Apelin is found in human sperm and testis and is raised in inflammatory pathological conditions.

Apelin/APJ receptor (R) is involved in many oxidative stress-induced pathological conditions. Since this system is not yet explored in male reproduction, we studied apelin/APJ-R in human semen and testis. Semen of 41 infertile patients with varicocele, genitourinary infections, unexplained infertility and 12 fertile men was analysed (WHO guidelines, 2021). Apelin was quantified by ELISA in seminal fluid and spermatozoa, interleukin (IL)-1ß in seminal fluid. Apelin/APJ-R were immunolocalized in spermatozoa and testis. Apelin was present in spermatozoa and its levels were negatively correlated with normal sperm morphology% (r = -0.857; p < 0.001), and positively with IL-1ß levels (r = 0.455; p < 0.001). Apelin and IL-1ß concentrations were increased in patients' samples with varicocele (apelin p < 0.01; IL-1ß p < 0.05) and infections (apelin p < 0.01; IL-1ß p < 0.001). By logistic regression analysis, apelin (OR 1.310; p = 0.011) and IL-1ß (OR 1.572; p = 0.005) were predictors of inflammatory diseases (varicocele, infections). Apelin and APJ-R immunofluorescence labels were weak in sperm tail of fertile men and intense along tail, cytoplasmic residues and post-acrosomal sheath of sperm from infertile men. In testis, apelin and APJ-R labels were evident in Leydig cells and weak inside the seminiferous tubule. Apelin/APJ-R system is present in human spermatozoa and testicular tissue and probably involved in human fertility.

Follicular Fluid Components in Reduced Ovarian Reserve, Endometriosis, and Idiopathic Infertility.

Follicular fluid (FF) molecules, and their increase or decrease, can contribute to appropriate follicular growth and oocyte maturation, thus being related to female infertility conditions. In this paper, we studied the changes and the relationships of some biochemical components, hormones, antioxidant enzymes, F2-Isoprostanes (F2-IsoPs), and resolvin (Rv) D1 in the FF of infertile women with different reproductive conditions such as endometriosis, reduced ovarian reserve, and idiopathic infertility during assisted reproductive techniques (ART). In the whole population, positive correlations between albumin (ALB)/iron (Fe), ALB/beta-2-microglobulin (B2MG), and F2-IsoPs/RvD1 were detected in the FF. In FF from aged women, increased levels of follicle stimulating hormone (FSH) and reduced anti-Müllerian hormone (AMH) levels were associated with a worse oocyte quality. The negative ART outcome was influenced by patient age and AMH, B2MG, and FSH levels. Moreover, the reduced ovarian reserve condition was characterised by a significant decrease in oocyte number and quality, AMH amount, and lactate dehydrogenase (LDH) activity, as well as by an increase in age and FSH levels. In the presence of endometriosis, high levels of MDA and RvD1 were detected in FF, with a decrease in luteinising hormone (LH). Finally, among the molecules examined, none characterised the condition of idiopathic infertility. These data could support the identification of new FF markers in different reproductive disorders, suggesting the need for personalised therapeutic approaches and optimised ART outcomes. In particular, the evaluation of resolvins and lipid mediators in FF could be a promising field of investigation with which to understand the entity of oxidative stress and inflammation in some female infertility conditions.

F4-Neuroprostane Effects on Human Sperm.

Swim-up selected human sperm were incubated with 7 ng F4-neuroprostanes (F4-NeuroPs) for 2 and 4 h. Sperm motility and membrane mitochondrial potential (MMP) were evaluated. The percentage of reacted acrosome was assessed by pisum sativum agglutinin (PSA). Chromatin integrity was detected using the acridine orange (AO) assay and localization of the ryanodine receptor was performed by immunofluorescence analysis. Sperm progressive motility (p = 0.02) and the percentage of sperm showing a strong MMP signal (p = 0.012) significantly increased after 2 h F4-NeuroP incubation compared to control samples. The AO assay did not show differences in the percentage of sperm with dsDNA between treated or control samples. Meanwhile, a significantly higher number of sperm with reacted acrosomes was highlighted by PSA localization after 4 h F4-NeuroP incubation. Finally, using an anti-ryanodine antibody, the immunofluorescence signal was differentially distributed at 2 and 4 h: a strong signal was evident in the midpiece and postacrosomal sheath (70% of sperm) at 2 h, whereas a dotted one appeared at 4 h (53% of sperm). A defined concentration of F4-NeuroPs in seminal fluid may induce sperm capacitation via channel ions present in sperm cells, representing an aid during in vitro sperm preparation that may increase the positive outcome of assisted fertilization.

