scholarly journals Activin A correlates with the worst outcomes in COVID-19 patients, and can be induced by cytokines via the IKK/NF-kappa B pathway

2021 ◽  
Author(s):  
Megan McAleavy ◽  
Qian Zhang ◽  
Jianing Xu ◽  
Li Pan ◽  
Matthew Wakai ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Activin A ◽  
Severe Form ◽  
Acute Respiratory Disease ◽  
Nf Kappa B ◽  
Sample Median ◽  
Longitudinal Outcomes ◽  
All Cause Mortality ◽  
Patients At Risk ◽  
Nf Kappab

SummaryA fraction of COVID-19 patients develop the most severe form, characterized by Acute Respiratory Disease Syndrome (ARDS). The molecular mechanisms causing COVID-19-induced ARDS have yet to be defined, though many studies have documented an increase in cytokines known as a “cytokine storm.” Here, we demonstrate that cytokines that activate the NF-kappaB pathway can induce Activin A and its downstream marker, FLRG. In hospitalized COVID-19 patients elevated Activin A/FLRG at baseline were predictive of the most severe longitudinal outcomes of COVID-19, including the need for mechanical ventilation, lack of clinical improvement and all-cause mortality. Patients with Activin A/FLRG above the sample median were 2.6/2.9 times more likely to die, relative to patients with levels below the sample median, respectively. The study indicates high levels of Activin A and FLRG put patients at risk of ARDS, and blockade of Activin A may be beneficial in treating COVID-19 patients experiencing ARDS.

scholarly journals The Activin/FLRG pathway associates with poor COVID-19 outcomes in hospitalized patients

2021 ◽  
Author(s):  
Megan McAleavy ◽  
Qian Zhang ◽  
Peter J. Ehmann ◽  
Jianing Xu ◽  
Matthew F. Wipperman ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Viral Load ◽  
Hospital Admission ◽  
Activin A ◽  
Severe Form ◽  
Cytokine Storm ◽  
Acute Respiratory Disease ◽  
Hamster Model ◽  
All Cause Mortality ◽  
Nf Kappab

A subset of hospitalized COVID-19 patients, particularly the aged and those with co-morbidities, develop the most severe form of the disease, characterized by Acute Respiratory Disease Syndrome (ARDS), coincident with experiencing a “cytokine storm." Here, we demonstrate that cytokines which activate the NF-kappaB pathway can induce Activin A. Patients with elevated Activin A, Activin B, and FLRG at hospital admission were associated with the most severe outcomes of COVID-19, including the requirement for mechanical ventilation, and all-cause mortality. A prior study showed that Activin A could decrease viral load, which indicated there might be a risk to giving COVID-19 patients an inhibitor of Activin. To evaluate this, the role for Activin A was examined in a hamster model of SARS-CoV2 infection, via blockade of Activin A signaling. The hamster model demonstrated that use of an anti-ActivinA antibody did not worsen the disease and there was no evidence for increase in lung viral load and pathology. The study indicates blockade of Activin signaling may be beneficial in treating COVID-19 patients experiencing ARDS.

scholarly journals Myeloma Bone Disease: Update on Pathogenesis and Novel Treatment Strategies

Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 202 ◽  
Author(s):  
Sonia Vallet ◽  
Julia-Marie Filzmoser ◽  
Martin Pecherstorfer ◽  
Klaus Podar
Keyword(s):  
Bone Disease ◽  
Molecular Mechanisms ◽  
Bone Fractures ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Nf Kappa B ◽  
Skeletal Involvement ◽  
Myeloma Bone Disease ◽  
Skeletal Related Events ◽  
Novel Treatment Strategies

Bone disease, including osteolytic lesions and/or osteoporosis, is a common feature of multiple myeloma (MM). The consequences of skeletal involvement are severe pain, spinal cord compressions, and bone fractures, which have a dramatic impact on patients’ quality of life and, ultimately, survival. During the past few years, several landmark studies significantly enhanced our insight into MM bone disease (MBD) by identifying molecular mechanisms leading to increased bone resorption due to osteoclast activation, and decreased bone formation by osteoblast inhibition. Bisphosphonates were the mainstay to prevent skeletal-related events in MM for almost two decades. Excitingly, the most recent approval of the receptor activator of NF-kappa B ligand (RANKL) inhibitor, denosumab, expanded treatment options for MBD, for patients with compromised renal function, in particular. In addition, several other bone-targeting agents, including bone anabolic drugs, are currently in preclinical and early clinical assessment. This review summarizes our up-to-date knowledge on the pathogenesis of MBD and discusses novel state-of-the-art treatment strategies that are likely to enter clinical practice in the near future.

