Pentraxin Research Articles

EVALUATION OF THE ASSOCIATION OF PLASMA PENTRAXIN-3 LEVELS WITH CAROTID INTIMA-MEDIA THICKNESS AND HIGH-SENSITIVE CRP IN PATIENTS WITH SUBCLINICAL HYPOTHYROIDISM.

Inflammation-related markers may predict cardiovascular diseases. In this study, it was aimed to assess pentraxin-3 (PTX-3) levels and its relationship with carotid intima-media thickness (CIMT) and high-sensitive C-reactive protein (hsCRP) in patients with subclinical hypothyroidism. Prospective cross-sectional study. This study included 60 patients (aged 30-60 years) with subclinical hypothyroidism and 30 healthy volunteers as controls. The demographic characteristics and anthropometric measurements were performed in all patients and controls. In addition, sonographic carotid artery examination, thyroid functional tests, lipid profile, hsCRP, and PTX-3 levels of the participants were investigated. The PTX-3, hsCRP levels and CIMT were higher in patients with subclinical hypothyroidism when compared to controls (p=0.008, p=0.001, p<0.001, respectively). The PTX-3 level was strongly correlated with hsCRP (r=0.865; p<0.001), but no such correlation was detected with CIMT (r=-0.255; p=0.50). In binominal logistic regression analysis, it was found that CIMT and serum uric acid levels were independent parameters associated with subclinical hypothyroidism. In ROC analysis, a cut-off value of >3.75 ng/mL for serum PTX-3 level predicted subclinical hypothyroidism with a sensitivity of 60% and specificity of 60.7% (AUC: 0.672, p=0.004). Showing inflammation and endothelial dysfunction, the PTX-3 may be a helpful marker in patients with subclinical hypothyroidism associated with increased risk for cardiovascular disease.

Gastroprotective effect of dapagliflozin in ethanol-induced gastric lesions in rats: Crosstalk between HMGB1/RAGE/PTX3 and TLR4/MyD88/VEGF/PDGF signaling pathways.

Alcohol abuse may lead to the development of gastric mucosal lesions. Dapagliflozin (DAPA), a sodium-glucose cotransporter-2 inhibitor, is clinically used to treat type 2 diabetes mellitus. However, studies showed protective effect of DAPA under various experimental conditions by alleviating oxidative stress and inflammation. The effect of DAPA on experimental gastric ulcer has not been studied yet. Therefore, we attempted to investigate DAPA's protective effect against ethanol (EtOH)-induced gastric lesions. Fifty-six (8-week-old) male Wistar rats were divided into seven groups. DAPA (1, 5, and 10mg/kg/day; p.o.) was given for seven days, plus a single dose of absolute EtOH (5ml/kg) on day 8. According to hematoxylin and eosin, and Alcian blue staining of gastric tissue sections, titratable acidity, and macroscopic assessments, DAPA high dose (10mg/kg) was the most protective, with lesser ulcerations, and higher mucin, relative to the lower two doses and the standard treatment omeprazole (OME). In rats pre-treated with DAPA high dose, colorimetric and ELISA analyses revealed significantly decreased oxidative stress, pro-inflammatory, and apoptosis indices and increased levels of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Western blot analysis revealed reduced pentraxin-3 (PTX3), high-mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), and myeloid differentiation factor 88 (MyD88) expression. These results were comparable in DAPA (10mg/kg) and OME pre-treated groups. Overall, DAPA exerted a dose-dependent protective effect against EtOH-induced gastric injury. Gastroprotective effects of DAPA (10mg/kg) may be associated with influencing HMGB1/RAGE/PTX3 and TLR4/MyD88/VEGF/PDGF pathways.

Is the Level of Pentraxin-3 a Valid Biomarker in Axial Spondyloarthritis?

