Elevated Serum Amyloid A Is Associated With Cognitive Impairment in Ischemic Stroke Patients

Background and PurposeThe impact of serum amyloid A on cognitive impairment after ischemic stroke is unclear. We aimed to investigate the association between serum amyloid A (SAA) levels and post-stroke cognitive impairment (PSCI) at 3 months after ischemic stroke.MethodsOne hundred and ninety-eight patients were enrolled prospectively from June 2020 to April 2021. The SAA concentrations were measured using a commercially available enzyme-linked immunosorbent assay kit after admission. Cognitive function was assessed using the Montreal Cognitive Assessment score at 3 months after the symptom onset. We defined a Montreal Cognitive Assessment score <25 as cognitive impairment.ResultsDuring 3-month follow-up, 80 patients (40.4%) were diagnosed as having PSCI. As compared with patients with cognitively normal ischemic stroke, those with PSCI were older, more likely to have diabetes and white matter lesions, and had a higher baseline National Institutes of Health stroke score and SAA levels. After adjustment for age, the National Institutes of Health stroke score and other covariates, the OR for the highest quartile of SAA compared with the lowest quartile was 5.72 (95% CI, 2.17–15.04, P = 0.001) for PSCI. Also, ordinal logistic regression analysis showed that higher SAA concentrations were associated with increased risk of PSCI severity (OR, 4.31; 95% CI, 1.81–10.33, P = 0.001). Similar results were found when the SAA levels were analyzed as a continuous variable.ConclusionsThis present study demonstrated that increased SAA levels might be associated with PSCI at 3 months after ischemic stroke.

Serum Amyloid A3 Promoter-Driven Luciferase Activity Enables Visualization of Diabetic Kidney Disease

The early detection of diabetic nephropathy (DN) in mice is necessary for the development of drugs and functional foods. The purpose of this study was to identify genes that are significantly upregulated in the early stage of DN progression and develop a novel model to non-invasively monitor disease progression within living animals using in vivo imaging technology. Streptozotocin (STZ) treatment has been widely used as a DN model; however, it also exhibits direct cytotoxicity to the kidneys. As it is important to distinguish between DN-related and STZ-induced nephropathy, in this study, we compared renal responses induced by the diabetic milieu with two types of STZ models: multiple low-dose STZ injections with a high-fat diet and two moderate-dose STZ injections to induce DN. We found 221 genes whose expression was significantly altered during DN development in both models and identified serum amyloid A3 (Saa3) as a candidate gene. Next, we applied the Saa3 promoter-driven luciferase reporter (Saa3-promoter luc mice) to these two STZ models and performed in vivo bioluminescent imaging to monitor the progression of renal pathology. In this study, to further exclude the possibility that the in vivo bioluminescence signal is related to renal cytotoxicity by STZ treatment, we injected insulin into Saa3-promoter luc mice and showed that insulin treatment could downregulate renal inflammatory responses with a decreased signal intensity of in vivo bioluminescence imaging. These results strongly suggest that Saa3 promoter activity is a potent non-invasive indicator that can be used to monitor DN progression and explore therapeutic agents and functional foods.

Acute-phase protein concentrations in serum of clinically healthy and diseased European bison (Bison bonasus) – preliminary study

Background This is the first report describing levels of APPs in European bison. Serum concentration of acute phase proteins (APPs) may be helpful to assess general health status in wildlife and potentially useful in selecting animals for elimination. Since there is a lack of literature data regarding concentration of APPs in European bisons, establishment of the reference values is also needed. Methods A total of 87 European bison from Polish populations were divided into two groups: (1) healthy: immobilized for transportation, placing a telemetry collar and routine diagnostic purposes; and (2) selectively culled due to the poor health condition. The serum concentration of haptoglobin, serum amyloid A and α1-acid-glycoprotein were determined using commercial quantitative ELISA assays. Since none of the variables met the normality assumptions, non-parametric Mann-Whitney U test was used for all comparisons. Statistical significance was set at p < 0.05. Statistical analyses were performed using Statistica 13.3 (Tibco, USA). Results The concentration of haptoglobin and serum amyloid A was significantly higher in animals culled (euthanised) due to the poor condition in respect to the clinically healthy European bison. The levels of α1-acid-glycoprotein did not show statistical difference between healthy and sick animals. Conclusions Correlation between APPs concertation and health status was proven, therefore the determination of selected APPs may be considered in future as auxiliary predictive tool in assessing European bison health condition.

