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Abundantly expressed serum amyloid A (SAA) protein under chronic inflammatory conditions gives rise to insoluble aggregates of SAA derivatives in multiple organs resulting in reactive amyloid A (AA) amyloidosis, a consequence of rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, familial Mediterranean fever, and Castleman's disease. An...
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... well with the mass spectrometry analysis of purified amyloid fibril protein, which identified it as SAA1 (described above). It was interesting to note that although the nuclear extracts from nontransgenic mice contained noticeable DNA-binding activity of SAF ( Fig. 5 A ), it did not contribute toward SAA1 expression because there was no detectable SAA1 mRNA in nontransgenic mice tissues (Fig. 5 D ). This finding could be due to the binding of SAF-2, a splice variant that inhibits the transactivation potential of SAF-1 (27), to the SAF-binding element of the SAA promoter. This possibility was evaluated in a DNA-binding assay. Ablation of the DNA-protein complex by SAF-2 Ab (Fig. 5 B , lane 18 ) indicated the presence of SAF-2 in the spleen nuclear extract of nontransgenic mice. Similar levels of SAF-2 were present in other tissues (data not shown). Overexpression of SAF-1 in the SAF-1 transgenic mice significantly increased the nuclear pool of SAF-1 (Fig. 5 C ), thus overcoming the inhibitory effect of SAF-2 and activating SAA1 expression. Because SAA1 expression is known to be induced by C/EBP and NF- B, EMSA was performed to measure the level these transcription factors in the liver, kidney, and spleen tissues of SAF-1 transgenic mice. Neither C/EBP nor NF- B activities were induced in any of these tissues of the SAF-1 transgenic mice (data not shown). This result is consistent with an earlier finding, which revealed that chronic inflammatory condition is not associated with NF- B or inducible C/EBP activities (18). To the contrary, SAF activity was found to remain high and contributed to persistent SAA expression (18). Together, the data indicate that SAF-1 is a major inducer of SAA1 expression in the amyloidotic tissues of the transgenic mice. Our finding that only aged SAF-1 transgenic mice spontaneously develop AA amyloidosis (Figs. 3 and 4) raises the question of whether younger SAF-1 transgenic mice are resistant or whether they might develop AA amyloidosis if exposed to additional inflammatory stimulus. To test these possibilities, we injected azocasein, a known inflammatory stimulus (28, 29), into the SAF-1 transgenic mice and compared their response with the nontransgenic mice. Amyloid-enhancing factor, in conjunction with an inflammatory stimulus, is traditionally used for the rapid induction of experimental amyloidosis in mice. We chose not to use amyloid- enhancing factor, because it markedly enhances the process and therefore holds the possibility of blurring the rate of amyloid development. Eight-week-old SAF-1 transgenic and nontransgenic mice received daily azocasein injections for different lengths of time, namely 7, 14, 21, and 42 days. At the end of each treatment period mice were sacrificed, and serum, spleen, kidney, liver, and other tissues were collected and stored at Ϫ 70°C. Paraffin-embedded sections of kidney and spleen tissues were stained with Congo red dye and examined for amyloid deposition (Fig. 6). As shown in Fig. 6 A ,amyloid deposits were not detected in nontransgenic mice until day 21 of azocasein treatment, and the deposits were much milder compared with that of SAF-1 transgenic mice. The rate of amyloid deposition was highly accelerated in SAF-1 transgenic mice and, although both groups of mice developed amyloids in multiple organs (Fig. 6, A and B ), at 42 days the severity score in the SAF-1 transgenic group was much higher (Table I). Immunohistochemical analysis indicated that amyloid-laden tissues contained AA amyloids that were highly prevalent in SAF-1 transgenic mice (Fig. 6 C ). To examine whether increased and/or prolonged acute phase response is accountable for the increased propensity of AA amyloid deposition in SAF-1 transgenic mice, we measured the plasma level of total SAA after a single injection of azocasein ( n ϭ 8 in each group). Results of this experiment indicated that SAF-1 transgenic mice express higher levels of SAA than the nontransgenic mice (Fig. 7). Moreover, whereas the SAA level in the nontransgenic mice almost returned to control values on day 21, SAF-1 transgenic mice continued to have higher levels. When compared between old and young SAF-1 transgenic and nontransgenic animals, 14-mo-old animals exhibited more robust SAA expression than young 8-wk-old mice. This result suggested that aged SAF-1 transgenic mice experience a much more increased and prolonged acute phase response, which accounts for the increased SAA levels in the circulations of these mice. Secondary or reactive AA amyloidosis is a fatal consequence of many chronic inflammatory diseases. Increased synthesis due to transcriptional induction of the amyloidogenic SAA1 gene during chronic inflammatory condition plays a central role in the development of AA amyloidosis. The transcriptional induction mechanism of SAA has therefore been intensely investigated. These studies led to the identification of the SAF-1 transcription factor, which is one of the primary regulators of SAA expression. To investigate whether SAF-1 plays any role in the pathogenesis of AA amyloidosis, we have developed a SAF-1 transgenic mouse model. Here, we show that Ͼ 75% of aged SAF-1 transgenic mice ...