Abstract Background Pentraxin-3 (PTX-3) is essential in inflammation, remodelling and regulation of inflammation in various rheumatic diseases. This study aimed to determine whether serum PTX-3 levels indicate increased inflammation and disease activity in patients with axial spondyloarthritis (AxSpA). Material and Methods The study comprised 50 AxSpA patients and 20 healthy controls (HC). Serum PTX-3, interleukin (IL)-17 and IL-23 levels were compared between AxSpA patients and the control group. The relationship between PTX-3 levels and acute-phase reactants and disease activity was examined. Disease activity was scored using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Ankylosing Spondylitis Disease Activity Score-CRP (ASDAS-CRP). Patients with AxSpA were also separated into two subgroups – non-radiographic AxSpA (nr-AxSpA) and radiographic AxSpA (r-AxSpA) – and compared based on their PTX-3 levels. PTX-3, IL-17 and IL-23 levels were measured using the enzyme-linked immunosorbent assay method. Results PTX-3 levels were higher in patients with AxSpA compared with the HC (2.69±2.03 vs 1.84±1.03 ng/mL, p=0.025). When patients were divided into nr-AxSpA and r-AxSpA subgroups, this difference was found to be only due to patients with r-AxSpA. The r-AxSpA group had significantly higher PTX-3 levels than the nr-AxSpA and HC groups (p=0.020 and p=0.016, respectively). There was no statistically significant difference in PTX-3 levels between the nr-AxSpA and HC groups (p=0.961). There was no correlation between PTX-3 levels and acute-phase reactants, IL-17, IL-23 and disease activity scores (BASDAI and ASDAS-CRP). Conclusion These findings support the hypothesis that PTX-3 levels are higher in patients with r-AxSpA, where chronic inflammation and structural progression are more pronounced and can be used as an inflammation marker. However, they demonstrate that this relationship does not exist in nr-AxSpA and that there is no correlation between disease activity and PTX-3 levels. Thus, PTX-3 levels may be associated with structural changes.

The Role of Long Pentraxin 3 and Nuclear Factor Kappa Beta in Vitiligo Occurrence and Disease Severity

Objectives. To reveal the role of long pentraxin 3 (PTX3) and nuclear factor kappa beta (NF‐kB) in vitiligo and their relationship with disease severity. Materials and Methods. The study groups consisted of a total of 54 patients, including 27 patients diagnosed with vitiligo and 27 healthy controls without any cutaneous disease. Patients with amelanotic, sharply demarcated, and chalk‐white macular lesions were defined as vitiligo. The diagnosis of vitiligo was confirmed by Wood’s lamp examination. No biopsies were taken from the lesions, and no additional laboratory testing was performed. Skin and hair pigmentations in lesions other than hands and feet were evaluated. Vitiligo grading was done using the largest macules overall. Spreading rates were evaluated in selected lesions with Wood’s lamp. The long pentraxin 3 and NF‐kB levels in serum samples of participants were measured by the ELISA method. Results. According to the Vitiligo European Task Force consensus 16 of 27, vitiligo patients were in the slow progressive phase, and 11 patients were in the active progressive phase. The serum PTX3 levels of the patients in the vitiligo group were found to be significantly higher than those of the control group (8.21 ± 2.11 ng/ml vs. 6.76 ± 1.90 ng/ml, p &lt; 0.03). Similarly, the serum NF‐kB levels of the patients in the vitiligo group were significantly higher than those of the patients in the control group (15.03 ± 3.45 ng/ml vs. 12.19 ± 4.20 ng/ml, p &lt; 0.01). A positive and significant correlation was found between serum NF‐kB and PTX3 (r = 0.677 and p &lt; 0.01). PTX3 and NF‐kB levels were significantly higher in patients in the active progressive phase than in patients in the slow progressive phase. PTX3 and NF‐kB values in the active progressive phase tended to be higher than those detected when the disease was in the slow progressive phase. Conclusions. High serum PTX3 and NF‐kB levels in vitiligo are evidence of impaired proinflammatory activity and innate and adaptive immunity.

Association of pentraxin in periodontitis patients with coronary artery disease.

Pentraxin 3 (PTX3) is a biomarker, associated with the pathogenesis of Periodontitis and coronary artery disease (CAD) individually, but their role in patients with both diseases remains unclear. The current study aims to evaluate the association of PTX in patients with concomitant periodontitis and CAD. In a case-control study, 240 participants were selected and divided into four groups. Nonperiodontitis + noncardiac = 60 patients, periodontitis + noncardiac (P + NC) = 60 patients, nonperiodontitis + cardiac (NP + C) = 60 patients, periodontitis + cardiac (P + C) = 60 patients. Demographic variables, cardiac and periodontal parameters were recorded. PTX was evaluated in the subgingival plaque and atheromatous plaque samples using real-time quantitative polymerase chain reaction and compared between the groups. The results were statistically analyzed. Among the demographic variables, age showed a significant difference between the groups. Systolic and diastolic blood pressure, low-density lipoprotein, and random blood sugar were significantly higher in NP + C and P + C groups (P ≤ 0.05). The plaque index, probing pocket depth, and clinical attachment loss were significantly higher in P + NC and P + C groups (P ≤ 0.05). PTX was significantly elevated in P + C group (P = 0.000). Pearson's correlation revealed a significant correlation between the periodontal parameters and PTX in both the cardiac and oral samples. PTX3 levels were elevated in CAD patients with periodontitis suggesting the influence of periodontal inflammation in the progression of CAD. PTX3 may serve as a diagnostic and prognostic tool for both periodontitis and CAD. This study could provide an understanding and awareness about the potential role of PTX3 in both periodontitis and CAD.

