Non-Thyroidal Illness in Chronic Renal Failure: Triiodothyronine Levels and Modulation of Extra-Cellular Superoxide Dismutase (ec-SOD).

Oxidative stress (OS) is implicated in several chronic diseases. Extra-cellular superoxide dismutase (ec-SOD) catalyses the dismutation of superoxide anions with a protective role in endothelial cells. In chronic kidney disease (CKD), OS and thyroid dysfunction (low fT3 syndrome) are frequently present, but their relationship has not yet been investigated. This cohort study evaluated ec-SOD activity in CKD patients during haemodialysis, divided into "acute haemodialytic patients" (AH, 1-3 months of treatment) and "chronic haemodialytic patients" (CH, treated for a longer period). We also evaluated plasmatic total antioxidant capacity (TAC) and its relationships with thyroid hormones. Two basal samples ("basal 1", obtained 3 days after the last dialysis; and "basal 2", obtained 2 days after the last dialysis) were collected. On the same day of basal 2, a sample was collected 5 and 10 min after the standard heparin dose and at the end of the procedure. The ec-SOD values were significantly higher in CH vs. AH in all determinations. Moreover, the same patients had lower TAC values. When the CH patients were divided into two subgroups according to fT3 levels (normal or low), we found significantly lower ec-SOD values in the group with low fT3 in the basal, 5, and 10 min samples. A significant correlation was also observed between fT3 and ec-SOD in the basal 1 samples. These data, confirming OS and low fT3 syndrome in patients with CKD, suggest that low fT3 concentrations can influence ec-SOD activity and could therefore potentially contribute to endothelial oxidative damage in these patients.

Anti-Inflammatory Effects of Olive Leaf Extract and Its Bioactive Compounds Oleacin and Oleuropein-Aglycone on Senescent Endothelial and Small Airway Epithelial Cells.

Olive tree by-products have been deeply studied as an invaluable source of bioactive compounds. Several in vitro and in vivo studies showed that olive leaf extract (OLE) has anti-inflammatory and antioxidant properties. Here, we wanted to assess the valuable benefits of two less-studied OLE components-3,4-DHPEA-EDA (Oleacin, OC) and 3,4-DHPEA-EA (Oleuropein-Aglycone, OA)-directly purified from OLE using a cost-effective and environmentally sustainable method, in line with the principles of circular economy. OLE, OC and OA were then tested in human cellular models involved in acute and chronic inflammation and in the pathogenesis of viral infections, i.e., lipopolysaccharide (LPS)-treated monocyte/macrophages (THP-1) and endothelial cells (HUVECs), senescent HUVECs and Poly(I:C)-treated small airway epithelial cells (hSAECs). Results showed that OC and OA are efficient in ameliorating almost all of the pro-inflammatory readouts (IL-1ß, TNF-α, IL-8, ICAM, VCAM) and reducing the release of IL-6 in all the cellular models. In hSAECs, they also modulate the expression of SOD2, NF-kB and also ACE2 and TMPRSS2, whose expression is required for SARS-CoV-2 virus entry. Overall, these data suggest the usefulness of OLE, OC and OA in controlling or preventing inflammatory responses, in particular those associated with viral respiratory infections and aging.

Total Antioxidant Capacity: Biochemical Aspects and Clinical Significance.

Despite the physiological role of oxidant molecules, oxidative stress (OS) could underlie several human diseases. When the levels of antioxidants are too low or too high, OS occurs, leading to damage at the molecular, tissue and cellular levels. Therefore, antioxidant compounds could represent a way to modulate OS and/or to maintain proper redox balance. This review provides an overview of the methods available to assess total antioxidant capacity (TAC) in biological systems to elucidate the correct terminology and the pathophysiological roles. The clinical context is fundamental to obtain a correct interpretation of TAC. Hence, we discuss metabolic syndrome and infertility, two clinical conditions that involve OS, including the potential prognostic role of TAC evaluation in monitoring antioxidant supplementation. This approach would provide more personalised and precise therapy.

