Tratamiento con tocilizumab en amiloidosis AA: informe de casos y revisión de la literatura / Tocilizumab treatment in aa amyloidosis: case report and literature review

Introducción: la amiloidosis AA puede ser una complicación de ciertos trastornos inflamatorios crónicos, aunque entre el 21% y 50% puede ser idiopática. No existe un tratamiento específico. El tocilizumab, dirigido contra el receptor de IL-6 y orientado a disminuir la producción de SAA, podría ser eficaz. Métodos: en este estudio informamos datos de 6 pacientes con amiloidosis AA tratados con tocilizumab monoterapia subcutáneo en el período 2011-2018. Los criterios de valoración principales fueron la mejora clínica y bioquímica de los órganos afectados y los parámetros bioquímicos marcadores de inflamación. Resultados: el riñón estaba afectado en todos los pacientes, manifestándose con caída del filtrado glomerular y síndrome nefrótico. La hemorragia digestiva se presentó en un paciente y otro tenía afectación pulmonar en la biopsia. Luego del posterior al tratamiento, todos mejoraron el hematocrito, la albúmina sérica y el índice de masa corporal. El SAA disminuyó en 5 pacientes. Un paciente mejoró su función renal, mientras 4 se mantuvieron estables. Tres pacientes disminuyeron los valores de proteinuria. Conclusión: el tratamiento con tocilizumab podría ser eficaz en el tratamiento de los pacientes con amiloidosis AA. (AU)

Introduction: AA amyloidosis can be a complication of certain chronic inflammatory disorders, although between 21% and 50% can be idiopathic. There is no specific treatment. Tocilizumab, directed against the IL-6 receptor and aimed at decreasing SAA production, could be effective. Methods: in this study, we report data from 6 patients with AA amyloidosis treated with subcutaneous tocilizumab monotherapy between the period 2011-2018. The main endpoints were the clinical and biochemical improvement of the affected organs and the biochemical parameters markers of inflammation. Results: the kidney was affected in all patients, manifesting with a fall in glomerular filtration rate and nephrotic syndrome. Gastrointestinal bleeding occurred in one patient and another had lung involvement on biopsy. After treatment, all improved hematocrit, serum albumin, and body mass index. SAA decreased in 5 patients. One patient improved his kidney function, while 4 remained stable. Three patients decreased proteinuria values. Conclusion: treatment with tocilizumab could be effective in the treatment of patients with AA amyloidosis. (AU)

ELISA of amyloid A in paired bronchoalveolar lavage fluid and serum samples of healthy horses / Detecção de amilóide A no lavado broncoalveolar de equinos hígidos

Pulmonary disorders are common in horses, and treatment efficiency depends on an adequate diagnosis. Amyloid A is the most sensitive indicator of pathology in horses. The objective of this study was to establish the concentration of amyloid A of bronchoalveolar lavage fluid (BALF) in healthy horses. Health condition of horses was considered normal based on physical examination, complete blood count, biochemical parameters, and BALF cytology. Blood and BALF were collected from thirty adult female horses. Amyloid A concentrations in serum and BALF were measured using commercial ELISA tests. Amyloid A was detected in serum (mean ± SD = 3.71±2.51) and BALF (mean ± SD = 0.000745±0.000785) of all horses. In conclusion, SAA can also be measured in bronchoalveolar fluid, affording early detection of respiratory infections or inflammatory conditions.(AU)

Distúrbios pulmonares são comuns nos cavalos e a eficiência do tratamento depende de um diagnóstico adequado e precoce. A amilóide A é um biomarcador sensível na deteccção de patologias inflamatórias e infecciososa em cavalos. O objetivo deste estudo foi estabelecer a concentração de amilóide A no líquido broncoalveolar (LBA) em cavalos saudáveis. Os cavalos foram considerados saudaveis baseado nos achados de normalidade do exame físico, hemograma, parâmetros bioquímicos e citologia do LBA. Sangue e LBA foram coletados de 30 fêmeas equinas adultas. Os níveis de Amilóide A no soro e no LBA foram mensurados por meio do teste de ELISA. A amilóide A foi detectada no soro (média ± DP = 3,71±2,51) e no LBA (média ± DP = 0,000745±0,000785) de todos os animais. Conclui-se que a amilóide A também pode ser mensurada no LBA, auxiliando no diagnóstico precoce de processos inflamatórios e infecciosos pulmonares.(AU)

Association of rs4638289 and rs7131332 polymorphisms of the serum amyloid A1 gene with Kawasaki disease / 中国当代儿科杂志

