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IntroductionThe accurate distinction between periprosthetic joint infections (PJI) and aseptic failures (AF) is of paramount importance due to differences in treatment. However, this could be challenging by using the current criteria. Various synovial fluid biomarkers are being assessed to improve the diagnostic accuracy. Myeloperoxidase (MPO), an enzyme contained in the granules of neutrophils, may be a promising biomarker for PJI.MethodsSynovial fluids of 99 patients (n = 65 PJI according to EBJIS criteria; n = 34 AF) were collected in two specialized orthopedic centers. PJI were divided into acute (n = 33) and low-grade (n = 32) according to previously published classification. An activity assay specific for active MPO was performed in each sample. Ability of MPO to correctly discriminate patients with PJI from AF was determined by ROC analysis. The best discriminating cut-off value was determined by calculating the J Youden index. For all analyses, a P value < 0.05 was considered statistically significant.ResultsActive MPO was higher in PJI than AF (P < 0.0001). The ROC analysis revealed a significant area under the curve (AUC: 0.86; 95% CI: 0.78–0.93, P < 0.0001). A cut-off value of 561.9 U/mL, with good sensitivity (0.69) and specificity (0.88), discriminated between AF and PJI (accuracy 75.76%, 95% CI: 66.11–83.81%, positive likelihood ratio 5.88, 95% CI: 2.31–14.98 and negative likelihood ratio 0.35, 95%CI: 0.24–0.51). No difference in MPO levels was found between acute and chronic low-grade PJI.ConclusionThe proposed assay appears to be a reliable and affordable tool for detecting the active MPO in synovial fluid, with promising characteristics of sensitivity and specificity in discriminating both acute and low-grade PJI from AF. Further studies are needed to confirm MPO diagnostic cut-off values and validate their use in the routine clinical practice.

Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are the two major neurodegenerative diseases causing dementia. Due to similar clinical phenotypes, differential diagnosis is challenging without specific biomarkers. Beta-site Amyloid Precursor Protein cleaving enzyme 1 (BACE1) is a β-secretase pivotal in AD pathogenesis. In AD and mild cognitive impairment subjects, BACE1 activity is increased in brain/cerebrospinal fluid, and plasma levels appear to reflect those in the brain. In this study, we aim to evaluate serum BACE1 activity in FTD, since, to date, there is no evidence about its role. The serum of 30 FTD patients and 30 controls was analyzed to evaluate (i) BACE1 activity, using a fluorescent assay, and (ii) Glial Fibrillary Acid Protein (GFAP) and Neurofilament Light chain (NfL) levels, using a Simoa kit. As expected, a significant increase in GFAP and NfL levels was observed in FTD patients compared to controls. Serum BACE1 activity was not altered in FTD patients. A significant increase in serum BACE1 activity was shown in AD vs. FTD and controls. Our results support the hypothesis that serum BACE1 activity is a potential biomarker for the differential diagnosis between AD and FTD.

Background. Neutrophil–lymphocyte ratio (NLR) is a noninvasive, inexpensive, and easily applicable marker of inflammation. Since immune dysregulation leading to inflammation is regarded as a hallmark of dementia, in particular Alzheimer’s disease (AD), we decided to investigate the potentials of NLR as a diagnostic and predictive biomarker in this clinical setting. Materials and Methods. NLR was measured in the blood of patients with AD (n = 103), amnestic type mild cognitive impairment (aMCI, n = 212), vascular dementia (VAD, n = 34), and cognitively healthy Controls (n = 61). One hundred twelve MCI patients underwent a regular clinical follow-up. Over a 36-months median follow-up, 80 remained stable, while 32 progressed to overt dementia. Results. NLR was higher in patients with aMCI or dementia compared to Controls; however, the difference was statistically significant only for aMCI (+13%, p=0.04) and AD (+20%, p=0.03). These results were confirmed by multivariate logistic analysis, which showed that high NLR was associated with an increase in the likelihood of receiving a diagnosis of aMCI (odd ratio (OR): 2.58, 95% confidence interval (CI): 1.36–4.89) or AD (OR: 3.13, 95%CI: 1.47–6.70), but not of VAD. NLR did not differ when comparing stable vs. progressing aMCI. Conclusions. This is the first report showing that NLR is significantly increased in MCI and AD but not in VAD. We also found that NLR was unable to predict the conversion from aMCI to AD. Further research on larger cohorts is warranted to definitely ascertain the application of NLR as a possible marker for aMCI and AD.