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... activity to the SAA promoter ( Fig. 5, A and C ), con- firming the role of SAF-1 as a regulator of SAA1 expression in vivo (Fig. 5 D ). Consistent with this finding, the amyloid-laden kidney tissue of human amyloid patients was also found to overexpress amyloidogenic SAA (Fig. 1 B ). Together, these data showed that, during the pathogenic condition of AA amyloidosis, SAA is expressed in the affected organs such as the kidney. It is not known yet whether such local synthesis of SAA plays any significant role in amyloid deposition. Contrarily, earlier studies have shown that amyloid deposits are derived from circulating SAA in complex with high-density lipoprotein and that these SAA molecules are synthesized in the liver (32, 33). In the present study, the circulating level of SAA in the amyloidosis-affected, aged SAF-1 transgenic mice in the absence of any inflammatory stimulus was found to be ϳ 100 g/ml, which is only 2-fold higher than that of age-matched nontransgenic mice (see Fig. 7, bars marked 0d for day 0). It is possible that such an increase in the circulating level of SAA is at least partly responsible for the amyloidosis detected in the transgenic mice (Fig. 3). Another attractive speculation is that overexpression of SAA in the affected tissue may have contributed to the severity of amyloidosis. Our finding of the SAA overexpression in spleen and kidney tissues in addition to the liver (Fig. 5) raises such a possibility. It is noteworthy to mention in this regard that previous reports have also shown overexpression of SAA in extrahepatic tissues in pathogenic conditions (34, 35). Compelling evidence of local synthesis of SAA in amyloid deposition is provided by the finding of brain-specific expression of mouse SAA1 (36, 37). Our data, presented here, do not rule out the contribution of circulating SAA in amyloid formation. The answer to the question of whether both local production and increased circulation of SAA are necessary for amyloid deposition is yet to be established. The present finding, however, suggests that local production most likely increases the propensity, because SAF-1 transgenic mice spontaneously developed amyloidosis in organs overexpressing SAA. Together, our findings of high levels of SAF-1 along with AA amyloid protein deposits in amyloid- laden human kidney tissue (Fig. 1) are highly consistent with the proposed role of SAF-1 in the pathogenesis of AA amyloidosis. An important result of the current study is the surprising appearance of significant AA deposits in Ͼ 75% of the aged SAF-1 transgenic mice (Figs. 3 and 4). Amyloidosis in aged SAF-1 transgenic mice was not due to normal age-related changes in the cytokine profile or metabolic processes, because age-matched nontransgenic littermates showed very few amyloid deposits. An explanation for this apparent age-related phenomenon in spontaneous AA amyloid development can be obtained from the results presented in Fig. 7. Acute phase response, as assessed by the persistent higher plasma SAA level following an inflammatory stimulus, was prolonged in the SAF-1 transgenic mice compared with nontransgenic mice. Based on this finding, we hypothesize that periodic and extended acute phase responses throughout the life- time of the mice lead to an increased and extended synthesis ...
