scholarly journals A European pharmacotherapeutic agent Roflumilast exploring integrated preclinical and clinical evidences for SARS CoV-2 mediated inflammation to organ damage

2021 ◽  
Author(s):  
yogendra Singh ◽  
Neeraj Fuloria ◽  
Shivkanya Fuloria ◽  
Vetriselvan Subramaniyan ◽  
Waleed Almalki ◽  
...  
Keyword(s):  
Immune Cell ◽  
Organ Damage ◽  
Pde4 Inhibitor ◽  
The European Union ◽  
Phosphodiesterase 4 ◽  
Organ Systems ◽  
Major Organ ◽  
Organ Tissue ◽  
Camp Levels ◽  
Inflammatory Burden

COVID-19 has spread globally, affecting almost 160 million individuals. Elderly and pre-existing patients (such as diabetes, heart disease and asthma), seems more susceptible to serious illness with COVID-19. Roflumilast was licensed for usage in the European Union in July 2010 as a phosphodiesterase-4 (PDE4) inhibitor. Roflumilast has been shown to decrease bleomycin-induced lung fibrosis, lung hydroxyproline, right heart thickning in animal prophylactic. The current study reviewed existing data that the PDE-4 inhibitor protects not just renal tissues but also other major organ systems after COVID-19 infection by decreasing immune cell infiltration. These immune-balancing effects of roflumilast were related with a decrease in oxidative and inflammatory burden, caspase-3 suppression, and increased PKA/cAMP levels in renal and other organ tissue.

scholarly journals Phosphodiesterase-4 Inhibition Reduces Cutaneous Inflammation and IL-1β Expression in a Psoriasiform Mouse Model but Does Not Inhibit Inflammasome Activation

2021 ◽  
Vol 22 (23) ◽  
pp. 12878
Author(s):  
Barbara Meier-Schiesser ◽  
Mark Mellett ◽  
Marigdalia K. Ramirez-Fort ◽  
Julia-Tatjana Maul ◽  
Annika Klug ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mice ◽  
Proinflammatory Cytokines ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Pde4 Inhibitor ◽  
Inflammasome Activation ◽  
Phosphodiesterase 4 ◽  
Oral Ulcers

Apremilast (Otezla®) is an oral small molecule phosphodiesterase 4 (PDE4) inhibitor approved for the treatment of psoriasis, psoriatic arthritis, and oral ulcers associated with Behçet’s disease. While PDE4 inhibition overall is mechanistically understood, the effect of apremilast on the innate immune response, particularly inflammasome activation, remains unknown. Here, we assessed the effect of apremilast in a psoriasis mouse model and primary human cells. Psoriatic lesion development in vivo was studied in K5.Stat3C transgenic mice treated with apremilast for 2 weeks, resulting in a moderate (2 mg/kg/day) to significant (6 mg/kg/day) resolution of inflamed plaques after 2-week treatment. Concomitantly, epidermal thickness dramatically decreased, the cutaneous immune cell infiltrate was reduced, and proinflammatory cytokines were significantly downregulated. Additionally, apremilast significantly inhibited lipopolysaccharide- or anti-CD3-induced expression of proinflammatory cytokines in peripheral mononuclear cells (PBMCs). Notably, inflammasome activation and secretion of IL-1β were not inhibited by apremilast in PBMCs and in human primary keratinocytes. Collectively, apremilast effectively alleviated the psoriatic phenotype of K5.Stat3 transgenic mice, further substantiating PDE4 inhibitor-efficiency in targeting key clinical, histopathological and inflammatory features of psoriasis. Despite lacking direct effect on inflammasome activation, reduced priming of inflammasome components upon apremilast treatment reflected the indirect benefit of PDE4 inhibition in reducing inflammation.

scholarly journals Human PDE4A8, a novel brain-expressed PDE4 cAMP-specific phosphodiesterase that has undergone rapid evolutionary change

