Multifractal Heart Rate Value Analysis: A Novel Approach for Diabetic Neuropathy Diagnosis.

Type 2 diabetes mellitus (T2DM) is characterized by several complications, such as retinopathy, renal failure, cardiovascular disease, and diabetic neuropathy. Among these, neuropathy is the most severe complication, due to the challenging nature of its early detection. The linear Hearth Rate Variability (HRV) analysis is the most common diagnosis technique for diabetic neuropathy, and it is characterized by the determination of the sympathetic-parasympathetic balance on the peripheral nerves through a linear analysis of the tachogram obtained using photoplethysmography. We aimed to perform a multifractal analysis to identify autonomic neuropathy, which was not yet manifest and not detectable with the linear HRV analysis. We enrolled 10 healthy controls, 10 T2DM-diagnosed patients with not-full-blown neuropathy, and 10 T2DM diagnosed patients with full-blown neuropathy. The tachograms for the HRV analysis were obtained using finger photoplethysmography and a linear and/or multifractal analysis was performed. Our preliminary results showed that the linear analysis could effectively differentiate between healthy patients and T2DM patients with full-blown neuropathy; nevertheless, no differences were revealed comparing the full-blown to not-full-blown neuropathic diabetic patients. Conversely, the multifractal HRV analysis was effective for discriminating between full-blown and not-full-blown neuropathic T2DM patients. The multifractal analysis can represent a powerful strategy to determine neuropathic onset, even without clinical diagnostic evidence.

Omega-3-Enriched Diet Improves Metabolic Profile in Prdx6-Deficient Mice Exposed to Microgravity.

BACKGROUND: Space travel has always been one of mankind's greatest dreams. Thanks to technological innovation, this dream is becoming more of a reality. Soon, humans (not only astronauts) will travel, live, and work in space. However, a microgravity environment can induce several pathological alterations that should be, at least in part, controlled and alleviated. Among those, glucose homeostasis impairment and insulin resistance occur, which can lead to reduced muscle mass and liver dysfunctions. Thus, it is relevant to shed light on the mechanism underlaying these pathological conditions, also considering a nutritional approach that can mitigate these effects. METHODS: To achieve this goal, we used Prdx6-/- mice exposed to Hindlimb Unloading (HU), a well-established experimental protocol to simulate microgravity, fed with a chow diet or an omega-3-enriched diet. RESULTS: Our results innovatively demonstrated that HU-induced metabolic alterations, mainly related to glucose metabolism, may be mitigated by the administration of omega-3-enriched diet. Specifically, a significant improvement in insulin resistance has been reported. CONCLUSIONS: Although preliminary, our results highlight the importance of specific nutritional approaches that can alleviate microgravity-induced harmful effects. These findings should be considered soon by those planning trips around the earth.

An Appraisal of the Oleocanthal-Rich Extra Virgin Olive Oil (EVOO) and Its Potential Anticancer and Neuroprotective Properties.

Dietary consumption of olive oil represents a key pillar of the Mediterranean diet, which has been shown to exert beneficial effects on human health, such as the prevention of chronic non-communicable diseases like cancers and neurodegenerative diseases, among others. These health benefits are partly mediated by the high-quality extra virgin olive oil (EVOO), which is produced mostly in Mediterranean countries and is directly made from olives, the fruit of the olive tree (Olea europaea L.). Preclinical evidence supports the existence of antioxidant and anti-inflammatory properties exerted by the polyphenol oleocanthal, which belongs to the EVOO minor polar compound subclass of secoiridoids (like oleuropein). This narrative review aims to describe the antioxidant and anti-inflammatory properties of oleocanthal, as well as the potential anticancer and neuroprotective actions of this polyphenol. Based on recent evidence, we also discuss the reasons underlying the need to include the concentrations of oleocanthal and other polyphenols in the EVOO's nutrition facts label. Finally, we report our personal experience in the production of a certified organic EVOO with a "Protected Designation of Origin" (PDO), which was obtained from olives of three different cultivars (Rotondella, Frantoio, and Leccino) harvested in geographical areas located a short distance from one another (villages' names: Gorga and Camella) within the Southern Italy "Cilento, Vallo di Diano and Alburni National Park" of the Campania Region (Province of Salerno, Italy).