Thrombospondin-2 as a potential noninvasive biomarker of hepatocyte injury but not liver fibrosis in children with MAFLD: A preliminary study.

Metabolic-associated fatty liver disease (MAFLD) requires close monitoring due to its increased incidence and progression to fibrosis, cirrhosis and even hepatocellular carcinoma. The search for non-invasive markers to diagnose liver fibrosis is ongoing. The aim of our study was to evaluate the serum levels of growth differentiation factor-15 (GDF-15), thrombospondin-2 (TSP2), pentraxin 3 (PTX3) and angiopoietin-like protein 8 (ANGPTL8) in children with MAFLD. Fifty-six overweight/obese children with suspected liver disease were included in this prospective study. MAFLD was diagnosed according to the latest consensus. Vibration-controlled transient elastography (TE) was performed to detect clinically significant liver fibrosis. Serum concentrations of GDF-15, TSP2, PTX3 and ANGPTL8 were measured by enzyme-linked immunosorbent assay (ELISA). Liver steatosis was diagnosed in abdominal ultrasound in 31 (55.36%) overweight/obese patients who were classified as the MAFLD group. Aspartate aminotransferase (AST)/platelet ratio (APRI) and liver stiffness measurement (LSM) values and TSP2 concentrations showed significantly higher values in patients in MAFLD than in the non-MAFLD group. TSP2 was significantly positively correlated with alanine transaminase (ALT), AST, γ-glutamyltransferase (GGT) and APRI in the study group. The receiver operating characteristics (ROC) analysis showed that the area under the curve (AUC) of LSM, APRI and serum TSP2 was significant for predicting MAFLD in obese children. In the multivariable regression model, LSM was the only significant parameter associated with the diagnosis of MAFLD in children. TSP2 may be a potential biomarker of hepatocyte injury in pediatric patients with MAFLD. None of the examined biomarkers were found to be effective non-invasive markers of liver fibrosis in children.

Canine amniotic fluid at birth: From a discarded sample to a potential diagnostic of neonatal maturity

The definition of new reliable markers for neonatal maturity evaluation is crucial in canine clinical practice. Concerns about the safety of amniotic sampling in pregnant dogs have prevented its collection for diagnostic purposes. Moreover, amniotic fluid had been considered waste material until the latest studies reported amniocentesis as a reliable and safe procedure, even in the canine species. In our study, amniotic fluid (n = 63) collected at birth from ten dogs undergoing elective Caesarean sections at term was analysed to discover new potential indices of canine neonatal maturity. Based on gestational age, mothers and puppies were divided into two groups: the early group (≤65 days from luteinizing hormone (LH) surge, n = 5) and the late group (>65 days from LH surge, n = 5). Amniotic parameters of the lightest and heaviest puppy in individual/each litter, with a birth weight difference of at least 20% among littermates, were also compared. In particular, the content of lecithin, sphingomyelin, surfactant protein A (SP-A), cortisol, and pentraxin 3 (PTX3) in amniotic fluid, which is considered predictive of foetal development in humans, were investigated. Maternal serum SP-A and cortisol were also measured simultaneously.All amniotic parameters were detectable in canine amniotic fluid. Interestingly, the concentrations of different amniotic parameters correlated with each other. Lecithin was positively correlated with sphingomyelin (p < 0.0001), maternal SP-A (p < 0.0005), and the ratio of amniotic and maternal cortisol (p < 0.004). Amniotic SP-A was inversely correlated to maternal SP-A (p < 0.05), lecithin (p < 0.005), and lecithin-sphingomyelin ratio (p < 0.05). A positive correlation was also recorded between amniotic and maternal cortisol (p < 0.008). Considering that all puppies were born alive and mature, these data could provide a potential range of expected amniotic values in full-term new-born dogs. Furthermore, since gestational age was positively correlated with both maternal and amniotic cortisol (p < 0.0001) and amniotic PTX3 (p < 0.05), amniotic fluid seems to be an attractive, innovative, and minimally invasive matrix with potential diagnostic and prognostic utility for the investigation of canine maturity.

Markers of extracellular matrix remodeling and systemic inflammation in patients with heritable thoracic aortic diseases.