2008 ◽  
Vol 411 (2) ◽  
pp. 361-369 ◽  
Author(s):  
Kirsty F. Mackenzie ◽  
Emma C. Topping ◽  
Bozena Bugaj-Gaweda ◽  
Chengjun Deng ◽  
York-Fong Cheung ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Immunohistochemical Analysis ◽  
Tissue Expression ◽  
Evolutionary Change ◽  
Terminal Region ◽  
Pde4 Inhibitor ◽  
Evolutionary Divergence ◽  
Phosphodiesterase 4 ◽  
Camp Levels ◽  
Rapid Evolutionary Change

We have isolated cDNAs encoding PDE4A8 (phosphodiesterase 4 isoform A8), a new human cAMP-specific PDE4 isoform encoded by the PDE4A gene. PDE4A8 has a novel N-terminal region of 85 amino acids that differs from those of the related ‘long’ PDE4A4, PDE4A10 and PDE4A11 isoforms. The human PDE4A8 N-terminal region has diverged substantially from the corresponding isoforms in the rat and other mammals, consistent with rapid evolutionary change in this region of the protein. When expressed in COS-7 cells, PDE4A8 localized predominantly in the cytosol, but approx. 20% of the enzyme was associated with membrane fractions. Cytosolic PDE4A8 was exquisitely sensitive to inhibition by the prototypical PDE4 inhibitor rolipram (IC50 of 11±1 nM compared with 1600 nM for PDE4A4), but was less sensitive to inhibition by cilomilast (IC50 of 101±7 nM compared with 61 nM for PDE4A4). PDE4A8 mRNA was found to be expressed predominantly in skeletal muscle and brain, a pattern that differs from the tissue expression of other human PDE4 isoforms and also from that of rat PDE4A8. Immunohistochemical analysis showed that PDE4A8 could be detected in discrete regions of human brain, including the cerebellum, spinal cord and cerebral cortex. The unique tissue distribution of PDE4A8, combined with the evolutionary divergence of its N-terminus, suggest that this isoform may have a specific function in regulating cAMP levels in human skeletal muscle and brain.

scholarly journals Systemic Consequences of Pulmonary Hypertension and Right-Sided Heart Failure

Circulation ◽  
2020 ◽  
Vol 141 (8) ◽  
pp. 678-693 ◽  
Author(s):  
Stephan Rosenkranz ◽  
Luke S. Howard ◽  
Mardi Gomberg-Maitland ◽  
Marius M. Hoeper
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Structural Changes ◽  
Immune Cell ◽  
Organ Damage ◽  
Multiple Organ ◽  
Clinical Syndrome ◽  
Morbidity And Mortality ◽  
High Morbidity ◽  
Organ Systems

Pulmonary hypertension (PH) is a feature of a variety of diseases and continues to harbor high morbidity and mortality. The main consequence of PH is right-sided heart failure which causes a complex clinical syndrome affecting multiple organ systems including left heart, brain, kidneys, liver, gastrointestinal tract, skeletal muscle, as well as the endocrine, immune, and autonomic systems. Interorgan crosstalk and interdependent mechanisms include hemodynamic consequences such as reduced organ perfusion and congestion as well as maladaptive neurohormonal activation, oxidative stress, hormonal imbalance, and abnormal immune cell signaling. These mechanisms, which may occur in acute, chronic, or acute-on-chronic settings, are common and precipitate adverse functional and structural changes in multiple organs which contribute to increased morbidity and mortality. While the systemic character of PH and right-sided heart failure is often neglected or underestimated, such consequences place additional burden on patients and may represent treatable traits in addition to targeted therapy of PH and underlying causes. Here, we highlight the current state-of-the-art understanding of the systemic consequences of PH and right-sided heart failure on multiple organ systems, focusing on self-perpetuating pathophysiological mechanisms, aspects of increased susceptibility of organ damage, and their reciprocal impact on the course of the disease.

