Disruption of the pentraxin 3/CD44 interaction as an efficient therapy for triple-negative breast cancers.

Due to the heterogeneity and high frequency of genome mutations in cancer cells, targeting vital protumour factors found in stromal cells in the tumour microenvironment may represent an ideal strategy in cancer therapy. However, the regulation and mechanisms of potential targetable therapeutic candidates need to be investigated. An in vivo study demonstrated that loss of pentraxin 3 (PTX3) in stromal cells significantly decreased the metastasis and growth of cancer cells. Clinically, our results indicate that stromal PTX3 expression correlates with adverse prognostic features and is associated with worse survival outcomes in triple-negative breast cancer (TNBC). We also found that transforming growth factor beta 1 (TGF-ß1) induces PTX3 expression by activating the transcription factor CCAAT/enhancer binding protein delta (CEBPD) in stromal fibroblasts. Following PTX3 stimulation, CD44, a PTX3 receptor, activates the downstream ERK1/2, AKT and NF-κB pathways to specifically contribute to the metastasis/invasion and stemness of TNBC MDA-MB-231 cells. Two types of PTX3 inhibitors were developed to disrupt the PTX3/CD44 interaction and they showed a significant effect on attenuating growth and restricting the metastasis/invasion of MDA-MB-231 cells, suggesting that targeting the PTX3/CD44 interaction could be a new strategy for future TNBC therapies.

The effect of insulin pump combined with ulinastatin on the levels of PCT, TG, PTX-3, and CX3CL1 in patients with diabetic ketoacidosis and pancreatitis.

ABSTRACT: The aim of this research is to observe the effect of insulin pump combined with Ulinastatin on the levels of procalcitonin (PCT), triglycerides (TG), pentraxin-3(PTX-3), and C-X3-C motif chemokine ligand 1 (CX3CL1) in patients with diabetic ketoacidosis and pancreatitis.A total of 72 patients with diabetic ketoacidosis and pancreatitis who were admitted to our hospital from February 2016 to February 2020 were selected as the research subjects. They were divided into study groups (36 cases, given insulin pump combined Ulinastatin treatment) and control group (36 cases, given insulin pump treatment). Statistics of changes in blood amylase (AMS), blood glucose, blood ketones, glycosylated hemoglobin (HbA1c), PCT, TG, PTX-3, and chemokine CX3CL in pancreatic tissue before and after treatment.After treatment, the clinical efficacy of the study group was significantly higher than that of the control group (94.44% vs 75.00%), the difference was significant (P < .05). After treatment, the clinical symptoms (abdominal distension, abdominal pain, body temperature, blood sugar, HbA1c and blood amylase) in the study group were significantly less time-to-normal than in the control group, and the difference was significant (P < .05). After treatment, the AMS, blood sugar, HbA1c, and blood ketones of the 2 groups were all lower than before treatment, and the study group's AMS, blood sugar, HbA1c, and blood ketones were all lower In the control group, the difference was significant (P < .05). After treatment, the 2 groups of PCT, TG, PTX-3, and CX3CL were all lower than before treatment, among which the study group PCT, TG, PTX-3, and CX3CL1 were lower than the control group, the difference was significant (P < .05). After treatment, the total adverse reaction rate of the 2 groups was not significantly different (P > .05), but the total adverse reaction rate of the study group was lower than that of the control group.The combination of insulin pump and ulinastatin in the treatment of patients with diabetic ketoacidosis complicated with acute pancreatitis has a effect, which can shorten the recovery time of clinical symptoms, reduce the levels of PCT, TG, PTX-3, and CX3CL1, and has fewer adverse reactions. It is worthy of clinical application.

12-months prospective Pentraxin-3 and metabolomic evaluation in multiple sclerosis patients treated with glatiramer acetate.