A Novel Mix of Polyphenols and Micronutrients Reduces Adipogenesis and Promotes White Adipose Tissue Browning via UCP1 Expression and AMPK Activation.

Background: Obesity is a pandemic disease characterized by excessive severe body comorbidities. Reduction in fat accumulation represents a mechanism of prevention, and the replacement of white adipose tissue (WAT) with brown adipose tissue (BAT) has been proposed as one promising strategy against obesity. In the present study, we sought to investigate the ability of a natural mixture of polyphenols and micronutrients (A5+) to counteract white adipogenesis by promoting WAT browning. Methods: For this study, we employed a murine 3T3-L1 fibroblast cell line treated with A5+, or DMSO as control, during the differentiation in mature adipocytes for 10 days. Cell cycle analysis was performed using propidium iodide staining and cytofluorimetric analysis. Intracellular lipid contents were detected by Oil Red O staining. Inflammation Array, along with qRT-PCR and Western Blot analyses, served to measure the expression of the analyzed markers, such as pro-inflammatory cytokines. Results: A5+ administration significantly reduced lipids' accumulation in adipocytes when compared to control cells (p < 0.005). Similarly, A5+ inhibited cellular proliferation during the mitotic clonal expansion (MCE), the most relevant stage in adipocytes differentiation (p < 0.0001). We also found that A5+ significantly reduced the release of pro-inflammatory cytokines, such as IL-6 and Leptin (p < 0.005), and promoted fat browning and fatty acid oxidation through increasing expression levels of genes related to BAT, such as UCP1 (p < 0.05). This thermogenic process is mediated via AMPK-ATGL pathway activation. Conclusion: Overall, these results demonstrated that the synergistic effect of compounds contained in A5+ may be able to counteract adipogenesis and then obesity by inducing fat browning.

The Protective Effect of a Unique Mix of Polyphenols and Micronutrients against Neurodegeneration Induced by an In Vitro Model of Parkinson's Disease.

Parkinson's disease (PD) is second-most common disabling neurological disorder worldwide, and unfortunately, there is not yet a definitive way to prevent it. Polyphenols have been widely shown protective efficacy against various PD symptoms. However, data on their effect on physio-pathological mechanisms underlying this disease are still lacking. In the present work, we evaluated the activity of a mixture of polyphenols and micronutrients, named A5+, in the murine neuroblastoma cell line N1E115 treated with 6-Hydroxydopamine (6-OHDA), an established neurotoxic stimulus used to induce an in vitro PD model. We demonstrate that a pretreatment of these cells with A5+ causes significant reduction of inflammation, resulting in a decrease in pro-inflammatory cytokines (IFN-γ, IL-6, TNF-α, and CXCL1), a reduction in ROS production and activation of extracellular signal-regulated kinases (ERK)1/2, and a decrease in apoptotic mechanisms with the related increase in cell viability. Intriguingly, A5+ treatment promoted cellular differentiation into dopaminergic neurons, as evident by the enhancement in the expression of tyrosine hydroxylase, a well-established dopaminergic neuronal marker. Overall, these results demonstrate the synergic and innovative efficacy of A5+ mixture against PD cellular pathological processes, although further studies are needed to clarify the mechanisms underlying its beneficial effect.

Activation of Peripheral Blood Mononuclear Cells and Leptin Secretion: New Potential Role of Interleukin-2 and High Mobility Group Box (HMGB)1.

