scholarly journals Small Peptides for Inhibiting Serum Amyloid A Aggregation

2021 ◽  
Author(s):  
Asis Jana ◽  
Augustus Greenwood ◽  
Ulrich H.E. Hansmann
Keyword(s):  
Amino Acids ◽  
Serum Amyloid A ◽  
Inflammatory Diseases ◽  
Life Time ◽  
Organ Damage ◽  
Serum Amyloid ◽  
Small Peptides ◽  
Dynamic Simulations ◽  
Drug Candidates ◽  
Amyloid A

Deposition of human Serum Amyloid A (SAA) amyloids in blood vessels, causing inflammation, thrombosis and eventually organ damage, are a commonly seen as a consequence of certain cancers and inflammatory diseases. Several attempts have been made to develop peptide-based drugs that inhibit or at least slow down SAA amyloidosis. We use extensive all-atom molecular dynamic simulations to compare three of these drug candidates for their ability to destabilize SAA fibrils, and to propose for the best candidate, the N-terminal sequence SAA1-5, a mechanism for inhibition. As the life-time of peptide drugs can be increased by replacing L-amino acids with their mirror D- amino acids, we have also studied corresponding D-peptides. We find that DRI-SAA1-5, formed of D-amino acids with the sequence of the peptide reversed, has similar inhibitory properties than the original L-peptide, and therefore may be a promising candidate for drugs targeting SAA amyloidosis.

scholarly journals Stability of Human Serum Amyloid A Fibrils

2020 ◽  
Author(s):  
Wenhua Wang ◽  
Ulrich H. E. Hansmann
Keyword(s):  
Serum Amyloid A ◽  
Salt Bridge ◽  
Fibril Formation ◽  
Serum Amyloid ◽  
Dynamic Simulations ◽  
Drug Candidates ◽  
Amyloid A ◽  
Fibril Structure ◽  
Acidic Conditions ◽  
The Stability

ABSTRACTIn systemic amyloidosis, Serum amyloid A (SAA) fibril deposits cause widespread damages to tissues and organs that eventually may lead to death. A therapeutically intervention therefore has either to dissolve these fibrils or inhibit their formation. However, only recently has the human SAA fibril structure be resolved at a resolution that is sufficient for development of drug candidates. Here, we use molecular dynamic simulations to probe the factors that modulate the stability of this fibril model. Our simulations suggest that fibril formation starts with the stacking of two misfolded monomers into metastable dimers, with the stacking depending on the N-terminal amyloidogenic regions of different chains forming anchors. The resulting dimers pack in a second step into a two-fold two-layer tetramer that is stable enough to nucleate fibril formation. The stability of the initial dimers is enhanced under acidic conditions by a strong salt bridge and side-chain hydrogen bond network in the C-terminal cavity (residues 23 - 51) but not affected by the presence of the disordered C-terminal tail.Table of Content Graphics

scholarly journals Role of Serum Amyloid A Protein in Various Diseases with Special Reference to Periodontal and Periapical Inflammation- A Review

2020 ◽  
Author(s):  
Syed Wali Peeran ◽  
Ahmed Elhassan ◽  
Mohammed Zameer ◽  
Syed Nahid Basheer ◽  
Mohammed Mustafa ◽  
...  
Keyword(s):  
Chronic Periodontitis ◽  
Serum Amyloid A ◽  
Inflammatory Diseases ◽  
Apical Periodontitis ◽  
Serum Amyloid ◽  
Amyloid A ◽  
Serum Amyloid A Protein ◽  
Health And Disease ◽  
Periapical Inflammation

Serum Amyloid A (SAA) is an Acute-Phase Protein (APP) produced as an innate nonspecific response to any tissue damage. Hence, it plays a significant role in chronic inflammatory diseases. In particular, SAA levels increase dramatically in chronic periodontitis and chronic apical periodontitis. Recent studies suggest this role of SAA in the pathogenesis of various diseases, including chronic periodontitis and chronic apical periodontitis. Thus, the focus of this review is to sum up the current understanding of the role of SAA in health and disease and to elaborate on possible mechanisms by which SAA could play a role in the pathogenesis of chronic periodontitis and chronic apical periodontitis.