In approximately 20% of patients with thoracic aortic aneurysms or dissections a heritable thoracic aortic disease (HTAD) is suspected. Several monogenic connective tissue diseases imply high risk of aortic disease, including both non-syndromic and syndromic forms. There are some studies assessing inflammation and extracellular matrix remodeling in patients with non-hereditary aortic disease, but such studies in patients with hereditary diseases are scarce. To quantify markers of extracellular matrix (ECM) and inflammation in patients with vascular connective tissue diseases versus healthy controls. Patients with Loeys-Dietz syndrome (LDS, n = 12), Marfan syndrome (MFS, n = 11), and familial thoracic aortic aneurysm 6 (FTAA6, n = 9), i.e., actin alpha 2 (ACTA2) pathogenic variants, were recruited. Exome or genome sequencing was performed for genetic diagnosis. Several markers of inflammation and ECM remodeling were measured in plasma by enzyme immunoassays. Flow cytometry of T-cell subpopulations was performed on a subgroup of patients. For comparison, blood samples were drawn from 14 healthy controls. (i) All groups of HTAD patients had increased levels matrix metalloproteinase-9 (MMP-9) as compared with healthy controls, also in adjusted analyses, reflecting altered ECM remodeling. (ii) LDS patients had increased levels of pentraxin 3 (PTX3), reflecting systemic inflammation. (iii) LDS patients have increased levels of soluble CD25, a marker of T-cell activation. Our data suggest that upregulated MMP-9, a matrix degrading enzyme, is a common feature of several subgroups of HTAD. In addition, LDS patients have increased levels of PTX3 reflecting systemic and in particular vascular inflammation.

Increased protein phosphatase 5 expression in inflammation-induced left ventricular dysfunction in rats

Titin phosphorylation contributes to left ventricular (LV) diastolic dysfunction. The independent effects of inflammation on the molecular pathways that regulate titin phosphorylation are unclear. We investigated the effects of collagen-induced inflammation and subsequent tumor necrosis factor-α (TNF-α) inhibition on mRNA expression of genes involved in regulating titin phosphorylation in 70 Sprague-Dawley rats. LV diastolic function was assessed with echocardiography. Circulating inflammatory markers were quantified by enzyme-linked immunosorbent assay and relative LV gene expression was assessed by Taqman® polymerase chain reaction. Differences in normally distributed variables between the groups were determined by two-way analysis of variance (ANOVA), followed by Tukey post-hoc tests. For non-normally distributed variables, group differences were determined by Kruskal-Wallis tests. Collagen inoculation increased LV relative mRNA expression of vascular cell adhesion molecule 1 (VCAM1), pentraxin 3 (PTX3), and inducible nitric oxide synthase (iNOS) compared to controls, indicating local microvascular inflammation. Collagen inoculation decreased soluble guanylate cyclase alpha-2 (sGCα2) and soluble guanylate cyclase beta-2 (sGCβ2) expression, suggesting downregulation of nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling. Inhibiting TNF-α prevented collagen-induced changes in VCAM1, iNOS, sGCα2 and sGCβ2 expression. Collagen inoculation increased protein phosphatase 5 (PP5) expression. Like LV diastolic dysfunction, increased PP5 expression was not prevented by TNF-α inhibition. Inflammation-induced LV diastolic dysfunction may be mediated by a TNF-α-independent increase in PP5 expression and dephosphorylation of the N2-Bus stretch element of titin, rather than by TNF-α-induced downregulation of NO-sGC-cGMP pathway-dependent titin phosphorylation. The steady rise in number of patients with inflammation-induced diastolic dysfunction, coupled with low success rates of current therapies warrants a better understanding of the systemic signals and molecular pathways responsible for decreased titin phosphorylation in development of LV diastolic dysfunction. The therapeutic potential of inhibiting PP5 upregulation in LV diastolic dysfunction requires investigation.

Pentraxin 3 Facilitates Shrimp-Allergic Responses in IgE-Activated Mast Cells.

Since food avoidance is currently the only way to prevent allergic reactions to shrimp, a better understanding of molecular events in the induction and progression of allergy, including food allergy, is needed for developing strategies to inhibit allergic responses. Pentraxin 3 (PTX3) is rapidly produced directly from inflammatory or damaged tissues and is involved in acute immunoinflammatory responses. However, the role of PTX3 in the development of immediate IgE-mediated shrimp allergy remains unknown. Wild-type BALB/c mice were immunized intraperitoneally and were challenged with shrimp extract. Serum IgE and PTX3 levels were analyzed. RBL-2H3 cells were stimulated with either dinitrophenyl (DNP) or serum of shrimp-allergic mice, and markers of degranulation, proinflammatory mediators, and phosphorylation of signal proteins were analyzed. We further examined the effect of PTX3 in shrimp extract-induced allergic responses in vitro and in vivo. Mice with shrimp allergy had increased PTX3 levels in the serum and small intestine compared with healthy mice. PTX3 augmented degranulation, the production of proinflammatory mediators, and activation of the Akt and MAPK signaling pathways in mast cells upon DNP stimulation. Furthermore, the expression of transcription factor CCAAT/enhancer-binding protein delta (CEBPD) was elevated in PTX3-mediated mast cell activation. Finally, the PTX3 inhibitor RI37 could attenuate PTX3-induced degranulation, proinflammatory mediator expression, and phosphorylation of the Akt and MAPK signaling. The results suggested that PTX3 can facilitate allergic responses. Our data provide new insight to demonstrate that PTX3 is a cause of allergic inflammation and that RI37 can serve as a therapeutic agent in shrimp allergy.

