Role of Dickkopf-3 in Blood Pressure Regulation in Mice and Hypertensive Rats.

BACKGROUND: Dkk3 (Dickkopf-3) is a secreted glycoprotein known for its proapoptotic and angiogenic activity. The role of Dkk3 in cardiovascular homeostasis is largely unknown. Remarkably, the Dkk3 gene maps within a chromosome segment linked to the hypertensive phenotype in spontaneously hypertensive rats (SHR). METHODS: We used Dkk3-/- mice or stroke-resistant (sr) and stroke-prone (sp) SHR to examine the role of Dkk3 in the central and peripheral regulation of blood pressure (BP). We used lentiviral expression vector to rescue Dkk3 in knockout mice or to induce Dkk3 overexpression or silencing in SHR. RESULTS: Genetic deletion of Dkk3 in mice enhanced BP and impaired endothelium-dependent acetylcholine-induced relaxation of resistance arteries. These alterations were rescued by restoring Dkk3 expression either in the periphery or in the central nervous system (CNS). Dkk3 was required for the constitutive expression of VEGF (vascular endothelium growth factor), and the action of Dkk3 on BP and endothelium-dependent vasorelaxation was mediated by VEGF-stimulated phosphatidylinositol-3-kinase pathway, leading to eNOS (endothelial NO synthase) activation both in resistance arteries and the CNS. The regulatory function of Dkk3 on BP was confirmed in SHR stroke-resistant and SHR stroke-prone in which was blunted in both resistance arteries and brainstem. In SHR stroke-resistant, lentiviral expression vector-induced Dkk3 expression in the CNS largely reduced BP, whereas Dkk3 knock-down further enhanced BP. In SHR stroke-prone challenged with a hypersodic diet, lentiviral expression vector-induced Dkk3 expression in the CNS displayed a substantial antihypertensive effect and delayed the occurrence of stroke. CONCLUSIONS: These findings demonstrate that Dkk3 acts as peripheral and central regulator of BP by promoting VEGF expression and activating a VEGF/Akt (protein kinase B)/eNOS hypotensive axis.

Telecoaching as a new training method for elderly people: a systematic review.

BACKGROUND: The numerous restrictive measures implemented during the recent COVID-19 pandemic have reduced the levels of physical activity (PA) carried out by elderly people and telecoaching (TC) could be a training method to maintain the recommended levels of PA. In fact, TC uses information and digital communications technologies, such as computers and mobile devices, to access training services remotely. Thus, this study aimed to systematically review the scientific literature to verify the application, efficacy, and safety of TC training programs. METHODS: PubMed, Scopus, and Web of Sciences databases were used for this review, and randomized controlled trials analyzing TC training programs for elderly people were included. Only articles written in English and published in the last decade were considered. RESULTS: 3 articles were included in the qualitative synthesis including 194 elderly people. The sample size ranged from 12 to 117 and the TC training program from 8 to 12 weeks. The TC training programs were applied to elderly people with metabolic diseases and respiratory diseases. TC training program was effective in elderly people with metabolic diseases while the benefits for respiratory diseases have yet to be clarified. CONCLUSION: TC seems to be a safe, effective, and injury-free training method, despite its limited application in elderly population. Future studies should better investigate this training method in elderly people in order to evaluate the effectiveness in a wider range of diseases.

Association between match-related physical activity profiles and playing positions in different tasks: A data driven approach.

Assessing the intensity characteristics of specific soccer drills (matches, small-side game, and match-based exercises) could help practitioners to plan training sessions by providing the optimal stimulus for every player. In this paper, we propose a data analytics framework to assess the neuromuscular or metabolic characteristics of a soccer-specific exercise in relation with the expected match intensity. GPS data describing the physical tasks' external intensity during an entire season of twenty-eight semi-professional soccer players competing at the fourth Italian division were used in this study. A supervised machine-learning approach was tested in order to detect difference in playing positions in different sport-specific drills. Moreover, a non-supervised machine-learning model was used to profile the match neuromuscular and metabolic characteristics. Players' playing positions during matches and match-based exercises are characterised by specific metabolic and neuromuscular characteristics related to tactical demands, while in the small-side game these differences are not detected. Additionally, our framework permits to evaluate if the match performance request is mirrored during training drills. Practitioners could evaluate the type of stimulus performed by a player in a specific training drill in order to assess if they reflect the matches characteristics of their specific playing position.