Zingiber officinale Roscoe Rhizome Extract Exerts Senomorphic and Anti-Inflammatory Activities on Human Endothelial Cells.

Aging is related to a low-grade and sterile inflammation called inflammaging, recognized as the main risk factor for age-related disease (ARD) development. Inflammaging is fostered by the repeated activation of immune cells, as well as by the accumulation of senescent cells. Recently, a number of natural compounds have gained attention to be tested as anti-aging therapies, based on their anti-inflammatory activity and/or ability to reduce the pro-inflammatory secretome of senescent cells (senomorphyc activity). Here, we investigated the anti-inflammatory and senomorphic properties of an Asian-native Zingiber officinale Roscoe extract (ZOE), commonly consumed as a food spice and herbal medicine. We employed two models of primary endothelial cells (HUVECs), such as the replicative-senescence and LPS-induced response, to investigate the anti-inflammatory/senomorphic effect of ZOE, and one cellular model of neuroinflammation, i.e., immortalized murine microglial cells (BV2). First, we found that the ZOE treatment induced the inhibition of NF-kB activation in BV2 cells. Among the constituents of ZOE, we showed that the terpenoid-enriched fraction (ZTE) was the component able to counteract the phosphorylation of NF-kB(p65), while 6-gingerol (GIN) and 6-shogaol (SHO) did not produce any significant effect. Further, we observed that the treatment with 10 µg/mL of ZOE exerted anti-inflammatory activity on LPS-stimulated young (y)HUVEC and senomorphyc activity on replicative senescent (s)HUVEC, significantly reducing the expression levels of IL-1ß, TNF -α, IL-8, MCP-1, and ICAM-1. Moreover, the ZTE treatment was able to significantly reduce the IL-8 levels secreted in the medium of both LPS-stimulated yHUVEC and sHUVEC. Overall, our data suggest a potential protective role of ZOE on neuroinflammation and endothelial inflammation/activation, thus suggesting its potential relevance in delaying/postponing ARD development and progression, characterized by endothelial dysfunction.

The Dual Role of Oxidants in Male (In)fertility: Every ROSe Has a Thorn.

The role of oxidative stress (OS) in male infertility as a primary etiology and/or concomitant cause in other situations, such as inflammation, varicocele and gonadotoxin effects, is well documented. While reactive oxygen species (ROS) are implicated in many important roles, from spermatogenesis to fertilization, epigenetic mechanisms which are transmissible to offspring have also recently been described. The present review is focused on the dual aspects of ROS, which are regulated by a delicate equilibrium with antioxidants due to the special frailty of spermatozoa, in continuum from physiological condition to OS. When the ROS production is excessive, OS ensues and is amplified by a chain of events leading to damage of lipids, proteins and DNA, ultimately causing infertility and/or precocious pregnancy termination. After a description of positive ROS actions and of vulnerability of spermatozoa due to specific maturative and structural characteristics, we linger on the total antioxidant capacity (TAC) of seminal plasma, which is a measure of non-enzymatic non-proteic antioxidants, due to its importance as a biomarker of the redox status of semen; the therapeutic implications of these mechanism play a key role in the personalized approach to male infertility.

MiR-422a promotes adipogenesis via MeCP2 downregulation in human bone marrow mesenchymal stem cells.