BACKGROUND: Pentraxin-3 (PTX-3) is involved in acute immunological responses and it is a pro-inflammatory protein and a novel biomarker of inflammatory diseases. It is demonstrated that PTX-3 is higher in cerebrospinal fluid (CSF) of aggressive Multiple Sclerosis (MS). Metabolomics, the identification of small endogenous molecules, offers a molecular profile of MS. Glatiramer acetate (GA) is a widely used treatment for (MS) but its mechanism of action is not completely defined. The aim of our study is to analyze PTX-3 and metabolomic profile in MS patients compared to controls and to investigate the effect of GA on PXT-3 and metabolic molecules during treatment in responder and not responder MS patients. METHODS: 28 unrelated MS patients and 27 age-and sex-matched controls were recruited. In serum, PTX-3 levels were measured by ELISA and Metabolomic panel was evaluated trough Nuclear Magnetic Resonance (NMR). According to clinical practice patients started GA treatment; PTX-3 and metabolomic identification were performed before and during treatment. Responders to treatment were identified if no evidence of instrumental, clinical relapses and disability progression (NEDA) occurred during follow up. RESULTS: Serum PTX-3 levels were higher in MS patients compared to matched controls (7,85 ± 2,19 vs 6,20 ± 1,63 ng/ml) (p = 0,03); metabolomic evaluation shows higher levels of lactate and lower levels of valine, tyrosine and tryptophan in MS patients compared to controls. During therapy, PTX-3 levels have been reduced statistically significant (p = 0,001) at six months and one year of treatment. After one year, of the twenty patients that completed the study, 55% were considered fully responders to treatment; in these patients the mean reduction of PTX-3 at one year was higher respect to not responders (-3,82 ± 1,24 ng/ml vs -2,32 ± 1,03 ng/ml p = 0,02) and we observed a higher reduction of lactate, tyrosine and hypoxanthine and an increase of hydroxyproline and ADP as well as of three oxidative phosphorylation markers, citrulline, ornithine and tryptophan approaching the metabolic profile of healthy subjects. DISCUSSION AND CONCLUSIONS: We demonstrated a metabolomic imbalance with mitochondrial dysfunction detected by higher levels of lactate and lower levels of tryptophan, tyrosine and valine in MS patients compared to healthy controls. The reduction of PTX-3 levels and the restoring of mitochondrial function, reducing oxidative stress by GA, allows to identify responder patients. Further and larger studies are needed to understand the predictive role of PTX-3 and metabolomic pattern in the identification of responder patients to GA.

Pentraxin 3: A promising therapeutic target for autoimmune diseases.

Pentraxin 3 (PTX3) is a prototypic humoral soluble pattern recognition molecule that exerts a pivotal role in innate immune response and inflammation, as well as in tissue damage and remodeling. Recently, emerging evidence has revealed that PTX3 is involved in the occurrence and development of various autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), systemic sclerosis (SSc), inflammatory bowel disease (IBD), multiple sclerosis (MS) and psoriasis, etc. In this review, we have succinctly summarized the complex immunological functions of PTX3 and mostly focused on recent findings of the pleiotropic activities played by PTX3 in the pathogenesis of autoimmune diseases, aiming at hopefully offering possible future therapeutic alternatives.

Quercetin reduces TNF-α-induced mesangial cell proliferation and inhibits PTX3 production: Involvement of NF-κB signaling pathway.

Lupus nephritis (LN) is an autoimmune disease caused by systemic lupus erythematosus. Excessive proliferation of mesangial cells is one of the most serious pathological manifestations of LN. In addition, the expression of PTX3 is elevated in the serum of patients with LN. Quercetin has good anti-inflammatory effects and immunomodulatory activities. In this study, the result of MTT indicated that quercetin treatment alleviated the excessive proliferation of mesangial cells. ELISA and immunofluorescence experiments showed that quercetin treatment inhibited the expression of PTX3. Three doses of quercetin (20, 40, and 80 µM) were selected for the experiment. It is noteworthy that the efficacy of quercetin at 80 µM was significantly better than that of other dose groups. And the effect in inhibiting PTX3 expression was comparable with that of the PDTC (80 µM) positive control. Western blot and qRT-PCR analysis revealed that quercetin treatment reduced the expression of nuclear factor-κB p65 and IKKß, increased the expression of IκBα, and inhibited the expression of PTX3. In conclusion, through inhibiting the activation of nuclear factor-κB signaling pathway, quercetin treatment could reduce the expression of PTX3 and inhibit the excessive proliferation of mesangial cells, suggesting that quercetin is a potential therapeutic drug for LN.