Inhibition of phosphodiesterase 4 amplifies cytokine-dependent induction of arginase in macrophages

2006 ◽  
Vol 290 (3) ◽  
pp. L534-L539 ◽  
Author(s):  
Aaron Erdely ◽  
Diane Kepka-Lenhart ◽  
Melissa Clark ◽  
Patti Zeidler-Erdely ◽  
Mirjana Poljakovic ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Arginase Activity ◽  
Raw 264.7 Cells ◽  
Pde4 Inhibitor ◽  
Chronic Obstructive ◽  
Raw 264.7 ◽  
Mrna Levels ◽  
Phosphodiesterase 4 ◽  
Camp Levels ◽  
Arginase I

Arginase is greatly elevated in asthma and is thought to play a role in the pathophysiology of this disease. As inhibitors of phosphodiesterase 4 (PDE4), the predominant PDE in macrophages, elevate cAMP levels and reduce inflammation, they have been proposed for use in treatment of asthma and chronic obstructive pulmonary disease. As cAMP is an inducer of arginase, we tested the hypothesis that a PDE4 inhibitor would enhance macrophage arginase induction by key cytokines implicated in asthma and other pulmonary diseases. RAW 264.7 cells were stimulated with IL-4 or transforming growth factor (TGF)-β, with and without the PDE4 inhibitor rolipram. IL-4 and TGF-β increased arginase activity 16- and 5-fold, respectively. Rolipram alone had no effect but when combined with IL-4 and TGF-β synergistically enhanced arginase activity by an additional 15- and 5-fold, respectively. The increases in arginase I protein and mRNA levels mirrored increases in arginase activity. Induction of arginase II mRNA was also enhanced by rolipram but to a much lesser extent than arginase I. Unlike its effect in RAW 264.7 cells, IL-4 alone did not increase arginase activity in human alveolar macrophages (AM) from healthy volunteers. However, combining IL-4 with agents to induce cAMP levels induced arginase activity in human AM significantly above the level obtained with cAMP-inducing agents alone. In conclusion, agents that elevate cAMP significantly enhance induction of arginase by cytokines. Therefore, consequences of increased arginase expression should be evaluated whenever PDE inhibitors are proposed for treatment of inflammatory disorders in which IL-4 and/or TGF-β predominate.

FEATURES OF FORMATION OF THE MAIN SYSTEMS AND ORGANS IN EARLY LARVAE OF MULLETS (LIZA AURATA, RISSO, 1810)

2017 ◽  
pp. 98-106
Author(s):  
Dariya Aleksandrovna Gavrilova ◽  
Maria Pavlovna Grushko
Keyword(s):  
Nervous System ◽  
Sample Selection ◽  
Early Ontogeny ◽  
Basal Cells ◽  
The Caspian Sea ◽  
Liza Aurata ◽  
Morphological Organization ◽  
Organ Systems ◽  
Major Organ ◽  
Well Differentiated

The aim of this work was to study peculiarities of mullet morphological organization during early ontogeny. Sample selection was made on board Caspian research and development Institute of Fisheries’ research vessel in period from June to September, 2015 in Russian waters of the Caspian Sea. Larvae aged 10 days could be characterized by heterochrony in the development of major organ systems. Nervous system and sense organs were well developed. The eyeball had all membranes well-differentiated, in the retina all the layers were formed. The olfactory fossae had cells of 3 types: olfactory receptor cells, supporting cells and basal cells. There was observed intensive formation of respiratory, cardiovascular, excretory and digestive systems. The early development of the nervous system and sensory organs of the larvae indicated adaptation of mullet to active life.

scholarly journals The Biological Effects of Forsythia Leaves Containing the Cyclic AMP Phosphodiesterase 4 Inhibitor Phillyrin

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2362
Author(s):  
Sansei Nishibe ◽  
Kumiko Mitsui-Saitoh ◽  
Junichi Sakai ◽  
Takahiko Fujikawa
Keyword(s):  
Cyclic Amp ◽  
Influenza A ◽  
Biological Effects ◽  
Polyphenolic Compounds ◽  
Pde4 Inhibitor ◽  
Food Material ◽  
Common Component ◽  
Phosphodiesterase 4 ◽  
Cyclic Amp Phosphodiesterase ◽  
Forsythia Suspensa