Methyl-CpG binding protein 2 (MeCP2) is a ubiquitous transcriptional regulator. The study of this protein has been mainly focused on the central nervous system because alterations of its expression are associated with neurological disorders such as Rett syndrome. However, young patients with Rett syndrome also suffer from osteoporosis, suggesting a role of MeCP2 in the differentiation of human bone marrow mesenchymal stromal cells (hBMSCs), the precursors of osteoblasts and adipocytes. Here, we report an in vitro downregulation of MeCP2 in hBMSCs undergoing adipogenic differentiation (AD) and in adipocytes of human and rat bone marrow tissue samples. This modulation does not depend on MeCP2 DNA methylation nor on mRNA levels but on differentially expressed miRNAs during AD. MiRNA profiling revealed that miR-422a and miR-483-5p are upregulated in hBMSC-derived adipocytes compared to their precursors. MiR-483-5p, but not miR-422a, is also up-regulated in hBMSC-derived osteoblasts, suggesting a specific role of the latter in the adipogenic process. Experimental modulation of intracellular levels of miR-422a and miR-483-5p affected MeCP2 expression through direct interaction with its 3' UTR elements, and the adipogenic process. Accordingly, the knockdown of MeCP2 in hBMSCs through MeCP2-targeting shRNA lentiviral vectors increased the levels of adipogenesis-related genes. Finally, since adipocytes released a higher amount of miR-422a in culture medium compared to hBMSCs we analyzed the levels of circulating miR-422a in patients with osteoporosis-a condition characterized by increased marrow adiposity-demonstrating that its levels are negatively correlated with T- and Z-scores. Overall, our findings suggest that miR-422a has a role in hBMSC adipogenesis by downregulating MeCP2 and its circulating levels are associated with bone mass loss in primary osteoporosis.

Salivary and serum irisin in healthy adults before and after exercise.

Irisin is an exercise-induced cytokine mainly secreted by myocytes. Circulating level of irisin can increase in response to acute exercise, promoting pleiotropic effects on health. Generally, irisin is evaluated in blood, however, its collection is invasive. Saliva sample would not have any risk associated with blood collection and would represent a less invasive method for irisin detection. Until now, there are only a few studies that have analyzed irisin levels in saliva. In the present research, five healthy male adults performed an incremental exercise until exhaustion on cycle ergometer. Serum and saliva samples were collected before exercise and 15min, 24h and 48h after reaching the exhaustion. Irisin was detected by ELISA assay. Serum and salivary irisin levels increased from baseline to 24h post exercise and reverted to basal levels after 48h of rest. A significant rise of both serum and salivary irisin level at 24h (p≤0.05) compared to baseline levels was found. Furthermore, a significant correlation between irisin percentage change in serum and saliva from baseline to 24h post exercise was detected (r=0.92, p<0.05). Despite the relatively limited sample, this research suggests that collecting saliva samples might represent a valid and less invasive method to detect irisin level changes induced by exercise.

Insulin-sensitizing effect and antioxidant action of alpha lipoic acid in oligomenorrheic women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a low-grade inflammatory disease characterized by anovulation and hyperandrogenism, associated with insulin-resistance. The aim of our study was to investigate the effects of a treatment with alpha-lipoic acid on clinical, endocrine, and metabolic features of women affected by PCOS. METHODS: In this pilot cohort study, 60 women (30 hyperinsulinemic and 30 normoinsulinemic patients; age 15-34 years) were enrolled and clinical, hormonal, and metabolic parameters were evaluated before and after a six-months treatment with alpha-lipoic acid 800 mg/daily. Investigations were performed during the early follicular phase of the menstrual cycles (spontaneous or progestin-induced cycles): after fasting overnight for 10-12 h, blood samples were collected for hormonal and metabolic assays and oral glucose tolerance test and pelvic ultrasound were performed. Total Antioxidant Capacity was expressed as LAG time. RESULTS: The treatment was able to increase the number of menstrual cycles during the 6 months considered in all patients and to reduce BMI in the normoinsulinemic population. In hyperinsulinemic patients we observed a statistically significant reduction in AUC-I as well as an increase of total antioxidant capacity. CONCLUSIONS: The relevant results in restoring menstrual cyclicity in both groups, in addition to the antioxidant effect, confirm that hyperinsulinemia influences only the metabolic response to the treatment, without predict the ovarian function. Even if alpha-lipoic acid mechanisms of action is not clear and further studies are needed to confirm these results, it could be considered a valid therapeutic alternative to traditional drugs, without side effects as reported.

