt) have been developed to counteract those events, and the beneficial effects of those peptides toward homeostasis have been associated with anti-inflammatory activities. Our lab is interested in delineating the mechanisms governing endothelial barrier function. Our goal is to establish new grounds on the development of efficient countermeasures against Acute Respiratory Distress Syndrome (ARDS), which has been associated with thousands of deaths worldwide due to COVID-19. Herein we demonstrate in vivo that GHRHAnt suppresses LPS-induced increase in bronchoalveolar lavage fluid (BALF) protein concentration, thus protecting the lungs against edema and inflammation.


Subject(s)
Bronchoalveolar Lavage Fluid/chemistry , Gonadotropin-Releasing Hormone/antagonists & inhibitors , Lipopolysaccharides , Animals , COVID-19/complications , Growth Hormone-Releasing Hormone , Inflammation/etiology , Inflammation/prevention & control , Male , Mice , Mice, Inbred C57BL , Proteins/chemistry , Pulmonary Edema/etiology , Pulmonary Edema/prevention & control , Reactive Oxygen Species , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/etiology , SARS-CoV-2
19.
JAMA Netw Open ; 4(12): e2141328, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1592856

ABSTRACT

Importance: Hospitalized patients with COVID-19 pneumonia have high rates of morbidity and mortality. Objective: To assess the efficacy of colchicine in hospitalized patients with COVID-19 pneumonia. Design, Setting, and Participants: The Estudios Clínicos Latino América (ECLA) Population Health Research Institute (PHRI) COLCOVID trial was a multicenter, open-label, randomized clinical trial performed from April 17, 2020, to March 28, 2021, in adults with confirmed or suspected SARS-CoV-2 infection followed for up to 28 days. Participants received colchicine vs usual care if they were hospitalized with COVID-19 symptoms and had severe acute respiratory syndrome or oxygen desaturation. The main exclusion criteria were clear indications or contraindications for colchicine, chronic kidney disease, and negative results on a reverse transcription-polymerase chain reaction test for SARS-CoV-2 before randomization. Data were analyzed from June 20 to July 25, 2021. Interventions: Patients were assigned in a 1:1 ratio to usual care or usual care plus colchicine. Colchicine was administered orally in a loading dose of 1.5 mg immediately after randomization, followed by 0.5 mg orally within 2 hours of the initial dose and 0.5 mg orally twice a day for 14 days or discharge, whichever occurred first. Main Outcomes and Measures: The first coprimary outcome was the composite of a new requirement for mechanical ventilation or death evaluated at 28 days. The second coprimary outcome was death at 28 days. Results: A total of 1279 hospitalized patients (mean [SD] age, 61.8 [14.6] years; 449 [35.1%] women and 830 [64.9%] men) were randomized, including 639 patients in the usual care group and 640 patients in the colchicine group. Corticosteroids were used in 1171 patients (91.5%). The coprimary outcome of mechanical ventilation or 28-day death occurred in 160 patients (25.0%) in the colchicine group and 184 patients (28.8%) in the usual care group (hazard ratio [HR], 0.83; 95% CI, 0.67-1.02; P = .08). The second coprimary outcome, 28-day death, occurred in 131 patients (20.5%) in the colchicine group and 142 patients (22.2%) in the usual care group (HR, 0.88; 95% CI, 0.70-1.12). Diarrhea was the most frequent adverse effect of colchicine, reported in 68 patients (11.3%). Conclusions and Relevance: This randomized clinical trial found that compared with usual care, colchicine did not significantly reduce mechanical ventilation or 28-day mortality in patients hospitalized with COVID-19 pneumonia. Trial Registration: ClinicalTrials.gov Identifier: NCT04328480.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/therapy , Colchicine/therapeutic use , Hospitalization , Intubation, Intratracheal , Respiration, Artificial , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Anti-Inflammatory Agents/adverse effects , COVID-19/mortality , COVID-19/pathology , Colchicine/adverse effects , Female , Humans , Inflammation/drug therapy , Inflammation/etiology , Male , Middle Aged , SARS-CoV-2 , Standard of Care
20.
Int J Mol Sci ; 22(23)2021 Nov 24.
Article in English | MEDLINE | ID: covidwho-1560167

ABSTRACT

Streptococcus pneumoniae is an important causative organism of respiratory tract infections. Although periodontal bacteria have been shown to influence respiratory infections such as aspiration pneumonia, the synergistic effect of S. pneumoniae and Porphyromonas gingivalis, a periodontopathic bacterium, on pneumococcal infections is unclear. To investigate whether P. gingivalis accelerates pneumococcal infections, we tested the effects of inoculating P. gingivalis culture supernatant (PgSup) into S. pneumoniae-infected mice. Mice were intratracheally injected with S. pneumoniae and PgSup to induce pneumonia, and lung histopathological sections and the absolute number and frequency of neutrophils and macrophages in the lung were analyzed. Proinflammatory cytokine/chemokine expression was examined by qPCR and ELISA. Inflammatory cell infiltration was observed in S. pneumoniae-infected mice and S. pnemoniae and PgSup mixed-infected mice, and mixed-infected mice showed more pronounced inflammation in lung. The ratios of monocytes/macrophages and neutrophils were not significantly different between the lungs of S. pneumoniae-infected mice and those of mixed-infected mice. PgSup synergistically increased TNF-α expression/production and IL-17 production compared with S. pneumoniae infection alone. We demonstrated that PgSup enhanced inflammation in pneumonia caused by S. pneumoniae, suggesting that virulence factors produced by P. gingivalis are involved in the exacerbation of respiratory tract infections such as aspiration pneumonia.


Subject(s)
Bacteroidaceae Infections/complications , Inflammation/pathology , Lung/pathology , Neutrophil Infiltration/immunology , Pneumonia, Pneumococcal/pathology , Porphyromonas gingivalis/physiology , Streptococcus pneumoniae/physiology , Animals , Bacteroidaceae Infections/microbiology , Chemokines/metabolism , Cytokines/metabolism , Inflammation/etiology , Lung/immunology , Lung/metabolism , Lung/microbiology , Mice , Mice, Inbred C57BL , Pneumonia, Pneumococcal/epidemiology , Pneumonia, Pneumococcal/metabolism , Pneumonia, Pneumococcal/microbiology
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