Effects and Mechanisms Activated by Treatment with Cationic, Anionic and Zwitterionic Liposomes on an In Vitro Model of Porcine Pre-Pubertal Sertoli Cells.

Liposomes have been successfully used as drug-delivery vehicles, but there are no clinical studies on improved fertility and the few reported experimental studies have been performed in animal models far from humans. The aim of this paper was to study the effects of treatment with cationic, anionic and zwitterionic liposomes on our superior mammalian model of porcine prepubertal Sertoli cells (SCs) to find a carrier of in vitro test drugs for SCs. Porcine pre-pubertal SCs cultures were incubated with different liposomes. Viability, apoptosis/necrosis status (Annexin-V/Propidium iodide assay), immunolocalisation of ß-actin, vimentin, the phosphorylated form of AMP-activated protein Kinase (AMPK)α and cell ultrastructure (Transmission Electron Microscopy, TEM) were analysed. Zwitterionic liposomes did not determine changes in the cell cytoplasm. The incubation with anionic and cationic liposomes modified the distribution of actin and vimentin filaments and increased the levels of the phosphorylated form of AMPKα. The Annexin/Propidium Iodide assay suggested an increase in apoptosis. TEM analysis highlighted a cytoplasmic vacuolisation. In conclusion, these preliminary data indicated that zwitterionic liposomes were the best carrier to use in an in vitro study of SCs to understand the effects of molecules or drugs that could have a clinical application in the treatment of certain forms of male infertility.

Can Dietary n-3 Polyunsaturated Fatty Acids Affect Apelin and Resolvin in Testis and Sperm of Male Rabbits?

Apelin and other novel adipokines have been associated with normal and pathological reproductive conditions in humans and animals. In this paper, we used a rabbit model to investigate if apelin and resolvin (RvD1) in testis and sperm are associated with the oxidative status of semen and serum testosterone of rabbits fed different diets enriched with flaxseed (alpha-linolenic acid, ALA) or with fish oil (eicosapentaenoic acid, EPA, docosapentaenoic acid, DPAn-3, and docosahexaenoic acid, DHA). Apelin and RvD1 were detected by ELISA and apelin and the apelin receptor by immunofluorescence. Increased levels of apelin in testes from both enriched diets were shown, particularly in the interstitial tissue of the FLAX group. The FLAX diet enhanced serum testosterone, and both enriched diets showed higher levels of malondialdehyde and RvD1 in the testis. In ejaculated sperm, apelin and its receptor were localized in the entire tail of the control and both treated groups. The ryanodine receptor was investigated in rabbit testis; the fluorescent signal was increased in mature elongated spermatids of the FLAX group. In conclusion, this data seems to indicate that FLAX increases the amount of apelin in testis, suggesting an involvement of this adipokine in male reproduction and probably a role in the resolution of the inflammatory status.

Lipoic/Capsaicin-Related Amides: Synthesis and Biological Characterization of New TRPV1 Agonists Endowed with Protective Properties against Oxidative Stress.