OBJECTIVE@#To study the association of the polymorphisms of the serum amyloid A1 (SAA1) gene at rs4638289 and rs7131332 loci with Kawasaki disease (KD) and its complication coronary artery lesion (CAL) in children.@*METHODS@#A total of 105 Han children with KD who were hospitalized and treated from 2013 to 2017 were enrolled as the KD group. A total of 100 Han children who underwent physical examination were enrolled as the control group. According to the presence or absence of CAL, the KD group was further divided into a CAL group with 23 children and a non-CAL (NCAL) group with 82 children. Polymerase chain reaction-restriction fragment length polymorphism was used to investigate the polymorphisms of the SAA1 gene at rs4638289 and rs7131332 loci.@*RESUKTS@#For the locus rs4638289 of the SAA1 gene, there were no significant differences between the KD and control groups in the genotype frequencies of AA, AT, and TT and the allele frequencies of A and T (P>0.05). But there were significant differences between the CAL and NCAL groups in the genotype frequencies of AA, AT, and TT (P=0.016), while there were no significant differences in the allele frequencies of A and T (P>0.05). AT genotype was a protective factor against CAL (OR=0.276, 95%CI: 0.099-0.772, P=0.011). For the locus rs7131332 of the SAA1 gene, there were no significant differences between the KD and control groups in the genotype frequencies of AA, AG, and GG and the allele frequencies of A and G (P>0.05). There were also no significant differences between the CAL and NCAL groups in the genotype frequencies of AA, AG, and GG and the allele frequencies of A and G (P>0.05).@*CONCLUSIONS@#Polymorphisms of the SAA1 gene at loci rs4638289 and rs7131332 are not associated with the onset of KD, while the polymorphism at the locus rs4638289 is associated with CAL in KD patients. KD patients with genotype AT may have a reduced risk of CAL.

Clinical Value of Serum Amyloid A and Misfolded Transthyretin for Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients / 中国实验血液学杂志

OBJECTIVE@#To evaluate the clinical value of serum amyloid A (SAA1/2) and misfolded transthyretin (TTR) for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) patients.@*METHODS@#30 R/R DLBCL patients were enrolled as observation group, 20 remission/stabilization DLBCL and 10 chronic lymphadenitis patients were enrolled as control group. SELDI technique, Tris-Tricine sodium dodecyl sulfate-polyacrylamide gel electro-phoresis, the shotgun-LTQ-MS method, and bioinformatics technique were used to detected and analyzed SAA and TTR in R/R DLBCL patients. SPSS 21.0 software was used to analyze the relationship between the high expression of SAA, misfolded TTR in serum and the clinicopathological features, survival time of R/R DLBCL. patients Chi-square test was used to analyze clinical count data, Kaplan-Meier curve was used for survival analysis, and Log-Rank test was used to compare single-factor survival differences.@*RESULTS@#The high expression of SAA and TTR (SAA@*CONCLUSION@#Both SAA and misfolded TTR are poor prognosis factors of R/R DLBCL patients.

Serum amyloid A levels in acute and chronic urticaria

Abstract: Background: Serum amyloid A is an acute-phase protein. There is no available data regarding serum amyloid A levels in patients with acute and chronic urticaria (CU). Objective: To investigate the association between serum amyloid A and urticaria. Methods: This was a case-control study of 81 patients who visited our Hospital between June and December 2016 with a diagnosis of urticaria. Eighty healthy controls (HC) who visited for routine health examination and physical checkups were recruited. Serum amyloid A and C-reactive protein levels were measured by automated methods. Results: Serum amyloid A and C-reactive protein levels were significantly higher in AU (Serum amyloid A: 207.1 (6.7-439.0) mg/L; C-reactive protein: 16.0 (0.2-90.0) mg/L) and CU (Serum amyloid A: 6.5 (2.5-35.8) mg/L; C-reactive protein: 1.0 (0.1-16.0) mg/L) compared with HC (Serum amyloid A: 5.04 (2.0-9.1) mg/L; C-reactive protein: 1.2 (0.1-5.6) mg/L), and in AU compared with CU (all P<0.05). There were no differences between the CU and HC group. In CU, Serum amyloid A levels in those with moderate/severe urticaria (median, 16.4 (9.7-35.8) mg/L) were higher than in those with mild urticaria (median, 5.7 (2.5-9.5) mg/L) and HC (all P<0.05). Serum amyloid A and C-reactive protein levels exceeded the normal lab range in 90.7% and 72.1% patients with AU compared with 28.9% and 13.2% patients with CU, respectively. Significant positive correlations were found between serum amyloid A and C-reactive protein (r = 0.562, P < 0.001). Study limitations: There was no comparison between active disease and remission. Conclusion: There was an association between serum amyloid A levels and urticaria. Higher serum amyloid A levels were associated with AU and more severe CU. Serum amyloid A may help to identify CU patients earlier.