Forsythia fruit (Forsythia suspensa Vahl (Oleaceae)) is a common component of Kampo medicines for treating the common cold, influenza, and allergies. The main polyphenolic compounds in the leaves of F. suspensa are pinoresinol β-d-glucoside, phillyrin and forsythiaside, and their levels are higher in the leaves of the plant than in the fruit. It is known that polyphenolic compounds stimulate lipid catabolism in the liver and suppress dyslipidemia, thereby attenuating diet-induced obesity and polyphenolic anti-oxidants might attenuate obesity in animals consuming high-fat diets. Recently, phillyrin was reported as a novel cyclic AMP phosphodiesterase 4 (PDE4) inhibitor derived from forsythia fruit. It was expected that the leaves of F. suspensa might display anti-obesity effects and serve as a health food material. In this review, we summarized our studies on the biological effects of forsythia leaves containing phillyrin and other polyphenolic compounds, particularly against obesity, atopic dermatitis, and influenza A virus infection, and its potential as a phytoestrogen.

The Src-family kinase Lyn in immunoreceptor signaling

Endocrinology ◽  
2021 ◽  
Author(s):  
Ben F Brian IV ◽  
Tanya S Freedman
Keyword(s):  
Autoimmune Disease ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Organ Damage ◽  
Src Family Kinase ◽  
Immune Cell Activation ◽  
Pathogen Elimination ◽  
Tissue Healing ◽  
Cancer Cell Signaling

Abstract Effective regulation of immune-cell activation is critical for ensuring that the immune response, and inflammation generated for the purpose of pathogen elimination, is limited in space and time to limit tissue damage. Autoimmune disease can occur when immunoreceptor signaling is dysregulated, leading to unrestrained inflammation and organ damage. Conversely, tumors can coopt the tissue-healing and immunosuppressive functions of hematopoietic cells to promote metastasis and evade therapy. The Src-family kinase Lyn is an essential regulator of immunoreceptor signaling, initiating both pro-inflammatory and suppressive signaling pathways in myeloid immune cells (e.g. neutrophils, dendritic cells, monocytes, macrophages) and in B lymphocytes. Defects in Lyn signaling are implicated in autoimmune disease, but mechanisms by which Lyn, expressed along with a battery of other Src-family kinases, may uniquely direct both positive and negative signaling remain incompletely defined. This review describes our current understanding of the activating and inhibitory contributions of Lyn to immunoreceptor signaling and how these processes contribute to myeloid and B-cell function. We also highlight recent work suggesting that the two proteins generated by alternative splicing of lyn, LynA and LynB, differentially regulate immune and cancer-cell signaling. These principles may also extend to other Lyn-expressing cells, such as neuronal and endocrine cells. Unraveling the common and cell-specific aspects of Lyn function could lead to new approaches to therapeutically targeting dysregulated pathways in pathologies from autoimmune and neurogenerative disease to cancer.

scholarly journals Development of preclinical and clinical models for immune-related adverse events following checkpoint immunotherapy: a perspective from SITC and AACR

2021 ◽  
Vol 9 (9) ◽  
pp. e002627
Author(s):  
Nicholas L Bayless ◽  
Jeffrey A Bluestone ◽  
Samantha Bucktrout ◽  
Lisa H Butterfield ◽  
Elizabeth M Jaffee ◽  
...  
Keyword(s):  
Adverse Events ◽  
Cancer Immunotherapy ◽  
Immune Cell ◽  
Cytotoxic T Lymphocyte ◽  
Action Plan ◽  
Treatment Strategies ◽  
Model Systems ◽  
Preclinical Model ◽  
Programmed Death ◽  
Organ Systems