Insights into the Relationship between Pentraxin-3 and Cancer

Although cancer can be cured if detected early and treated effectively, it is still a leading cause of death worldwide. Tumor development can be limited by an appropiate immune response, but it can be promoted by chronic extensive inflammation through metabolic dysregulation and angiogenesis. In the past decade, numerous efforts have been made in order to identify novel candidates with predictive values in cancer diagnostics. In line with this, researchers have investigated the involvement of pentraxin-3 (PTX-3) in cellular proliferation and immune escape in various types of cancers, although it has not been clearly elucidated. PTX-3 is a member of the long pentraxin subfamily which plays an important role in regulating inflammation, innate immunity response, angiogenesis, and tissue remodeling. Increased synthesis of inflammatory biomarkers and activation of different cellular mechanisms can induce PTX-3 expression in various types of cells (neutrophils, monocytes, lymphocytes, myeloid dendritic cells, fibroblasts, and epithelial cells). PTX-3 has both pro- and anti-tumor functions, thus dual functions in oncogenesis. This review elucidates the potential usefulness of PTX-3 as a serum biomarker in cancer. While future investigations are needed, PTX-3 is emerging as a promising tool for cancer's diagnosis and prognosis, and also treatment monitoring.

Diagnostic performance of serum pentraxin-3 in pediatric acute appendicitis: a prospective diagnostic validation study

IntroductionPediatric acute appendicitis (PAA) is a pathology with a high rate of diagnostic error. The search for new diagnostic tools is justified by the high morbidity and healthcare costs associated with diagnostic error.MethodsWe designed a prospective study to validate serum pentraxin-3 (PTX3) as a diagnostic tool in PAA. Participants were divided into three groups: (1) patients with no underlying pathology (2) patients with non-surgical abdominal pain and (3) patients with a confirmed diagnosis of PAA. For further analyses, patients in group 3 were divided into complicated or uncomplicated PAA. Quantitative variables were expressed as medians and interquartile ranges and categorical variables as percentages. Quantitative variables were compared using the Kruskal–Wallis test and the Mann–Whitney U test. Diagnostic performance was evaluated with ROC curves.ResultsThis study included 215 patients divided into group 1 (n = 63), group 2 (n = 53) and group 3 (n = 99). Median serum PTX3 values were 2.54 (1.70–2.95) ng/mL, 3.29 (2.19–7.64) ng/mL and 8.94 (6.16–14.05) in groups 1, 2 and 3, respectively (p = 0.001). Patients with complicated PAA showed significantly higher values than patients with uncomplicated PAA (p = 0.04). The AUC (group 2 vs. 3) was 0.77 (95% CI 0.69–0.85) and the best cut-off point was at 7.28 ng/mL, with a sensitivity of 61.3% and a specificity of 73.1%. The AUC (complicated vs. uncomplicated PAA) was 0.65 (95% CI 0.54–0.77) and the best cut-off point was 12.33 ng/mL, with a sensitivity of 51.72% and a specificity of 72.73%.ConclusionsThe diagnostic ability of serum PTX3 in PAA is only moderate and therefore it cannot be considered a definitive diagnostic test. The discriminatory ability of PTX3 between complicated and uncomplicated PAA is poor. These findings, which contrast with those reported to date, should be validated with future properly designed prospective studies.

Clinical Utility of Circulating Pentraxin 3 as a Prognostic Biomarker in Coronavirus Disease 2019: A Systematic Review and Meta-analysis.