Objective: Chronic obstructive pulmonary disease (COPD) is one of the main causes of morbidity and mortality in the United States. Oxidative stress due to cigarette smoking seems to be one of the major driving mechanisms in COPD pathogenesis. Since the scavenger receptor B1 (SR-B1) appears to play a key role in med iating the uptake for ɑ-tocopherol and other antioxidants in lung tissue, we aimed to investigate its role in COPD pathogenesis. Methods: Lung tissue biopsies were obtained from 12 subjects; 6 of these had a diagnosis of COPD in a stable clinical state, the others 6 were current (n = 1) or ex-smokers (n = 5) with normal lung function (controls). 4-Hydroxynonenal (4-HNE)–SR-B1 adducts were detected by immunoprecipitation. ɑ-tocopherol concentration was determined by HPLC. Results: SR-B1 levels were lower in COPD patients and these results par allel with lower levels of vitamin E in lung tissue found in COPD patients . This effect can be the consequence of oxidative posttranslational modifications, confirmed by the binding of the peroxidation product 4-HNE to SR-B1 possibly leading to its degradation. Conclusions: The loss of SR-B1 may be involved in lung ɑ-tocopherol content decrease with the consequence of making lung tissue more susceptible to oxidative damage as suggested by the SR-B1–4-HNE adduct formation, and more prone to COPD development. Thus, our findings suggest a novel role of SR-B1 in pathomechani sms underlying COPD. Significance statement Chronic obstructive pulmonary disease (COPD) is one of the main causes of morbidity and mortality in the United States. Oxidative stress has been suggested to be the major driving mechanism in COPD pathogenesis. Loss of scavenger receptor BI (SR-B1) significantly decreases tocopherol lung content making lung tissue more susceptible to oxidative damage. The results of our study show that SR-B1 levels were lower in COPD patients and these results parallel with lower levels of vitamin E in lung tissue. Our findings suggest a novel role of SR- B1 in pathomechanisms underlying COPD.

HDL-cholesterol quality, including cholesterol distribution in HDL subfractions, is emerging as a key discriminant in dictating the effects of these lipoproteins on cardiovascular health. This study aims at elucidating the relationship between cholesterol distribution in HDL subfractions and CVD risk factors as well as diet quality and energy density in a population of pre- and postmenopausal women. Seventy-two women aged 52 ± 6 years were characterized metabolically and anthropometrically. Serum HDL-C subfractions were quantified using the Lipoprint HDL System. Cholesterol distribution in large HDL subfractions was lower in overweight individuals and study participants with moderate to high estimated CVD risk, hypertension, or insulin resistance. Cholesterol distribution in large, as opposed to small, HDL subfractions correlated negatively with insulin resistance, circulating triglycerides, and visceral adipose tissue (VAT). VAT was an independent positive and negative predictor of cholesterol distribution in large and small HDL subfractions, respectively. Furthermore, an increase in energy intake could predict a decrease in cholesterol levels in large HDL subfractions while lipid intake positively predicted cholesterol levels in small HDL subfractions. Cholesterol distribution in HDL subfractions may represent an additional player in shaping CVD risk and a novel potential mediator of the effect of diet on cardiovascular health.

Abstract Background Cholangiocarcinoma (CCA) is an aggressive disease with poor prognosis. A molecular classification based on mutational, methylation and transcriptomic features could allow identifying tailored therapies to improve CCA patient outcome. Proteomic remains partially unexplored; here, we analyzed the proteomic profile of five intrahepatic cholangiocarcinoma (ICC) derived from Italian patients undergone surgery and one normal bile duct cell line. Methods Proteome profile was investigated by using 2D electrophoresis followed by Mass Spectrometry (MS). To validate proteomic data, the expression of four overexpressed proteins (CAT, SOD, PRDX6, DBI/ACBP) was evaluated by immunohistochemistry in an independent cohort of formalin fixed, paraffin-embedded (FFPE) ICC tissues. We also compared proteomic data with those obtained by transcriptomic profile evaluated by microarray analysis of the same tissues. Results We identified 19 differentially expressed protein spots, which were further characterized by MS; 13 of them were up- and 6 were down-regulated in ICC. These proteins are mainly involved in redox processes (CAT, SODM, PRDX2, PRDX6), in metabolism (ACBP, ACY1, UCRI, FTCD, HCMS2), and cell structure and organization (TUB2, ACTB). CAT is overexpressed in 86% of patients, PRDX6 in 73%, SODM in 100%, and DBI/ACBP in 81% compared to normal adjacent tissues. A concordance of 50% between proteomic and transcriptomic data was observed. Conclusions This study pointed out that the impairment of the metabolic and antioxidant systems, with a subsequent accumulation of free radicals, might be a key step in CCA development and progression.