scholarly journals Metabonomic-Transcriptome Integration Analysis on Osteoarthritis and Rheumatoid Arthritis

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Ningyang Gao ◽  
Li Ding ◽  
Jian Pang ◽  
Yuxin Zheng ◽  
Yuelong Cao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gap Junction ◽  
Molecular Mechanisms ◽  
Linear Models ◽  
Principal Component ◽  
Enrichment Analysis ◽  
Pathway Enrichment Analysis ◽  
Nf Kappa B ◽  
Linear Module ◽  
Hedgehog Acyltransferase

Purpose. This study is aimed at exploring the potential metabolite/gene biomarkers, as well as the differences between the molecular mechanisms, of osteoarthritis (OA) and rheumatoid arthritis (RA). Methods. Transcriptome dataset GSE100786 was downloaded to explore the differentially expressed genes (DEGs) between OA samples and RA samples. Meanwhile, metabolomic dataset MTBLS564 was downloaded and preprocessed to obtain metabolites. Then, the principal component analysis (PCA) and linear models were used to reveal DEG-metabolite relations. Finally, metabolic pathway enrichment analysis was performed to investigate the differences between the molecular mechanisms of OA and RA. Results. A total of 976 DEGs and 171 metabolites were explored between OA samples and RA samples. The PCA and linear module analysis investigated 186 DEG-metabolite interactions including Glycogenin 1- (GYG1-) asparagine_54, hedgehog acyltransferase- (HHAT-) glucose_70, and TNF receptor-associated factor 3- (TRAF3-) acetoacetate_35. Finally, the KEGG pathway analysis showed that these metabolites were mainly enriched in pathways like gap junction, phagosome, NF-kappa B, and IL-17 pathway. Conclusions. Genes such as HHAT, GYG1, and TRAF3, as well as metabolites including glucose, asparagine, and acetoacetate, might be implicated in the pathogenesis of OA and RA. Metabolites like ethanol and tyrosine might participate differentially in OA and RA progression via the gap junction pathway and phagosome pathway, respectively. TRAF3-acetoacetate interaction may be involved in regulating inflammation in OA and RA by the NF-kappa B and IL-17 pathway.

PGE2 and thrombin induce myofibroblast transdifferentiation via activinA and CTGF in endometrial stromal cells

Endocrinology ◽  
2021 ◽  
Author(s):  
Kazuya Kusama ◽  
Yuta Fukushima ◽  
Kanoko Yoshida ◽  
Mana Azumi ◽  
Mikihiro Yoshie ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Molecular Mechanisms ◽  
Type I Collagen ◽  
Activin A ◽  
Tissue Growth ◽  
Marker Genes ◽  
Type I ◽  
Endometrial Stromal Cells ◽  
Mesenchymal Transition ◽  
Endometrial Cells

Abstract Endometriosis is characterized by inflammation and fibrotic changes. Our previous study using a mouse model showed that proinflammatory factors present in peritoneal hemorrhage exacerbated inflammation in endometriosis-like grafts, at least in part through the activation of prostaglandin (PG) E2 receptor and protease-activated receptor (PAR). In addition, menstruation-related factors, PGE2 and thrombin, a PAR1 agonist (P/T) induced epithelial-mesenchymal transition (EMT) of endometrial cells under hypoxia. However, the molecular mechanisms by which P/T induce development of endometriosis have not been fully characterized. To investigate the effects of P/T, RNA extracted from endometrial stromal cells (ESCs) treated with P/T were subjected to RNA sequence analysis, and identified activin A, FOS, GATA2 as upregulated genes. Activin A increased the expression of connective tissue growth factor (CTGF) and mesenchymal marker genes in ESCs. CTGF induced the expression of fibrosis marker type I collagen, fibronectin, and α-smooth muscle actin (αSMA), indicating fibroblast to myofibroblast transdifferentiation (FMT) of ESCs. In addition, activin A, FOS, GATA2, CTGF, and αSMA were localized in endometriosis lesions. Taken together, our data show that P/T induce changes resembling EMT and FMT in ectopic ESCs derived from retrograde menstruation, and that these are associated with fibrotic changes in the lesions. Pharmacological means that block P/T-induced activin A and CTGF signaling may be strategies to inhibit fibrosis in endometriotic lesions.

scholarly journals I(kappa)B(gamma) inhibits DNA binding of NF-kappaB p50 homodimers by interacting with residues that contact DNA.