Pentraxin 3 (PTX3) is involved in inflammation regulation and has a certain association with infectious diseases. However, its specific correlation with infectious diseases remains controversial. This study aimed to analyze the association between them and explore the possible role of PTX3 in the prognosis of coronavirus disease 2019 (COVID-19). Five databases (PubMed, Cochrane Library, Embase, Clinicaltrials.gov, and gray literature) were searched. Outcomes were expressed as a standardized mean difference (SMD) and 95% confidence intervals (CI). The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of included articles. Stata 12 and Meta-DiSc were applied to analyze the pooled data. Receiver operating characteristic (ROC) curves were conducted to determine the prognostic value of PTX3 for mortality. Six articles met the inclusion criteria. Circulating PTX3 levels had a nonsignificant difference between intensive care unit (ICU) and non-ICU patients with COVID-19 [SMD 1.37 (-0.08, 2.81); I2 = 93.9%, P < 0.01], while the PTX3 levels in nonsurvival COVID-19 patients was significantly lower than those in survival patients [SMD -1.41 (-1.92, -0.91); I2 = 66.4%,P=0.051]. Circulating PTX3 had good mortality prediction ability (area under ROC curve, AUC = 0.829) in COVID-19. Funnel plots and Egger's tests showed low probabilities of publication bias. Through sensitivity analysis, the results of this study were robust. This study found that PTX3 was differentially expressed between survival and nonsurvival patients with COVID-19, while there was no significant difference between ICU and non-ICU patients. Meanwhile, circulating PTX3 may be a good biomarker for monitoring the prognosis of COVID-19, which may provide new ideas and directions for clinical and scientific research.

Akt-Activated Endothelium Increases Cancer Cell Proliferation and Resistance to Treatment in Ovarian Cancer Cell Organoids.

Ovarian cancer (OC) is a heterogeneous disease characterized by its late diagnosis (FIGO stages III and IV) and the importance of abdominal metastases often observed at diagnosis. Detached ovarian cancer cells (OCCs) float in ascites and form multicellular spheroids. Here, we developed endothelial cell (EC)-based 3D spheroids to better represent in vivo conditions. When co-cultured in 3D conditions, ECs and OCCs formed organized tumor angiospheres with a core of ECs surrounded by proliferating OCCs. We established that Akt and Notch3/Jagged1 pathways played a role in angiosphere formation and peritoneum invasion. In patients' ascites we found angiosphere-like structures and demonstrated in patients' specimens that tumoral EC displayed Akt activation, which supports the importance of Akt activation in ECs in OC. Additionally, we demonstrated the importance of FGF2, Pentraxin 3 (PTX3), PD-ECGF and TIMP-1 in angiosphere organization. Finally, we confirmed the role of Notch3/Jagged1 in OCC-EC crosstalk relating to OCC proliferation and during peritoneal invasion. Our results support the use of multicellular spheroids to better model tumoral and stromal interaction. Such models could help decipher the complex pathways playing critical roles in metastasis spread and predict tumor response to chemotherapy or anti-angiogenic treatment.

Pentraxin 3 regulates tyrosine kinase inhibitor-associated cardiomyocyte contraction and mitochondrial dysfunction via ERK/JNK signalling pathways

BackgroundHepatocellular carcinoma (HCC) patients suffer varying degrees of heart dysfunction after tyrosine kinase inhibitor (TKI) treatment. Interestingly, HCC patients often have higher levels of pentraxin 3 (PTX3), and PTX3 inhibition was found to improve left ventricular dysfunction in animal models. ObjectivesWe sought to assess the therapeutic potential of PTX3 inhibition on TKI-associated cardiotoxicity. MethodsWe used a human embryonic stem cell line, RUES2, to generate cardiomyocyte cultures (RUES2-CM) for functional testing. We also assessed heart function and PTX3 expression levels in 16 HCC patients who received TKI treatment, 3 HCC patients who did not receive TKIs, and 7 healthy volunteers. ResultsSignificantly higher PTX3 expression was noted in HCC patients with TKI treatment versus those without, and 38% of male and 33% of female patients had QTc prolongation after TKI treatment. Treatment of cardiomyocyte cultures with sorafenib also increased PTX3 expression and induced cytoskeletal remodelling, contraction reduction, sodium current inhibition, and mitochondrial respiratory dysfunction. PTX3 colocalised with CD44 in cardiomyocytes, and cardiomyocyte contraction, mitochondrial respiratory function, and regular cytoskeletal and apoptotic protein expression were restored with PTX3 inhibition. CD44 knockdown confirmed PTX3/CD44 signalling. These results suggest a possible mechanism in which sorafenib treatment increases PTX3 expression, thereby resulting in reduced extracellular signal-regulated kinase (ERK) 1/2 expression that affects cardiomyocyte contraction, while also activating c-Jun N-terminal kinase (JNK) downstream pathways to disrupt mitochondrial respiration and trigger apoptosis. ConclusionsTKI-induced cardiotoxicity may be partly mediated by the upregulation of PTX3, and thus PTX3 inhibition has potential as a therapeutic strategy.