Randomized, Double-Blind, Placebo-Controlled Trial to Test the Effects of a Nutraceutical Combination Monacolin K-Free on the Lipid and Inflammatory Profile of Subjects with Hypercholesterolemia.

BACKGROUND: Nutraceutical combinations (NCs) against hypercholesterolemia are increasing in the marketplace. However, the availability of NCs without monacolin K is scarce even though the statin-intolerant population needs it. METHODS: This study is a parallel-group, randomized, placebo-controlled, double-blind trial. We evaluated the effects of the NC containing phytosterols, bergamot, olive fruits, and vitamin K2 on lipid profile and inflammatory biomarkers in 118 subjects (mean age ± SD, 57.9 ± 8.8 years; 49 men and 69 women) with hypercholesterolemia (mean total cholesterol ± SD, 227.4 ± 20.8 mg/dL) without clinical history of cardiovascular diseases. At baseline and 6 and 12 weeks of treatment, we evaluated lipid profile (total, LDL and HDL cholesterol, and triglycerides), safety (liver, kidney, and muscle parameters), and inflammatory biomarkers such as hs-CRP, leukocytes, interleukin-32, and interleukin-38 and inflammatory-microRNAs (miRs) miR-21, miR-126, and miR-146a. RESULTS: Compared to the placebo, at 6 and 12 weeks, NC did not significantly reduce total cholesterol (p = 0.083), LDL cholesterol (p = 0.150), and triglycerides (p = 0.822). No changes were found in hs-CRP (p = 0.179), interleukin-32 (p = 0.587), interleukin-38 (p = 0.930), miR-21 (p = 0.275), miR-126 (p = 0.718), miR-146a (p = 0.206), myoglobin (p = 0.164), and creatine kinase (p = 0.376). Among the two reported, only one adverse event was probably related to the nutraceutical treatment. CONCLUSIONS: The evaluated nutraceutical combination did not change serum lipid profile and inflammatory parameters, at least not with the daily dose applied in the present study.

Inflammation and Oxidative Stress in Seminal Plasma: Search for Biomarkers in Diagnostic Approach to Male Infertility.

Oxidative and inflammatory damage underlie several conditions related to male infertility, including varicocele. Free light chains of immunoglobulins (FLCs) are considered markers of low-grade inflammation in numerous diseases. Coenzyme Q10 (CoQ10), a lipidic antioxidant and anti-inflammatory compound, is involved in spermatozoa energy metabolism and motility. We aimed to evaluate FLCs' seminal levels in patients with varicocele in comparison to control subjects and to correlate them with CoQ10 and Total Antioxidant Capacity (TAC) in human semen. Sixty-five patients were enrolled. Semen analysis was performed; patients were divided into three groups: controls, 12 normozoospermic patients, aged 34 (33-41) years; varicocele (VAR), 29 patients, aged 33 (26-37) years; and idiopathic, 24 oligo-, astheno- and oligoasthenozoospermic patients aged 37 (33.5-40.5) years. FLCs (κ and λ) were assayed by turbidimetric method; CoQ10 by HPLC; TAC by spectrophotometric method. λ FLCs showed a trend toward higher levels in VAR vs. controls and the idiopathic group. VAR showed a trend toward lower κ FLCs levels vs. the other two groups. When comparing κ/λ ratio, VAR showed significantly lower levels vs. controls and idiopathic. Moreover, CoQ10 seminal levels showed higher levels in VAR and idiopathic compared to controls. Data reported here confirm lower levels of κ/λ ratio in VAR and suggest a possible application in personalized medicine as clinical biomarkers for male infertility.

Curcumin, Polydatin and Quercetin Synergistic Activity Protects from High-Glucose-Induced Inflammation and Oxidative Stress.