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... activity to the SAA promoter ( Fig. 5, A and C ), con- firming the role of SAF-1 as a regulator of SAA1 expression in vivo (Fig. 5 D ). Consistent with this finding, the amyloid-laden kidney tissue of human amyloid patients was also found to overexpress amyloidogenic SAA (Fig. 1 B ). Together, these data showed that, during the pathogenic condition of AA amyloidosis, SAA is expressed in the affected organs such as the kidney. It is not known yet whether such local synthesis of SAA plays any significant role in amyloid deposition. Contrarily, earlier studies have shown that amyloid deposits are derived from circulating SAA in complex with high-density lipoprotein and that these SAA molecules are synthesized in the liver (32, 33). In the present study, the circulating level of SAA in the amyloidosis-affected, aged SAF-1 transgenic mice in the absence of any inflammatory stimulus was found to be ϳ 100 g/ml, which is only 2-fold higher than that of age-matched nontransgenic mice (see Fig. 7, bars marked 0d for day 0). It is possible that such an increase in the circulating level of SAA is at least partly responsible for the amyloidosis detected in the transgenic mice (Fig. 3). Another attractive speculation is that overexpression of SAA in the affected tissue may have contributed to the severity of amyloidosis. Our finding of the SAA overexpression in spleen and kidney tissues in addition to the liver (Fig. 5) raises such a possibility. It is noteworthy to mention in this regard that previous reports have also shown overexpression of SAA in extrahepatic tissues in pathogenic conditions (34, 35). Compelling evidence of local synthesis of SAA in amyloid deposition is provided by the finding of brain-specific expression of mouse SAA1 (36, 37). Our data, presented here, do not rule out the contribution of circulating SAA in amyloid formation. The answer to the question of whether both local production and increased circulation of SAA are necessary for amyloid deposition is yet to be established. The present finding, however, suggests that local production most likely increases the propensity, because SAF-1 transgenic mice spontaneously developed amyloidosis in organs overexpressing SAA. Together, our findings of high levels of SAF-1 along with AA amyloid protein deposits in amyloid- laden human kidney tissue (Fig. 1) are highly consistent with the proposed role of SAF-1 in the pathogenesis of AA amyloidosis. An important result of the current study is the surprising appearance of significant AA deposits in Ͼ 75% of the aged SAF-1 transgenic mice (Figs. 3 and 4). Amyloidosis in aged SAF-1 transgenic mice was not due to normal age-related changes in the cytokine profile or metabolic processes, because age-matched nontransgenic littermates showed very few amyloid deposits. An explanation for this apparent age-related phenomenon in spontaneous AA amyloid development can be obtained from the results presented in Fig. 7. Acute phase response, as assessed by the persistent higher plasma SAA level following an inflammatory stimulus, was prolonged in the SAF-1 transgenic mice compared with nontransgenic mice. Based on this finding, we hypothesize that periodic and extended acute phase responses throughout the life- time of the mice lead to an increased and extended synthesis ...
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... SAA that crosses the threshold level sanction deposition of amyloid fibrils. Interestingly, old nontransgenic mice contained the same plasma level of SAA as young transgenic mice at the early stages of acute phase response up to day 4, but the level rapidly declined thereafter in the old nontransgenic mice as compared with young transgenic mice, where the higher level persisted for extended period (Fig. 7). A persistent higher level of SAA appears to be a key factor in the development of AA amyloidosis, and SAF-1 plays a role in this process (18). The rapid decline of SAA levels in aged nontransgenic mice may explain why these mice did not develop AA amyloidosis. In reactive AA amyloidosis, although the contribution of a precursor SAA1 protein is clear, it remains unknown why some patients develop amyloidosis while others with similar high levels of SAA1 in the system remain free of this pathology. It has been speculated that additional inflammation-responsive molecular components are necessary for the amyloid deposition. In correlation, SAA transgenic mice overexpressing high levels of SAA1 did not develop AA amyloidosis without an additional inflammatory stimulus (36, 37). Conversely, no such stimulus was needed for amyloid development in the aged SAF-1 transgenic mice. We pos- tulate that in addition to the increased level of amyloidogenic SAA via transcriptional induction of this gene, inflammation-responsive stimulus provides an additional component(s) for the onset of amyloid deposits. The increased propensity for amyloid development in the young SAF-1 transgenic mice in response to the amyloid- inducing stimulus provided by azocasein injection supports this notion. Consistent with our finding, AA amyloidosis development in IL-6 transgenic mice was found to be age-dependent, with AA deposits being first evident at 3 mo of age and increasing over the next 6 mo (38). Interestingly, IL-6 has been shown to activate SAF-1 (16 –18), which raises the possibility that one of the effects of this cytokine in the IL-6 transgenic mice could be the activation of endogenous SAF-1. Thus, SAF-1 appears to be a crucial mol- ecule responsible for the development of AA amyloidosis. Tissue-specific expression of SAA has been implicated as play- ing a determining role in the pathogenesis of a number diseases, including Alzheimer’s disease, arthritis, and atherosclerosis, where SAA is overexpressed in the specific cell types of the brain (39), synovium (40 – 42), and artery (43, 44). The regulation of SAA genes in these diverse cell types most likely involves different combinations of transcription factors that are active in the cells of the affected tissues. A paradigm is the elucidation of the tissue- specific expression of SAA1 and SAA2 in hepatic and epithelial cells (45) and SAA1 expression in aortic smooth muscle and hepatic cells (46). High levels of C/EBP activity in the liver have been found to be beneficial for SAA expression in the hepatic cells (11, 12, 14, 46), and such action of C/EBP is further potentiated by NF- B activity (13–15, 47). Interestingly, SAF-1 is found to be very active in many tissue-specific cells, including synoviocytes and chondrocytes of the arthritic joint (22, 48) and macrophage cells of the atherosclerotic plaque (49). Recent evidence also im- plicates SAF-1 in the human SAA1 and SAA2 expression in the trophoblast cells during early fetal development (50). The data presented in this paper establish that SAF-1 is involved in the development of AA amyloidosis by inducing amyloidogenic SAA1 expression in multiple tissues. Further studies will determine the potential impact of tissue-specific expression mechanisms in controlling the severity of the ...