α-Lipoic acid is a sulfur-containing nutrient endowed with pleiotropic actions and a safe biological profile selected to replace the unsaturated alkyl acid of capsaicin with the aim of obtaining lipoic amides potentially active as a TRPV1 ligand and with significant antioxidant properties. Thus, nine compounds were obtained in good yields following a simple synthetic procedure and tested for their functional TRPV1 activity and radical-scavenger activity. The safe biological profile together with the protective effect against hypoxia damage as well as the in vitro antioxidant properties were also evaluated. Although less potent than capsaicin, almost all lipoic amides were found to be TRPV1 agonists and, specifically, compound 4, the lipoic analogue of capsaicin, proved to be the best ligand in terms of efficacy and potency. EPR experiments and in vitro biological assays suggested the potential protective role against oxidative stress of the tested compounds and their safe biological profile. Compounds 4, 5 and 9 significantly ameliorated the mitochondrial membrane potential caused by hypoxia condition and decreased F2-isoprostanes, known markers of oxidative stress. Thus, the experimental results encourage further investigation of the therapeutic potential of these lipoic amides.

Circulating 4-F4t-Neuroprostane and 10-F4t-Neuroprostane Are Related to MECP2 Gene Mutation and Natural History in Rett Syndrome.

Neuroprostanes, a family of non-enzymatic metabolites of the docosahexaenoic acid, have been suggested as potential biomarkers for neurological diseases. Objective biological markers are strongly needed in Rett syndrome (RTT), which is a progressive X-linked neurodevelopmental disorder that is mainly caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene with a predominant multisystemic phenotype. The aim of the study is to assess a possible association between MECP2 mutations or RTT disease progression and plasma levels of 4(RS)-4-F4t-neuroprostane (4-F4t-NeuroP) and 10(RS)-10-F4t-neuroprostane (10-F4t-NeuroP) in typical RTT patients with proven MECP2 gene mutation. Clinical severity and disease progression were assessed using the Rett clinical severity scale (RCSS) in n = 77 RTT patients. The 4-F4t-NeuroP and 10-F4t-NeuroP molecules were totally synthesized and used to identify the contents of the plasma of the patients. Neuroprostane levels were related to MECP2 mutation category (i.e., early truncating, gene deletion, late truncating, and missense), specific hotspot mutations (i.e., R106W, R133C, R168X, R255X, R270X, R294X, R306C, and T158M), and disease stage (II through IV). Circulating 4-F4t-NeuroP and 10-F4t-NeuroP were significantly related to (i) the type of MECP2 mutations where higher levels were associated to gene deletions (p ≤ 0.001); (ii) severity of common hotspot MECP2 mutation (large deletions, R168X, R255X, and R270X); (iii) disease stage, where higher concentrations were observed at stage II (p ≤ 0.002); and (iv) deficiency in walking (p ≤ 0.0003). This study indicates the biological significance of 4-F4t-NeuroP and 10-F4t-NeuroP as promising molecules to mark the disease progression and potentially gauge genotype-phenotype associations in RTT.

Relevance of seminal F2-dihomo-IsoPs, F2-IsoPs and F4-NeuroPs in idiopathic infertility and varicocele.

The aim of this paper was to investigate the relevance of isoprostanoids i.e., F2-isoprostanes (F2-IsoPs), F4-neuroprostanes (F4-NeuroPs) and F2-dihomo-isoprostanes (F2-dihomo-IsoPs) in semen quality. Isoprostanoid levels were detected in semen of fertile and infertile men with varicocele or idiopathic infertility. Semen quality was assessed by light microscopy and transmission electron microscopy; the relationships between isoprostanes and semen parameters were also explored. F2-IsoPs levels were significantly different in the varicocele group compared to idiopathic infertile group and fertile men (P < 0.01 and P < 0.001 respectively). Moreover, F2-dihomo-IsoP values were significantly higher in varicocele group respect to fertile men (P < 0.05). No significant statistical differences were found regarding F4-NeuroP concentrations. In the whole population, F2-IsoPs positively correlated with F2-dihomo-IsoPs and both isoprostanoids showed a positive correlation with immaturity and a negative correlation with sperm motility. F2-IsoP levels were positively correlated with the percentage of immaturity in infertile varicocele groups (P < 0.01) whereas a significant relationship between F4-NeuroP values and the percentage of sperm necrosis was shown in idiopathic infertility group (P < 0.01). A significant negative correlation of F4-NeuroPs with sperm morphology was detected in infertile varicocele subjects (P < 0.05). This study suggests that isoprostanoid semen levels appear to be associated with male infertility being related to the sperm quality and confirming the important role of fatty acids profiling in human sperm maturation.