Evaluation of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Single Intravenous Dose of Miridesap in Healthy Japanese Subjects.

This phase 1 study characterized the safety, tolerability, pharmacokinetics, and pharmacodynamics of miridesap (GSK2315698) following an intravenous (IV) infusion in healthy Japanese men. Subjects in Cohort 1 received 1-hour IV infusions of 10, 20, and 40 mg of miridesap or placebo, and subjects in Cohort 2 received a 15-hour IV infusion of 20 mg/h of miridesap or placebo. No treatment-related adverse events were reported. No new safety signals were identified for either vital signs or clinical laboratory parameters. A dose-dependent increase was observed in miridesap exposure (area under the concentration-time curve and maximum observed drug concentration) in the 10 to 40 mg/h dose range after a 1-hour IV infusion of miridesap. Rapid depletion of circulating serum amyloid P component was observed after the initiation of miridesap infusion. Serum amyloid P component concentrations fell in a dose-dependent manner following administration of miridesap.

ALK2/ALK3-BMPR2/ACVR2A Mediate BMP2-Induced Downregulation of Pentraxin 3 Expression in Human Granulosa-Lutein Cells.

Bone morphogenetic protein 2 (BMP2) belongs to the transforming growth factor-ß superfamily and plays a critical role in regulating ovarian follicle function. Currently, the role of BMP2 during cumulus expansion remains to be determined. The aim of this study was to investigate the effect of BMP2 on the regulation of pentraxin 3 (PTX3) expression (the major component of cumulus expansion) and the underlying mechanisms in human granulosa-lutein (hGL) cells. Both primary and immortalized hGL cells were used as research models. Our results showed that treatment with BMP2 significantly suppressed the basal and luteinizing hormone-induced upregulation of PTX3. In addition, BMP2 stimulated the phosphorylation of SMAD1/5/8, and this effect was abolished by the addition of BMP type I receptor inhibitors, dorsomorphin homolog 1, and dorsomorphin but not SB431542. Moreover, the knockdown of activin receptorlike kinase 2/3 or BMP receptor type II/activin receptor type IIB receptors completely reversed the BMP2-induced phosphorylation of SMAD1/5/8 and restored PTX3 expression. Similarly, the knockdown of SMAD4 completely reversed the suppressive effect of BMP2 on the expression of PTX3. These results improve our understanding of the molecular mechanisms of BMP2 signaling. Our findings suggest that BMP2 may be involved in the regulation of cumulus expansion during the periovulatory stage.

Proteomics profiling reveals inflammatory biomarkers of antidepressant treatment response: Findings from the CO-MED trial.

Animal and human studies suggest an association between depression and aberrant immune response. Further, common inflammatory markers may change during the course of antidepressant treatment in patients. The objective of this study was to evaluate changes in inflammatory markers and clinical outcomes from subjects enrolled in the Combining Medications to Enhance Depression Outcome (CO-MED) trial. At baseline and week 12 (treatment completion), plasma samples of 102 participants were analyzed via a multiplex assay comprised of inflammatory markers using a 27-plex standard assay panel plus a 4-plex human acute phase xMAP technology based platform. We carried out analyses in two steps. First, t-tests were used to identify inflammatory marker levels that changed between baseline and week 12. For markers that were altered, logistic regression models were then conducted to look for associated changes in remission at week 12. Among the 31 inflammatory markers analyzed, several cytokines (IL-5, IFN-γ, IL-13), two chemokines (Eotaxin-1/CCL11, RANTES) and an acute-phase reactant (serum amyloid P component) showed change from baseline to week 12. However, only two indicated differential remission responses. Interestingly, increased levels of Eotaxin-1/CCL11 correlated with remission at week 12, whereas decreased levels of IFN-γ correlated with non-remission at week 12. Results suggest that these inflammatory proteins may serve as predictors of treatment response.