Chronic hyperglycemia, the diagnostic biomarker of Type 2 Diabetes Mellitus (T2DM), is a condition that fosters oxidative stress and proinflammatory signals, both involved in the promotion of cellular senescence. Senescent cells acquire a proinflammatory secretory phenotype, called SASP, exacerbating and perpetuating the detrimental effects of hyperglycemia. Bioactive compounds can exert antioxidant and anti-inflammatory properties. However, the synergistic anti-inflammatory and antioxidant effects of the most extensively investigated natural compounds have not been confirmed yet in senescent cells and in hyperglycemic conditions. Here, we exposed young and replicative senescent HUVEC (yHUVEC and sHUVEC) to a high-glucose (HG) condition (45 mM) and treated them with Polydatin (POL), Curcumin (CUR) and Quercetin (QRC), alone or in combination (MIX), to mirror the anti-inflammatory component OxiDefTM contained in the novel nutraceutical GlicefenTM (Mivell, Italy). In both yHUVEC and sHUVEC, the MIX significantly decreased the expression levels of inflammatory markers, such as MCP-1, IL-1ß and IL-8, and ROS production. Importantly, in sHUVEC, a synergistic effect of the MIX was observed, suggesting its senomorphic activity. Moreover, the MIX was able to reduce the expression level of RAGE, a receptor involved in the activation of proinflammatory signaling. Overall, our data suggest that the consumption of nutraceuticals containing different natural compounds could be an adjuvant supplement to counteract proinflammatory and pro-oxidative signals induced by both hyperglycemic and senescence conditions.

Oxidative Stress in Metabolic and Endocrine Diseases: Basic and Translational Aspects.

The aim of this Special Issue is to highlight oxidative stress (OS) as a mechanism underlying a major risk factor for several human diseases [...].

Circulating irisin levels in functional hypothalamic amenorrhea: a new bone damage index? A pilot study.

PURPOSE: Patients with functional hypothalamic amenorrhea (FHA) could commonly have bone damage, often preceded by metabolic alterations due to a relative energy deficit state. To date, there are no markers capable of predicting osteopenia before it is manifested on DXA. Irisin is a myokine that promotes the differentiation of osteoblastic cells and appears to be inversely correlated with the incidence of bone fragility and fractures in postmenopausal women. The aim of this study was to measure irisin levels in FHA patients and to correlate it with bone density parameters. METHODS: Thirty-two patients with FHA and 19 matched controls underwent the same clinical and laboratory evaluation. RESULTS: Irisin and body mass index (BMI) were significantly lower in the case group than in healthy controls (2.03 ± 0.12 vs. 2.42 ± 0.09 p < 0.05 and 19.43 ± 2.26 vs. 22.72 ± 0.67 p < 0.05, respectively). Additionally, total body mass density (BMD g/cm2) was significantly lower in the case group than in the healthy controls (1.09 ± 0.08 vs. 1.14 ± 0.05, p < 0.05), without signs of osteopenia. CONCLUSIONS: The FHA group showed lower irisin levels associated with significantly reduced BMD parameters that did not reach the severity of osteopenia. Therefore, we could speculate that irisin could predict DXA results in assessing modifications of body composition parameters. Future research is warranted to study these parameters in a larger population to confirm our results, so that irisin could be used as a predictor and screening method for bone deprivation. Furthermore, irisin is strictly related to energy metabolism and could be an indirect marker of nutritional status in FHA patients, identifying earlier states of energy deficit.

MicroRNAs as Factors in Bidirectional Crosstalk Between Mitochondria and the Nucleus During Cellular Senescence.