Fatty Acid Profile and Metabolism Are Related to Human Sperm Parameters and Are Relevant in Idiopathic Infertility and Varicocele.

OBJECTIVES: Fatty acids (FA) modulate oxidative stress, reactive oxygen species (ROS) production, and inflammatory processes in spermatogenesis. METHODS: The amount of 17 different FAs and the level of F2-isoprostanes (F2-IsoPs) and cytoplasmic phospholipase A2 (cPLA2) were compared and correlated to sperm characteristics; these last ones were evaluated by light and electronic microscopy in varicocele and idiopathic infertile patients. RESULTS: Total n-3 polyunsaturated acids (PUFAs) and docosahexaenoic acid (DHA), one of the n-3 PUFAs, were significantly reduced in idiopathic infertile men compared to controls (P < 0.05). In the whole studied population, oleic acid and total monounsaturated acids (MUFAs) correlated negatively with sperm concentration, progressive motility, normal morphology, vitality, and fertility index and positively with sperm necrosis. Eicosapentaenoic acid (EPA) amount was positively correlated with the percentage of sperm necrosis and cPLA2 level and negatively with sperm concentration. Sperm vitality was negatively correlated with the saturated fatty acids (SFAs). In infertile groups, cPLA2 was negatively correlated with DHA and n-3 PUFAs (both P < 0.05) and positively with EPA (P < 0.05). In the varicocele group, sperm vitality was negatively correlated with palmitoleic acid and total n-6 PUFAs (P < 0.05); sperm apoptosis was positively correlated with the total SFA percentage (P < 0.05). CONCLUSIONS: FA composition in sperm membrane and the metabolism of sperm FAs are interrelated parameters, both relevant in sperm maturation processes and fertility.

Cytosolic phospholipase A2 and F2 isoprostanes are involved in semen quality and human infertility-A study on leucocytospermia, varicocele and idiopathic infertility.

Phospholipase A2 (PLA2 ) is involved in eicosanoid release, and F2 -isoprostanes (F2 -IsoPs), as free radical-generated eicosanoids released by PLA2 , are indicators of oxidative stress in different human conditions. This study investigated the interplay between cytosolic PLA2 (cPLA2 ), F2 -IsoPs and sperm features in male infertility, when the involvement of oxidative stress has been reported. Semen evaluation was performed following WHO guidelines, sperm ultrastructure was detected by transmission electron microscopy indicating a fertility index, and the percentages of sperm immaturity, apoptosis and necrosis. In sperm cells and seminal plasma, cPLA2 levels were determined by immunological method, whereas F2 -IsoPs by mass spectrometry. Sperm concentration, morphology, vitality and fertility index values were significantly lower in infertile groups compared with fertile men. An increase in sperm apoptosis and necrosis (p < .01), apoptosis (p < .01) and immaturity (p < .001) was detected in leucocytospermia, idiopathic infertility and varicocele, respectively. Seminal cPLA2 showed the highest value in varicocele group (p < .05), whereas seminal F2 -IsoPs increased in varicocele (p < .001) and leucocytospermia (p < .05) groups. In the whole population, F2 -IsoP and cPLA2 levels were positively correlated (p < .05). On the contrary, F2 -IsoPs and cPLA2 were not significantly different when investigated in sperm cells. Our data indicate that fatty acid oxidation/metabolism plays a role in different male reproductive pathological conditions.

Inflammatory protein response in CDKL5-Rett syndrome: evidence of a subclinical smouldering inflammation.