Amiloidosis AA: Estudio de cohorte en una institución / AA amyloidosis. A single institution cohort study

La amiloidosis AA causa principalmente disfunción renal, lo que lleva a un elevado riesgo de mortalidad a mediano plazo. Existe escasa información epidemiológica sobre la amiloidosis AA en Argentina, por lo que el objetivo de este trabajo fue describir las características epidemiológicas de esta enfermedad en un hospital de tercer nivel en nuestro país. Se realizó una cohorte prospectiva de todos los pacientes consecutivos con evidencia de amiloidosis AA, por inmunohistoquímica de tejidos, incluidos en el Registro Institucional de Amiloidosis del Hospital Italiano de Buenos Aires, desde el 01/04/2012 hasta el 31/12/2017. De los 121 pacientes del registro, se incluyeron 18 con AA para el análisis. Del total incluido, 50% (9) eran mujeres, con una mediana de edad de 53.5 (rango intercuartil, RII 46-61) años. El 88.9% (16) presentó compromiso renal, todos tuvieron proteinuria, y 6 requirieron diálisis. Seis tuvieron infiltración amiloide del aparato digestivo. La latencia entre la aparición de la enfermedad subyacente y el diagnóstico de AA tuvo una mediana de 27 (RII 8-35) años. La enfermedad subyacente fue de origen inflamatorio en 6 casos. En el 50% (9) de los enfermos la causa de amiloidosis AA fue desconocida. En el restante 50% esas causas se asemejan a las de países desarrollados. A su vez, nuestros resultados resaltan la importancia de su diagnóstico diferencial para identificar el tratamiento o seguimiento más adecuado según el cuadro que presente cada paciente.

There is limited epidemiological information on AA amyloidosis in Argentina, so the objective of this study was to describe the epidemiological characteristics of this disease in a tertiary hospital in our country. We designed a prospective clinical cohort of all consecutive patients with AA amyloidosis confirmed by immunohistochemistry in tissue from the Institutional Registry of Amyloidosis of the Hospital Italiano de Buenos Aires, in the period 04/01/2012- 12/31/2017. Of the 121 patients in the registry, 18 were included with AA for the analysis. Of the total included, 50% (9) were female, with a median age of 53.5 (interquartile range, RII 46-61) years. The 88.9% (16) of cohort presented renal compromise, all had proteinuria, and 6 required dialysis. Six had amyloid infiltration of the digestive system. The latency between the onset of the underlying disease and the diagnosis of AA had a median of 27 (RII 8-35) years. The underlying disease was of inflammatory origin in 6 cases. In 50% (9) of the patients the cause of AA amyloidosis was unknown. In the remaining 50%, these causes resemble those observed in developed countries. Furthermore, our results highlight the importance of their differential diagnosis to identify the most appropriate treatment or follow-up according to the situation presented by each patient.

Circulation levels of acute phase proteins pentraxin 3 and serum amyloid A in atherosclerosis have correlations with periodontal inflamed surface area

Abstract Objectives One of the plausible mechanisms in the relationship between periodontitis and coronary artery disease (CAD) is the systemic inflammatory burden comprised of circulating cytokines/mediators related to periodontitis. This study aims to test the hypothesis that periodontal inflamed surface area (PISA) is correlated with higher circulating levels of acute phase reactants (APR) and pro-inflammatory cytokines/mediators and lower anti-inflammatory cytokines/mediators in CAD patients. Material and Methods Patients aged from 30 to 75 years who underwent coronary angiography with CAD suspicion were included. Clinical periodontal parameters (probing depth - PD, clinical attachment loss, and bleeding on probing - BOP) were previously recorded and participants were divided into four groups after coronary angiography: Group 1: CAD (+) with periodontitis (n=20); Group 2: CAD (+) without periodontitis (n=20); Group 3: CAD (-) with periodontitis (n=21); Group 4: CAD (-) without periodontitis (n = 16). Serum interleukin (IL) −1, −6, −10, tumor necrosis factor (TNF)-α, serum amyloid A (SAA), pentraxin (PTX) 3, and high-sensitivity C-reactive protein (hs-CRP) levels were measured with ELISA. Results Groups 1 and 3 showed periodontal parameter values higher than Groups 2 and 4 (p<0.0125). None of the investigated serum parameters were statistically significantly different between the study groups (p>0.0125). In CAD (-) groups (Groups 3 and 4), PISA has shown positive correlations with PTX3 and SAA (p<0.05). Age was found to predict CAD significantly according to the results of the multivariate regression analysis (Odds Ratio: 1.17; 95% Confidence Interval: 1.08-1.27; p<0.001). Conclusions Although age was found to predict CAD significantly, the positive correlations between PISA and APR in CAD (-) groups deserve further attention, which might depend on the higher PISA values of periodontitis patients. In further studies conducted in a larger population, the stratification of age groups would provide us more accurate results.

Decrease in Serum Amyloid a Protein Levels Following Three-month Stays in Negatively Charged Particle-dominant Indoor Air Conditions / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>The changes in serum adipokines and cytokines related to oxidative stress were examined during 3 months 'Off to On' and 'On to Off' periods using negatively charged particle-dominant indoor air conditions (NCPDIAC).</p><p><b>METHODS</b>Seven volunteers participated in the study, which included 'OFF to 3 months ON' periods (ON trials) for a total of 16 times, and 'ON to 3 months OFF' (OFF trials) periods for a total of 13 times.</p><p><b>RESULTS</b>With the exception of one case, serum amyloid A (SAA) levels decreased significantly during the ON trials.</p><p><b>CONCLUSION</b>Considering that SAA is an acute phase reactive protein such as C reactive protein (CRP), this observed decrease might indicate the prevention of cardiovascular and atherosclerotic changes, since an increase in high-sensitive CRP is associated with the subsequent detection of these events.</p>