A Progressive Build-up of Perineuronal Nets in the Somatosensory Cortex Is Associated with the Development of Chronic Pain in Mice.

Chronic pain is sustained by a maladaptive form of neuronal plasticity occurring in all stations of the pain neuraxis, including cortical regions of the pain matrix. We report that chronic inflammatory pain induced by unilateral injection of complete Freund's adjuvant (CFA) in the hindpaw of male mice was associated with a progressive build-up of perineuronal nets (PNNs) in the contralateral somatosensory cortex (SSC), medial prefrontal cortex (mPFC), and reticular thalamic nucleus. In the SSC, the density of PNNs labeled by Wisteria floribunda agglutinin (WFA) was increased at both 3 and 7 d following CFA injection, but only after 7 d in the mPFC. The number of parvalbumin (PV)-positive interneurons enwrapped by WFA+/PNNs was also increased in all three brain regions of mice injected with CFA. Remarkably, PNN degradation induced by intracortical infusion of chondroitinase-ABC significantly reduced mechanical and thermal pain, and also reversed the increased frequency of IPSCs recorded in layer 5 pyramidal neurons of the contralateral SSC in CFA-injected mice. These findings suggest a possible relationship between cortical PNNs and nociceptive sensitization, and support the hypothesis that PNNs maintain their plasticity in the adult life and regulate cortical responses to sensory inputs.SIGNIFICANCE STATEMENT The brain extracellular matrix not only provides structural support, but also regulates synapse formation and function, and modulates neuronal excitability. We found that chronic inflammatory pain in mice enhances the density of perineuronal nets (PNNs) in the somatosensory cortex and medial prefrontal cortex. Remarkably, enzymatic degradation of PNNs in the somatosensory cortex caused analgesia and reversed alterations of inhibitory synaptic transmission associated with chronic pain. These findings disclose a novel mechanism of nociceptive sensitization and support a role for PNNs in mechanisms of neuronal plasticity in the adult brain.

Diffusioosmotic and convective flows induced by a nonelectrolyte concentration gradient.

Glucose is an important energy source in our bodies, and its consumption results in gradients over length scales ranging from the subcellular to entire organs. Concentration gradients can drive material transport through both diffusioosmosis and convection. Convection arises because concentration gradients are mass density gradients. Diffusioosmosis is fluid flow induced by the interaction between a solute and a solid surface. A concentration gradient parallel to a surface creates an osmotic pressure gradient near the surface, resulting in flow. Diffusioosmosis is well understood for electrolyte solutes, but is more poorly characterized for nonelectrolytes such as glucose. We measure fluid flow in glucose gradients formed in a millimeter-long thin channel and find that increasing the gradient causes a crossover from diffusioosmosis-dominated to convection-dominated flow. We cannot explain this with established theories of these phenomena which predict that both scale linearly. In our system, the convection speed is linear in the gradient, but the diffusioosmotic speed has a much weaker concentration dependence and is large even for dilute solutions. We develop existing models and show that a strong surface-solute interaction, a heterogeneous surface, and accounting for a concentration-dependent solution viscosity can explain our data. This demonstrates how sensitive nonelectrolyte diffusioosmosis is to surface and solution properties and to surface-solute interactions. A comprehensive understanding of this sensitivity is required to understand transport in biological systems on length scales from micrometers to millimeters where surfaces are invariably complex and heterogeneous.

Toward a New Conceptual Approach to "Intensity" in Soccer Player's Monitoring: A Narrative Review.