Activation of innate immunity and low-grade inflammation contributes to hyperglycemia and an onset of Type 2 Diabetes Mellitus (T2DM). Interleukin-2 (IL-2), leptin, High Mobility Group Box-1 (HMGB-1), and increased glucose concentrations are mediators of these processes also by modulating peripheral blood mononuclear cells (PBMCs) response. The aim of this study was to investigate if HMGB-1 and IL-2 turn on PBMCs and their leptin secretion. In isolated human PBMCs and their subpopulations from healthy individuals and naïve T2DM patients, leptin release, pro-inflammatory response and Toll-like Receptors (TLRs) activation was measured. After treatment with IL-2 and HMGB1, NK (Natural Killer) have the highest amount of leptin secretion, whilst NK-T have the maximal release in basal conditions. TLR4 (TAK242) and/or TLR2 (TLR2-IgA) inhibitors decreased leptin secretion after IL-2 and HMGB1 treatment. A further non-significant increase in leptin secretion was reported in PBMCs of naive T2DM patients in response to IL-2 and HMGB-1 stimulation. Finally, hyperglycemia or hyperinsulinemia might stimulate leptin secretion from PBMCs. The amount of leptin released from PBMCs after the different treatments was enough to stimulate the secretion of IL-1ß from monocytes. Targeting leptin sera levels and secretion from PBMCs could represent a new therapeutic strategy to counteract metabolic diseases such as T2DM.

Polyphenols and Ischemic Stroke: Insight into One of the Best Strategies for Prevention and Treatment.

Ischemic stroke (IS) is still among the leading causes of death and disability worldwide. The pathogenic mechanisms beyond its development are several and are complex and this is the main reason why a functional therapy is still missed. The beneficial effects of natural compounds against cardiovascular diseases and IS have been investigated for a long time. In this article, we reviewed the association between the most studied polyphenols and stroke protection in terms of prevention, effect on acute phase, and rehabilitation. We described experimental and epidemiological studies reporting the role of flavonols, phenolic acid, and stilbens on ischemic mechanisms leading to stroke. We analyzed the principal animal models used to evaluate the impact of these micronutrients to cerebral blood flow and to molecular pathways involved in oxidative stress and inflammation modulation, such as sirtuins. We reported the most significant clinical trials demonstrated as the persistent use of polyphenols is clinically relevant in terms of the reduction of vascular risk factors for IS, such as Atrial Fibrillation. Interestingly, different kinds of polyphenols provide brain protection by activating different pathways and mechanisms, like inducing antithrombotic effect, such as Honokiol. For this reason, we discussed an appropriate integrative use of them as a possible therapeutic alternative against stroke.

Tyrosol May Prevent Obesity by Inhibiting Adipogenesis in 3T3-L1 Preadipocytes.

Tyrosol (TR), a major polyphenol found in extra virgin olive oil (EVOO), exerts several antioxidant effects. However, only scarce evidences are present regarding its activity on adipocytes and obesity. This study evaluated the role of TR in adipogenesis. Murine 3T3-L1 preadipocytes were incubated with TR (300 and 500 µM), and TR administration inhibited adipogenesis by downregulation of several adipogenic factors (leptin and aP2) and transcription factors (C/EBPα, PPARγ, SREBP1c, and Glut4) and by modulation of the histone deacetylase sirtuin 1. After complete differentiation, adipocytes treated with 300 and 500 µM TR showed a reduction of 20% and 30% in lipid droplets, respectively. Intracellular triglycerides were significantly reduced after TR treatment (p < 0.05). Mature adipocytes treated with TR at 300 and 500 µM showed a marked decrease in the inflammatory state and oxidative stress as shown by the modulation of specific biomarkers (TNF, IL6, ROS, and SOD2). TR treatment also acted on the early stage of differentiation by reducing cell proliferation (~40%) and inducing cell cycle arrest during Mitotic Expansion Clonal (first 48 h of differentiation), as shown by the increase in both S1 phase and p21 protein expression. We also showed that TR induced lipolysis by activating the AMPK-ATGL-HSL pathway. In conclusion, we provided evidence that TR reduces 3T3-L1 differentiation through downregulation of adipogenic proteins, inflammation, and oxidative stress. Moreover, TR may trigger adipose tissue browning throughout the induction of the AMPK-ATGL-UCP1 pathway and, subsequently, may have promise as a potential therapeutic agent for the treatment and prevention of obesity.

Upregulation of serum and glucocorticoid-regulated kinase 1 exacerbates brain injury and neurological deficits after cardiac arrest.