We conducted a systematic review and meta-analysis to investigate the possible difference in the SARS-CoV-2 viral load between asymptomatic and symptomatic COVID-19 patients. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed in abstracting data and assessing validity. We searched MEDLINE, Scopus, Web of Science and Google Scholar for all investigations in the English language, reporting data on the threshold cycle (Ct) from real-time RT-PCR assays for the RNA-dependent RNA polymerase (RdRp), envelope (E) and nucleocapsid (N) SARS-CoV-2 genes in asymptomatic and symptomatic COVID-19 patients. Results: Overall, 703 COVID-19 patients (553 symptomatic and 150 asymptomatic) were analyzed. Five investigations reported the mean age of patients, evidencing that asymptomatic patients were younger than symptomatic patients (34.0 vs. 40.3 years, respectively). Pooled data regarding the levels of expression of the RdRp gene revealed no significant difference between symptomatic and asymptomatic subjects. Similarly, no differences were observed comparing the mean Ct values for the E and N genes. Based on real-time RT-PCR data, no differences exist in the viral load between symptomatic and asymptomatic COVID-19 subjects considering Ct values for RdRp, E and N genes’ expression. Asymptomatic subjects may represent a reservoir of the infection and significantly contribute to the maintenance of the pandemic.

Although substantial progress has been made in the last two decades, there are still important unfilled gaps in the understanding of the pathomechanism of Alzheimer’s disease (AD) [...]

While human and animal leishmaniasis affect several millions of people worldwide, L. infantum is the species responsible for visceral leishmaniasis in Europe, Middle East, and America. Antileishmanial drugs present issues associated with drug toxicity and increasing parasite resistance. Therefore, the study of this parasite with a focus on new potential drug targets is extremely useful. Accordingly, we purified and characterized a transglutaminase (TGase) from L. infantum promastigotes. While Tgases are known to be involved in cell death and autophagy, it appears that these functions are very important for parasites’ virulence. For the first time, we showed a Ca2+- and GTP-dependent TGase in Leishmania corresponding to a 54 kDa protein, which was purified by two chromatographic steps: DEAE-Sepharose and Heparin-Sepharose. Using polyclonal antibodies against a 50-amino-acid conserved region of the catalytic core of human TGase 2, we revealed two other bands of 66 and 75 kDa. The 54 kDa band appears to be different from the previously reported TGase, which was shown to be Ca2+- independent. Future research should address the identification of the purified enzyme sequence and, subsequently, its cloning to more comprehensively investigate its pathophysiological function and possible differences from mammal enzymes.

Cerebrovascular diseases and the subsequent brain hypoperfusion are at the basis of vascular dementia. Dyslipidemia, marked by an increase in circulating levels of triglycerides and LDL-cholesterol and a parallel decrease in HDL-cholesterol, in turn, is pivotal in promoting atherosclerosis which represents a common feature of cardiovascular and cerebrovascular diseases. In this regard, HDL-cholesterol has traditionally been considered as being protective from a cardiovascular and a cerebrovascular prospective. However, emerging evidence suggests that their quality and functionality play a more prominent role than their circulating levels in shaping cardiovascular health and possibly cognitive function. Furthermore, the quality of lipids embedded in circulating lipoproteins represents another key discriminant in modulating cardiovascular disease, with ceramides being proposed as a novel risk factor for atherosclerosis. This review highlights the role of HDL lipoprotein and ceramides in cerebrovascular diseases and the repercussion on vascular dementia. Additionally, the manuscript provides an up-to-date picture of the impact of saturated and omega-3 fatty acids on HDL circulating levels, functionality and ceramide metabolism.

A wealth of evidence suggests that Lipoprotein-associated phospholipase A2 (Lp-PLA2) plays a relevant role in atherogenesis and inflammation, which in turn are associated with the risk of developing dementia. The aim of this study was to evaluate whether serum Lp-PLA2 activity might be an early and/or late biomarker for different forms of dementia. Serum Lp-PLA2 activity was assessed in older patients with mild cognitive impairment (MCI, n = 166; median clinical follow-up = 29 months), Late-Onset Alzheimer’s disease (LOAD, n = 176), vascular dementia (VAD, n = 43), dementia characterized by an overlap between LOAD and VAD (AD-VAD MIXED dementia) (n = 136), other dementia subtypes (n = 45), and cognitively normal controls (n = 151). We found a significant trend towards higher levels of Lp-PLA2 activity in VAD compared with the other groups (ANOVA, p = 0.028). Similarly, Lp-PLA2 activity was greater in MCI converting to VAD compared with those that did not or did convert to the other types of dementia (ANOVA, p = 0.011). After adjusting for potential confounders, high levels of Lp-PLA2 activity were associated with the diagnosis of VAD (O.R. = 2.38, 95% C.I. = 1.06–5.10), but not with other types of dementia. Our data suggest that increased serum Lp-PLA2 activity may represent a potential biomarker for the diagnosis of VAD.