ABSTRACT: Pillitteri, G, Clemente, FM, Petrucci, M, Rossi, A, Bellafiore, M, Bianco, A, Palma, A, and Battaglia, G. Toward a new conceptual approach to "intensity" in soccer player's monitoring: A narrative review. J Strength Cond Res 37(9): 1896-1911, 2023-In the last decade, monitoring physiological and match-related demands in soccer has become an increasingly common practice in sports sciences. One of the great challenges during monitoring process is the identification of key indicators that permit to generalize evidence and sustain decision-making process during training prescription. Actually, one of the major debates in the scientific community and among practitioners is the identification of the "intensity" concept. Defining a given training session or exercise based on "intensity" is difficult due to the fact that a huge amount of indicators are available (related both to the performed activities and to the athletes' psychophysiological responses). These indicators can lead to specific outcomes with different interpretations. The current narrative review aims to discuss the different measures approaches used in soccer to describe the intensity for both internal and external demands. In addition, a second purpose of this review is to propose general recommendations for combining intensity indicators with the aim of defining an overall intensity score of a training session or drill.

Relationship between external and internal load indicators and injury using machine learning in professional soccer: a systematic review and meta-analysis.

This study verified the relationship between internal load (IL) and external load (EL) and their association on injury risk (IR) prediction considering machine learning (ML) approaches. Studies were included if: (1) participants were male professional soccer players; (2) carried out for at least 2 sessions, exercises, or competitions; (3) correlated training load (TL) with non-contact injuries; (4) applied ML approaches to predict TL and non-contact injuries. TL included: IL indicators (Rating of Perceived Exertion, RPE; Session-RPE, Heart Rate, HR) and EL indicators (Global Positioning System, GPS variables); the relationship between EL and IL through index, ratio, formula; ML indicators included performance measures, predictive performance of ML methods, measure of feature importance, relevant predictors, outcome variable, predictor variable, data pre-processing, features selection, ML methods. Twenty-five studies were included. Eleven addressed the relationship between EL and IL. Five used EL/IL indexes. Five studies predicted IL indicators. Three studies investigated the association between EL and IL with IR. One study predicted IR using ML. Significant positive correlations were found between S-RPE and total distance (TD) (r = 0.73; 95% CI (0.64 to 0.82)) as well as between S-RPE and player load (PL) (r = 0.76; 95% CI (0.68 to 0.84)). Association between IL and EL and their relationship with injuries were found. RPE, S-RPE, and HR were associated with different EL indicators. A positive relationship between EL and IL indicators and IR was also observed. Moreover, new indexes or ratios (integrating EL and IL) to improve knowledge regarding TL and fitness status were also applied. ML can predict IL indicators (HR and RPE), and IR. The present systematic review was registered in PROSPERO (CRD42021245312).

X-ray multiscale 3D neuroimaging to quantify cellular aging and neurodegeneration postmortem in a model of Alzheimer's disease.

PURPOSE: Modern neuroimaging lacks the tools necessary for whole-brain, anatomically dense neuronal damage screening. An ideal approach would include unbiased histopathologic identification of aging and neurodegenerative disease. METHODS: We report the postmortem application of multiscale X-ray phase-contrast computed tomography (X-PCI-CT) for the label-free and dissection-free organ-level to intracellular-level 3D visualization of distinct single neurons and glia. In deep neuronal populations in the brain of aged wild-type and of 3xTgAD mice (a triply-transgenic model of Alzheimer's disease), we quantified intracellular hyperdensity, a manifestation of aging or neurodegeneration. RESULTS: In 3xTgAD mice, the observed hyperdensity was identified as amyloid-ß and hyper-phosphorylated tau protein deposits with calcium and iron involvement, by correlating the X-PCI-CT data to immunohistochemistry, X-ray fluorescence microscopy, high-field MRI, and TEM. As a proof-of-concept, X-PCI-CT was used to analyze hippocampal and cortical brain regions of 3xTgAD mice treated with LY379268, selective agonist of group II metabotropic glutamate receptors (mGlu2/3 receptors). Chronic pharmacologic activation of mGlu2/3 receptors significantly reduced the hyperdensity particle load in the ventral cortical regions of 3xTgAD mice, suggesting a neuroprotective effect with locoregional efficacy. CONCLUSIONS: This multiscale micro-to-nano 3D imaging method based on X-PCI-CT enabled identification and quantification of cellular and sub-cellular aging and neurodegeneration in deep neuronal and glial cell populations in a transgenic model of Alzheimer's disease. This approach quantified the localized and intracellular neuroprotective effects of pharmacological activation of mGlu2/3 receptors.