Pretreatment Serum Amyloid A and C-reactive Protein Comparing with Epstein-Barr Virus DNA as Prognostic Indicators in Patients with Nasopharyngeal Carcinoma: A Prospective Study / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The measuring Epstein-Barr virus (EBV) DNA is an important predictor of nasopharyngeal carcinoma (NPC). This study evaluated the predictive value of pretreatment serum amyloid A (SAA) and C-reactive protein (CRP) comparing with EBV DNA in patients with NPC. MATERIALS AND METHODS: In an observational study of 419 non-metastatic NPC patients, we prospectively evaluated the prognostic effects of pretreatment SAA, CRP, and EBV DNA on survival. The primary end-point was progress-free survival (PFS). RESULTS: The median level of SAA and CRP was 4.28 mg/L and 1.88 mg/L, respectively. For the high-SAA group (> 4.28 mg/L) versus the low-SAA (≤ 4.28 mg/L) group and the high-CRP group (> 1.88 mg/L) versus the low-CRP (≤ 1.88 mg/L) group, the 5-year PFS was 64.5% versus 73.1% (p=0.013) and 65.2% versus 73.3% (p=0.064), respectively. EBV DNA detection showed a superior predictive result, the 5-year PFS in the EBV DNA ≥ 1,500 copies/mL group was obviously different than the EBV DNA < 1,500 copies/mL group (62.2% versus 77.8%, p < 0.001). Multifactorial Cox regression analysis confirmed that in the PFS, the independent prognostic factors were including EBV DNA (hazard ratio [HR], 1.788; p=0.009), tumour stage (HR, 1.903; p=0.021), and node stage (HR, 1.498; p=0.049), but the SAA and CRP were not included in the independent prognostic factors. CONCLUSION: The results of SAA and CRP had a certain relationship with the prognosis of NPC, and the prognosis of patients with high level of SAA and CRP were poor. However, the predictive ability of SAA and CRP was lower than that of EBV DNA.

Differential protein expression in patients with urosepsis / 中华创伤杂志(英文版)

PURPOSE@#Urosepsis in adults comprises approximately 25% of all sepsis cases, and is due to complicated urinary tract infections in most cases. However, its mechanism is not fully clarified. Urosepsis is a very complicated disease with no effective strategy for early diagnosis and treatment. This study aimed to identify possible target-related proteins involved in urosepsis using proteomics and establish possible networks using bioinformatics.@*METHODS@#Fifty patients admitted to the Urology Unit of Lanzhou General PLA (Lanzhou, China), from October 2012 to October 2015, were enrolled in this study. The patients were further divided into shock and matched-pair non-shock groups. 2-DE technique, mass spectrometry and database search were used to detect differentially expressed proteins in serum from the two groups.@*RESULTS@#Six proteins were found at higher levels in the shock group compared with non-shock individuals, including serum amyloid A-1 protein (SAA1), apolipoprotein L1 (APOL1), ceruloplasmin (CP), haptoglobin (HP), antithrombin-III (SERPINC1) and prothrombin (F2), while three proteins showed lower levels, including serotransferrin (TF), transthyretin (TTR) and alpha-2-macroglobulin (A2M).@*CONCLUSION@#Nine proteins were differentially expressed between uroseptic patients (non-shock groups) and severe uroseptic patients (shock groups), compared with non-shock groups, serum SAA1, APOL1,CP, HP, SERPINC1and F2 at higher levels, while TF, TTR and A2M at lower levels in shock groups.these proteins were mainly involved in platelet activation, signaling and aggregation, acute phase protein pathway, lipid homeostasis, and iron ion transport, deserve further research as potential candidates for early diagnosis and treatment. (The conclusion seems too simple and vague, please re-write it. You may focus at what proteins have been expressed and introduce more detail about its significance.).

Relationships of Inflammatory Factors and Risk Factors with Different Target Organ Damage in Essential Hypertension Patients / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Atherosclerosis (AS) is an inflammatory disease. Inflammation was considered to play a role in the whole process of AS. This study aimed to analyze the relationships of inflammatory factors and risk factors with different target organ damages (TOD) in essential hypertension (EH) patients and to explore its clinical significance.</p><p><b>METHODS</b>A total of 294 EH patients were selected and divided into four groups according to their conditions of TOD. Forty-eight healthy subjects were selected as control. The clinical biochemical parameters, serum amyloid A, serum tryptase, and lipoprotein-associated phospholipase A2 (Lp-PLA2) in each group were detected, and the related risk factors were also statistically analyzed.</p><p><b>RESULTS</b>Fibrinogen (Fbg) was the most significant independent risk factor in acute coronary syndrome (ACS) group (odds ratio [OR]: 22.242, 95% confidence interval [CI]: 6.458-76.609, P< 0.001) with the largest absolute value of the standardized partial regression coefficient B' (b': 1.079). Lp-PLA2 was the most significant independent risk factor in stroke group (OR: 13.699, 95% CI: 5.236-35.837, P< 0.001) with b' = 0.708. Uric acid (UA) was the most significant independent risk factor in renal damage group (OR: 15.307, 95% CI: 4.022-58.250, P< 0.001) with b' = 1.026.</p><p><b>CONCLUSIONS</b>Fbg, Lp-PLA2, and UA are the strongest independent risk factors toward the occurrence of ACS, ischemic stroke, and renal damage in EH patients, thus exhibiting the greatest impacts on the occurrence of ACS, ischemic stroke, and renal damage in EH patients, respectively.</p>

Are pulmonary hemostasis and fibrinolysis out of balance in equine chronic pneumopathies?