Cardiopulmonary arrest (CA) is the leading cause of death and disability in the United States. CA-induced brain injury is influenced by multifactorial processes, including reduced cerebral blood flow (hypoperfusion) and neuroinflammation, which can lead to neuronal cell death and functional deficits. We have identified serum and glucocorticoid-regulated kinase-1 (SGK1) as a new target in brain ischemia previously described in the heart, liver, and kidneys (i.e., diabetes and hypertension). Our data suggest brain SGK1 mRNA and protein expression (i.e., hippocampus), presented with hypoperfusion (low cerebral blood flow) and neuroinflammation, leading to further studies of the potential role of SGK1 in CA-induced brain injury. We used a 6-min asphyxia cardiac arrest (ACA) rat model to induce global cerebral ischemia. Modulation of SGK1 was implemented via GSK650394, a SGK1-specific inhibitor (1.2 µg/kg icv). Accordingly, treatment with GSK650394 attenuated cortical hypoperfusion and neuroinflammation (via Iba1 expression) after ACA, whereas neuronal survival was enhanced in the CA1 region of the hippocampus. Learning/memory deficits were observed 3 days after ACA but ameliorated with GSK650394. In conclusion, SGK1 is a major contributor to ACA-induced brain injury and neurological deficits, while inhibition of SGK1 with GSK650394 provided neuroprotection against CA-induced hypoperfusion, neuroinflammation, neuronal cell death, and learning/memory deficits. Our studies could lead to a novel, therapeutic target for alleviating brain injury following cerebral ischemia.NEW & NOTEWORTHY Upregulation of SGK1 exacerbates brain injury during cerebral ischemia. Inhibition of SGK1 affords neuroprotection against cardiac arrest-induced hypoperfusion, neuroinflammation, neuronal cell death, and neurological deficits.

Insulin and Exendin-4 Reduced Mutated Huntingtin Accumulation in Neuronal Cells.

Patients with diabetes mellitus (DM) are more prone to develop cognitive decline and neurodegenerative diseases. A pathological association between an autosomal dominant neurological disorder caused by brain accumulation in mutated huntingtin (mHTT), known as Huntington disease (HD), and DM, has been reported. By using a diabetic mouse model, we previously suggested a central role of the metabolic pathways of HTT, further suggesting the relevance of this protein in the pathology of DM. Furthermore, it has also been reported that intranasal insulin (Ins) administration improved cognitive function in patients with neurodegenerative disorders such as Alzheimer disease, and that exendin-4 (Ex-4) enhanced lifespan and ameliorated glucose homeostasis in a mouse model of HD. Although antioxidant properties have been proposed, the underlying molecular mechanisms are still missing. Therefore, the aim of the present study was to investigate the intracellular pathways leading to neuroprotective effect of Ins and Ex-4 hypoglycemic drugs by using an in vitro model of HD, developed by differentiated dopaminergic neurons treated with the pro-oxidant neurotoxic compound 6-hydroxydopamine (6-ohda). Our results showed that 6-ohda increased mHTT expression and reduced HTT phosphorylation at Ser421, a post-translational modification, which protects against mHTT accumulation. Pre-treatment with Ins or Ex-4 reverted the harmful effect induced by 6-ohda by activating AKT1 and SGK1 kinases, and by reducing the phosphatase PP2B. AKT1 and SGK1 are crucial nodes on the Ins activation pathway and powerful antioxidants, while PP2B dephosphorylates HTT contributing to mHTT neurotoxic effect. In conclusion, present results highlight that Ins and Ex-4 may counteract the neurotoxic effect induced by mHTT, opening novel pharmacological therapeutic strategies against neurodegenerative disorders, with the main focus on HD, still considered an orphan illness.

Prdx6 Plays a Main Role in the Crosstalk Between Aging and Metabolic Sarcopenia.