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... acute phase re- sponse is accountable for the increased propensity of AA amyloid deposition in SAF-1 transgenic mice, we measured the plasma level of total SAA after a single injection of azocasein (n 8 in each group). Results of this experiment indicated that SAF-1 trans- genic mice express higher levels of SAA than the nontransgenic mice (Fig. 7). Moreover, whereas the SAA level in the nontrans- genic mice almost returned to control values on day 21, SAF-1 transgenic mice continued to have higher levels. When compared between old and young SAF-1 transgenic and nontransgenic ani- mals, 14-mo-old animals exhibited more robust SAA expression than young 8-wk-old mice. This result ...
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... high-density lipoprotein and that these SAA molecules are synthesized in the liver (32,33). In the present study, the circulating level of SAA in the amyloidosis-affected, aged SAF-1 transgenic mice in the absence of any inflammatory stimulus was found to be 100 g/ml, which is only 2-fold higher than that of age-matched nontransgenic mice (see Fig. 7, bars marked 0d for day 0). It is possible that such an increase in the circulating level of SAA is at least partly responsible for the amy- loidosis detected in the transgenic mice (Fig. 3). Another attractive speculation is that overexpression of SAA in the affected tissue may have contributed to the severity of amyloidosis. Our ...
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... in aged SAF-1 trans- genic mice was not due to normal age-related changes in the cy- tokine profile or metabolic processes, because age-matched non- transgenic littermates showed very few amyloid deposits. An explanation for this apparent age-related phenomenon in sponta- neous AA amyloid development can be obtained from the results presented in Fig. 7. Acute phase response, as assessed by the per- sistent higher plasma SAA level following an inflammatory stim- ulus, was prolonged in the SAF-1 transgenic mice compared with nontransgenic mice. Based on this finding, we hypothesize that periodic and extended acute phase responses throughout the life- time of the mice lead to an ...
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... of amyloid fibrils. Interestingly, old nontransgenic mice contained the same plasma level of SAA as young transgenic mice at the early stages of acute phase response up to day 4, but the level rapidly declined thereafter in the old nontransgenic mice as com- pared with young transgenic mice, where the higher level persisted for extended period (Fig. 7). A persistent higher level of SAA appears to be a key factor in the development of AA amyloidosis, and SAF-1 plays a role in this process (18). The rapid decline of SAA levels in aged nontransgenic mice may explain why these mice did not develop AA ...
Citations
... SAP is a member of the pentraxin family and plays a key role in innate immunity and inflammation, and serum amyloid A (SAA) is an acute-phase protein, which is upregulated by a variety of inflammatory stimuli (39). In IS patients who were treated with thrombolysis, the baseline (before thrombolysis treatment) SAP remained significantly and independently associated with 3-month death (40). ...
Ischemic stroke (IS) is the second leading cause of death worldwide. Multimodal neuroimaging techniques that have significantly facilitated the diagnosis of hyperacute IS are not widely used in underdeveloped areas and community hospitals owing to drawbacks such as high cost and lack of trained operators. Moreover, these methods do not have sufficient resolution to detect changes in the brain at the cellular and molecular levels after IS onset. In contrast, blood-based biomarkers can reflect molecular and biochemical alterations in both normal and pathophysiologic processes including angiogenesis, metabolism, inflammation, oxidative stress, coagulation, thrombosis, glial activation, and neuronal and vascular injury, and can thus provide information complementary to findings from routine examinations and neuroimaging that is useful for diagnosis. In this review, we summarize the current state of knowledge on blood-based biomarkers of hyperacute IS including those associated with neuronal injury, glial activation, inflammation and oxidative stress, vascular injury and angiogenesis, coagulation and thrombosis, and metabolism as well as genetic and genomic biomarkers. Meanwhile, the blood sampling time of the biomarkers which are cited and summarized in the review is within 6 h after the onset of IS. Additionally, we also discuss the diagnostic and prognostic value of blood-based biomarkers in stroke patients, and future directions for their clinical application and development.