Purpose. The success of total joint arthroplasty (TJA) has led to consistent growth in the use of arthroplasty in progressively younger patients. However, more than 10 percent of patients require revision surgery due to implant failure caused by aseptic or septic inflammation. Among the latter, surgical site infection (SSI) represents one of the worst complications of TJA, potentially resulting in the removal of the prosthesis. The aim of our study was to identify potential risk factors for SSIs in a population of patients undergoing TJA. Methods. TJA were prospectively recruited at Casa di Cura Santa Maria Maddalena from February 2019 to April 2020. Age, sex, major comorbidities, American Society of Anesthesiologists (ASA) class, length of surgery, type of surgical suture, total hospital length of stay, and clinical laboratory data were collected. The study population was then divided into two groups: Group A, normal postoperative course, and Group B, patients who developed SSI at follow-up (17-25 days). Results. 25/760 (3.3%) patients developed SSIs at follow-up. Clinical and demographic parameters were not different between the two groups. Total leucocyte and neutrophil values at discharge resulted to be significatively higher in Group B compared to Group A (p=0.025 and p=0.016, respectively). Values of 7860/μL for total leucocyte and 5185/μL for neutrophil count at discharge significantly predicted the future development of SSI (AUC 0.623 and AUC 0.641, respectively; p

Accumulating evidence suggests that high consumption of natural antioxidants promotes health by reducing oxidative stress and, thus, the risk of developing cardiovascular diseases. Similarly, fermentation of natural compounds with lactic acid bacteria (LAB), such as Lactiplantibacillus plantarum, enhances their beneficial properties as regulators of the immune, digestive, and cardiovascular system. We investigated the effects of fermentation with Lactiplantibacillus plantarum on the antioxidant and immunomodulatory effects of Pushgay berries (Vaccinium floribundum, Ericaceae family) in human umbilical vein endothelial cells (HUVECs) and macrophage cell line RAW264.7. Polyphenol content was assayed by Folin–Ciocalteu and HPLC-MS/MS analysis. The effects of berries solutions on cell viability or proliferation were assessed by WST8 (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt and Lactate dehydrogenase (LDH) release, Trypan blue exclusion test, and Alamar blue assay. Antioxidant activity was evaluated by a cell-based chemiluminescent probe for the detection of intracellular H2O2 production in HUVECs. Heme oxygenase-1 (HO-1) expression levels were investigated by RT-qPCR. Glutathione reductase (GR), glutathione peroxidase (Gpx), superoxide dismutase (SOD), and catalase (CAT) activities, as markers of intracellular antioxidant defense, were evaluated by spectrophotometric analysis. The immunomodulatory activity was examined in RAW 264.7 by quantification of inducible nitric oxide synthase (iNOS) and Tumor Necrosis Factor—alpha (TNFα) by RT-qPCR. Data showed that fermentation of Pushgay berries (i) enhances the content of quercetin aglycone, and (ii) increases their intracellular antioxidant activity, as indicated by the reduction in H2O2-induced cell death and the decrease in H2O2-induced HO-1 gene expression in HUVECs treated for 24 h with fermented berries solution (10 µg/mL). Moreover, treatment with Pushgay berries for 72 h (10 µg/mL) promotes cells growth in RAW 264.7, and only fermented Pushgay berries increase the expression of iNOS in the same cell line. Taken together, our results show that LAB fermentation of Pushgay berries enhances their antioxidant and immunomodulatory properties.

Background: Oxidative stress (OxS) has been linked to several pregnancy-related complications. Previous studies demonstrated that lactoferrin (LF) has the ability to modulate inflammation, OxS and the immune function. Therefore, we aimed to observe whether vaginal LF administration was able to decrease OxS in the amniotic fluid (AF) of pregnant women undergoing mid-trimester genetic amniocentesis.Methods: In this open-label clinical study, 60 pregnant women were divided into three groups: CONTROLS (n = 20), not treated with LF; LACTO 4HRS (n = 20), treated with LF 4 h prior to amniocentesis; LACTO 12HRS (n = 20), treated with LF 12 h prior to amniocentesis. Thiobarbituric acid reactive substances (TBARS), total antioxidant status (TAS) and oxidative stress index (OSI) were measured in AF samples. In addition, the in vitro antioxidant activity of LF on a cell line was tested.Results: LF decreased the concentration of TBARS in the AF, with LACTO 4HRS demonstrating the lowest value compared with CONTROLS (P < 0.0001). LACTO 4HRS had higher TAS and lower OSI than CONTROLS (P < 0.0001 for both). In vitro, LF was effective against the oxidative challenge regardless of the time of pretreatment.Conclusion: In conclusion, LF decreased both in vivo and in vitro OxS. LF administration may represent an intriguing clinical solution as an adjuvant to treat complications of pregnancy related to inflammation and OxS.Trial Registration:Clinicaltrials.gov, NCT02695563. Registered 01 March 2016—Retrospectively registered, https://clinicaltrials.gov/show/NCT02695563.

