Targeting JAK-STAT Pathway for Various Inflammatory Diseases and Viral Infections

2020 ◽  
pp. 257-268
Author(s):  
Christina Gavegnano ◽  
Raymond F. Schinazi
Keyword(s):  
Viral Infections ◽  
Inflammatory Diseases ◽  
Stat Pathway

scholarly journals Antimalarial drugs—are they beneficial in rheumatic and viral diseases?—considerations in COVID-19 pandemic

2021 ◽  
Author(s):  
Bogna Grygiel-Górniak
Keyword(s):  
Connective Tissue ◽  
Viral Infections ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Antiviral Drugs ◽  
In Vivo Studies ◽  
Viral Diseases ◽  
Cardiac Complications

AbstractThe majority of the medical fraternity is continuously involved in finding new therapeutic schemes, including antimalarial medications (AMDs), which can be useful in combating the 2019-nCoV: coronavirus disease (COVID-19). For many decades, AMDs have been widely used in the treatment of malaria and various other anti-inflammatory diseases, particularly to treat autoimmune disorders of the connective tissue. The review comprises in vitro and in vivo studies, original studies, clinical trials, and consensus reports for the analysis, which were available in medical databases (e.g., PubMed). This manuscript summarizes the current knowledge about chloroquine (CQ)/hydroxychloroquine (HCQ) and shows the difference between their use, activity, recommendation, doses, and adverse effects on two groups of patients: those with rheumatic and viral diseases (including COVID-19). In the case of connective tissue disorders, AMDs are prescribed for a prolonged duration in small doses, and their effect is observed after few weeks, whereas in the case of viral infections, they are prescribed in larger doses for a short duration to achieve a quick saturation effect. In rheumatic diseases, AMDs are well tolerated, and their side effects are rare. However, in some viral diseases, the effect of AMDs is questionable or not so noticeable as suggested during the initial prognosis. They are mainly used as an additive therapy to antiviral drugs, but recent studies have shown that AMDs can diminish the efficacy of some antiviral drugs and may cause respiratory, kidney, liver, and cardiac complications.

scholarly journals Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Anna C. Aschenbrenner ◽  
◽  
Maria Mouktaroudi ◽  
Benjamin Krämer ◽  
Marie Oestreich ◽  
...  
Keyword(s):  
Immune System ◽  
Disease Severity ◽  
Whole Blood ◽  
Viral Infections ◽  
Inflammatory Diseases ◽  
Target Prediction ◽  
Data Driven ◽  
Host Responses ◽  
Drug Candidates ◽  
Drug Target Prediction

Abstract Background The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases call for a better characterization and understanding of the changes in the immune system. Methods In order to dissect COVID-19-driven immune host responses, we performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis. Additionally, publicly available data was used to show the distinction from COVID-19 to other diseases. Reverse drug target prediction was used to identify known or novel drug candidates based on finding from data-driven findings. Results Here, we profiled whole blood transcriptomes of 39 COVID-19 patients and 10 control donors enabling a data-driven stratification based on molecular phenotype. Neutrophil activation-associated signatures were prominently enriched in severe patient groups, which was corroborated in whole blood transcriptomes from an independent second cohort of 30 as well as in granulocyte samples from a third cohort of 16 COVID-19 patients (44 samples). Comparison of COVID-19 blood transcriptomes with those of a collection of over 3100 samples derived from 12 different viral infections, inflammatory diseases, and independent control samples revealed highly specific transcriptome signatures for COVID-19. Further, stratified transcriptomes predicted patient subgroup-specific drug candidates targeting the dysregulated systemic immune response of the host. Conclusions Our study provides novel insights in the distinct molecular subgroups or phenotypes that are not simply explained by clinical parameters. We show that whole blood transcriptomes are extremely informative for COVID-19 since they capture granulocytes which are major drivers of disease severity.