1996 ◽  
Vol 16 (11) ◽  
pp. 6477-6485 ◽  
Author(s):  
S Bell ◽  
J R Matthews ◽  
E Jaffray ◽  
R T Hay
Keyword(s):  
Dna Binding ◽  
Binding Activity ◽  
Nf Kappa B ◽  
Protein Footprinting ◽  
I Kappa B Alpha ◽  
Dna Binding Activity ◽  
Cellular Genes ◽  
Phosphate Backbone ◽  
Nf Kappab ◽  
Contact Dna

NF-(kappa)B is an inducible transcription factor that activates many cellular genes involved in stress and immune response and whose DNA binding activity and cellular distribution are regulated by I(kappa)B inhibitor proteins. The interaction between NF-(kappa)B p50 and DNA was investigated by protein footprinting using chemical modification and partial proteolysis. Both methods confirmed lysine-DNA contacts already found in the crystal structure (K-147, K-149, K-244, K-275, and K-278) but also revealed an additional contact in the lysine cluster K-77-K-78-K-80 which was made on an extended DNA. Molecular modelling of such a DNA-protein complex revealed that lysine 80 is ideally placed to make phosphate backbone contacts in the extended DNA. Thus, it seems likely that the entire AB loop, containing lysines 77, 78, and 80, forms a C-shaped clamp that closes around the DNA recognition site. The same protein footprinting approaches were used to probe the interaction of p50 with the ankyrin repeat containing proteins I(kappa)B(gamma) and I(kappa)B(alpha). Lysine residues in p50 that were protected from modification by DNA were also protected from modification by I(kappa)B(gamma) but not I(kappa)B(alpha). Similarly, proteolytic cleavage at p50 residues which contact DNA was inhibited by bound I(kappa)B(gamma) but was enhanced by the presence of I(kappa)B(alpha). Thus, I(kappa)B(gamma) inhibits the DNA binding activity of p50 by direct interactions with residues contacting DNA, whereas the same residues remain exposed in the presence of I(kappa)B(alpha), which binds to p50 but does not block DNA binding.

scholarly journals Nuclear Transcription Factor Kappa B (NF-кB) and Molecular Damage Mechanisms in Acute Cardiovascular Diseases. A Review

2018 ◽  
Vol 4 (2) ◽  
pp. 65-72 ◽  
Author(s):  
Roxana Buzas ◽  
Alexandru Florin Rogobete ◽  
Sonia Elena Popovici ◽  
Tudor Mateescu ◽  
Teodora Hoinoiu ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Transcription Factor ◽  
Cardiovascular Diseases ◽  
Molecular Mechanisms ◽  
Severe Form ◽  
Molecular Therapy ◽  
Atheromatous Plaque ◽  
Early Evaluation ◽  
Nuclear Transcription Factor ◽  
Molecular Damage

Abstract Worldwide, cardiovascular diseases (CVDs) represent one of the main causes of morbidity and mortality, and acute coronary syndromes are responsible for a large number of sudden cardiac deaths. One of the main challenges that still exist in this area is represented by the early detection and targeted monitoring of the pathophysiology involved in CVDs. During the last couple of years, researchers have highlighted the importance of molecular and epigenetic mechanisms involved in the initiation and augmentation of CVDs, culminating in their most severe form represented by acute myocardial infarction. One of the most studied molecular factors involved in this type of pathology is represented by nuclear transcription factor kappa B (NF-κB), as well as the involvement of microRNAs (miRNAs). It has been suggested that miRNAs can also be involved in the complex process of atheromatous plaque vulnerabilization that leads to an acute cardiac event. In this review paper, we describe the most important molecular mechanisms involved in the pathogenesis of CVDs and atheromatous plaque progression and vulnerabilization, which include molecular mechanisms dependent on NF-κB. For this paper, we used international databases (PubMed and Scopus). The keywords used for the search were “miRNAs biomarkers”, “miRNAs in cardiovascular disease”, “NF-κB in cardiovascular disease”, “molecular mechanism in cardiovascular disease”, and “myocardial NF-κB mechanisms”. Numerous molecular reactions that have NF-κB as a trigger are involved in the pathogenesis of CVDs. Moreover, miRNAs play an important role in initiating and aggravating certain segments of CVDs. Therefore, miRNAs can be used as biomarkers for early evaluation of CVDs. Furthermore, in the future, miRNAs could be used as a targeted molecular therapy in order to block certain mechanisms responsible for inducing CVDs and leading to acute cardiovascular events.