Mucus form H. aspersa muller has been reported to have several therapeutic proprieties, such as antimicrobial activity, skin protection and wound repair. In this study, we have analyzed H. aspersa mucus (Helixcomplex) bio-adhesive efficacy and its defensive properties against the ozone (O3) (0.5 ppm for 2 hours) exposure in human keratinocytes and reconstructed human epidermis models. Cytotoxicity, tissue morphology and cytokine levels were determined. We confirmed HelixComplex regenerative and bio-adhesive properties, the latter possibly via the characteristic mucopolysaccharide composition. In addition, HelixComplex was able to protect from O3 exposure by preventing oxidative damage and the consequent pro-inflammatory response in both 2D and 3D models. Based on this study, it is possible to suggest HelixComplex as a potentially new protective technology against pollution induced skin damage.

Background: The prevalence and prognostic implications of metabolic syndrome (MetS) in patients infected by the SARS-CoV-2 remain unclear. We performed a systematic review and meta-analysis of prevalence and mortality risk in COVID-19 patients with MetS. Methods: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed in abstracting data and assessing validity. We searched MEDLINE and Scopus to locate every article published up to 1 September 2021, reporting data on MetS among COVID-19 patients. The pooled prevalence of MetS was calculated using a random effects model and presented using the related 95% confidence interval (CI), while the mortality risk was estimated using the Mantel-Haenszel random effects models with odds ratio (OR) and related 95% CI. Statistical heterogeneity was measured using the Higgins I2 statistic. Results: Six studies, enrolling 209.569 COVID-19 patients [mean age 57.2 years, 114.188 males (54.4%)] met the inclusion criteria and were included in the final analysis. The pooled prevalence of dyslipidaemia was 20.5% of cases (95% CI: 6.7–47.8%, p = 0.03), with high heterogeneity (I2 = 98.9%). Pre-existing MetS was significantly associated with higher risk of short-term mortality (OR: 2.30, 95% CI: 1.52–3.45, p < 0.001), with high heterogeneity (I2 = 89.4%). Meta-regression showed a direct correlation with male gender (p = 0.03), hypertension (p < 0.001), DM (p = 0.01) and hyperlipidaemia (p = 0.04), but no effect when considering age (p = 0.75) and chronic pulmonary disease (p = 0.86) as moderators. Conclusions: MetS represents a major comorbidity in about 20% of COVID-19 patients and it is associated with a 230% increased risk of short-term mortality.

Rett syndrome (RTT) is a monogenic neurodevelopmental disorder primarily caused by mutations in X-linked MECP2 gene, encoding for methyl-CpG binding protein 2 (MeCP2), a multifaceted modulator of gene expression and chromatin organization. Based on the type of mutation, RTT patients exhibit a broad spectrum of clinical phenotypes with various degrees of severity. In addition, as a complex multisystem disease, RTT shows several clinical manifestations ranging from neurological to non-neurological symptoms. The most common non-neurological comorbidities include, among others, orthopedic complications, mainly scoliosis but also early osteopenia/osteoporosis and a high frequency of fractures. A characteristic low bone mineral density dependent on a slow rate of bone formation due to dysfunctional osteoblast activity rather than an increase in bone resorption is at the root of these complications. Evidence from human and animal studies supports the idea that MECP2 mutation could be associated with altered epigenetic regulation of bone-related factors and signaling pathways, including SFRP4/WNT/β-catenin axis and RANKL/RANK/OPG system. More research is needed to better understand the role of MeCP2 in bone homeostasis. Indeed, uncovering the molecular mechanisms underlying RTT bone problems could reveal new potential pharmacological targets for the treatment of these complications that adversely affect the quality of life of RTT patients for whom the only therapeutic approaches currently available include bisphosphonates, dietary supplements, and physical activity.

Background: A wealth of experimental and epidemiological evidence suggest that Apolipoprotein A-I (ApoA-I), the main protein constituent of high-density lipoprotein (HDL), may protect against Alzheimer disease (AD). To investigate this potential role, we conducted a meta-analysis of the published studies on the relationship between serum ApoA-I and AD occurrence. Methods: We screened MEDLINE, EMBASE, Web of Science, and Scopus, for cross-sectional studies published from inception to 1 March 2021, comparing the ApoA-I serum levels between patients with AD and cognitively normal controls. Results: From an initial screening of 245 articles, 5 studies, including 397 AD patients (mean age 75.0 years, 234 females) and 367 controls (mean age 69.2 years, 182 females), met the inclusion criteria. Compared to healthy controls, AD subjects had a lower ApoA-I serum level. The pooled weighted mean difference from a random-effects model was −0.31 g/L (p < 0.0001) (95% Confidence Interval: [−0.62–0.01], with high heterogeneity (I2 = 100%). The Egger’s test confirmed an absence of publication bias (t = 0.62, p = 0.576). Conclusions: Our study showed that AD patients present lower serum levels of ApoA-I compared to cognitively normal individuals. Further studies on large population samples are required to support this finding.