Bone-Conditioned Medium Changes Gene Expression in Bone-Derived Fibroblasts.

PURPOSE: Autologous bone is used for augmentation in the course of oral implant placement. Bone grafts release paracrine signals that can modulate mesenchymal cell differentiation in vitro. The detailed genetic response of the bone-derived fibroblasts to these paracrine signals has remained elusive. Paracrine signals accumulate in bone-conditioned medium (BCM) prepared from porcine cortical bone chips. MATERIALS AND METHODS: In this study, bone-derived fibroblasts were exposed to BCM followed by a whole genome expression profiling and downstream quantitative reverse transciptase polymerase chain reaction of the most strongly regulated genes. RESULTS: The data show that ADM, IL11, IL33, NOX4, PRG4, and PTX3 were differentially expressed in response to BCM in bone-derived fibroblasts. The transforming growth factor beta (TGF-ß) receptor 1 antagonist SB431542 blocked the effect of BCM on the expression of the gene panel, except for IL33. CONCLUSION: These in vitro results extend existing evidence that cortical bone chips release paracrine signals that provoke a robust genetic response in mesenchymal cells that is not exclusively mediated via the TGF-ß receptor. The present data provide further insights into the process of graft consolidation.

Assessment of the prophylactic role of aspirin and/or clopidogrel on experimentally induced acute myocardial infarction in hypercholesterolemic rats.

INTRODUCTION: Hyperlipidemia is a risk factor for cardiovascular diseases such as acute infarction. Inflammation and platelet activation are critical phenomena in acute myocardial infarction (AMI). AIM: The aim of the study was to assess potential protective effects of aspirin and/or clopidogrel on AMI in hypercholesterolemic rats. METHODS: Forty adult male Wistar rats were divided into five groups (eight rats in each). Group I included normal healthy rats. The other 32 rats were subjected to induction of hypercholesterolemia by high-fat diet for 3 weeks, followed by induction of AMI by subcutaneous injections of isoproterenol (85 mg/kg/day, for 2 days). Rats were divided into the following groups: group II, rats with induced hypercholesterolemia and AMI; group III, hypercholesterolemic rats that received aspirin 30 mg/kg/day orally for 7 days before induction of AMI; group IV, hypercholesterolemic rats that received clopidogrel 10 mg/kg/day orally for 7 days before induction of AMI; and group V, hypercholesterolemic rats treated with both aspirin and clopidogrel in the same doses for 7 days before induction of AMI. Serum levels of pentraxin 3 (PTX3), transforming growth factor-ß1 (TGF-ß1), creatine kinase (CK), lactate dehydrogenase (LDH), total cholesterol and triglycerides were estimated in all rats. RESULTS: Isoproterenol-induced AMI in hypercholesterolemic rats was associated with an increase in serum levels of PTX3, TGF-ß1, CK and LDH. Aspirin and/or clopidogrel pretreatment for 1 week led to a reduction of their levels as compared with non-treated rats. However, the reduction caused by combination of aspirin and clopidogrel was more than that caused by each drug separately. CONCLUSION: Combination of aspirin and clopidogrel could be a therapeutic option for hypercholesterolemic patients to attenuate the complex vascular inflammatory process which is a key step in the setting of AMI.

A RTK-based functional RNAi screen reveals determinants of PTX-3 expression.