Effects of ozone on sickness and depressive-like behavioral and biochemical phenotypes and their relations to serum amyloid A and kynurenine in blood

Ozone (O3) is an air pollutant which primarily damages the lungs, but growing evidence supports that O3 exposure can also affect the brain. Serum amyloid A (SAA) and kynurenine have been identified as circulating factors that are upregulated by O3, and both can contribute to depressive-like behaviors in mice. However, little is known about the relations of O3 exposure to sickness and depressive-like behaviors in experimental settings. In this study, we evaluated O3 dose-, time- and sex- dependent changes in circulating SAA in context of pulmonary inflammation and damage, sickness and depressive-like behavioral changes, and systemic changes in kynurenine and indoleamine 2,3-dioxygenase (IDO), an enzyme that regulates kynurenine production and contributes to inflammation-induced depressive-like behaviors. Our results in Balb/c and CD-1 mice showed that 3ppm O3, but not 2 or 1ppm O3, caused elevations in serum SAA and pulmonary neutrophils, and these responses resolved by 48 hours. Sickness and depressive-like behaviors were observed at all O3 doses (1-3ppm), although the detection of certain behavioral changes varied by dose. We also found that Ido1 mRNA expression was increased in the brain and spleen 24 hours after 3ppm O3, and that kynurenine was increased in blood. Together, these findings indicate that acute O3 exposure induces transient symptoms of sickness and depressive-like behaviors which may occur in the presence or absence of overt pulmonary neutrophilia and systemic increases of SAA. We also present evidence that the IDO/kynurenine pathway is upregulated systemically following an acute exposure to O3 in mice.

An Observational, Non-Interventional Study for the Follow-up of Patients with Amyloidosis Who Received Miridesap Followed by Dezamizumab in a Phase 1 Study

Background: Miridesap depletes circulating serum amyloid P (SAP) and dezamizumab (anti-SAP monoclonal antibody) targets SAP on amyloid deposits, triggering amyloid removal. In a Phase 1, first-in-human study (FIHS), progressive amyloid removal was observed in some patients after ≤3 cycles of miridesap/dezamizumab.Methods: This observational, non-interventional study in patients who received miridesap/dezamizumab during the FIHS (planned follow-up: 5 years) evaluated response to treatment based on routine assessments of disease status and key organ function. In a post hoc analysis, patients responding to treatment in the FIHS during follow-up were identified as responders and further categorized as sustained or declining responders.Results: In the FIHS, 17/23 patients were treatment responders. Of these patients, seven (immunoglobulin light chain [AL], n=6; serum amyloid A, n=1) were considered sustained responders and ten (fibrinogen-a alpha chain [AFib], n=5; AL, n=4; apolipoprotein A-I, n=1) were considered declining responders. We primarily present responder patient-level data for functional, cardiac, laboratory and imaging assessments conducted during the follow-up period, with non-responder data presented as supplementary.Conclusion: No further development of miridesap/dezamizumab is planned in amyloidosis. However, long-term follow-up of these patients may provide insight into whether active removal of amyloid deposits has an impact on disease progression. Trial registration: ClinicalTrials.gov, NCT01777243. Registered 28 January 2013, https://clinicaltrials.gov/ct2/show/study/NCT01777243.