Mitochondria are essential organelles that generate most of the chemical energy to power the cell through ATP production, thus regulating cell homeostasis. Although mitochondria have their own independent genome, most of the mitochondrial proteins are encoded by nuclear genes. An extensive bidirectional communication network between mitochondria and the nucleus has been discovered, thus making them semi-autonomous organelles. The nucleus-to-mitochondria signaling pathway, called Anterograde Signaling Pathway can be deduced, since the majority of mitochondrial proteins are encoded in the nucleus, less is known about the opposite pathway, the so-called mitochondria-to-nucleus retrograde signaling pathway. Several studies have demonstrated that non-coding RNAs are essential "messengers" of this communication between the nucleus and the mitochondria and that they might have a central role in the coordination of important mitochondrial biological processes. In particular, the finding of numerous miRNAs in mitochondria, also known as mitomiRs, enabled insights into their role in mitochondrial gene transcription. MitomiRs could act as important mediators of this complex crosstalk between the nucleus and the mitochondria. Mitochondrial homeostasis is critical for the physiological processes of the cell. Disruption at any stage in their metabolism, dynamics and bioenergetics could lead to the production of considerable amounts of reactive oxygen species and increased mitochondrial permeability, which are among the hallmarks of cellular senescence. Extensive changes in mitomiR expression and distribution have been demonstrated in senescent cells, those could possibly lead to an alteration in mitochondrial homeostasis. Here, we discuss the emerging putative roles of mitomiRs in the bidirectional communication pathways between mitochondria and the nucleus, with a focus on the senescence-associated mitomiRs.

Can plasma antioxidants prevent DNA damage in oxidative stress condition induced by growth hormone deficiency? A pilot study.

Adult growth hormone deficiency (GHD), a condition characterized by increased oxidative stress, is related to augmented cardiovascular, metabolic and oncological risk. A case-control observational study has been performed to evaluate DNA oxidative damage analysing the production of thymidine-glycol in lymphocytes and its correlation with plasma antioxidant levels, evaluated as Total Antioxidant Capacity (TAC). GHD was diagnosed using GHRH 50µg iv+arginine 0,5 g/Kg test, with peak GH response <9 µg/L when BMI was <30 kg/m2 or <4 µg/L when BMI was >30 kg/m2. Three groups were identified: total GHD (n = 16), partial GHD (n = 11), and controls (n = 12). Thymidine-glycol, TAC and IGF-1 have been determined respectively in lymphocytes, plasma and serum samples. When considering thymidine-glycol, we found a significant difference between total vs partial GHD and controls. Unexpectedly thymidine-glycol was lower in total GHD, also accompanied with a significant increase in plasmatic TAC. Our results showed that in adult GHD condition, the production of antioxidant species, in response to increased oxidative stress, could exert a protective effect on thymidine-glycol formation, and consequently on DNA intracellular damages. This pilot study could be inserted in the complex scenario of oxidative damage of GHD, a subtle, yet poorly defined condition, worthy of further insights.

Anti-SASP and anti-inflammatory activity of resveratrol, curcumin and ß-caryophyllene association on human endothelial and monocytic cells.

A challenging and promising new branch of aging-related research fields is the identification of natural compounds able to modulate the senescence-associated secretory phenotype (SASP), which characterizes senescent cells and can contribute to fuel the inflammaging. We investigated both the anti-SASP and anti-inflammatory activities of a nutritional supplement, namely Fenoxidol™, composed of turmeric extract bioCurcumin (bCUR), Polydatin (the natural glycosylated precursor of Resveratrol-RSV), and liposomal ß-caryophyllene (BCP), in two human cellular models, such as the primary endothelial cell line, HUVECs and the monocytic cell line, THP-1. Replicative and Doxorubicin-induced senescent HUVECs, both chosen as cellular models of SASP, and lipopolysaccharides (LPS)-stimulated THP-1, selected as a model of the inflammatory response, were treated with the three single natural compounds or with a combination of them (MIX). In both senescent HUVEC models, MIX treatment significantly reduced IL-1ß and IL-6 expression levels and p16ink4a protein, and also increased SIRT1 protein level, as well as downregulated miR-146a and miR-21 expression, two of the so-called inflamma-miRNAs, more effectively than the single compounds. In THP-1 cells stimulated with LPS, the MIX showed a significant effect in decreasing IL-1ß, IL-6, TNF-α, and miR-146a expression levels and Caspase-1 activation, in association with an up-regulation of SIRT1 protein, compared to the single compounds. Overall, our results suggest that the three analysed compounds can have a combined effect in restraining SASP in senescent HUVECs as well as the inflammatory response in LPS-stimulated THP-1 cells.