Repeated episodes of transient reduction of oxygen exposure simulating aircraft cabin conditions enhance resilience to stress in mice.

Pilots and crew of domestic flights are exposed to transient periods of mild reductions of partial pressure of inspired oxygen each day, and this might have functional consequence on their performance in the long range. Here, we exposed mice to mild reductions of oxygen exposure (ROE) four times per day for 21 days by lowering oxygen partial pressure to levels corresponding to an altitude of about 2300 m, which is the quote of pressurization of the air cabin. Four groups of mice were studied: unstressed or stressed mice exposed to ROE or normoxic conditions. Mice were exposed to chronic unpredictable stress (CUS) for 28 days, and ROE was delivered in the last 21 days of CUS. In normoxic mice, CUS caused anhedonia in the sucrose preference test, anxiety-like behaviour in the open field test, learning impairment in the Morris water maze, reduced hippocampal neurogenesis, increased serum corticosterone levels and increased expression of depression-related genes (Pclo, Mthfr and Grm5) in the hippocampus. All these changes were reversed by ROE, which had little or no effect in unstressed mice. These findings suggest that ROE simulating air cabin conditions of domestic flights may enhance resilience to stress improving mood, anxiety and learning ability.

One-Pot Synthesis of Oxidation-Sensitive Supramolecular Gels and Vesicles.

Polypeptide-based nanoparticles offer unique advantages from a nanomedicine perspective such as biocompatibility, biodegradability, and stimuli-responsive properties to (patho)physiological conditions. Conventionally, self-assembled polypeptide nanostructures are prepared by first synthesizing their constituent amphiphilic polypeptides followed by postpolymerization self-assembly. Herein, we describe the one-pot synthesis of oxidation-sensitive supramolecular micelles and vesicles. This was achieved by polymerization-induced self-assembly (PISA) of the N-carboxyanhydride (NCA) precursor of methionine using poly(ethylene oxide) as a stabilizing and hydrophilic block in dimethyl sulfoxide (DMSO). By adjusting the hydrophobic block length and concentration, we obtained a range of morphologies from spherical to wormlike micelles, to vesicles. Remarkably, the secondary structure of polypeptides greatly influenced the final morphology of the assemblies. Surprisingly, wormlike micellar morphologies were obtained for a wide range of methionine block lengths and solid contents, with spherical micelles restricted to very short hydrophobic lengths. Wormlike micelles further assembled into oxidation-sensitive, self-standing gels in the reaction pot. Both vesicles and wormlike micelles obtained using this method demonstrated to degrade under controlled oxidant conditions, which would expand their biomedical applications such as in sustained drug release or as cellular scaffolds in tissue engineering.

Validity and Reliability of an Inertial Sensor Device for Specific Running Patterns in Soccer.

Electronic performance tracking devices are largely employed in team sports to monitor performance and improve training. To date, global positioning system (GPS) based devices are those mainly used in soccer training. The aim of this study was to analyse the validity and reliability of the inertial sensor device (ISD) in monitoring distance and speed in a soccer-specific circuit and how their performance compare to a GPS system. 44 young male soccer players (age: 14.9 ± 1.1, range 9-16, years, height: 1.65 ± 0.10 m, body mass: 56.3 ± 8.9 kg) playing in a non-professional soccer team in Italy, participated in the study. We assessed the players trough a soccer running sport-specific circuit. An ISD and a GPS were used to assess distance and speed. Data was compared to a video reference system, and the difference were quantified by means of the root mean square error (RMSE). Significant differences were found for both GPS and ISD devices for distance and speed. However, lower error for distance (dRMSE 2.23 ± 1.01 m and 5.75 ± 1.50 m, respectively) and speed (sRMSE 0.588 ± 0.152 m·s-1 and 1.30 ± 0.422 m·s-1, respectively) were attained by the ISD compared to the GPS. Overall, our results revealed a statistically significant difference between systems in data monitoring for either distance and speed. However, results of this study showed that a smaller error was obtained with the ISD than the GPS device. Despite caution is warranted within the interpretation of these results, we observed a better practical applicability of the ISD due to its small size, lower cost and the possibility to use the device indoor.