With the increase in average life expectancy, several individuals are affected by age-associated non-communicable chronic diseases (NCDs). The presence of NCDs, such as type 2 diabetes mellitus (T2DM), leads to the reduction in skeletal muscle mass, a pathological condition defined as sarcopenia. A key factor linking sarcopenia with cellular senescence and diabetes mellitus (DM) is oxidative stress. We previously reported as the absence of Peroxiredoxin 6 (Prdx6), an antioxidant enzyme implicated in maintaining intracellular redox homeostasis, induces an early-stage of T2DM. In the present study we sought to understand the role of Prdx6 in the crosstalk between aging and diabetic sarcopenia, by using Prdx6 knockout (Prdx6-/-) mice. Absence of Prdx6 reduced telomeres length and Sirtuin1 (SIRT1) nuclear localization. An increase in Sa-ß-Gal activity and p53-p21 pro-aging pathway were also evident. An impairment in IGF-1 (Insulin-like Groth Factor-1)/Akt-1/mTOR pathway leading to a relative increase in Forkhead Box O1 (FOXO1) nuclear localization and in a decrease of muscle differentiation as per lower levels of myoblast determination protein 1 (MyoD) was observed. Muscle atrophy was also present in Prdx6-/- mice by the increase in Muscle RING finger 1 (MuRF1) levels and proteins ubiquitination associated to a reduction in muscle strength. The present study, innovatively, highlights a fundamental role of Prdx6, in the crosstalk between aging, sarcopenia, and DM.

Far Infrared Technology (FIT) Therapy Patches, Protects from Inflammation, Oxidative Stress and Promotes Cellular Vitality.

BACKGROUND: It is known from the most recent literature that far-infrared (FIR) radiations promote a broad spectrum of therapeutic benefits for cells and tissues. OBJECTIVE: To identify molecular mechanisms by which FIT patches, as a far infrared technology, protects against damage caused by inflammatory process and oxidative stress. METHODS: Endothelial cells (HUVEC, Human Umbilical Vein Endothelial Cells) were used as in vitro experimental model. HUVEC were stimulated with a pro-inflammatory cytokine, TNF-α, or hydrogen peroxide (H2O2) to induce oxidative stress. As markers of inflammation were evaluated: VCAM1 (Vascular Cell Adhesion Molecule 1), ICAM1 (Intercellular Adhesion Molecule 1) and E-Selectin by Western Blot analysis. Oxidative stress was assessed by cytofluorimetric analysis. The experiments were performed on control cells (no patch) or in cells treated with the FIT infrared technology applied on the basis of the culture plate. RESULTS: HUVEC stimulated with TNF-α and treated with FIT patches had significant reduction of the expression of VCAM1, ICAM1 and E-Selectin (p<0.05). HUVEC stimulated with H2O2 and treated with FIT patches were significantly protected from oxidative stress (p <0.01) when compared to control cells. We measured cell viability and proliferation in HUVEC and HEK-293 (Human embryonic kidney cells) cells by MTT assay. HEK-293 and HUVEC treated with FIT patches showed a significantly higher percentage of basal vitality compared to control cells (p<0.0001 for HEK-293, p<0.05 for HUVEC). CONCLUSION: FIT therapy patches - infrared technology, through these protective mechanisms, could be used in all pathologies where an increase in inflammation, oxidative stress and degenerative state are present.

In vitro elimination of epidermal growth factor receptor-overexpressing cancer cells by CD32A-chimeric receptor T cells in combination with cetuximab or panitumumab.