Clinical examination, bronchoalveolar lavage fluid (BALF) cytology, acute-phase protein, and pulmonary hemostasis and fibrinolysis marker (fibrinogen, serum amyloid A [SAA], and D-dimer) results were compared between control and respiratory disease-affected horses. Using a clinical scoring system, horses (n = 58) were classified as respiratory disease-free (Controls, n = 15) or with recurrent airway obstruction (RAO; n = 18), inflammatory airway disease (n = 14) or chronic interstitial pneumopathy (n = 11). There were no significant differences in fibrinogen concentrations among groups, but there was a trend toward a lower value in controls (median 0.0024 g/L) than in horses with chronic pneumopathies (median 0.0052 g/L), in particular, those with RAO (median 0.0062 g/L). Fibrinogen concentration was positively correlated with percentage of neutrophils in BALF (r(s) = 0.377, p = 0.004). SAA concentrations were low; 65.5% of samples were below the detection limit. D-dimer concentrations were also low and quantifiable concentrations were only obtained after ultrafiltration and only in RAO (median 0.1 mg/L). In conclusion, there was limited evidence of increased coagulatory activity in chronic pneumopathies, apart from RAO. It is uncertain whether fibrinogen and D-dimer concentrations increased due to their role as acute-phase proteins or as a misbalance of coagulation and fibrinolysis.

Augmented Serum Amyloid A1/2 Mediated by TNF-induced NF-κB in Human Serous Ovarian Epithelial Tumors

Tumor necrosis factor-α (TNF) is well known to be involved in the immune system and ovarian inflammation. Ovarian cancer is an inflammation-related malignancy that lacks early screening strategies, resulting in late diagnosis followed by high mortality. Based on our previous data, TNF induced abundant serum amyloid A (SAA), an acute phase protein linked to inflammation, in ovarian granulosal cells. To date, the regulation and expression of SAA in ovarian cancer is not fully elucidated. Here, we investigated the relationship between TNF and SAA by comparing human normal ovarian tissues and serous ovarian tumors. We found that SAA1/2 was significantly expressed in tumor tissues, but no or trace expression levels in normal tissues. TNF was also significantly upregulated in ovarian tumor tissues compared to normal tissues. Moreover, TNF significantly increased SAA1/2 levels in human ovarian cancer cell lines, OVCAR-3 and SKOV-3, in a time-dependent manner. Since the SAA1 promoter contains two nuclear factor (NF)-κB sites, we examined whether TNF regulates SAA1 promoter activity. Deletion analysis revealed that the proximal NF-κB site (−95/−85) played a critical role in regulating TNF-induced SAA1 promoter activity. Within 2 h after intraperitoneal injection of lipopolysaccharide, a product known to stimulate release of TNF, SAA preferably localized to ovarian epithelial cells and the thecal-interstitial layers compared to granulosal cell layers. Based on Gene Expression Omnibus (GEO) database, SAA1/2 and TNF were dominantly expressed in advanced grade ovarian cancer. Taken together, the accumulation of SAA1/2 in ovarian cancer could be mediated by TNF-induced NF-κB activation.

Localization of Serum Amyloid A3 in the Mouse Ovary

Tumor necrosis factor-α (TNF-α) induces serum amyloid A (SAA) 3 among acute-phase proteins in mouse granulosa cells by activating NF-κB signaling via p55 TNF-α receptor type 1. However, the localization of SAA3 within the ovary is unknown. Here we investigated ovarian localization of SAA3 in a mouse ovulation model and in response to IL-1β, a proinflammatory mediator. For the ovulation model, equine chorionic gonadotropin (eCG; 2.5 IU) was administered to mice subcutaneously (sc) to stimulate follicular development on day 25 of age and then 50 h after eCG, human chorionic gonadotropin (hCG; 2.5 IU) was administered sc to induce ovulation. The mouse ovulation model was characterized by the localization of CYP19 mRNA expression to granulosa layers of larger follicles. SAA3 mRNA, determined by in situ hybridization, was broadly expressed throughout the whole ovary. Granulosa layers and small follicles expressed higher SAA3 mRNA compared to thecal-interstitial layers and large follicles, respectively. Interestingly, atretic follicles contained cells expressing intense SAA3 mRNA. After ovulation, SAA3 mRNA expression was intensely evident in ruptured follicles and corpora lutea (CL). The intraperitoneal administration of IL-1β revealed the intense and extensive appearance of specific cells expressing SAA3 mRNA around follicles and in CL. In addition, Gene Expression Omnibus (GEO) database analysis supported expression pattern of SAA3 mRNA observed in mouse ovulation model. Taken together, SAA3 was broadly distributed through the whole ovary, but intensely expressed in atretic follicles and CL. Furthermore, proinflammatory mediators could trigger the intense appearance of SAA3 around follicles and in CL.