Pseudomonas aeruginosa is a Gram-negative bacterium that commonly infects subjects with weakened immune system causing deadly infections above all at pulmonary level. During infection, P. aeruginosa produces a well-organized bacterial structure, called biofilm, activating the quorum-sensing (QS) signaling, a mechanism of gene regulation. In this work, we synthesized already known QS inhibitors (QSi) designed on the scaffold of the N-(3-oxododecanoyl) homoserine lactone (3O-C12-HSL) QS molecule and conjugated them with ciprofloxacin to inhibit P. aeruginosa biofilm formation and increase the antibiotic susceptibility of clinical strains. We identified, for the first time, a QSi conjugated with ciprofloxacin (ET37), that is able to reduce the formation of biofilm and the onset of tolerant clones in P. aeruginosa clinical strains. This compound could have a wide application in clinical setting. The possibility to affect biofilm formation in chronically infected patients, such as patients affected by cystic fibrosis, and to reduce the onset of ciprofloxacin resistance would improve patient healing and allow to decrease antibiotic drug dosage.

The burden of neurological diseases continues to increase as they still are the leading cause of disability and the second-leading cause of death worldwide [...]

Several lines of epidemiological evidence link increased levels of high-density lipoprotein-cholesterol (HDL-C) with lower risk of Alzheimer’s disease (AD). This observed relationship might reflect the beneficial effects of HDL on the cardiovascular system, likely due to the implication of vascular dysregulation in AD development. The atheroprotective properties of this lipoprotein are mostly due to its proteome. In particular, apolipoprotein (Apo) A-I, E, and J and the antioxidant accessory protein paraoxonase 1 (PON1), are the main determinants of the biological function of HDL. Intriguingly, these HDL constituent proteins are also present in the brain, either from in situ expression, or derived from the periphery. Growing preclinical evidence suggests that these HDL proteins may prevent the aberrant changes in the brain that characterize AD pathogenesis. In the present review, we summarize and critically examine the current state of knowledge on the role of these atheroprotective HDL-associated proteins in AD pathogenesis and physiopathology.

Type-2 diabetes (T2D) and its cardiovascular complications are related to sex. Increasing evidence suggests that paraoxonase 1 (PON1) activity, an antioxidant enzyme bound to high-density lipoproteins (HDL), is implicated in the onset and clinical progression of T2D. Since we previously showed that PON1 is a sexual dimorphic protein, we now investigated whether sex might impact the relationship between PON1 and this chronic disease. To address this aim, we assessed PON1 activity in the sera of 778 patients, including controls (women, n = 383; men, n = 198) and diabetics (women, n = 79; men = 118). PON1 activity decreased in both women and men with T2D compared with controls (p < 0.05 and p > 0.001, respectively), but the change was 50% larger in the female cohort. In line with this result, the enzyme activity was associated with serum glucose level only in women (r = −0.160, p = 0.002). Notably, only within this gender category, lower PON1 activity was independently associated with increased odds of being diabetic (odds ratio (95% Confidence interval: 2.162 (1.075–5.678)). In conclusion, our study suggests that PON1-deficiency in T2D is a gender-specific phenomenon, with women being more affected than men. This could contribute to the partial loss of female cardiovascular advantage associated with T2D.

Background: It has been suggested that circulating Paraoxonase-1 (PON1) and apolipoprotein A1 (APOA1), which closely interacts with the antioxidant enzyme, could be implicated in Alzheimer’s disease (AD) and vascular dementia (VaD) development. This study aimed to evaluate PON1 changes in serum and cerebrospinal fluid (CSF) as evidence for its association with AD or VaD. Methods: Serum PON-arylesterase activity was measured in patients with AD, VaD, and CONTROLS distributed in two cohorts: Ferrara cohort (FC: n = 503, age = 74 years) and Amsterdam Dementia cohort (ADC: n = 71, age = 65 years). In the last cohort, CSF PON-arylesterase, CSF β-amyloid1-42, p-tau and t-tau, and imaging biomarkers were also measured. Results: AD and VaD patients of FC showed significantly lower levels of serum PON-arylesterase compared to CONTROLS, but this outcome was driven by older subjects (>71 years, p < 0.0001). In the younger ADC, a similar decreasing (but not significant) trend was observed in serum and CSF. Intriguingly, PON-arylesterase per APOA1 correlated with t-tau in AD group (r = −0.485, p = 0.002). Conclusion: These results suggest that decreased peripheral PON-arylesterase might be a specific feature of older AD/VaD patients. Moreover, we showed that PON-arylesterase/APOA1 is inversely related to neurodegeneration in AD patients, suggesting a prognostic usefulness of this composite parameter.