Inflammatory and Obstructive Disorders of Salivary Glands

1987 ◽  
Vol 66 (1_suppl) ◽  
pp. 675-679 ◽  
Author(s):  
A. Blitzer
Keyword(s):  
Salivary Glands ◽  
Fine Needle Aspiration ◽  
Chronic Conditions ◽  
Viral Infections ◽  
Inflammatory Diseases ◽  
Needle Aspiration ◽  
Ct Scans ◽  
Fine Needle ◽  
Inflammatory Conditions ◽  
Chronic Sialadenitis

Obstructive and inflammatory diseases of the salivary glands can have a congenital, traumatic, metabolic, or infectious-inflammatory cause. The acute inflammatory conditions include bacterial and viral infections, and the chronic conditions include sialoliths, strictures, chronic sialadenitis, sialectasis, and lymphoepithelial disease. The neoplastic diseases can cause obstruction and/or infection and often make the diagnosis elusive. In addition to a working knowledge of possible etiology, one needs experience with clinical examination, salivary analysis, sialography, CT scans, MRI, and fine-needle aspiration and cytology in order successfully to evaluate and manage patients with these conditions.

Inflammatory and Obstructive Disorders of Salivary Glands

1987 ◽  
Vol 66 (2_suppl) ◽  
pp. 675-679 ◽  
Author(s):  
A. Blitzer
Keyword(s):  
Salivary Glands ◽  
Fine Needle Aspiration ◽  
Chronic Conditions ◽  
Viral Infections ◽  
Inflammatory Diseases ◽  
Needle Aspiration ◽  
Ct Scans ◽  
Fine Needle ◽  
Inflammatory Conditions ◽  
Chronic Sialadenitis

Obstructive and inflammatory diseases of the salivary glands can have a congenital, traumatic, metabolic, or infectious-inflammatory cause. The acute inflammatory conditions include bacterial and viral infections, and the chronic conditions include sialoliths, strictures, chronic sialadenitis, sialectasis, and lymphoepithelial disease. The neoplastic diseases can cause obstruction and/or infection and often make the diagnosis elusive. In addition to a working knowledge of possible etiology, one needs experience with clinical examination, salivary analysis, sialography, CT scans, MRI, and fine-needle aspiration and cytology in order successfully to evaluate and manage patients with these conditions.

scholarly journals C5a and C5aR1 are key drivers of microvascular platelet aggregation in clinical entities spanning from aHUS to COVID-19

2021 ◽  
Author(s):  
Sistiana Aiello ◽  
Sara Gastoldi ◽  
Miriam Galbusera ◽  
Piero Luigi Ruggenenti ◽  
Valentina Portalupi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Ex Vivo ◽  
Inflammatory Diseases ◽  
Thrombus Formation ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Uremic Syndrome

Unrestrained activation of the complement system till the terminal products, C5a and C5b-9, plays a pathogenetic role in acute and chronic inflammatory diseases. In endothelial cells, complement hyperactivation may translate into cell dysfunction, favoring thrombus formation. The aim of this study was to investigate the role of the C5a/C5aR1 axis as opposite to C5b-9 in inducing endothelial dysfunction and loss of anti-thrombogenic properties. In vitro and ex vivo assays with serum from patients with atypical hemolytic uremic syndrome (aHUS) -a prototype rare disease of complement-mediated microvascular thrombosis due to genetically determined alternative pathway dysregulation- and cultured microvascular endothelial cells, demonstrated that the C5a/C5aR1 axis is a key player of endothelial thromboresistance loss. C5a added to normal human serum, fully recapitulated the pro-thrombotic effects of aHUS serum. Mechanistic studies showed that C5a caused RalA-mediated exocytosis of vWF and P-selectin from Weibel-Palade bodies, which favored further vWF binding on the endothelium and platelet adhesion and aggregation. In patients with severe COVID-19 -who suffered from acute activation of complement triggered by SARS-CoV-2 infection- we found the same C5a-dependent pathogenic mechanisms. These results highlight C5a/C5aR1 as a common pro-thrombogenic effector spanning from genetic rare diseases to viral infections, and may have clinical implications. Selective C5a/C5aR1 blockade could have advantages over C5 inhibition, since the former preserves the formation of C5b-9 that is critical to control bacterial infections that often develop as comorbidities in severely ill patients. (Clinicaltrials.gov identifier NCT02464891)

scholarly journals New prospects for local etiotropic treatment of acute respiratory viral infections