... Furthermore, murine overexpression increases the risk of severe arthritis (58). Like P. gingivalis, serum amyloid A is suspected to be involved in the pathogenesis of arthritis, atherosclerosis, amyloidosis and Alzheimer's disease (59)(60)(61)(62). Lastly, the 3rd most down-regulated gene, DHX37, harbors a rare frameshift mutation that segregates with Alzheimer's disease in one family (63). ...
Porphyromonas gingivalis, a bacterium associated with periodontal disease, is a suspected cause of Alzheimer’s disease. This bacterium is reliant on gingipain proteases, which cleave host proteins after arginine and lysine residues. To characterize gingipain susceptibility, we performed enrichment analyses of arginine and lysine proportion proteome-wide. Genes differentially expressed in brain samples with detected P. gingivalis reads were also examined. Genes from these analyses were tested for functional enrichment and specific neuroanatomical expression patterns. Proteins in the SRP-dependent cotranslational protein targeting to membrane pathway were enriched for these residues and previously associated with periodontal and Alzheimer’s disease. These ribosomal genes are up-regulated in prefrontal cortex samples with detected P. gingivalis sequences. Other differentially expressed genes have been previously associated with dementia (ITM2B, MAPT, ZNF267, and DHX37). For an anatomical perspective, we characterized the expression of the P. gingivalis associated genes in the mouse and human brain. This analysis highlighted the hypothalamus, cholinergic neurons, and the basal forebrain. Our results suggest markers of neural P. gingivalis infection and link the cholinergic and gingipain hypotheses of Alzheimer’s disease.
... It is made available under a The copyright holder for this preprint this version posted August 10, 2020. . https://doi.org/10.1101.08.09.243402 doi: bioRxiv preprint et al. 1999Alpana Ray et al. 2006;Getz, Krishack, and Reardon 2016;Targońska-Stępniak and Majdan 2014) . Lastly, the 3rd most down-regulated gene, DHX37 , harbours a rare frameshift mutation that segregates with Alzheimer's disease in one family ) . ...
Porphyromonas gingivalis, a keystone species in the development of periodontal disease, is a suspected cause of Alzheimer's disease. This bacterium is reliant on gingipain proteases, which cleave host proteins after arginine and lysine residues. To characterize gingipain susceptibility, we performed enrichment analyses of arginine and lysine proportion proteome-wide. Proteins in the SRP-dependent cotranslational protein targeting to membrane pathway were enriched for these residues and previously associated with periodontal and Alzheimer's disease. These ribosomal genes are up-regulated in prefrontal cortex samples with detected P. gingivalis sequences. Other differentially expressed genes have been previously associated with dementia (ITM2B, MAPT, ZNF267, and DHX37). For an anatomical perspective, we characterized the expression of the P. gingivalis associated genes in the mouse and human brain. This analysis highlighted the hypothalamus, cholinergic neurons, and the basal forebrain. Our results suggest markers of neural P. gingivalis infection and link the gingipain and cholinergic hypotheses of Alzheimer's disease.
... Importantly, genes associated with myelination in pathway analysis showed differential , and CAST) with FDR q value = 1.47E-04. SAF-1 is a transcription factor that responds to inflammatory stimuli and contributes to the development of insoluble amyloid A aggregates in amyloidosis [39]. NFAT is a complex transcription factor that is implicated in neurodegenerative changes like the induction of dystrophic neurites and dendritic spine loss, due to the activation of calcineurin signaling by amyloid-beta [40]. ...
Multiple systems atrophy (MSA) is a rare neurodegenerative disorder characterized by the accumulation of α-synuclein in glial cells and neurodegeneration in the striatum, substantia nigra, and cerebellum. Aberrant miRNA regulation has been associated with neurodegeneration, including alterations of specific miRNAs in brain tissue, serum, and cerebrospinal fluid from MSA patients. Still, a causal link between deregulation of miRNA networks and pathological changes in the transcriptome remains elusive. We profiled ~ 800 miRNAs in the striatum of MSA patients in comparison to healthy individuals to identify specific miRNAs altered in MSA. In addition, we performed a parallel screening of 700 transcripts associated with neurodegeneration to determine the impact of miRNA deregulation on the transcriptome. We identified 60 miRNAs with abnormal levels in MSA brains that are involved in extracellular matrix receptor interactions, prion disease, inflammation, ubiquitin-mediated proteolysis, and addiction pathways. Using the correlation between miRNA expression and the abundance of their known targets, miR-124-3p, miR-19a-3p, miR-27b-3p, and miR-29c-3p were identified as key regulators altered in MSA, mainly contributing to neuroinflammation. Finally, our study also uncovered a potential link between Alzheimer’s disease (AD) and MSA pathologies that involves miRNAs and deregulation of BACE1. Our results provide a comprehensive appraisal of miRNA alterations in MSA and their effect on the striatal transcriptome, supporting that aberrant miRNA expression is highly correlated with changes in gene transcription associated with MSA neuropathology, in particular those driving inflammation, disrupting myelination, and potentially impacting α-synuclein accumulation via deregulation of autophagy and prion mechanisms.