Blockade of the pentraxin 3/CD44 interaction attenuates lung injury-induced fibrosis.

Fibrosing interstitial lung diseases (fILD) are potentially fatal with limited therapeutic options and no effective strategies to reverse fibrogenesis. Myofibroblasts are chief effector cells in fibrosis that excessively deposit collagen in the pulmonary interstitium and lead to progressive impairment of gaseous exchange. Plasma and lung specimens from patients with fILD were applied for detecting pentraxin 3 (PTX3) abundance by ELISA and Immunohistochemistry. Masson's trichrome and Sirius red stains and hydroxyproline assay were performed for assessing collagen accumulation in the lungs of bleomycin-exposed conditional Ptx3-deficient and PTX3-neutralizing antibody (αPTX3i)-treated mice. Downstream effectors including signaling pathways and fibrotic genes were examined for assessing CD44-involved PTX3-induced fibrosis in HFL1 and primary mouse fibroblasts. PTX3 was upregulated in the lungs and plasma of bleomycin-exposed mice and correlated with disease severity and adverse outcomes in fILD patients. Decreased collagen accumulation, attenuation of alveolar fibrosis and fibrotic markers, and improved lung function were observed in bleomycin-exposed conditional Ptx3-deficient mice. PTX3 activates lung fibroblasts to differentiate towards migrative and highly collagen-expressing myofibroblasts. Lung fibroblasts with CD44 inactivation attenuated the PI3K-AKT1, NF-κB, and JNK signaling pathways and fibrotic markers. αPTX3i mimic-based therapeutic studies demonstrated abrogation of the migrative fibroblast phenotype and myofibroblast activation in vitro. Notably, αPTX3i inhibited lung fibrosis, reduced collagen deposition, increased mouse survival, and improved lung function in bleomycin-induced pulmonary fibrosis. The present study reveals new insights into the involvement of the PTX3/CD44 axis in fibrosis and suggests PTX3 as a promising therapeutic target in fILD patients.

Association of polymorphisms in long pentraxin 3 and its plasma levels with COVID-19 severity.

COVID-19 is an infectious respiratory disease caused by SARS-CoV-2. Pentraxin 3 (PTX3) is involved in the activation and regulation of the complement system, demonstrating an important role in the pathogenesis of COVID-19. The aim was toevaluate the association of single nucleotide polymorphisms in PTX3 and its plasma levels with the severity of COVID-19. This is a retrospective cohort study, carried out between August 2020 and July 2021, including patients with confirmed COVID-19 hospitalized in 2 hospitals in the Northeast Region of Brazil. Polymorphisms in PTX3 (rs1840680 and rs2305619) were determined by real-time PCR. PTX3 plasma levels were measured by ELISA. Serum levels of interleukin (IL)-6, IL-8, and IL-10 were determined by flow cytometry. A multivariate logistic regression model was used to identify parameters independently associated with COVID-19 severity. P values < 0.05 were considered significant. The study included 496 patients, classified as moderate (n = 267) and severe (n = 229) cases. The PTX3 AA genotype (rs1840680) was independently associated with protection against severe COVID-19 (P = 0.037; odds ratio = 0.555). PTX3 plasma levels were significantly associated with COVID-19 severity and mortality (P < 0.05). PTX3 levels were significantly correlated with IL-6, IL-8, IL-10, C-reactive protein, total leukocytes, neutrophil-to-lymphocyte ratio, urea, creatinine, ferritin, length of hospital stay, and higher respiratory rate (P < 0.05). Our results revealed a protective effect of the PTX3 AA genotype (rs1840680) on the development of severe forms of COVID-19. Additionally, PTX3 plasma levels were associated with the severity of COVID-19. The results of this study provide evidence of an important role of PTX3 in the immunopathology of COVID-19.

Correlation between serum levels of PTX-3, SIL-2R, inflammatory markers, and APACHE II scores in patients with severe acute pancreatitis.