Serum amyloid A inhibits dendritic cell differentiation by suppressing GM-CSF receptor expression and signaling

In this study, we report that an acute phase reactant, serum amyloid A (SAA), strongly inhibits dendritic cell differentiation induced by GM-CSF plus IL-4. SAA markedly decreased the expression of MHCII and CD11c. Moreover, SAA decreased cell surface GM-CSF receptor expression. SAA also decreased the expression of PU.1 and C/EBPα, which play roles in the expression of GM-CSF receptor. This inhibitory response by SAA is partly mediated by the well-known SAA receptors, Toll-like receptor 2 and formyl peptide receptor 2. Taken together, we suggest a novel insight into the inhibitory role of SAA in dendritic cell differentiation.

Serum amyloid A promotes the inflammatory response via p38-MAPK/SR-BI pathway in THP-1 macrophages / 生理学报

To investigate the effect and mechanism of serum amyloid A (SAA) on the expression of scavenger receptor class B type I (SR-BI) and inflammatory response in THP-1 macrophages, the human THP-1 cells were treated with SAA and p38-MAPK agonist (anisomycin) or p38-MAPK inhibitor (SB203580). Then, the expressions of SR-BI, phosphorylated p38-MAPK and inflammatory factors (MCP-1, TNF-α, IL-1β) were examined by real-time quantitative PCR, Western blotting and ELISA, respectively. The results showed that, compared with control group, SAA increased the levels of inflammatory factors (MCP-1, TNF-α, IL-1β), down-regulated the expressions of SR-BI, and up-regulated the expression of phosphorylated p38-MAPK protein in a concentration- and time-dependent manner in THP-1 cells (P < 0.05). After treatment with SAA and p38-MAPK agonist (anisomycin) in THP-1 cells, the expression of SR-BI was down-regulated, and the levels of inflammatory factors and phosphorylated p38-MAPK protein expression were increased, compared with the group only treated by SAA (P < 0.05). In contrast, the SR-BI expression was up-regulated, whereas inflammatory factors and phosphorylated p38-MAPK protein expressions were decreased after the cells were treated with SAA and p38-MAPK inhibitor (SB203580) (P < 0.05). The results suggest that SAA-promoted inflammatory response in THP-1 macrophages may be through the phosphorylation of p38-MAPK and inhibition of SR-BI expression.

Novas perspectivas para o papel de amilóide sérica A (SAA) na obesidade e resistência à insulina / New insights into the role of serum amyloid A (SAA) on obesity and insulin resistance

Chronic low-grade endotoxemia is an important player in obesity and insulin resistance associated to a high-fat diet (HFD). On the other hand, although it is known that intense endotoxemia and infection reduce appetite and induce intense catabolism, leading to weight loss during the acute inflammatory phase, the late effects of an intense endotoxemia were previously unexplored. Here we report that, besides the concurrent effects, multiple and intense endotoxemia causes long lasting biochemical alterations in the adipose tissue that intensify the harmful effects of a HFD. Mice submitted to multiple and severe endotoxemia had increased the adipose tissue expression of TLR-4, CD14 and SAA3, remaining altered after one week in recovery. When associated to a HFD, mice previously submitted to acute endotoxemia showed a more severe weight gain and impaired insulin sensitivity. Adopting the HFD as an obesogenic stimulus, we evaluated the participation of the protein serum amyloid A (SAA) in obesity development. Using a SAA-targeted antisense oligonucleotide, we observed that the depletion of SAA prevented metabolic alterations, endotoxin elevation, weight gain and insulin resistance in a diet-induced obesity protocol. Inadequate sleep is another important factor to be considered in the obesity epidemic. We found that sleep restriction (SR) causes biochemical and morphological alterations in mice adipose tissue. The levels of serum resistin and the adipose tissue mRNA expression of resistin, TNF-α and IL-6 were increased after SR. When associated to a HFD, mice previously submitted to SR gained more weight with increased macrophage infiltration in the epididymal adipose tissue, and insulin resistance. SAA is also part of the initial biochemical alterations caused by SR. It was observed that the expression of SAA in liver and adipose tissue is upregulated, with return to baseline when sleep is restored. Furthermore, 48 hours of total sleep restriction in healthy human volunteers also caused a serum elevation in SAA concentrations. Considering that SAA induces cell proliferation, we suggest that situations with an increase in SAA production and the consecutive preadipocyte proliferation would prime the adipose tissue to further adipocyte differentiation and hypertrophy. Furthermore, we suggest that SAA alter LPS signaling, possibly inhibiting its clearance. The mechanism associating inflammation and obesity is complex and encompass a diversity of factors; the inflammatory protein SAA may be one of them. In conclusion, our data describes the relationship between SAA, acute inflammation, sleep restriction and obesity