BACKGROUND: Mutations in the cyclin-dependent kinase-like 5 gene cause a clinical variant of Rett syndrome (CDKL5-RTT). A role for the acute-phase response (APR) is emerging in typical RTT caused by methyl-CpG-binding protein 2 gene mutations (MECP2-RTT). No information is, to date, available on the inflammatory protein response in CDKL5-RTT. We evaluated, for the first time, the APR protein response in CDKL5-RTT. METHODS: Protein patterns in albumin- and IgG-depleted plasma proteome from CDKL5-RTT patients were evaluated by two-dimensional gel electrophoresis/mass spectrometry. The resulting data were related to circulating cytokines and compared to healthy controls or MECP2-RTT patients. The effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) were evaluated. RESULTS: CDKL5-RTT mutations resulted in a subclinical attenuated inflammation, specifically characterized by an overexpression of the complement component C3 and CD5 antigen-like, both strictly related to the inflammatory response. Cytokine dysregulation featuring a bulk increase of anti-inflammatory cytokines, predominantly IL-10, could explain the unchanged erythrocyte sedimentation rate and atypical features of inflammation in CDKL5-RTT. Omega-3 PUFAs were able to counterbalance the pro-inflammatory status. CONCLUSION: For the first time, we revealed a subclinical smouldering inflammation pattern in CDKL5-RTT consisting in the coexistence of an atypical APR coupled with a dysregulated cytokine response.

Persistent Unresolved Inflammation in the Mecp2-308 Female Mutated Mouse Model of Rett Syndrome.

Rett syndrome (RTT) is a rare neurodevelopmental disorder usually caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). Several Mecp2 mutant mouse lines have been developed recapitulating part of the clinical features. In particular, Mecp2-308 female heterozygous mice, bearing a truncating mutation, are a validated model of the disease. While recent data suggest a role for inflammation in RTT, little information on the inflammatory status in murine models of the disease is available. Here, we investigated the inflammatory status by proteomic 2-DE/MALDI-ToF/ToF analyses in symptomatic Mecp2-308 female mice. Ten differentially expressed proteins were evidenced in the Mecp2-308 mutated plasma proteome. In particular, 5 positive acute-phase response (APR) proteins increased (i.e., kininogen-1, alpha-fetoprotein, mannose-binding protein C, alpha-1-antitrypsin, and alpha-2-macroglobulin), and 3 negative APR reactants were decreased (i.e., serotransferrin, albumin, and apolipoprotein A1). CD5 antigen-like and vitamin D-binding protein, two proteins strictly related to inflammation, were also changed. These results indicate for the first time a persistent unresolved inflammation of unknown origin in the Mecp2-308 mouse model.

Red blood cells in Rett syndrome: oxidative stress, morphological changes and altered membrane organization.

In this review, we summarize the current evidence on the erythrocyte as a previously unrecognized target cell in Rett syndrome, a rare (1:10 000 females) and devastating neurodevelopmental disorder caused by loss-of-function mutations in a single gene (i.e. MeCP2, CDKL5, or rarely FOXG1). In particular, we focus on morphological changes, membrane oxidative damage, altered membrane fatty acid profile, and aberrant skeletal organization in erythrocytes from patients with typical Rett syndrome and MeCP2 gene mutations. The beneficial effects of ω-3 polyunsaturated fatty acids (PUFAs) are also summarized for this condition to be considered as a 'model' condition for autism spectrum disorders.

Oxidative brain damage in Mecp2-mutant murine models of Rett syndrome.