scholarly journals Serum amyloid A induces G-CSF expression and neutrophilia via Toll-like receptor 2

Blood ◽  
2009 ◽  
Vol 113 (2) ◽  
pp. 429-437 ◽  
Author(s):  
Rong L. He ◽  
Jian Zhou ◽  
Crystal Z. Hanson ◽  
Jia Chen ◽  
Ni Cheng ◽  
...  
Keyword(s):  
Serum Amyloid A ◽  
Inflammatory Diseases ◽  
Serum Amyloid ◽  
Proteinase K ◽  
In Vivo Studies ◽  
Toll Like Receptor ◽  
Amyloid A ◽  
Toll Like Receptor 2

Abstract The acute-phase protein serum amyloid A (SAA) is commonly considered a marker for inflammatory diseases; however, its precise role in inflammation and infection, which often result in neutrophilia, remains ambiguous. In this study, we demonstrate that SAA is a potent endogenous stimulator of granulocyte colony-stimulated factor (G-CSF), a principal cytokine-regulating granulocytosis. This effect of SAA is dependent on Toll-like receptor 2 (TLR2). Our data demonstrate that, in mouse macrophages, both G-CSF mRNA and protein were significantly increased after SAA stimulation. The induction of G-CSF was blocked by an anti-TLR2 antibody and markedly decreased in the TLR2-deficient macrophages. SAA stimulation results in the activation of nuclear factor–κB and binding activity to the CK-1 element of the G-CSF promoter region. In vitro reconstitution experiments also support that TLR2 mediates SAA-induced G-CSF expression. In addition, SAA-induced secretion of G-CSF was sensitive to heat and proteinase K treatment, yet insensitive to polymyxin B treatment, indicating that the induction is a direct effect of SAA. Finally, our in vivo studies confirmed that SAA treatment results in a significant increase in plasma G-CSF and neutrophilia, whereas these responses are ablated in G-CSF– or TLR2-deficient mice.

scholarly journals The effect of SARS-COV-2 Infections on Amyloid Formation of Serum Amyloid A

2021 ◽  
Author(s):  
Asis K Jana ◽  
Augustus B. Greenwood ◽  
Ulrich H.E. Hansmann
Keyword(s):  
Envelope Protein ◽  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Molecular Dynamic Simulations ◽  
Amyloid Formation ◽  
Dynamic Simulations ◽  
Amyloid A ◽  
The Stability ◽  
Inflammatory Syndrome

A marker for the severeness and disease progress of COVID-19 is overexpression of serum amyloid A (SAA) to levels that in other diseases are associated with a risk for SAA amyloidosis. This secondary illness is characterized by formation and deposition of SAA amyloids in blood vessels, causing inflammation, thrombosis and sometimes organ failure, with symptoms resembling the multisystem inflammatory syndrome (MIS) observed in some COVID-19 survivors. Hence, in order to understand better the danger of SAA amyloidosis in the context of COVID-19 we have used molecular dynamic simulations to study the effect of a SARS-COV-2 protein segment on SAA amyloid formation. We find that presence of the nine-residue segment SK9, located on the Envelope protein, increases the propensity for SAA fibril formation by three mechanisms: it reduces the stability of the lipid-transporting hexamer shifting the equilibrium toward monomers, it increases the frequency of aggregation-prone configurations in the resulting chains, and it raises the stability of SAA fibrils. Our results therefore suggest that SAA amyloidosis -related pathologies are a long-term risk of SARS-COV-2 infections.

Small Peptides for Inhibiting Serum Amyloid A Aggregation

2021 ◽  
Vol 12 (10) ◽  
pp. 1613-1621
Author(s):  
Asis K. Jana ◽  
Augustus B. Greenwood ◽  
Ulrich H. E. Hansmann
Keyword(s):  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Small Peptides ◽  
Amyloid A

scholarly journals Elevated Serum Amyloid a Levels Are not Specific for Sarcoidosis but Associate with a Fibrotic Pulmonary Phenotype