Developmental abnormalities in cortical GABAergic system in mice lacking mGlu3 metabotropic glutamate receptors.

Polymorphic variants of the gene encoding for metabotropic glutamate receptor 3 (mGlu3) are linked to schizophrenia. Because abnormalities of cortical GABAergic interneurons lie at the core of the pathophysiology of schizophrenia, we examined whether mGlu3 receptors influence the developmental trajectory of cortical GABAergic transmission in the postnatal life. mGlu3-/- mice showed robust changes in the expression of interneuron-related genes in the prefrontal cortex (PFC), including large reductions in the expression of parvalbumin (PV) and the GluN1 subunit of NMDA receptors. The number of cortical cells enwrapped by perineuronal nets was increased in mGlu3-/- mice, suggesting that mGlu3 receptors shape the temporal window of plasticity of PV+ interneurons. Electrophysiological measurements of GABAA receptor-mediated responses revealed a more depolarized reversal potential of GABA currents in the somata of PFC pyramidal neurons in mGlu3-/- mice at postnatal d 9 associated with a reduced expression of the K+/Cl- symporter. Finally, adult mGlu3-/- mice showed lower power in electroencephalographic rhythms at 1-45 Hz in quiet wakefulness as compared with their wild-type counterparts. These findings suggest that mGlu3 receptors have a strong impact on the development of cortical GABAergic transmission and cortical neural synchronization mechanisms corroborating the concept that genetic variants of mGlu3 receptors may predispose to psychiatric disorders.-Imbriglio, T., Verhaeghe, R., Martinello, K., Pascarelli, M. T., Chece, G., Bucci, D., Notartomaso, S., Quattromani, M., Mascio, G., Scalabrì, F., Simeone, A., Maccari, S., Del Percio, C., Wieloch, T., Fucile, S., Babiloni, C., Battaglia, G., Limatola, C., Nicoletti, F., Cannella, M. Developmental abnormalities in cortical GABAergic system in mice lacking mGlu3 metabotropic glutamate receptors.

5-HT2A receptor-dependent phosphorylation of mGlu2 receptor at Serine 843 promotes mGlu2 receptor-operated Gi/o signaling.

The serotonin 5-HT2A and glutamate mGlu2 receptors continue to attract particular attention, given their implication in psychosis associated with schizophrenia and the mechanism of action of atypical antipsychotics and a new class of antipsychotics, respectively. A large body of evidence indicates a functional crosstalk between both receptors in the brain, but the underlying mechanisms are not entirely elucidated. Here, we have explored the influence of 5-HT2A receptor upon the phosphorylation pattern of mGlu2 receptor in light of the importance of specific phosphorylation events in regulating G protein-coupled receptor signaling and physiological outcomes. Among the five mGlu2 receptor-phosphorylated residues identified in HEK-293 cells, the phosphorylation of Ser843 was enhanced upon mGlu2 receptor stimulation by the orthosteric agonist LY379268 only in cells co-expressing the 5-HT2A receptor. Likewise, administration of LY379268 increased mGlu2 receptor phosphorylation at Ser843 in prefrontal cortex of wild-type mice but not 5-HT2A-/- mice. Exposure of HEK-293 cells co-expressing mGlu2 and 5-HT2A receptors to 5-HT also increased Ser843 phosphorylation state to a magnitude similar to that measured in LY379268-treated cells. In both HEK-293 cells and prefrontal cortex, Ser843 phosphorylation elicited by 5-HT2A receptor stimulation was prevented by the mGlu2 receptor antagonist LY341495, while the LY379268-induced effect was abolished by the 5-HT2A receptor antagonist M100907. Mutation of Ser843 into alanine strongly reduced Gi/o signaling elicited by mGlu2 or 5-HT2A receptor stimulation in cells co-expressing both receptors. Collectively, these findings identify mGlu2 receptor phosphorylation at Ser843 as a key molecular event that underlies the functional crosstalk between both receptors.