Rett syndrome (RTT) is a rare neurodevelopmental disorder affecting almost exclusively females, caused in the overwhelming majority of the cases by loss-of-function mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). High circulating levels of oxidative stress (OS) markers in patients suggest the involvement of OS in the RTT pathogenesis. To investigate the occurrence of oxidative brain damage in Mecp2 mutant mouse models, several OS markers were evaluated in whole brains of Mecp2-null (pre-symptomatic, symptomatic, and rescued) and Mecp2-308 mutated (pre-symptomatic and symptomatic) mice, and compared to those of wild type littermates. Selected OS markers included non-protein-bound iron, isoprostanes (F2-isoprostanes, F4-neuroprostanes, F2-dihomo-isoprostanes) and 4-hydroxy-2-nonenal protein adducts. Our findings indicate that oxidative brain damage 1) occurs in both Mecp2-null (both -/y and stop/y) and Mecp2-308 (both 308/y males and 308/+ females) mouse models of RTT; 2) precedes the onset of symptoms in both Mecp2-null and Mecp2-308 models; and 3) is rescued by Mecp2 brain specific gene reactivation. Our data provide direct evidence of the link between Mecp2 deficiency, oxidative stress and RTT pathology, as demonstrated by the rescue of the brain oxidative homeostasis following brain-specifically Mecp2-reactivated mice. The present study indicates that oxidative brain damage is a previously unrecognized hallmark feature of murine RTT, and suggests that Mecp2 is involved in the protection of the brain from oxidative stress.

Oxygenated metabolites of n-3 polyunsaturated fatty acids as potential oxidative stress biomarkers: total synthesis of 8-F3t-IsoP, 10-F4t-NeuroP and [D4]-10-F4t-NeuroP.

A wide variety of metabolic products of polyunsaturated fatty acids is of paramount importance for improving our medical knowledge in the field of oxidized lipids. Two novel metabolites of n-3 polyunsaturated fatty acids, 8-F3t-IsoP and 10-F4t-NeuroP as well as a deuterated derivative thereof were synthesized based on an acetylenic intermediate. An original approach achieved lateral chain insertion of 8-F3t-IsoP by a ring-closing alkyne metathesis/semi-reduction strategy together with a temporary tether.

Effects of ω-3 PUFAs supplementation on myocardial function and oxidative stress markers in typical Rett syndrome.

Rett syndrome (RTT) is a devastating neurodevelopmental disorder with a 300-fold increased risk rate for sudden cardiac death. A subclinical myocardial biventricular dysfunction has been recently reported in RTT by our group and found to be associated with an enhanced oxidative stress (OS) status. Here, we tested the effects of the naturally occurring antioxidants ω-3 polyunsaturated fatty acids (ω-3 PUFAs) on echocardiographic parameters and systemic OS markers in a population of RTT patients with the typical clinical form. A total of 66 RTT girls were evaluated, half of whom being treated for 12 months with a dietary supplementation of ω-3 PUFAs at high dosage (docosahexaenoic acid ~71.9 ± 13.9 mg/kg b.w./day plus eicosapentaenoic acid ~115.5 ± 22.4 mg/kg b.w./day) versus the remaining half untreated population. Echocardiographic systolic longitudinal parameters of both ventricles, but not biventricular diastolic measures, improved following ω-3 PUFAs supplementation, with a parallel decrease in the OS markers levels. No significant changes in the examined echocardiographic parameters nor in the OS markers were detectable in the untreated RTT population. Our data indicate that ω-3 PUFAs are able to improve the biventricular myocardial systolic function in RTT and that this functional gain is partially mediated through a regulation of the redox balance.

Subclinical inflammatory status in Rett syndrome.

Inflammation has been advocated as a possible common central mechanism for developmental cognitive impairment. Rett syndrome (RTT) is a devastating neurodevelopmental disorder, mainly caused by de novo loss-of-function mutations in the gene encoding MeCP2. Here, we investigated plasma acute phase response (APR) in stage II (i.e., "pseudo-autistic") RTT patients by routine haematology/clinical chemistry and proteomic 2-DE/MALDI-TOF analyses as a function of four major MECP2 gene mutation types (R306C, T158M, R168X, and large deletions). Elevated erythrocyte sedimentation rate values (median 33.0 mm/h versus 8.0 mm/h, P < 0.0001) were detectable in RTT, whereas C-reactive protein levels were unchanged (P = 0.63). The 2-DE analysis identified significant changes for a total of 17 proteins, the majority of which were categorized as APR proteins, either positive (n = 6 spots) or negative (n = 9 spots), and to a lesser extent as proteins involved in the immune system (n = 2 spots), with some proteins having overlapping functions on metabolism (n = 7 spots). The number of protein changes was proportional to the severity of the mutation. Our findings reveal for the first time the presence of a subclinical chronic inflammatory status related to the "pseudo-autistic" phase of RTT, which is related to the severity carried by the MECP2 gene mutation.