AIM: The aim of the present study was to explore the role of receptor tyrosine kinases (RTKs) in the regulation of expression of PTX-3, a protector in atherosclerosis. METHODS: Human monocytic U937 cells were infected with a shRNA lentiviral vector library targeting human RTKs upon LPS stimuli and PTX-3 expression was determined by ELISA analysis. The involvement of downstream signaling in the regulation of PTX-3 expression was analyzed by both Western blotting and ELISA assay. RESULTS: We found that knocking down of ERBB2/3, EPHA7, FGFR3 and RET impaired PTX-3 expression without effects on cell growth or viability. Moreover, inhibition of AKT, the downstream effector of ERBB2/3, also reduced PTX-3 expression. Furthermore, we showed that FGFR3 inhibition by anti-cancer drugs attenuated p38 activity, in turn induced a reduction of PTX-3 expression. CONCLUSION: Altogether, our study demonstrates the role of RTKs in the regulation of PTX-3 expression and uncovers a potential cardiotoxicity effect of RTK inhibitor treatments in cancer patients who have symptoms of atherosclerosis or are at the risk of atherosclerosis.

Pentraxin-3 in chronic heart failure: the CORONA and GISSI-HF trials.

AIMS: Pentraxin-3 (PTX3) is a component of the humoral arm of innate immunity which can regulate inflammatory processes. Since the role of inflammation in the progression of chronic heart failure (HF) is debated, we investigated the prognostic value of PTX3 and the effect of a statin in two large populations of patients with HF. METHODS AND RESULTS: Plasma levels of PTX3 were measured at randomization and after 3 months in 1457 patients enrolled in the Controlled Rosuvastatin Multinational Trial in HF (CORONA) and 1233 patients enrolled in the GISSI-Heart Failure trial (GISSI-HF). The relationships between baseline PTX3 levels or their changes over time and mortality were evaluated with multivariable Cox proportional hazard models including clinical factors, high sensitivity C-reactive protein (hsCRP), and N-terminal pro brain natriuretic peptide (NT-proBNP). PTX3 concentration [median (Q1-Q3) = 5.34 (3.55-7.64) ng/mL, n = 2690] was higher in females, in older patients, and those with lower body mass index. Baseline elevated PTX3 was associated with a higher risk of all-cause mortality [759 events, hazard ratio (HR) for 1 SD increase 1.20, 95% confidence interval (CI) 1.12-1.30, P < 0.0001], cardiovascular mortality (587 events, HR 1.27, 95% CI 1.17-1.38, P < 0.0001), or hospitalization for worsening HF (720 events, HR 1.21, 95% CI 1.12-1.30, P < 0.0001), and marginally improved discrimination. Three-month changes in PTX3 were associated with fatal events after adjustment for hsCRP or NT-proBNP. Rosuvastatin lowered hsCRP levels but significantly raised PTX3. CONCLUSION: In two independent clinical trials that enrolled patients with chronic HF, PTX3 was consistently associated with outcomes. The opposite effects of a statin on hsCRP and PTX3 call for further investigation. TRIAL REGISTRATION: NCT00336336 (GISSI-HF), NCT00206310 (CORONA).

Serum amyloid P component accelerates the formation and enhances the stability of amyloid fibrils in a physiologically significant under-saturated solution of amyloid-ß42.

The mechanism whereby an under-saturated solution of amyloid-ß (Aß)42 precipitates as ß sheets in vivo in Alzheimer's disease remains to be elucidated. Herein we present in vitro evidence that serum amyloid P component may mediate this process through its acceleration of amyloid formation from an under-saturated solution of Aß42 and subsequently its stabilization of the amyloid fibrils formed over physiologically significant timeframes. Our observations support serum amyloid P component as a therapeutic target in Alzheimer's disease.

Sustained pharmacological depletion of serum amyloid P component in patients with systemic amyloidosis.

Serum amyloid P component (SAP) is a universal constituent of amyloid deposits and contributes to their formation and/or persistence. We therefore developed CPHPC ((R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexa-noyl]pyrrolidine-2 carboxylic acid), a novel bis(D-proline) drug, to specifically target SAP and report here a first, exploratory, open label proof of principle study in systemic amyloidosis. CPHPC produced sustained, >95% depletion of circulating SAP in all patients and c. 90% reduction in the SAP content of the two amyloidotic organs that became available. There were no significant adverse effects of either SAP depletion or CPHPC itself. No accumulation of amyloid was demonstrable by SAP scintigraphy in any patient on the drug. In hereditary fibrinogen amyloidosis, which is inexorably progressive, proteinuria was reduced in four of five patients receiving CPHPC and renal survival was prolonged compared to a historical control group. These promising clinical observations merit further study.