Cetuximab and panitumumab bind the human epidermal growth factor receptor (EGFR). Although the chimeric cetuximab (IgG1) triggers antibody-dependent-cellular-cytotoxicity (ADCC) of EGFR positive target cells, panitumumab (a human IgG2) does not. The inability of panitumumab to trigger ADCC reflects the poor binding affinity of human IgG2 Fc for the FcγRIII (CD16) on natural killer (NK) cells. However, both human IgG1 and IgG2 bind the FcγRII (CD32A) to a similar extent. Our study compares the ability of T cells, engineered with a novel low-affinity CD32A131R -chimeric receptor (CR), and those engineered with the low-affinity CD16158F -CR T cells, in eliminating EGFR positive epithelial cancer cells (ECCs) in combination with cetuximab or panitumumab. After T-cell transduction, the percentage of CD32A131R -CR T cells was 74 ± 10%, whereas the percentage of CD16158F -CR T cells was 46 ± 15%. Only CD32A131R -CR T cells bound panitumumab. CD32A131R -CR T cells combined with the mAb 8.26 (anti-CD32) and CD16158F -CR T cells combined with the mAb 3g8 (anti-CD16) eliminated colorectal carcinoma (CRC), HCT116FcγR+ cells, in a reverse ADCC assay in vitro. Crosslinking of CD32A131R -CR on T cells by cetuximab or panitumumab and CD16158F -CR T cells by cetuximab induced elimination of triple negative breast cancer (TNBC) MDA-MB-468 cells, and the secretion of interferon gamma and tumor necrosis factor alpha. Neither cetuximab nor panitumumab induced Fcγ-CR T antitumor activity against Kirsten rat sarcoma (KRAS)-mutated HCT116, nonsmall-cell-lung-cancer, A549 and TNBC, MDA-MB-231 cells. The ADCC of Fcγ-CR T cells was associated with the overexpression of EGFR on ECCs. In conclusion, CD32A131R -CR T cells are efficiently redirected by cetuximab or panitumumab against breast cancer cells overexpressing EGFR.

Proposed Tandem Effect of Physical Activity and Sirtuin 1 and 3 Activation in Regulating Glucose Homeostasis.

Sirtuins (SIRTs) are seven nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases enzymes (SIRT1-7) that play an important role in maintaining cellular homeostasis. Among those, the most studied are SIRT1 and SIRT3, a nuclear SIRT and a mitochondrial SIRT, respectively, which significantly impact with an increase in mammals' lifespan by modulating metabolic cellular processes. Particularly, when activated, both SIRT1 and 3 enhance pancreatic ß-cells' insulin release and reduce inflammation and oxidative stress pancreatic damage, maintaining then glucose homeostasis. Therefore, SIRT1 and 3 activators have been proposed to prevent and counteract metabolic age-related diseases, such as type 2 diabetes mellitus (T2DM). Physical activity (PA) has a well-established beneficial effect on phenotypes of aging like ß-cell dysfunction and diabetes mellitus. Recent experimental and clinical evidence reports that PA increases the expression levels of both SIRT1 and 3, suggesting that PA may exert its healthy contribute even by activating SIRTs. Therefore, in the present article, we discuss the role of SIRT1, SIRT3, and PA on ß-cell function and on diabetes. We also discuss the possible interaction between PA and activation of SIRTs as a possible therapeutic strategy to maintain glucose hemostasis and to prevent T2DM and its complications, especially in the elderly population.

Age-Dependent Levels of Protein Kinase Cs in Brain: Reduction of Endogenous Mechanisms of Neuroprotection.

Neurodegenerative diseases are among the leading causes of mortality and disability worldwide. However, current therapeutic approaches have failed to reach significant results in their prevention and cure. Protein Kinase Cs (PKCs) are kinases involved in the pathophysiology of neurodegenerative diseases, such as Alzheimer's Disease (AD) and cerebral ischemia. Specifically ε, δ, and γPKC are associated with the endogenous mechanism of protection referred to as ischemic preconditioning (IPC). Existing modulators of PKCs, in particular of εPKC, such as ψεReceptor for Activated C-Kinase (ψεRACK) and Resveratrol, have been proposed as a potential therapeutic strategy for cerebrovascular and cognitive diseases. PKCs change in expression during aging, which likely suggests their association with IPC-induced reduction against ischemia and increase of neuronal loss occurring in senescent brain. This review describes the link between PKCs and cerebrovascular and cognitive disorders, and proposes PKCs modulators as innovative candidates for their treatment. We report original data showing εPKC reduction in levels and activity in the hippocampus of old compared to young rats and a reduction in the levels of δPKC and γPKC in old hippocampus, without a change in their activity. These data, integrated with other findings discussed in this review, demonstrate that PKCs modulators may have potential to restore age-related reduction of endogenous mechanisms of protection against neurodegeneration.

Peroxiredoxin6, a Multitask Antioxidant Enzyme Involved in the Pathophysiology of Chronic Noncommunicable Diseases.