Recent advances in cancer immunotherapy have completely revolutionized cancer treatment strategies. Nonetheless, the increasing incidence of immune-related adverse events (irAEs) is now limiting the overall benefits of these treatments. irAEs are well-recognized side effects of some of the most effective cancer immunotherapy agents, including antibody blockade of the cytotoxic T-lymphocyte-associated protein 4 and programmed death protein 1/programmed-death ligand 1 pathways. To develop an action plan on the key elements needed to unravel and understand the key mechanisms driving irAEs, the Society for Immunotherapy for Cancer and the American Association for Cancer Research partnered to bring together research and clinical experts in cancer immunotherapy, autoimmunity, immune regulation, genetics and informatics who are investigating irAEs using animal models, clinical data and patient specimens to discuss current strategies and identify the critical next steps needed to create breakthroughs in our understanding of these toxicities. The genetic and environmental risk factors, immune cell subsets and other key immunological mediators and the unique clinical presentations of irAEs across the different organ systems were the foundation for identifying key opportunities and future directions described in this report. These include the pressing need for significantly improved preclinical model systems, broader collection of biospecimens with standardized collection and clinical annotation made available for research and integration of electronic health record and multiomic data with harmonized and standardized methods, definitions and terminologies to further our understanding of irAE pathogenesis. Based on these needs, this report makes a set of recommendations to advance our understanding of irAE mechanisms, which will be crucial to prevent their occurrence and improve their treatment.

scholarly journals Genetic regulation of homeostatic immune architecture in the lungs of Collaborative Cross mice

2021 ◽  
Author(s):  
Brea K Hampton ◽  
Kara L. Jensen ◽  
Alan C. Whitmore ◽  
Colton L. Linnertz ◽  
Paul Maurizio ◽  
...  
Keyword(s):  
Immune Cell ◽  
Genetic Regulation ◽  
Reference Population ◽  
Collaborative Cross ◽  
System Stability ◽  
Mouse Strains ◽  
Cell Populations ◽  
Immune Homeostasis ◽  
Heritable Variation ◽  
Organ Systems

Variation in immune homeostasis, immune system stability, in organ systems such as the lungs is likely to shape the host response to infection at these exposed tissues. We evaluated immune homeostasis in immune cell populations in the lungs of the Collaborative Cross (CC) mouse genetic reference population. We found vast heritable variation in leukocyte populations with the frequency of many of these cell types showing distinct patterns relative to classic inbred strains C57BL/6J and BALB/cJ. We identified 28 quantitative trait loci (QTL) associated with variation in baseline lung immune cell populations, including several loci that broadly regulate the abundance of immune populations from distinct developmental lineages, and found that many of these loci have predictive value for influenza disease outcomes, demonstrating that genetic determinants of homeostatic immunity in the lungs regulate susceptibility to virus-induced disease. All told, we highlight the need to assess diverse mouse strains in understanding immune homeostasis and resulting immune responses.

scholarly journals SARS-CoV-2 infection in the Syrian hamster model causes inflammation as well as type I interferon dysregulation in both respiratory and non-respiratory tissues including the heart and kidney

2021 ◽  
Author(s):  
Magen E. Francis ◽  
Una Goncin ◽  
Andrea Kroeker ◽  
Cynthia Swan ◽  
Robyn Ralph ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Clinical Symptoms ◽  
Type I Interferons ◽  
Host Responses ◽  
Type I ◽  
Hamster Model ◽  
Organ Systems ◽  
Major Organ ◽  
Kidney Liver ◽  
Multiorgan Disease

AbstractCOVID-19 (coronavirus disease 2019) caused SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is a disease affecting several organ systems. A model that captures all clinical symptoms of COVID-19 as well as long-haulers disease is needed. We investigated the host responses associated with infection in several major organ systems including the respiratory tract, the heart, and the kidneys after SARS-CoV-2 infection in Syrian hamsters. We found significant increases in inflammatory cytokines (IL-6, IL-1beta, and TNF) and type II interferons whereas type I interferons were inhibited. Examination of extrapulmonary tissue indicated inflammation in the kidney, liver, and heart which also lacked type I interferon upregulation. Histologically, the heart had evidence of mycarditis and microthrombi while the kidney had tubular inflammation. These results give insight into the multiorgan disease experienced by people with COVID-19 and possibly the prolonged disease in people with post-acute sequelae of SARS-CoV-2 (PASC).

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