... (Uhlar and Whitehead (1999a), Copyright John Wiley and Sons, 2011, used by permission) IL-6 in non-hepatic cells. SAF is a 477 aa zinc-finger protein that becomes phosphorylated during inflammation (Ray et al. 2004a) and a mouse transgenic for SAF-1 production developed prominent amyloid deposition (Ray et al. 2006). IL-6 is known to bind to gp130 leading to the activation of the STAT3 pathway. ...
Serum amyloid A (SAA) proteins were isolated and named over 50 years ago. They are small (104 amino acids) and have a striking relationship to the acute phase response with serum levels rising as much as 1000-fold in 24 hours. SAA proteins are encoded in a family of closely-related genes and have been remarkably conserved throughout vertebrate evolution. Amino-terminal fragments of SAA can form highly organized, insoluble fibrils that accumulate in "secondary" amyloid disease. Despite their evolutionary preservation and dynamic synthesis pattern SAA proteins have lacked well-defined physiologic roles. However, considering an array of many, often unrelated, reports now permits a more coordinated perspective. Protein studies have elucidated basic SAA structure and fibril formation. Appreciating SAA's lipophilicity helps relate it to lipid transport and metabolism as well as atherosclerosis. SAA's function as a cytokine-like protein has become recognized in cell-cell communication as well as feedback in inflammatory, immunologic, neoplastic and protective pathways. SAA likely has a critical role in control and possibly propagation of the primordial acute phase response. Appreciating the many cellular and molecular interactions for SAA suggests possibilities for improved understanding of pathophysiology as well as treatment and disease prevention.
... Mechanistically, MAZ regulates transcription of mmp1 and mmp9 in in-flamed joint tissue (34,35). MAZ-expressing animals have heightened susceptibility to develop serum amyloidosis, a condition associated with chronic inflammation due to rheumatoid arthritis and Crohn's disease (36). Consistent with the previous data, we have shown that intestinal epithelial MAZ expression is sufficient to enhance the acute inflammatory response in complementary models of infectious and chemically induced colitis. ...
Myc-associated zinc finger (MAZ) is a transcription factor highly upregulated in chronic inflammatory disease and several human cancers. In the current study, we found that MAZ protein is highly expressed in human ulcerative colitis and colon cancer. However, the precise role for MAZ in the progression of colitis and colon cancer is not well defined. To determine the function of MAZ, a novel mouse model of intestine epithelial specific MAZ overexpression was generated. Expression of MAZ in intestinal epithelial cells was sufficient to enhance inflammatory injury in two complementary models of colitis. Moreover, MAZ expression increased tumorigenesis in an in vivo model of inflammation-induced colon cancer and was important for growth of human colon cancer cell lines in vitro and in vivo . Mechanistically, MAZ is critical in the regulation of oncogenic STAT3 signaling. MAZ expressing mice have enhanced STAT3 activation in the acute response to colitis. Moreover, MAZ was essential for cytokine and bacteria-induced STAT3 signaling in colon cancer cells. Furthermore, we show that STAT3 is essential for MAZ-induced colon tumorigenesis using a chemical inhibitor. These data indicate an important functional role for MAZ in the inflammatory progression of colon cancer through regulation of STAT3 signaling and suggest MAZ is a potential therapeutic target to dampen STAT3 signaling in colon cancer.
... Also, the acute phase protein SAA1 was upregulated by Dex in both resting and infected macrophages, which is consistent with previous studies (50,51). Aggregates of SAA1 can be seen in many inflammatory diseases, including CD, resulting in a condition called amyloidosis (52). Previous studies have pointed out the value of considering glucocorticoid treatment in cases of inflammatory disease-associated amyloidosis (53), and our results add weight to this debate by showing that glucocorticoids may increase SAA1 levels in macrophages contributing to amyloidosis in CD. ...