Endotoxemia crônica de baixo grau tem um importante papel na obesidade e resistência à insulina associada a uma ração hiperlipídica. Por outro lado, embora se saiba que a endotoxemia intensa e infecção reduzam o apetite e induzam a um intenso catabolismo, conduzindo a perda de peso durante a fase aguda da inflamação, os efeitos tardios da endotoxemia intensa nunca foram explorados. Aqui mostramos que, além dos efeitos correntes, a endotoxemia aguda provoca alterações bioquímicas prolongadas no tecido adiposo que intensificam os efeitos deletérios de uma ração hiperlipídica. Camundongos submetidos à endotoxemia aguda apresentaram aumento na expressão de TLR-4, CD14 e SAA3 no tecido adiposo, permanecendo alteradas após uma semana em recuperação. Quando associado a uma ração hiperlipídica, os camundongos previamente submetidos à endotoxemia aguda mostraram um ganho de peso mais pronunciado e uma maior resistência à insulina. Adotando a ração hiperlipídica como um estímulo obesogênico, foi avaliada a participação da proteína amilóide sérica A (SAA) no desenvolvimento da obesidade. Usando um oligonucleotídeo antisense anti-SAA, observamos que a depleção da SAA previne as alterações metabólicas, elevação de endotoxina, ganho de peso e resistência à insulina associadas a ração rica em gordura. O sono inadequado é outro fator importante a ser considerado na epidemia de obesidade. Descobrimos que a restrição do sono (SR) provoca alterações bioquímicas e morfológicas no tecido adiposo de camundongos. A concentração de resistina no soro e a expressão de mRNA no tecido adiposo de resistina, TNF-α e IL- 6 foram aumentadas após SR. Quando associado a uma ração hiperlipídica, os camundongos submetidos previamente à SR ganharam mais massa com aumento da infiltração de macrófagos no tecido adiposo epididimal, e resistência à insulina. SAA também faz parte das alterações bioquímicas iniciais provocadas pelo SR. Observou-se que a expressão de SAA no fígado e tecido adiposo é regulada positivamente, com retorno ao basal quando o sono é restaurado. Além disso, 48 horas de restrição de sono total em voluntários humanos saudáveis também causou uma elevação nas concentrações séricas de SAA. Considerando que SAA induz proliferação, sugerimos que situações onde ocorra aumento na produção de SAA e a consecutiva proliferação celular, o tecido adiposo se tornaria predisposto a futura diferenciação e hipertrofia. Além disso, sugerimos que SAA altera a sinalização de LPS, possivelmente inibindo sua depuração. O mecanismo de associação entre a inflamação e a obesidade é complexo e inclui uma diversidade de fatores; a proteína inflamatória SAA pode ser um deles. Em conclusão, nossos dados descrevem a relação entre SAA, inflamação aguda, restrição do sono e obesidade

Evaluation of procalcitonin, C-reactive protein, interleukin-6 & serum amyloid A as diagnostic biomarkers of bacterial infection in febrile patients.

Background & objectives: Early identification of bacterial infection in patients with fever is important for prompt treatment. However, the available parameters such as C-reactive protein (CRP) and leukocyte counts are not very specific. This study was aimed to assess the diagnostic value of procalcitonin (PCT), CRP, interleukin-6 (IL-6) and serum amyloid A (SAA) for bacterial infection in febrile patients. Methods: Serum samples were collected from febrile patients between January and December 2012 and processed for blood cultures. PCT, IL-6, CRP and SAA levels were measured. The patients were divided into three groups according to the final diagnosis: bacteraemia group (group1), bacterial infection with negative blood culture (group 2) and non-bacterial infection group (group 3). Results: There were significant (P<0.05) difference in the levels of PCT, CRP, IL-6 and SAA among the three groups. The PCT levels of patients with gram-positive bacterial infections were lower than gram-negative bacterial infections (0.53 vs 2.13, P < 0.01). The best cut-off value to detect bacterial infections was 0.26 ng/ml for PCT. PCT, CRP, IL-6 and SAA had areas under the curve of 0.804, 0.693, 0.658 and 0.687, respectively. Interpretation & conclusions: Our results showed PCT as a valuable marker of bacterial infections in febrile patients. PCT was superior to CRP, IL-6 or SAA in the early identification of bacterial infection. More prospective and large scale studies are warranted to confirm these findings.