2019 ◽  
pp. 105-108
Author(s):  
A. A. Krivopalov ◽  
V. A. Shatalov ◽  
S. V. Shervashidze
Keyword(s):  
Respiratory Tract ◽  
Respiratory System ◽  
Safety Profile ◽  
Viral Infections ◽  
Inflammatory Diseases ◽  
Upper Respiratory Tract ◽  
Positive Experience ◽  
High Efficacy ◽  
Upper Respiratory ◽  
Respiratory Viral Infections

According to WHO, the respiratory system diseases are currently inside the ten most common pathologies. The modern strategy for treating influenza and ARVI gives priority to the antiviral and immunostimulating agents, but the symptomatic drugs, which include preparations based on silver and its compounds, also play an important role. The large positive experience in using silver preparations supported by numerous clinical studies shows their high efficacy and satisfactory safety profile in the treatment of infectious and inflammatory diseases of the nose and upper respiratory tract in children and adults.

scholarly journals Cutaneous Manifestations of Zika in Peru

2019 ◽  
Vol 24 (1) ◽  
pp. 33-40
Author(s):  
Willy Ramos ◽  
Miguel Luna ◽  
Tania Alarcón ◽  
Gerardo Jiménez ◽  
Jesús Díaz ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Lupus Erythematosus ◽  
Viral Infections ◽  
Inflammatory Diseases ◽  
Maculopapular Rash ◽  
Medical Advice ◽  
The Body ◽  
Cutaneous Manifestations ◽  
Primary Care Health ◽  
Care Health

This article aims to describe the cutaneous manifestations observed in the Zika epidemic in Peru during 2016 and 2017, as well as discuss the potential differential diagnoses. During the outbreak, the main reason for seeking medical advice was the development of a pruriginous maculopapular rash with a marked papular component, which started on the chest and later generalized to the rest of the body. Similar manifestations were noted in adults, children, and pregnant women. Other manifestations such as conjunctivitis, edema, or petechiae on the palate were rare. We suggest that in areas that are endemic for arboviral infections, in the differential diagnosis of a rash one must consider infections such as dengue, Zika, or chikungunya viruses. In nonendemic areas, the diagnosis is more difficult, as the rash may result from other viral infections not transmitted by arthropods and/or reactive or inflammatory diseases (urticaria, atopic dermatitis, systemic lupus erythematosus). We recommend that primary care health personnel are trained in the recognition of the mucocutaneous lesions caused by Zika virus infection, which could contribute to the identification of suspicious cases, particularly pregnant women.

Scutellaria baicalensis Ameliorates Acute Lung Injury by Suppressing Inflammation In Vitro and In Vivo

2017 ◽  
Vol 45 (01) ◽  
pp. 137-157 ◽  
Author(s):  
Jian-Jung Chen ◽  
Chung-Chun Huang ◽  
Heng-Yuan Chang ◽  
Pei-Ying Li ◽  
Yu-Chia Liang ◽  
...  
Keyword(s):  
Lung Injury ◽  
Viral Infections ◽  
Inflammatory Diseases ◽  
Water Extract ◽  
Scutellaria Baicalensis ◽  
Raw 264.7 Cells ◽  
Necrosis Factor Alpha ◽  
Anti Inflammatory

Scutellaria baicalensis has been widely used as both a dietary ingredient and traditional herbal medicine in Taiwan to treat inflammation, cancer, and bacterial and viral infections of the respiratory tract and gastrointestinal tract. This paper aims to investigate the in vitro and in vivo anti-inflammatory effects of S. baicalensis. In HPLC analysis, the fingerprint chromatogram of the water extract of S. baicalensis (WSB) was established. The anti-inflammatory effects of WSB were inverstigated using lipopolysaccharide (LPS)-stimulated mouse macrophage (RAW264.7) in vitro and LPS-induced lung injury in vivo. WSB attenuated the production of LPS-induced nitric oxide (NO), tumor necrosis factor-alpha (TNF-[Formula: see text], interleukin-[Formula: see text] (IL-1[Formula: see text], and IL-6 in vitro and in vivo. Pretreatment with WSB markedly reduced the LPS-induced histological alterations in lung tissues. Furthermore, WSB significantly reduced the number of total cells and the protein concentration levels in the BALF. WSB blocked protein expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), phosphorylation of I[Formula: see text]B-[Formula: see text] protein and MAPKs in LPS-stimulated RAW 264.7 cells and LPS-induce lung injury was also blocked. This study suggests that WSB possesses anti-inflammatory effects in vitro and in vivo, and the results suggested that WSB may be a potential therapeutic candidate for the treatment of inflammatory diseases.