Inflammatory lung disease in Rett syndrome.

Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly linked to mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2). Respiratory dysfunction, historically credited to brainstem immaturity, represents a major challenge in RTT. Our aim was to characterize the relationships between pulmonary gas exchange abnormality (GEA), upper airway obstruction, and redox status in patients with typical RTT (n = 228) and to examine lung histology in a Mecp2-null mouse model of the disease. GEA was detectable in ~80% (184/228) of patients versus ~18% of healthy controls, with "high" (39.8%) and "low" (34.8%) patterns dominating over "mixed" (19.6%) and "simple mismatch" (5.9%) types. Increased plasma levels of non-protein-bound iron (NPBI), F2-isoprostanes (F2-IsoPs), intraerythrocyte NPBI (IE-NPBI), and reduced and oxidized glutathione (i.e., GSH and GSSG) were evidenced in RTT with consequently decreased GSH/GSSG ratios. Apnea frequency/severity was positively correlated with IE-NPBI, F2-IsoPs, and GSSG and negatively with GSH/GSSG ratio. A diffuse inflammatory infiltrate of the terminal bronchioles and alveoli was evidenced in half of the examined Mecp2-mutant mice, well fitting with the radiological findings previously observed in RTT patients. Our findings indicate that GEA is a key feature of RTT and that terminal bronchioles are a likely major target of the disease.

Pathology of perinatal brain damage: background and oxidative stress markers.

PURPOSE: To review historical scientific background and new perspective on the pathology of perinatal brain damage. The relationship between birth asphyxia and subsequent cerebral palsy has been extensively investigated. The role of new and promising clinical markers of oxidative stress (OS) is presented. METHODS: Electronic search of PubMed-Medline/EMBASE database has been performed. Laboratory and clinical data involving case series from the research group are reported. RESULTS: The neuropathology of birth asphyxia and subsequent perinatal brain damage as well as the role of electronic fetal monitoring are reported following a review of the medical literature. CONCLUSIONS: This review focuses on OS mechanisms underlying the neonatal brain damage and provides different perspective on the most reliable OS markers during the perinatal period. In particular, prior research work on neurodevelopmental diseases, such as Rett syndrome, suggests the measurement of oxidized fatty acid molecules (i.e., F4-Neuroprostanes and F2-Dihomo-Isoprostanes) closely related to brain white and gray matter oxidative damage.

Redox Homeostasis and Nrf2-Regulated Mechanisms Are Relevant to Male Infertility.

Infertility represents a significant global health challenge, affecting more than 12% of couples worldwide, and most cases of infertility are caused by male factors. Several pathological pathways are implicated in male infertility. The main mechanisms involved are driven by the loss of reduction-oxidation (redox) homeostasis and the resulting oxidative damage as well as the chronic inflammatory process. Increased or severe oxidative stress leads to sperm plasma membrane and DNA oxidative damage, dysregulated RNA processing, and telomere destruction. The signaling pathways of these molecular events are also regulated by Nuclear factor-E2-related factor 2 (Nrf2). The causes of male infertility, the role of oxidative stress in male infertility and the Keap1-Nrf2 antioxidant pathway are reviewed. This review highlights the regulatory role of Nrf2 in the balance between oxidants and antioxidants as relevant mechanisms to male fertility. Nrf2 is involved in the regulation of spermatogenesis and sperm quality. Establishing a link between Nrf2 signaling pathways and the regulation of male fertility provides the basis for molecular modulation of inflammatory processes, reactive oxygen species generation, and the antioxidant molecular network, including the Nrf2-regulated antioxidant response, to improve male reproductive outcomes.