SIGNIFICANCE: Chronic noncommunicable diseases (NCDs) are the leading causes of disability and death worldwide. NCDs mainly comprise diabetes mellitus, cardiovascular diseases, chronic obstructive pulmonary disease, cancer, and neurological degenerative diseases, which kill more than 80% of population, especially the elderly, worldwide. Recent Advances: Several recent theories established NCDs as multifactorial diseases, where a combination of genetic, epigenetic, and environmental factors contributes to their pathogenesis. Nevertheless, recent findings suggest that the common factor linking all these pathologies is an increase in oxidative stress and the age-related loss of the antioxidant mechanisms of defense against it. Impairment in mitochondrial homeostasis with consequent deregulation in oxidative stress balance has also been suggested. CRITICAL ISSUES: Therefore, antioxidant proteins deserve particular attention for their potential role against NCDs. In particular, peroxiredoxin(Prdx)6 is a unique antioxidant enzyme, belonging to the Prdx family, with double properties, peroxidase and phospholipase activities. Through these activities, Prdx6 has been shown to be a powerful antioxidant enzyme, implicated in the pathogenesis of different NCDs. Recently, we described a phenotype of diabetes mellitus in Prdx6 knockout mice, suggesting a pivotal role of Prdx6 in the pathogenesis of cardiometabolic diseases. FUTURE DIRECTIONS: Increasing awareness on the role of antioxidant defenses in the pathogenesis of NCDs may open novel therapeutic approaches to reduce the burden of this pandemic phenomenon. However, knowledge of the role of Prdx6 in NCD prevention and pathogenesis is still not clarified.

Peroxiredoxin 6 Is a Key Antioxidant Enzyme in Modulating the Link between Glycemic and Lipogenic Metabolism.

Insulin action and often glucose-stimulated insulin secretion are reduced in obesity. In addition, the excessive intake of lipids increases oxidative stress leading to overt type 2 diabetes mellitus (T2DM). Among the antioxidative defense systems, peroxiredoxin 6 (PRDX6) is able to reduce H2O2 and short chain and phospholipid hydroperoxides. Increasing evidences suggest that PRDX6 is involved in the pathogenesis of atherosclerosis and T2DM, but its role in the etiopathology of obesity and its complications is still not known. Therefore, in the present study, we sought to investigate this association by using PRDX6 knockout mice (PRDX6-/-). Metabolic parameters, like carbon dioxide (VCO2) production, oxygen consumption (VO2), and the respiratory exchange ratio (RER), were determined using metabolic cages. Intraperitoneal insulin and glucose tolerance tests were performed to evaluate insulin sensitivity and glucose tolerance, respectively. Liver and pancreas histochemical analyses were also evaluated. The expression of enzymes involved in lipid and glucose metabolism was analyzed by real-time PCR. Following 24 weeks of high-fat-diet (HFD), PRDX6-/- mice showed weight gain and higher food and drink intake compared to controls. VO2 consumption and VCO2 production decreased in PRDX6-/- mice, while the RER was lower than 0.7 indicating a prevalent lipid metabolism. PRDX6-/- mice fed with HFD showed a further deterioration on insulin sensitivity and glucose-stimulated insulin secretion. Furthermore, in PRDX6-/- mice, insulin did not suppress adipose tissue lipolysis with consequent hepatic lipid overload and higher serum levels of ALT, cholesterol, and triglycerides. Interestingly, in PRDX6-/- mice, liver and adipose tissue were associated with proinflammatory gene upregulation. Finally, PRDX6-/- mice showed a higher rate of nonalcoholic steatohepatitis (NASH) compared to control. Our results suggest that PRDX6 may have a functional and protective role in the development of obesity-related metabolic disorders such as liver diseases and T2DM and may be considered a potential therapeutic target against these illnesses.

FGF-2b and h-PL Transform Duct and Non-Endocrine Human Pancreatic Cells into Endocrine Insulin Secreting Cells by Modulating Differentiating Genes.