Role of Serum Amyloid A in Abdominal Aortic Aneurysm and Related Cardiovascular Diseases

Epidemiological data positively correlate plasma serum amyloid A (SAA) levels with cardiovascular disease severity and mortality. Studies by several investigators have indicated a causal role for SAA in the development of atherosclerosis in animal models. Suppression of SAA attenuates the development of angiotensin II (AngII)-induced abdominal aortic aneurysm (AAA) formation in mice. Thus, SAA is not just a marker for cardiovascular disease (CVD) development, but it is a key player. However, to consider SAA as a therapeutic target for these diseases, the pathway leading to its involvement needs to be understood. This review provides a brief description of the pathobiological significance of this enigmatic molecule. The purpose of this review is to summarize the data relevant to its role in the development of CVD, the pitfalls in SAA research, and unanswered questions in the field.

Serum amyloid A as a marker of ankylosing spondylitis activity

Serum amyloid A protein A (SAA) is a normal serum protein (serving as a precursor of fibrillar tissue protein AA), synthesized in the liver and a rapidly responding marker of the acute phase of inflammation. A constant high concentration of SAA is one of the factors in the development of AA-amyloidosis. As a rule, secondary amyloidosis develops in patients with long-term and poorly controlled inflammatory diseases, including rheumatic diseases, one of which is ankylosing spondylitis (AS).Objective: to assess the level of SAA in AS patients and its relationship with indicators of disease activity.Patients and methods. The study included 124 patients with AS who met the modified New York 1984 criteria. The disease activity and functional status of patients were assessed according to the recommendations of Russian experts. SAA and CRP, ESR in blood serum were measured in all patients.Results and discussion. The median SAA concentration was 12.5 mg/L [4; 71.6]. Of 124 patients, 31% had SAA levels <5 mg/L and 69% had >5 mg/L. A strong correlation was found between the levels of SAA and CRP (r=0.80, p<0.000001), no significant relationship was found between SAA and ESR (r=0.31, p=0.92). The correlation between the AS activity according to the BASDAI index and SAA was weak (r=0.3, p<0.002), the correlation with ASDAS-CRP was moderate (r=0.54, p<0.00001).Conclusion. A statistically significant relationship was found between SAA and CRP levels, as well as the AS activity indices. Research has shown that SAA can be used as one of the markers of inflammation in AS.

Serum Amyloid A promotes Acetaminophen-induced liver injury by damaging sinusoidal endothelial cell and exacerbating platelet aggregation in liver

BackgroundAcetaminophen (APAP) is the most commonly used non-prescription antipyretic and analgesic drugs. Overuse of APAP can cause hepatotoxicity. Liver sinusoidal endothelial cells (LSECs) damage is an important early event in APAP-induced liver injury. Serum amyloid A (SAA) is an acute phase protein that mainly produced by hepatocytes, and promotes endothelial dysfunction via a pro-inflammatory and pro-thrombotic effect in atherosclerosis and renal disease. However, the role of SAA in APAP-induced liver injury remains unclear.MethodsIn this study, we used neutralizing antibody (anti-SAA) or antagonistic small peptide derived from sequence of human SAA1/2 (SAA-pep) to block the functional activity of Saa1/2 in mouse serum. Immunohistochemistry staining, Evans blue and platelet adhesion assays were performed to examine the liver damage, the integrity of sinusoidal endothelium and platelets accumulation in APAP-induce liver injury.ResultsOur study showed that in the early stage of APAP-induced acute liver injury in mice, the intrahepatic and serum Saa1/2 levels were significantly increased within 24 hours, and then gradually reduced to normal level from 3 days. Neutralization of Saa1/2 by antibodies or peptides effectively prevented the destruction of hepatic sinusoids, reduced the intrahepatic hemorrhage and platelet accumulation in liver, as well as increased the survival rate of mice treated with lethal dose of APAP. In vitro experiments showed that Saa1/2 aggravated LSECs death induced by APAP. Moreover, Saa1/2 promoted platelets adhesion on LSECs via Tlr2/Vcam-1 axis.ConclusionOur findings suggest that Saa1/2 promotes APAP-induced liver injury by damaged LSECs and exacerbated platelets aggregation. This study provides a potential target for intervention of acute liver injury/failure caused by hepatotoxic drugs such as APAP.