Combinatorial Intracellular Delivery Screening of Anticancer Drugs.

Conventional drug solubilization strategies limit the understanding of the full potential of poorly water-soluble drugs during drug screening. Here, we propose a screening approach in which poorly water-soluble drugs are entrapped in poly(2-(methacryloyloxyethyl phosphorylcholine)-poly(2-(diisopropylaminoethyl methacryate) (PMPC-PDPA) polymersomes (POs) to enhance drug solubility and facilitate intracellular delivery. By using a human pediatric glioma cell model, we demonstrated that PMPC-PDPA POs mediated intracellular delivery of cytotoxic and epigenetic drugs by receptor-mediated endocytosis. Additionally, when delivered in combination, drug-loaded PMPC-PDPA POs triggered both an enhanced drug efficacy and synergy compared to that of a conventional combinatorial screening. Hence, our comprehensive synergy analysis illustrates that our screening methodology, in which PMPC-PDPA POs are used for intracellular codelivery of drugs, allows us to identify potent synergistic profiles of anticancer drugs.

Polypyrrole and polyaniline nanocomposites with high photothermal conversion efficiency.

The simple and scalable synthesis of poly[2-(methacryloyloxy)ethyl phosphorylcholine] (PMPC)-coated conducting polymer (CP) nanocomposites is described. These functional nanocomposites exhibit tunable absorption in the near-infrared region with relatively high photothermal efficiencies. More importantly, their potential for bio-imaging and therapeutic treatment is proven by cellular uptake and cytotoxicity studies.

Migraine and Sport in a Physically Active Population of Students: Results of a Cross-Sectional Study.

OBJECTIVE: In this study, we explored the relationship between migraine and sport in a physically active population of students, analyzing the risk of migraine among sporty students. BACKGROUND: The relationship between sport and migraine is controversial; moreover, several studies report on sport as a migraine trigger, but there is evidence that physical activity could have a relevant role in migraine prevention. METHODS: A cross-sectional survey was conducted using the validated ID-migraine questionnaire including specific demo-anthropometric (gender, age, weight, height) and sports variables on a potentially active student population of the University of Palermo. Evaluation in putative migraine subjects of clinical features and disability was explored through the administration of the Italian version of the Migraine Disability Assessment Scale. Statistical analyses were performed using univariate and logistic regression analyses. RESULTS: Three hundred and ninety-three out of 520 students (210 F, mean age: 23.5 ± 0.7 years; 183 M; mean age: 20.5 ± 0.7 years) participated in this study. Migraine screened positive in 102 subjects (26.0%) and its prevalence was significantly higher among females (P < .001). An increased risk of migraine was found in females, and a protective effect of sport on the risk of migraine among females, but not among males. CONCLUSIONS: The role of exercise in migraine is still unclear. This study supports a protective role of sport in migraine reporting a protective effect in females. Further studies are needed to deepen the association between sport and migraine.

Food literacy predictors and associations with physical and emergent literacy in pre-schoolers: results from the Training-to-Health Project.