scholarly journals Molecular mechanisms of interleukin-10-mediated inhibition of NF-kappaB activity: a role for p50

2004 ◽  
Vol 135 (1) ◽  
pp. 64-73 ◽  
Author(s):  
F. DRIESSLER ◽  
K. VENSTROM ◽  
R. SABAT ◽  
K. ASADULLAH ◽  
A. J. SCHOTTELIUS
Keyword(s):  
Molecular Mechanisms ◽  
Interleukin 10 ◽  
Nf Kappab

scholarly journals The molecular and cellular basis of corticosteroid resistance

2003 ◽  
Vol 179 (3) ◽  
pp. 301-310 ◽  
Author(s):  
IC Chikanza ◽  
D Kozaci ◽  
Y Chernajovsky
Keyword(s):  
Rheumatoid Arthritis ◽  
Peripheral Blood ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Intracellular Signalling ◽  
Signalling Pathways ◽  
Peripheral Blood Mononuclear ◽  
Intracellular Signalling Pathways ◽  
Nf Kappab

Corticosteroids (CS) can modulate gene expression and are often used to treat a range of immunological and inflammatory diseases such as asthma, inflammatory bowel disease and rheumatoid arthritis. However, a proportion of patients fail to show an adequate response. On this basis patients have been subdivided into CS-sensitive (SS) and -resistant (SR) subgroups. The ability of CS to inhibit peripheral blood T cell proliferation in vitro has also been used similarly. In rheumatoid arthritis (RA), the in vitro-defined SS and SR subgroups correlate with the clinical responses to CS therapy. The mechanisms responsible for this observation are unknown but they appear to involve a number of known molecular events related to the described mechanisms of action of CS. These include alterations in the functional status of CS receptor-alpha, perturbations of the cytokine and hormonal milieu and intracellular signalling pathways. Peripheral blood mononuclear cells (MNCs) from SR significantly overexpress activated NF-kappaB. In vitro, CS fail to significantly inhibit concanavalin A (conA)-induced NF-kappaB activation in MNCs from SR RA patients. The alterations in the intracellular signalling pathways may explain in part our observations seen in SR RA subjects, CS fail to significantly inhibit conA-induced interleukin (IL)-2 and IL-4 secretion and lipopolysaccharide-induced IL-8 and IL-1beta secretion in vitro. CS therapy fails to reduce the circulating levels of IL-8 and IL-1beta in RA patients. In asthma, CS fail to induce L10 in SR asthma patients. Other molecular mechanisms such as enhanced AP-1 expression and alterations in the MAP kinase pathway are most likely to be involved too and we are currently investigating such possibilities. A full understanding of the molecular basis of SR will lead to the development of more rational therapeutic strategies.

scholarly journals Estimating the proportion of coronavirus disease 2019 (COVID-19) cases among households in France: a cross-sectional study based on individuals with myocardial infarction history

2020 ◽  
Author(s):  
Laurie Fraticelli ◽  
Julie Freyssenge ◽  
Clément Claustre ◽  
Mikaël Martinez ◽  
Abdesslam Redjaline ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Telephone Survey ◽  
Cross Sectional Study ◽  
Severe Form ◽  
Infection Rates ◽  
Cross Sectional ◽  
The Past ◽  
Health Measures ◽  
Increased Risk ◽  
All Cause Mortality

AbstractBackgroundPrevious studies have identified that adults with cardiovascular diseases were disproportionately associated with a significantly increased risk of a severe form of COVID-19 and all-cause mortality. We aimed to describe the diagnosed COVID-19 cases and to estimate the symptomatic and asymptomatic suspected cases among individuals with pre-existing myocardial infarction myocardial infarction and their relatives in lockdown period. Methods: We conducted a two-week cross-sectional telephone survey, from May 4 to May 15, 2020, including all households with at least one individual with pre-existing cardiovascular disease in the past two years. We defined a suspected COVID-19 case when living with at least one individual tested positive to COVID-19, or when an individual has been in contact with a suspected or confirmed case since the March 1rst, or when a relative from the same house has been hospitalized or deceased for COVID-19.ResultsWe observed high rates of compliance with health measures during the lockdown period, regardless of age or risk factors. Among individuals with myocardial infarction history, two were COVID-19 confirmed, 13·37% were suspected (94/703) of whom 70·21% (66/94) asymptomatic.ConclusionsIndividuals with myocardial infarction history presented different symptoms association with more respiratory signs. This population, which is older and associated with more comorbidities, is exposed to a high risk of complication in the event of contamination. Infection rates are relevant to adjusting the management of emergency departments in our region.

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