Pitavastatin improves plasma pentraxin 3 and arterial stiffness in atherosclerotic patients with hypercholesterolemia.

OBJECTIVE: To investigate the effect of pitavastatin on asymptomatic atherosclerosis in patients with hypercholesterolemia. METHODS: Thirty-five outpatients with hypercholesterolemia (61.5+/-12.8 yr) were administered 2 mg oral pitavastatin daily for 6 months. Plasma pentraxin 3 (PTX3), a novel inflammatory marker of atherosclerosis, was measured together with the serum hsCRP and carotid-artery intima-media thickness (IMT). RESULTS: Significant improvement of the LDL-C/HDL-C and log (TG/HDL-C) ratios began to be observed from 1 month after using pitavastatin. Significant correlation of the initial PTX3 value was observed with the initial plaque score (PS) (p=0.038, r=0.246), but not between the hsCRP and plasma PTX3 or PS. When patients were divided into 3 groups based on the initial PTX3 values, a significant decrease of the plasma PTX3 was obtained in the highest PTX3 group alone (p=0.034). The change in the plasma PTX3 value (DeltaPTX3) was significantly correlated with the Delta mean IMT during the study period (p=0.008, r=0.456). CONCLUSION: Pitavastatin significantly reduced the elevated plasma levels of PTX3 in patients with hypercholesterolemia by its pleiotropic effect against atherosclerotic inflammation. This study showed for the first time that the plasma PTX3 might be a useful blood parameter for direct detection of active atherosclerotic change.

Regulation of PTX3, a key component of humoral innate immunity in human dendritic cells: stimulation by IL-10 and inhibition by IFN-gamma.

The protopypic long pentraxin 3 (PTX3) is a unique, humoral pattern-recognition receptor, which plays a nonredundant function in innate resistance to pathogens. Dendritic cells (DC) of myelomonocytic origin, but not plasmacytoid DC, are a major source of PTX3 in response to Toll-like receptor (TLR) engagement. The present study was designed to explore the regulation of PTX3 production in DC. PTX3 production was induced by TLR ligands, CD40 ligand, and interleukin (IL)-1beta and was suppressed by dexamethasone, 1alpha, 25-dihydroxivitamin D3, and prostaglandin E2. It was unexpected that lipopolysaccharide (LPS)-stimulated PTX3 production was enhanced by IL-10 and inhibited by IL-4 and interferon-gamma (IFN-gamma). Enhancement of PTX3 production by IL-10 was also evident when Pam3 Cys-Ser-(Lys)4.3HCl, a TLR2-TLR1 agonist, polyionisicpolycytidylic acid, a TLR3 agonist, and IL-1beta were used as stimuli. The effect of IL-10 was blocked by an anti-IL-10 monoclonal antibody (mAb) or an anti-IL-10 receptor alpha mAb, which also reduced the LPS-induced production. Thus, production of PTX3 in DC is subjected to a distinct regulatory network, with inhibition by IFN-gamma and enhancement by IL-10. The amplification by IL-10 of production of a nonredundant component of fluid-phase innate immunity mirrors the IL-10 stimulatory function on B cells in adaptive immunity. As PTX3 is also an extracellular matrix component, IL-10-enhanced PTX3 production may play a role in orchestration of tissue remodeling in chronic inflammation.

[Novel therapeutic approach to amyloidosis: no implications as yet for patients with Alzheimer's disease]. / Nieuwe therapeutische benadering van amyloïdose: vooralsnog geen implicaties voor patiënten met de ziekte van Alzheimer.