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 585
Author(s):  
Els Beijer ◽  
Claudia Roodenburg-Benschop ◽  
Milou C. Schimmelpennink ◽  
Jan C. Grutters ◽  
Bob Meek ◽  
...  
Keyword(s):  
Serum Amyloid A ◽  
Inflammatory Diseases ◽  
Elevated Serum ◽  
Serum Levels ◽  
Serum Amyloid ◽  
Eosinophilic Granulomatosis With Polyangiitis ◽  
Amyloid A ◽  
Underlying Mechanisms ◽  
Granulomatous Diseases

Elevated Serum Amyloid A (SAA) levels have been found in several inflammatory diseases, including sarcoidosis. SAA is suggested to be involved in sarcoidosis pathogenesis by involvement in granuloma formation and maintenance. We hypothesized that SAA serum levels would be higher in sarcoidosis compared to other non-infectious granulomatous and non-granulomatous diseases. SAA levels were measured in serum from sarcoidosis, Hypersensitivity pneumonitis (HP), and (eosinophilic) granulomatosis with polyangiitis ((E)GPA) patients. Idiopathic pulmonary fibrosis (IPF) patients were included as non-granulomatous disease group. SAA levels of patients with sarcoidosis (31.0 µg/mL), HP (23.4 µg/mL), (E)GPA (36.9 µg/mL), and IPF (22.1 µg/mL) were all higher than SAA levels of healthy controls (10.1 µg/mL). SAA levels did not differ between the diagnostic groups. When SAA serum levels were analyzed in sarcoidosis subgroups, fibrotic sarcoidosis patients showed higher SAA levels than sarcoidosis patients without fibrosis (47.8 µg/mL vs. 29.4 µg/mL, p = 0.005). To conclude, the observation that fibrotic sarcoidosis patients have higher SAA levels, together with our finding that SAA levels were also increased in IPF patients, suggests that SAA may next to granulomatous processes also reflect the process of fibrogenesis. Further studies should clarify the exact role of SAA in fibrosis and the underlying mechanisms involved.

scholarly journals Serum Amyloid A Proteins Induce Pathogenic TH17 Cells and Promote Inflammatory Disease

2019 ◽  
Author(s):  
June-Yong Lee ◽  
Jason A. Hall ◽  
Lina Kroehling ◽  
Lin Wu ◽  
Tariq Najar ◽  
...  
Keyword(s):  
T Cells ◽  
Serum Amyloid A ◽  
Inflammatory Diseases ◽  
Lymphoid Cells ◽  
Serum Amyloid ◽  
Intestinal Epithelial ◽  
T Cell Signaling ◽  
Cell Behaviors ◽  
Amyloid A ◽  
Barrier Tissues

SummaryLymphoid cells that produce IL-17 cytokines protect barrier tissues from pathogenic microbes, but are also prominent effectors of inflammation and autoimmune disease. T-helper (TH17) cells, defined by RORγt-dependent production of IL-17A and IL-17F, exert homeostatic functions in the gut upon microbiota-directed differentiation from naïve CD4+ T cells. In the non-pathogenic setting, their cytokine production is regulated by serum amyloid A proteins (SAA1 and SAA2) secreted by adjacent intestinal epithelial cells. However, TH17 cell behaviors vary markedly according to their environment. Here we show that SAAs additionally direct a pathogenic pro-inflammatory TH17 cell differentiation program, acting directly on T cells in collaboration with STAT3-activating cytokines. Using loss- and gain-of-function mouse models, we show that SAA1, SAA2, and SAA3 have distinct systemic and local functions in promoting TH17-mediated inflammatory diseases. These studies suggest that T cell signaling pathways modulated by the SAAs may be attractive targets for anti-inflammatory therapies.

scholarly journals High-Density Lipoproteins and Serum Amyloid A (SAA)

2021 ◽  
Vol 23 (2) ◽  
Author(s):  
Nancy R. Webb
Keyword(s):  
Serum Amyloid A ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Density Lipoprotein ◽  
High Density ◽  
Serum Amyloid ◽  
High Density Lipoproteins ◽  
Amyloid A