Crohn’s disease (CD) is a chronic inflammatory bowel disorder characterized by deregulated inflammation triggered by environmental factors. Notably, adherent-invasive Escherichia coli (AIEC), a bacterium with the ability to survive within macrophages is believed to be one of such factors. Glucocorticoids are the first line treatment for CD and to date, it is unknown how they affect bactericidal and inflammatory properties of macrophages against AIEC. The aim of this study was to evaluate the impact of glucocorticoid treatment on AIEC infected macrophages. First, THP-1 cell-derived macrophages were infected with a CD2-a AIEC strain, in the presence or absence of the glucocorticoid dexamethasone (Dex) and mRNA microarray analysis was performed. Differentially expressed mRNAs were confirmed by TaqMan-qPCR. In addition, an amikacin protection assay was used to evaluate the phagocytic and bactericidal activity of Dex-treated macrophages infected with E. coli strains (CD2-a, HM605, NRG857c, and HB101). Finally, cytokine secretion and the inflammatory phenotype of macrophages were evaluated by ELISA and flow cytometry, respectively. The microarray analysis showed that CD2-a, Dex, and CD2-a + Dex-treated macrophages have differential inflammatory gene profiles. Also, canonical pathway analysis revealed decreased phagocytosis signaling by Dex and anti-inflammatory polarization on CD2-a + Dex macrophages. Moreover, amikacin protection assay showed reduced phagocytosis upon Dex treatment and TaqMan-qPCR confirmed Dex inhibition of three phagocytosis-associated genes. All bacteria strains induced TNF-α, IL-6, IL-23, CD40, and CD80, which was inhibited by Dex. Thus, our data demonstrate that glucocorticoids impair phagocytosis and induce anti-inflammatory polarization after AIEC infection, possibly contributing to the survival of AIEC in infected CD patients.
... SAA levels range between 1 to >3,000 mg/L, with higher levels occurring when production is upregulated to potentially a 1000-fold during acute inflammation [34,35]. SAA is synthesised by hepatocytes under regulatory control of proinflammatory cytokines such as tumour necrosis factor (TNF), interleukin 1 (IL-1), interleukin 6 (IL-6) and transcription factors such as SAA activating factor and lipopolysaccharide [36][37][38]. Additionally, the hepatic clearance of SAA during both acute and chronic inflammation is reduced, adding to the elevated levels seen [39]. ...
BACKGROUND: Amyloidosis is a disorder arising from the variable physiological effects of dysregulated, extracellular protein deposition. There are >30 different subtypes, all possessing the same histological characteristics and the two major organs affected are the kidneys and the heart. AIMS AND HYPOTHESIS: To evaluate current UK histological practices leading to a misdiagnosis of amyloidosis; To establish proteomics as a new diagnostic technique for identifying amyloid, in the UK; To investigate the usefulness of a relatively new biomarker i.e. Retinol Binding Protein (RBP), across amyloid subtypes and correlate values with biopsy findings, which has not previously been done; To identify the cause of death in patients with Stage III/ IV cardiac amyloidosis using, for the first time, Implantable Loop Recorders; To present the first comprehensive review of Light Chain Deposition Disease highlighting the relationship between haematological response and overall prognosis. RESULTS: In 65% of cases where renal amyloidosis was misdiagnosed as minimal change disease, Congo red staining was not undertaken and in 35% of cases neither Congo red staining, with cross-polarised light visualisation, nor electron microscopy was undertaken. Proteomics has now been established as a specific and sensitive technique by which to diagnose amyloid and the subtype, demonstrated by distinguishing Fibrinogen Aα-Chain (AFib) renal biopsies from other subtypes. Urinary RBP/Creatinine (RCR) correlated with the: degree of tubular atrophy, number of light chains, eGFR, presence of glycosuria and degree of tubular phosphate reabsorption. RCR values were especially high in AFib and AA amyloidosis. Pulseless Electrical Activity was identified as the terminal rhythm in patients with Stage III/IV cardiac amyloidosis and this was preceded by a high degree AV block. Deep clonal responses to chemotherapy are associated with improved renal and overall outcomes in LCDD and should be pursued even in advanced chronic kidney disease.