To investigate the correlation of serum pentraxin 3 (PTX-3), soluble interleukin-2 receptor (SIL-2R), C-reactive protein (CRP), procalcitonin (PCT) levels, and acute physiology and chronic health evaluation II (APACHE II) scores in patients with severe acute pancreatitis (SAP). A total of 30 patients with SAP from October 2020 to October 2021 were selected as the SAP group, and 42 patients with mild acute pancreatitis (MAP) or moderate-severe acute pancreatitis (MSAP) was selected as the control group. The serum levels of PTX-3, SIL-2R, CRP, PCT, and APACHE II scores were evaluated. The serum levels of PTX-3, SIL-2R, CRP, PCT, and APACHE II scores at admission in the SAP group were significantly higher than those in the control group (all P < .05). Spearman analysis showed that serum PTX-3, SIL-2R, CRP, and PCT levels were positively correlated with APACHE II scores (all P < .05). The mortality rate within 28 days was 26.7% in the SAP group; moreover, the serum PTX-3, SIL-2R, CRP, and PCT levels and APACHE II scores at admission in the death group were significantly higher than those in the survival group (all P < .05). The receiver operating curve showed that the combined prediction value of all indicators (PTX-3 + SIL-2R + CRP + PCT + APACHE II) was superior to the single indicators, and the diagnostic sensitivity and specificity were 90.9% and 84.2%, respectively. Serum PTX-3, SIL-2R, CRP, and PCT levels and APACHE II scores have high guiding significance in early diagnosis and prognostic evaluation of SAP patients.

Long pentraxin 3 (PTX3) levels predict death, intubation and thrombotic events among hospitalized patients with COVID-19.

PTX3 is an important mediator of inflammation and innate immunity. We aimed at assessing its prognostic value in a large cohort of patients hospitalized with COVID-19. Levels of PTX3 were measured in 152 patients hospitalized with COVID-19 at San Gerardo Hospital (Monza, Italy) since March 2020. Cox regression was used to identify predictors of time from admission to in-hospital death or mechanical ventilation. Crude incidences of death were compared between patients with PTX3 levels higher or lower than the best cut-off estimated with the Maximally Selected Rank Statistics Method. Upon admission, 22% of the patients required no oxygen, 46% low-flow oxygen, 30% high-flow nasal cannula or CPAP-helmet and 3% MV. Median level of PTX3 was 21.7 (IQR: 13.5-58.23) ng/ml. In-hospital mortality was 25% (38 deaths); 13 patients (8.6%) underwent MV. PTX3 was associated with risk of death (per 10 ng/ml, HR 1.08; 95%CI 1.04-1.11; P<0.001) and death/MV (HR 1.04; 95%CI 1.01-1.07; P=0.011), independently of other predictors of in-hospital mortality, including age, Charlson Comorbidity Index, D-dimer and C-reactive protein (CRP). Patients with PTX3 levels above the optimal cut-off of 39.32 ng/ml had significantly higher mortality than the others (55% vs 8%, P<0.001). Higher PTX3 plasma levels were found in 14 patients with subsequent thrombotic complications (median [IQR]: 51.4 [24.6-94.4] versus 21 [13.4-55.2]; P=0.049). High PTX3 levels in patients hospitalized with COVID-19 are associated with a worse outcome. The evaluation of this marker could be useful in prognostic stratification and identification of patients who could benefit from immunomodulant therapy.

The Relationship of Carotid Intima-Media Thickness with Cell Adhesion Molecules and Pentraxin-3 in Patients with Psoriatic Arthritis

Abstract Aim Cardiovascular morbidity is increased in patients with psoriatic arthritis (PsA) compared to the general population. Several recent studies have indicated that pentraxin 3 (PTX-3) and cell adhesion molecules (CAMs) might be independent biomarkers of subclinical atherosclerosis. In this study, we aimed to determine the relationship of CAMs and PTX-3 with carotid intima media thickness (CIMT) in patients with PsA and to compare CIMT and serum levels of these biomarkers in patients with healthy controls (HCs). Method PsA patients fulfilling the CASPAR (Classification criteria for Psoriatic Arthritis) criteria without traditional cardiovascular (CV) comorbidity and HCs without autoimmune and/or CV disease were included in this cross-sectional study. Carotid artery Doppler ultrasound examinations were conducted by a single radiologist blinded to the participants’ clinical characteristics. Serum vascular adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E-selectin, and PTX-3 concentrations were analized. Results 43 PsA patients (27 females, mean age 42.49±11.70 years, and a mean disease duration of 9.37±7.96 years) and 37 HCs (28 females, mean age 42.16±11.38 years) were included. In regression analyses, age and PTX-3 were found to be the best predictors of CIMT in patients with PsA. CIMT was significantly higher in PsA patients compared with HCs (0.63±0.18 vs. 0.49±0.10 mm, p&lt;0.01). In te PsA group, serum levels of PTX-3, ICAM-1, and VCAM-1 were also significantly higher than HCs. CIMT correlated positively with age, disease duration, PTX-3, ICAM-1, and VCAM-1 (p&lt;0.05). Conclusion In our study, age and serum level of PTX-3 were found to be the predictors of CIMT in patients with PsA without CV comorbidity. This outcome highlights the importance of monitoring CIMT and serum level of PTX-3 as CV risk factors in PsA patients.