Oxidative Stress and Low-Grade Inflammation in Polycystic Ovary Syndrome: Controversies and New Insights.

The pathophysiology of Polycystic Ovary Syndrome (PCOS) is quite complex and different mechanisms could contribute to hyperandrogenism and anovulation, which are the main features of the syndrome. Obesity and insulin-resistance are claimed as the principal factors contributing to the clinical presentation; in normal weight PCOS either, increased visceral adipose tissue has been described. However, their role is still debated, as debated are the biochemical markers linked to obesity per se. Oxidative stress (OS) and low-grade inflammation (LGI) have recently been a matter of researcher attention; they can influence each other in a reciprocal vicious cycle. In this review, we summarize the main mechanism of radical generation and the link with LGI. Furthermore, we discuss papers in favor or against the role of obesity as the first pathogenetic factor, and show how OS itself, on the contrary, can induce obesity and insulin resistance; in particular, the role of GH-IGF-1 axis is highlighted. Finally, the possible consequences on vitamin D synthesis and activation on the immune system are briefly discussed. This review intends to underline the key role of oxidative stress and low-grade inflammation in the physiopathology of PCOS, they can cause or worsen obesity, insulin-resistance, vitamin D deficiency, and immune dyscrasia, suggesting an inverse interaction to what is usually considered.

Plasma levels of interleukin-38 in healthy aging and in type 2 diabetes.

Plasma levels of interleukin (IL)-38 were evaluated in patients with type 2 diabetes (T2DM) and healthy controls. Plasma IL-38 was higher in T2DM patients and positively related to waist/hip ratio, HbA1c, uric acid, liver function tests, triglycerides and total proteins. Patients suffering from diabetic nephropathy had the highest IL-38 levels.

Corrigendum to "Anabolic Hormone Deficiencies in Heart Failure with Reduced or Preserved Ejection Fraction and Correlation with Plasma Total Antioxidant Capacity".

[This corrects the article DOI: 10.1155/2020/5798146.].

Celecoxib Exerts Neuroprotective Effects in ß-Amyloid-Treated SH-SY5Y Cells Through the Regulation of Heme Oxygenase-1: Novel Insights for an Old Drug.

The formation and aggregation of amyloid-ß-peptide (Aß) into soluble and insoluble species represent the pathological hallmarks of Alzheimer's disease (AD). Over the last few years, however, soluble Aß (sAß) prevailed over fibrillar Aß (fAß) as determinant of neurotoxicity. One of the main therapeutic strategies for challenging neurodegeneration is to fight against neuroinflammation and prevent free radical-induced damage: in this light, the heme oxygenase/biliverdin reductase (HO/BVR) system is considered a promising drug target. The aim of this work was to investigate whether or not celecoxib (CXB), a selective inhibitor of the pro-inflammatory cyclooxygenase-2, modulates the HO/BVR system and prevents lipid peroxidation in SH-SY5Y neuroblastoma cells. Both sAß (6.25-50 nM) and fAß (1.25-50 nM) dose-dependently over-expressed inducible HO (HO-1) after 24 h of incubation, reaching statistical significance at 25 and 6.25 nM, respectively. Interestingly, CXB (1-10 µM, for 1 h) further enhanced Aß-induced HO-1 expression through the nuclear translocation of the transcriptional factor Nrf2. Furthermore, 10 µM CXB counteracted the Aß-induced ROS production with a mechanism fully dependent on HO-1 up-regulation; nevertheless, 10 µM CXB significantly counteracted only 25 nM sAß-induced lipid peroxidation damage in SH-SY5Y neurons by modulating HO-1. Both carbon monoxide (CORM-2, 50 nM) and bilirubin (50 nM) significantly prevented ROS production in Aß-treated neurons and favored both the slowdown of the growth rate of Aß oligomers and the decrease in oligomer/fibril final size. In conclusion, these results suggest a novel mechanism through which CXB is neuroprotective in subjects with early AD or mild cognitive impairment.