Background: Diabetes mellitus (DM) is a multifactorial disease orphan of a cure. Regenerative medicine has been proposed as novel strategy for DM therapy. Human fibroblast growth factor (FGF)-2b controls ß-cell clusters via autocrine action, and human placental lactogen (hPL)-A increases functional ß-cells. We hypothesized whether FGF-2b/hPL-A treatment induces ß-cell differentiation from ductal/non-endocrine precursor(s) by modulating specific genes expression. Methods: Human pancreatic ductal-cells (PANC-1) and non-endocrine pancreatic cells were treated with FGF-2b plus hPL-A at 500 ng/mL. Cytofluorimetry and Immunofluorescence have been performed to detect expression of endocrine, ductal and acinar markers. Bromodeoxyuridine incorporation and annexin-V quantified cells proliferation and apoptosis. Insulin secretion was assessed by RIA kit, and electron microscopy analyzed islet-like clusters. Results: Increase in PANC-1 duct cells de-differentiation into islet-like aggregates was observed after FGF-2b/hPL-A treatment showing ultrastructure typical of islets-aggregates. These clusters, after stimulation with FGF-2b/hPL-A, had significant (p < 0.05) increase in insulin, C-peptide, pancreatic and duodenal homeobox 1 (PDX-1), Nkx2.2, Nkx6.1, somatostatin, glucagon, and glucose transporter 2 (Glut-2), compared with control cells. Markers of PANC-1 (Cytokeratin-19, MUC-1, CA19-9) were decreased (p < 0.05). These aggregates after treatment with FGF-2b/hPL-A significantly reduced levels of apoptosis. Conclusions: FGF-2b and hPL-A are promising candidates for regenerative therapy in DM by inducing de-differentiation of stem cells modulating pivotal endocrine genes.

Effects of parasitic infection and reproduction on corticosterone plasma levels in Galápagos land iguanas, Conolophus marthae and C. subcristatus.

In vertebrates, one main feature of stress response is the release of glucocorticoids (corticosterone in reptiles), steroid hormones whose synthesis is regulated by the hypothalamic-pituitary-adrenal axis (HPA). In the Galápagos Islands, populations of land iguanas are differentially impacted by a tick-transmitted apicomplexan hemoparasite of genus Hepatozoon, which could cause diseases and ultimately reduce fitness. Using competitive enzyme-linked immunosorbent assays (ELISA), we examined baseline plasma corticosterone levels of two syntopic and highly parasitized populations of the land iguana species Conolophus marthae and C. subcristatus in Wolf volcano (Isabela Island). We also used a poorly parasitized population of C. subcristatus from the same island (Bahia Urbina) as a reference. To better interpret the observed glucocorticoids patterns, we simultaneously performed the count of white blood cells (WBCs) in all individuals and investigated the reproductive status of females. We did not find evidence in support of either a positive or negative relationship between the tick load, hemoparasite infection, and glucocorticoid plasma concentration in C. marthae and C. subcristatus at Wolf volcano. The comparison between parasitized and non-parasitized sites (V. Wolf and Bahia Urbina) would instead suggest an inverse relationship between corticosterone and parasites. Our findings support association between corticosterone plasma levels and reproduction.

Sex-Genetic Interaction in the Risk for Cerebrovascular Disease.

Cerebrovascular disease (CeVD) is one of the major causes of death and a leading cause of disability worldwide. CeVD is a complex and multifactorial disease caused by the interaction of environment and genetic factors. Women have lower CeVD incidence than men until an advanced age, when the incidence of CeVD rises dramatically in women. Therefore, sex has been validated as an important risk factor in the etiology of CeVD, especially ischemic stroke. Although the importance of sex steroids have been heavily studied in the mechanism of neuronal injury, the experimental and clinical data suggest that hormones do not fully account for male versus female CeVD patterns. Sex-specific genetic processes have been implicated in the different rate of risk for atherosclerosis and CeVD. In this review, we discuss sex-specific CeVD processes, describe the hormonal impact on the risk for CeVD, the results from studies in transgenic animals, and from human genetic studies. Moreover, heritability of ischemic stroke in women and men as well as identification of possible sex-specific biomarkers for CeVD are discussed. Understanding the complex interactions between hormonal and genetic mechanisms in the CeVD risk will allow for new sex-specific approaches in disease treatment and prevention in clinical practice.