OBJECTIVE: Food literacy (FL) is a crucial need encompassing basic literacy and fundamental movement skills. The present study aimed to investigate the FL level in pre-schoolers and to evaluate the effect of potential predictors and the associations with gross motor and emergent literacy skills. DESIGN: Cross-sectional study conducted within the Training-to-Health Project. SETTING: Kindergartens (n 21) in the Palermo City Council, Italy. PARTICIPANTS: Pre-school children aged 3-6 years (n 921) followed education sessions on nutritional topics, practical activities and compiled prearranged sheets. FL was assessed by the five-domain toolkit 'preschool-FLAT'; gross motor and emergent literacy skills were assessed by the Italian version of the gross motor development test and the PRCR-2/2009, respectively. Correlation and regression analyses were performed to assess relationships between FL scores and gender, age, weight, height, BMI, gross motor and emergent literacy skills. RESULTS: Independent predictors (ß, se) of higher FL were female gender (1·06, 0·315, P < 0·01), older age (0·08, 0·019, P < 0·001) and greater height (0·13, 0·03, P < 0·001). The adjusted coefficients were significant for quotient of gross motor development and in particular for the locomotor component (0·03, 0·01, P < 0·01 and 0·16, 0·046, P < 0·001, respectively). Almost all associations with the emergent literacy skills were significant (ß = -0·02 to 0·47). CONCLUSIONS: The study suggests that children raised in an environment where both cognitive and motor skills are enhanced can have better chances of increasing FL and success at school. Thus, the need for monitoring FL and its predictors since early age is highlighted.

The Dichotomic Role of Macrophage Migration Inhibitory Factor in Neurodegeneration.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine expressed by different cell types and exerting multiple biological functions. It has been shown that MIF may be involved in several disorders, including neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), and Huntington disease (HD), that represent an unmet medical need. Therefore, further studies are needed to identify novel pathogenetic mechanisms that may translate into tailored therapeutic approaches so to improve patients' survival and quality of life. Here, we reviewed the preclinical and clinical studies investigating the role of MIF in ALS, PD, and HD. The emerging results suggest that MIF might play a dichotomic role in these disorders, exerting a protective action in ALS, a pathogenetic action in HD, and a yet undefined and debated role in PD. The better understanding of the role of MIF in these diseases could allow its use as a novel diagnostic and therapeutic tool for the monitoring and treatment of the patients and for eventual biomarker-driven therapeutic approaches.

Brain Overexpression of Uncoupling Protein-2 (UCP2) Delays Renal Damage and Stroke Occurrence in Stroke-Prone Spontaneously Hypertensive Rats.

The downregulation of uncoupling protein-2 (UCP2) is associated with increased brain and kidney injury in stroke-prone spontaneously hypertensive rats (SHRSP) fed with a Japanese style hypersodic diet (JD). Systemic overexpression of UCP2 reduces organ damage in JD-fed SHRSP. We examined the effect of brain-specific UCP2 overexpression on blood pressure (BP), stroke occurrence and kidney damage in JD-fed SHRSP. Rats received a single i.c.v. injection of a lentiviral vector encoding UCP2 (LV-UCP2), or an empty vector. The brain delivery of LV-UCP2 significantly delayed the occurrence of stroke and kidney damage. The large reduction of proteinuria observed after LV-UCP2 injection was unexpected, because BP levels were unchanged. At the time of stroke, rats treated with LV-UCP2 still showed a large UCP2 upregulation in the striatum, associated with increases in OPA1 and FIS1 protein levels, and reductions in PGC1-α, SOD2, TNFα mRNA levels and NRF2 protein levels. This suggested UCP2 overexpression enhanced mitochondrial fusion and fission and reduced oxidative damage and inflammation in the striatum of JD-fed SHRSP rats. Our data suggest the existence of central mechanisms that may protect against hypertension-induced organ damage independently of BP, and strengthen the suitability of strategies aimed at enhancing UCP2 expression for the treatment of hypertensive damage.

The Role of Macrophage Migration Inhibitory Factor in Alzheimer's Disease: Conventionally Pathogenetic or Unconventionally Protective?

Recent preclinical and clinical observations have offered relevant insights on the etiopathogenesis of late onset Alzheimer's disease (AD) and upregulated immunoinflammatory events have been described as underlying mechanisms involved in the development of AD. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine produced by several cells of the innate and adaptive immune system, as well as non-immune cells. In the present review, we highlight experimental, genetic, and clinical studies on MIF in rodent models of AD and AD patients, and we discuss emerging therapeutic opportunities for tailored modulation of the activity of MIF, that may potentially be applied to AD patients. Dismantling the exact role of MIF and its receptors in AD may offer novel diagnostic and therapeutic opportunities in AD.