... TFs displaying at least a 2-fold change between ApoE2 + A and ApoE3 + A treatments are listed. Table 3 TFs found to change in the ApoE2 + A treatment, relative to the ApoE3 + A treatment, and which have links to AD/inflammation TF Relative to ApoE3 + A AD Inflammation Vitamin D receptor (VDR) 68.7 Y [37] Y [49] Retinioid X receptor (RXR) 32.9 Y [50] Y [51,52] Mothers against decapentaplegic homolog (Smad)-3 16.9 Y [53] N Estrogen receptor element (ERE) 2.15 Y [54][55][56][57] Y [58] Yin Yang 1 (YY1) 2.11 Y [59] N Peroxisome proliferator-activated receptor (PPAR) 0.402 Y [60][61][62][63] Y [64,65] Interleukin-6 response-element-binding-protein (IL-6-RE-BP) 0.023 N Y [66] Signal transducer and activator of transcription (STAT)-3 0.019 Y [67,68] Y ApoA-I gene (AIC) promoter C region 0.016 Y [69] N p53 0.010 Y [70,71] Y [72,73] NFκB 6.29 × 10-3 Y [16,74] Y [75] X-box binding protein 1 (XBP-1) 1.96 × 10-3 Y [76] N PUR 1.4 × 10-3 Y [77] N Myc-associated zinc finger protein (MAZ) 1.22 × 10-4 Y [78,79] Y [80] Panomics Inc. (Santa Clara, CA, USA). Hybridization, probe binding and detection were performed according to manufacturer's instructions. ...
Neuroinflammation plays a critical role in neuronal dysfunction and death of Alzheimer's disease (AD). ApoE4 is a major risk factor of AD, while ApoE2 is neuroprotective. Little is known about the roles of ApoE isoforms in the neuroinflammation seen in AD. Their roles and mechanisms in A-induced/neuroinflammation were investigated in this study using in vivo and in vitro models. Rat astrocytes were treated with lipid-poor recombinant hApoE and/or A 42. Mouse astrocyte lines-expressing lipidated hApoE were treated with A 42 and/or vitamin D receptor (VDR) agonist, 1,25-dihydroxyvitamin D 3. Cells and media were harvested for cytokine ELISA, RNA isolated for qRT-PCR, and nuclear protein for transcription factor (TF) arrays and EMSA. hApoE-transgenic and AD mice were mated to generate hApoE2/AD and hApoE4/AD mice. Mice were euthanized at 6 months of age. Brain tissues were collected for cytokine ELISA array, A ELISA, immunoblotting, and immunohistochemistry. hApoE4/AD mice had significantly higher levels of inflammatory cytokines than hApoE2/AD mice. Lipidated hApoE4 significantly promoted inflammatory gene expression induced by A 42 but not recombinant hApoE4 in astrocytes as compared to controls. Lipidated hApoE3 provided a certain degree of protection against A 42-induced inflammatory response but not recombinant hApoE3 as compared to controls. Both lipidated and recombinant hApoE2 provided protection against A 42-induced inflammatory response compared to controls. TF array revealed that ApoE2 strongly activated VDR in A 42-treated astrocytes. Application of 1,25-dihydroxyvitamin D 3 completely inhibited A-induced inflammatory gene expression in hApoE4-expressing astrocytes. The results suggest that ApoE4 promotes, but ApoE2 inhibits, AD/A-induced neuroinflammation via VDR signaling. Targeting VDR signaling or active form of VD3 may relieve AD neuroinflammation or/and neurodegeneration.
... 35 The process is triggered by circulating tumor necrosis factor, interleukins, and transcription factors, which upregulate gene expression of the amyloid protein. 36,37 The most common disorders associated with secondary amyloidosis are rheumatoid arthritis, juvenile idiopathic arthritis, spondyloarthropathies, inflammatory bowel disease, and familial Mediterranean fever, with an estimated prevalence of 10% to 25%. 38,39 The development of cardiomyopathy is variable, and appears to be highest in patients with rheumatoid arthritis. ...
Amyloidosis is a systemic disorder that results from abnormal protein metabolism, producing amyloid fibrils that are subsequently deposited within vital organs. Cardiac involvement is typically associated with the specific subtypes of immunoglobulin lightchain, transthyretin, secondary amyloidosis, and dialysis-related amyloidosis. The hallmark of cardiac amyloidosis is the development of restrictive cardiomyopathy and heart failure, usually with a preserved left ventricular ejection fraction. The diagnosis is based on the integration of clinical signs and symptoms, echocardiography, cardiac magnetic resonance imaging, nuclear scintigraphy, electrocardiography, and cardiac biomarkers. Traditionally, management of heart failure symptoms and prevention of heart failure exacerbations have been the cornerstones of therapy. However, various treatments are currently under investigation that aim to eliminate or neutralize the underlying amyloidogenic substrate. Herein, we provide a focused review and discussion of the cardiovascular manifestations, epidemiologic and clinical characteristics, diagnostic modalities, and treatment strategies of cardiac amyloidosis.