Many disorders, such as Alzheimer's disease and diabetes, are characterised by the misfolding and aggregation of proteins. Pepys et al. described a new approach of destabilizing these aggregates by removing an associated protein, serum amyloid P. This offers opportunities for treating amyloidosis and possibly other protein folding diseases. Understanding the mechanism of this unique disease process and the different elements involved is necessary for future drug development.

Ligand-binding sites in human serum amyloid P component.

Amyloid P component (AP) is a naturally occurring glycoprotein that is found in serum and basement membranes. AP is also a component of all types of amyloid, including that found in individuals who suffer from Alzheimer's disease and Down's syndrome. Because AP has been found to bind strongly and specifically to certain glycosaminoglycans that are components of amyloid deposits, AP may play an important role in the maintenance of amyloid. In the present work, we isolated and identified two proteolytic fragments of AP that are responsible for its heparin-binding activity. Neither fragment corresponds to published heparin-binding sequences. The structural requirements for activity of the peptides (amino acid residues 27-38 and 192-203 of AP) were examined by means of solid-phase inhibition assays with synthetic peptides. AP-(192-203)-peptide inhibits the Ca(2+)-dependent binding of AP to heparin with an IC50 of 25 microM, while the IC50 of AP-(27-38)-peptide and AP-(33-38)-peptide are 10 microM and 2 microM, respectively. The understanding of the structure and function of active AP peptides will be useful for development of amyloid-targeted diagnostics and therapeutics.

Long pentraxins: an emerging group of proteins with diverse functions.

The earliest described pentraxins, C reactive protein (CRP) and serum amyloid P component (SAP), are cytokine-inducible acute phase proteins implicated in innate immunity whose concentrations in the blood increase dramatically upon infection or trauma. The highly conserved family of pentraxins was thought to consist solely of approximately 25 kDa proteins. Recently, several distinct larger proteins have been identified in which only the C-terminal halves show characteristic features of the pentraxin family. One of the recently described "long" pentraxins (TSG-14/PTX3) is inducible by TNF or IL-1 and is produced during the acute phase response. Other newly identified long pentraxins are constitutively expressed proteins associated with sperm-egg fusion (apexin/p50), may function at the neuronal synapse (neuronal pentraxin I, NPI), or may serve yet other, unknown functions (NPII and XL-PXN1). Evidence obtained by molecular modeling and by direct physicochemical analysis suggests that TSG-14 protein retains some characteristic structural features of the pentraxins, including the formation of pentameric complexes.

Effects of calcium, magnesium, and phosphorylcholine on secondary structures of human C-reactive protein and serum amyloid P component observed by infrared spectroscopy.

The secondary structures of human C-reactive protein (CRP) and serum amyloid P component (SAP) in D2O-based solutions in the presence or absence of calcium, magnesium, and phosphorylcholine have been investigated using Fourier transform infrared spectroscopy. Quantitative analysis provided estimations of about 50% beta-sheet, 12% alpha-helix, 24% beta-turn, and 14% unordered structure for CRP and about 54% beta-sheet, 12% alpha-helix, 25% beta-turn, and 9% unordered structure for SAP. With both proteins significant calcium-dependent changes were observed in conformation-sensitive amide I regions assigned to each type of structure. The CRP spectrum was also affected by magnesium, but the changes differed from those induced by calcium. The SAP spectrum was not affected by magnesium. Phosphorylcholine in the presence of calcium also affected the spectrum of CRP but not the spectrum of SAP. Our present study provides the first direct comparison of the secondary structures of the pentraxins human CRP and SAP and hamster female protein (Dong, A., Caughey, B., Caughey, W. S., Bhat, K. S., and Coe, J. E. (1992) Biochemistry 32, 9364-9370). These findings suggest that the three pentraxins have similar secondary structure compositions and calcium-dependent conformational changes, but differ significantly in their responses to phosphorylcholine and magnesium. Such properties are expected to be relevant to the incompletely understood roles of these highly conserved proteins including binding to nuclear proteins, complement activation, and association with amyloids.