scholarly journals How fragile we are. Influence of STimulator of INterferon Genes, STING, variants on pathogen recognition and immune response efficiency

2021 ◽  
Author(s):  
Jeremy Morere ◽  
Cecilia Hognon ◽  
Tom Miclot ◽  
Tao Jiang ◽  
Elise Dumont ◽  
...  
Keyword(s):  
Immune Response ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Inflammatory Diseases ◽  
Dynamical Behavior ◽  
Structural Features ◽  
Type I Interferons ◽  
Machine Learning Techniques ◽  
Type I ◽  
Interaction Patterns

The STimulator of INterferon Genes (STING) protein is a cornerstone of the human immune response. Its activation by cGAMP upon the presence of cytosolic DNA stimulates the production of type I interferons and inflammatory cytokines which are crucial for protecting cells from infections. STING signaling pathway can also influence both tumor-suppressive and tumor-promoting mechanisms, rendering it an appealing target for drug design. In the human population, several STING variants exist and exhibit dramatic differences in their activity, impacting the efficiency of the host defense against infections. Understanding the differential molecular mechanisms exhibited by these variants is of utmost importance notably towards personalized medicine treatments against diseases such as viral infections (COVID-19, Dengue...), cancers, or auto-inflammatory diseases. Owing to micro-seconds scale molecular modeling simulations and post-processing by contacts analysis and Machine Learning techniques, we reveal the dynamical behavior of four STING variants (wild type, G230A, R293Q, and G230A-R293Q) and we rationalize the variability of efficiency observed experimentally. Our results show that the decrease of STING activity is linked to a stiffening of key-structural features of the binding cavity, together with changes of the interaction patterns within the protein.

scholarly journals The Jak/Stat pathway mediates disease tolerance during systemic bacterial infection in Drosophila

2021 ◽  
Author(s):  
Arun Prakash ◽  
Mickael Bonnet ◽  
Katy M. Monteith ◽  
Pedro F. Vale
Keyword(s):  
Bacterial Infection ◽  
Tissue Damage ◽  
Viral Infections ◽  
Systemic Infection ◽  
Negative Regulator ◽  
Sexually Dimorphic ◽  
Disease Tolerance ◽  
Males And Females ◽  
Systemic Bacterial Infection ◽  
Stat Pathway

Disease tolerance describes a hosts ability to maintain health independently of the ability to clear microbe loads. However, we currently know little about the mechanisms that underlie disease tolerance or how known mechanisms of tissue damage signalling and repair may contribute to variation in tolerance. The Jak/Stat pathway plays a pivotal role in Drosophila humoral innate immunity, signalling tissue damage and triggering cellular renewal, making it a potential mechanism underlying the disease tolerance phenotype. Here, we show that disrupting the Jak/Stat pathway in Drosophila melanogaster alters disease tolerance during Pseudomonas entomophila systemic infection. Overall, flies with disrupted Jak/Stat show variation in survival that is not explained by variation in pathogen loads. For instance, mutations disrupting the function of ROS producing dual oxidase (duox) or the negative regulator of Jak/Stat, Socs36E render males less tolerant to systemic bacterial infection but not females. We also investigated whether the negative regulator of Jak/Stat, G9a which has previously been associated with tolerance of viral infections is also implicated in tolerance of bacterial infection. While female flies lacking G9a showed higher mortality and reduced bacterial clearance, disease tolerance did not differ between G9a mutants and the wildtype. This suggests that G9a does not affect tolerance during systemic bacterial infection as it appears to do with viral infection. Overall, our findings highlight that Jak/Stat signalling mediates disease tolerance during systemic bacterial infection and that this response differs between males and females. Our work therefore suggests that differences in Jak/Stat mediated disease tolerance may be a potential source of sexually dimorphic response to infection in Drosophila.

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