Ação da proteína amiloide sérica A em melanomas / Activity of serum amyloid A protein in melanomas

Concentrações séricas basais da proteína amiloide sérica A (SAA) estão significativamente aumentadas em pacientes com câncer e alguns autores sugerem uma relação causal. Trabalho anterior do grupo mostrou que a SAA induz a proliferação de duas linhagens de glioblastoma humano e afeta os processos de invasividade in vitro, sustentando um papel pró-tumoral para esta proteína. Com base nesse trabalho, investigamos a abrangência dos efeitos de SAA para outro tipo de célula tumoral e para isso escolhemos um painel de linhagens de melanoma humano e uma linhagem primária obtida a partir de aspirado de linfonodo de paciente com melanoma, por nós isolada. Observamos que apesar da célula precursora de melanomas, isto é, melanócito, não produzir SAA, todas as linhagens de melanoma produziram a proteína e expressaram alguns dos seus receptores. Além disso, quando estas células foram estimuladas com SAA houve uma inibição da proliferação em tempos curtos de exposição (48 horas) e efeitos citotóxicos após um tempo maior (7 dias). A SAA também afetou processos de invasividade e a produção das citocinas IL-6, IL-8 e TNF-α. Aos avaliarmos o efeito da SAA na interação das células de melanoma com células do sistema imune, vimos que a SAA ativou uma resposta imune anti-tumoral aumentando a expressão de moléculas co-estumolatórias, como CD69 e HLA-DR, e sua função citotóxica. Ainda, vimos que a produção de TNF-α, IFN-γ, IL-10, IL-1ß e IL-8 estimuladas por SAA podem contribuir com os efeitos desta. De forma geral estes resultados nos levam a crer que a SAA tem atividade anti-tumoral em melanomas. Finalizando, com base na importância do desenvolvimento da resistência às terapias atuais para o melanoma, observamos que em células resistentes ao PLX4032, um inibidor de BRAF, os efeitos imunomodulatórios induzidos pela SAA estão abolidos, possivelmente identificando um novo componente da resistência

Basal serum concentrations of the protein serum amyloid A are significantly increased in cancer patients and some authors suggest a causal relationship. Previous work of our research group showed that SAA induces proliferation of two cell lines of human glioblastoma and affects invasiveness processes in vitro, supporting a pro-tumor role for this protein. Based on this work, we investigated the extent of SAA effects to another type of tumor cell and we chose a panel of human melanoma cell lines and primary line obtained from a patient with melanoma by lymph node aspirate. Melanoma cells were isolated by us. We observed that while the precursor cells of melanoma, melanocytes, do not produce SAA, all melanoma cell lines expressed the protein and produced some of their receptors. Moreover, when these cells were stimulated with SAA there was an inhibition of proliferation in short exposure times (48 hours) and cytotoxic effects after a longer period (7 days). SAA also affected invasive procedures and the production of the cytokines IL-6, IL-8 and TNF-α. To evaluate the SAA effect in the interaction of melanoma cells with immune system cells, we found that SAA activated an anti-tumor immune response by increasing the expression of co-estimulatory molecules such as CD69 and HLA-DR, and their cytotoxic function. Furthermore, we found that the production of TNF-α, IFN-γ, IL-10, IL-1ß and IL-8 stimulated by SAA can contribute to this effect. In general these results lead us to believe that the SAA has anti-tumor activity in melanomas. Finally, based on the importance of the resistance development to current therapies for melanoma we observed that in cells resistant to PLX4032, a BRAF inhibitor, the immunomodulatory effects induced by SAA are abolished, possibly identifying a new resistance component

The prognostic value of serum C-reactive protein-bound serum amyloid A in early-stage lung cancer / 癌症

<p><b>BACKGROUND</b>Elevated levels of serum C-reactive protein (CRP) have been reported to have prognostic significance in lung cancer patients. This study aimed to further identify CRP-bound components as prognostic markers for lung cancer and validate their prognostic value.</p><p><b>METHODS</b>CRP-bound components obtained from the serum samples from lung cancer patients or healthy controls were analyzed by differential proteomics analysis. CRP-bound serum amyloid A (CRP-SAA) was evaluated by co-immunoprecipitation (IP). Serum samples from two independent cohorts with lung cancer (retrospective cohort, 242 patients; prospective cohort, 222 patients) and healthy controls (159 subjects) were used to evaluate the prognostic value of CRP-SAA by enzyme-linked immunosorbent assay.</p><p><b>RESULTS</b>CRP-SAA was identified specifically in serum samples from lung cancer patients by proteomic analysis. CRP binding to SAA was confirmed by co-IP in serum samples from lung cancer patients and cell culture media. The level of CRP-SAA was significantly higher in patients than in healthy controls (0.37 ± 0.58 vs. 0.03 ± 0.04, P < 0.001). Elevated CRP-SAA levels were significantly associated with severe clinical features of lung cancer. The elevation of CRP-SAA was associated with lower survival rates for both the retrospective (hazard ration [HR] = 2.181, 95% confidence interval [CI] = 1.641-2.897, P < 0.001) and the prospective cohorts (HR = 2.744, 95% CI = 1.810-4.161, P < 0.001). Multivariate Cox analysis showed that CRP-SAA was an independent prognostic marker for lung cancer. Remarkably, in stages I-II patients, only CRP-SAA, not total SAA or CRP, showed significant association with overall survival in two cohorts. Moreover, univariate and multivariate Cox analyses also showed that only CRP-SAA could be used as an independent prognostic marker for early-stage lung cancer patients.</p><p><b>CONCLUSION</b>CRP-SAA could be a better prognostic marker for lung cancer than total SAA or CRP, especially in early-stage patients.</p>