Inflammation is a complex systemic response evolved to cope with cellular injury, either due to infectious agents or, in general, with sporadic events challenging tissue integrity and function. Researchers involved in different fields have the tendency to look at the inflammatory response with different angles, according to their specific interest. Established its complexity, one of the most evident features of the inflammatory response is the generation of a pro-oxidative environment due to the production of high fluxes of pro-oxidant species. This production begins locally, close to the sites of tissue damage or infection, but eventually becomes a chronic challenge for the organism, if the inflammatory response is not properly controlled. In this review, we focus on this specific aspect of chronic, low-level sub-clinical inflammatory response. We propose the term “OxInflammation” as a novel operative term describing a permanent pro-oxidative feature that interact, in a positive feed-back manner, to a not yet clinically detectable inflammatory process, leading in a long run (chronically) to a systemic/local damage, as a consequence of the cross talk between inflammatory, and oxidative stress mediators. Therefore, it could be useful to analyze inflammatory markers in pathologies where there is an alteration of the redox homeostasis, although an inflammatory status is not clinically evident.

Objective. “Oxinflammation” is a recently coined term that defines the deleterious crosstalk between inflammatory and redox systemic processes, which underlie several diseases. Oxinflammation could be latently responsible for the predisposition of certain healthy individuals to disease development. The oxinflammatory pathway has been recently suggested to play a crucial role in regulating the activity of TNF-related apoptosis-inducing ligand (TRAIL), a TNF superfamily member that can mediate multiple signals in physiological and pathological processes. Therefore, we investigated the associations between TRAIL and key players of vascular redox homeostasis. Methods. We measured circulating TRAIL levels relative to praoxonas-1, lipoprotein phospholipase-A2, and ceruloplasmin levels in a cohort of healthy subjects (n=209). Results. Multivariate analysis revealed that ceruloplasmin levels were significantly inversely associated with TRAIL levels (r=−0.431, p

Objective: At present, there is growing demand for alternative, or additional, treatments to hormone replacement therapy for menopause-related hot flashes (HF). Antioxidant supplements have been recently proposed as possible candidates for this purpose, regardless of the absence of clear evidence in support of a link between these vasomotor symptoms and oxidative stress (OxS). The aim of our study was to evaluate the association between HF and OxS serum markers in a large sample of middle-aged women. Materials and methods: We conducted a cross-sectional study on 245 perimenopausal and early postmenopausal women (age 45–60 years). The variables examined were presence of self-reported HF and levels of 8-iso-prostaglandin F2α, 8-OH-deoxy-2′-guanosine, advanced oxidation protein products, total antioxidant power, uric acid, thiols, and paroxonase-1. Results: Seventy-six women (31%) reported to suffer from HF (either medium or high intensity). None of the peripheral markers of OxS examined was found to be significantly associated with the presence of HF. Conclusion: Taken together, our data suggest that systemic OxS might not be implicated with the onset of the climacteric vasomotor symptoms that most commonly affect women experiencing perimenopause and early postmenopause.

Objective. Tumor necrosis factor- (TNF-) related apoptosis-inducing ligand (TRAIL) is attracting attention for its role in the physiopathology of metabolic disease/diabetes. Evidence suggests that it might protect against metabolic abnormalities driven by obesity-induced dysregulated secretion of adipokines, but this role of TRAIL has not yet been fully established. On this basis, we aimed to investigate the potential association between TRAIL and adipokine levels in a cohort of subjects in which age/gender/hormonal interferences were excluded. Methods. Serum levels of TRAIL and a panel of adipokines were measured in postmenopausal women (n=147) stratified according to waist circumference measures as normal, overweight, or obese. The panel of adipokines included interleukin- (IL-) 6, IL-8, IL-1β, adipsin, lipocalin-2/neutrophil gelatinase-associated lipocalin (ngal), TNF-alpha, monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, hepatocyte growth factor, resistin, leptin, adiponectin, and nerve growth factor. Results. Low serum TRAIL concentration (deciles I–IV) was significantly and inversely correlated with resistin and lipocalin 2/ngal levels (r=−0.502 and p

Paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-associated protein that endows its carrier with (lipo-)lactonase-dependent antioxidative features. Low levels of PON1 activity have been observed in association with obesity, a major risk factor for cardiovascular disease (CVD). Considering the well-recognized atheroprotective role of PON1, exogenous/endogenous factors that might modulate its levels/activity are raising great interest. Since adipokines represent a molecular link between obesity and CVD, we here explored the possible impact of these substances on PON1 activity/expression. The levels of interleukin (IL)-6, IL-8, tumor necrosis factor alpha, monocyte chemoattractant protein-1, hepatocyte growth factor, resistin, leptin, and adiponectin were measured along with arylesterase, paraoxonase, and lactonase activities of PON1 in 107 postmenopausal women. Moreover, the direct effect of resistin on PON1 expression was evaluated in vitro. Multivariate analysis revealed that only resistin was significantly and inversely correlated with PON1-lactonase activities (r = −0.346, p < 0.001) regardless of confounding factors such as age or HDL-cholesterol. It is worth noting that no statistical link was found between adipokine and arylesterase or paraoxonase, the two promiscuous activities of PON1. Notably, resistin down-regulated PON1 expression occurred in hepatocellular carcinoma cultures. Our study suggests that resistin might be a negative modulator of PON1 expression and anti-oxidative activity.

Several studies showed that hydroxyethyl starch (HES), a synthetic colloid used in volume replacement therapies, interferes with leukocyte-endothelium interactions. Although still unclear, the mechanism seems to involve the inhibition of neutrophils’ integrin. With the aim to provide direct evidence of the binding of HES to neutrophils and to investigate the influence of HES on neutrophil chemotaxis, we isolated and treated the cells with different concentrations of fluorescein-conjugated HES (HES-FITC), with or without different stimuli (N-Formylmethionine-leucyl-phenylalanine, fMLP, or IL-8). HES internalization was evaluated by trypan blue quenching and ammonium chloride treatment. Chemotaxis was evaluated by under-agarose assay after pretreatment of the cells with HES or a balanced saline solution. The integrin interacting with HES was identified by using specific blocking antibodies. Our results showed that HES-FITC binds to the plasma membrane of neutrophils without being internalized. Additionally, the cell-associated fluorescence increased after stimulation of neutrophils with fMLP (p < 0.01) but not IL-8. HES treatment impaired the chemotaxis only towards fMLP, event mainly ascribed to the inhibition of CD-11b (Mac-1 integrin) activity. Therefore, the observed effect mediated by HES should be taken into account during volume replacement therapies. Thus, HES treatment could be advantageous in clinical conditions where a low activation/recruitment of neutrophils may be beneficial, but may be harmful when unimpaired immune functions are mandatory.

Inflammation plays an important role in pregnancy, and cytokine and matrix metalloproteases (MMPs) imbalance has been associated with premature rupture of membranes and increased risk of preterm delivery. Previous studies have demonstrated that lactoferrin (LF), an iron-binding protein with anti-inflammatory properties, is able to decrease amniotic fluid (AF) levels of IL-6. Therefore, we aimed to evaluate the effect of vaginal LF administration on amniotic fluid PGE2 level and MMP-TIMP system in women undergoing genetic amniocentesis. One hundred and eleven women were randomly divided into controls (n=57) or treated with LF 4 hours before amniocentesis (n=54). Amniotic fluid PGE2, active MMP-9 and MMP-2, and TIMP-1 and TIMP-2 concentrations were determined by commercially available assays and the values were normalized by AF creatinine concentration. PGE2, active MMP-9, and its inhibitor TIMP-1 were lower in LF-treated group than in controls (p

Epithelial-to-Mesenchymal Transition (EMT) is relevant in malignant growth and frequently correlates with worsening disease progression due to its implications in metastases and resistance to therapeutic interventions. Although EMT is known to occur in several types of solid tumors, the information concerning tumors arising from the epithelia of the bile tract is still limited. In order to approach the problem of EMT in cholangiocarcinoma, we decided to investigate the changes in protein expression occurring in two cell lines under conditions leading to growth as adherent monolayers or to formation of multicellular tumor spheroids (MCTS), which are considered culture models that better mimic the growth characteristics of in-vivo solid tumors. In our system, changes in phenotypes occur with only a decrease in transmembrane E-cadherin and vimentin expression, minor changes in the transglutaminase protein/activity but with significant differences in the proteome profiles, with declining and increasing expression in 6 and in 16 proteins identified by mass spectrometry. The arising protein patterns were analyzed based on canonical pathways and network analysis. These results suggest that significant metabolic rearrangements occur during the conversion of cholangiocarcinomas cells to the MCTS phenotype, which most likely affect the carbohydrate metabolism, protein folding, cytoskeletal activity, and tissue sensitivity to oxygen.