Abstract Purpose of Review Serum amyloid A (SAA) is a highly sensitive acute phase reactant that has been linked to a number of chronic inflammatory diseases. During a systemic inflammatory response, liver-derived SAA is primarily found on high-density lipoprotein (HDL). The purpose of this review is to discuss recent literature addressing the pathophysiological functions of SAA and the significance of its association with HDL. Recent Findings Studies in gene-targeted mice establish that SAA contributes to atherosclerosis and some metastatic cancers. Accumulating evidence indicates that the lipidation state of SAA profoundly affects its bioactivities, with lipid-poor, but not HDL-associated, SAA capable of inducing inflammatory responses in vitro and in vivo. Factors that modulate the equilibrium between lipid-free and HDL-associated SAA have been identified. Summary HDL may serve to limit SAA’s bioactivities in vivo. Understanding the factors leading to the release of systemic SAA from HDL may provide insights into chronic disease mechanisms.

scholarly journals Analytical Validation of Two Point-of-Care Assays for Serum Amyloid A Measurements in Cats

Animals ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 2518
Author(s):  
Damián Escribano ◽  
Alba Ortín Bustillo ◽  
Luis Pardo Marín ◽  
Andrea Navarro Rabasco ◽  
Pablo Ruiz Herrera ◽  
...  
Keyword(s):  
Gold Standard ◽  
Serum Amyloid A ◽  
Performance Test ◽  
Limit Of Detection ◽  
Inflammatory Diseases ◽  
Point Of Care ◽  
Serum Amyloid ◽  
Analytical Validation ◽  
Serum Samples ◽  
Amyloid A

Serum Amyloid A (SAA) is one of the most sensitive tests to detect inflammation in cats. In this study, two point-of-care assays for SAA measurements in cats (FUJI DRI-CHEM IMMUNO AU CARTRIDGE vf-SAA (method A), and CUBE-VET analyser (Method B), were analytically evaluated. Regarding the imprecision precision only the method A showed intra-assay and inter-assay CV < 10% at all concentrations. Both assays showed linearity with r close to 1 and the recovery were in the range of 81–112% for assay A and 85–125% for assay B and the limit of detection were 3.75 and 0.5 mg/dL for method A and B, respectively. A previously validated method for SAA quantification SAATIA; LZ-SAA (method C) was used as gold-standard to evaluate the accuracy of the assays. Significant correlations (p < 0.0001) were found between assays A and C (r = 0.94) and B and C (r = 0.91). In addition, an overlap performance test was made using serum samples from cats with non-inflammatory and cats with inflammatory. Both assays showed higher median SAA concentrations in cats with inflammatory diseases than in cats without inflammatory diseases (p < 0.0001). In conclusion, this manuscript provides data about the possible application of two point-of-care assays for the measurement of SAA concentration in cats.

scholarly journals Cleavage, down-regulation and aggregation of serum amyloid A

2019 ◽  
Author(s):  
Wenhua Wang ◽  
Prabir Khatua ◽  
Ulrich H.E. Hansmann
Keyword(s):  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Amyloid Formation ◽  
Dynamic Simulations ◽  
Over Expression ◽  
Amyloid A ◽  
Serum Amyloid A Protein ◽  
Ph Increase ◽  
The One

AbstractVarious diseases cause over-expression of the serum amyloid A protein (SAA), which leads in some, but not all, cases to amyloidosis as a secondary disease. The response to the over-expression involves dissociation of SAA hexamer and subsequent cleavage of the released monomers, most commonly yielding fragments SAA1−76 of the full-sized SAA1−104. We report results from molecular dynamic simulations that probe the role of this cleavage for down-regulating activity and the concentration of SAA. We propose a mechanism that relies on two elements. First, the probability to assemble into hexamers is lower for the fragments than it is for the full-sized protein. Second, unlike other fragments SAA1−76 can switch between two distinct configurations. The first kind is easy to proteolyze (allowing a fast reduction of SAA concentration) but prone to aggregation, while the situation is opposite for the second kind. If the time scale for amyloid formation is longer than the one for proteolysis, the aggregation-prone species dominates. However, if environmental conditions such as low pH increase the risk of amyloid formation, the ensemble shifts toward the more protected form. We speculate that SAA amyloidosis is a failure of the switching mechanism leading to accumulation of the aggregation-prone species and subsequent amyloid formation.

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