Hyaluronic acid from bluefin tuna by-product: Structural analysis and pharmacological activities.

The fishing and aquaculture industries generate a huge amount of waste during processing and preservation operations, especially those of tuna. Recovering these by-products is a major economic and environmental challenge for manufacturers seeking to produce new active biomolecules of interest. A new hyaluronic acid was extracted from bluefin tuna's vitreous humour to assess its antioxidant and pharmacological activities. The characterization by infrared spectroscopy (FT-IR), nuclear magnetic resonance ((1D1H) and 2D (1H COSY, 1H/13C HSQC)) and size exclusion chromatography (SEC/MALS/DRI/VD) revealed that the extracted polysaccharide was a hyaluronic acid with high uronic acid content (55.8 %) and a weight average molecular weight of 888 kDa. This polymer possesses significant anti-radical activity and ferrous chelating capacity. In addition, pharmacological evaluation of its anti-inflammatory and analgesic potential, using preclinical models, in comparison with reference drugs (Dexamethasone, diclofenac, and acetylsalicylate of lysine), revealed promising anti-inflammatory activity as well as interesting peripheral and central antinociceptive activity. Therefore, our new hyaluronic acid compound may therefore serve as a potential drug candidate for the treatment of pain sensation and inflammation of various pathological origins.

Beneficial Effect of Bee Venom and Its Major Components on Facial Nerve Injury Induced in Mice.

Peripheral nerve injury (PNI) is a health problem that affects many people worldwide. This study is the first to evaluate the potential effect of bee venom (BV) and its major components in a model of PNI in the mouse. For that, the BV used in this study was analyzed using UHPLC. All animals underwent a distal section-suture of facial nerve branches, and they were randomly divided into five groups. Group 1: injured facial nerve branches without any treatment. Group 2: the facial nerve branches were injured, and the normal saline was injected similarly as in the BV-treated group. Group 3: injured facial nerve branches with local injections of BV solution. Group 4: injured facial nerve branches with local injections of a mixture of PLA2 and melittin. Group 5: injured facial nerve branches with local injection of betamethasone. The treatment was performed three times a week for 4 weeks. The animals were submitted to functional analysis (observation of whisker movement and quantification of nasal deviation). The vibrissae muscle re-innervation was evaluated by retrograde labeling of facial motoneurons in all experimental groups. UHPLC data showed 76.90 ± 0.13%, 11.73 ± 0.13%, and 2.01 ± 0.01%, respectively, for melittin, phospholipase A2, and apamin in the studied BV sample. The obtained results showed that BV treatment was more potent than the mixture of PLA2 and melittin or betamethasone in behavioral recovery. The whisker movement occurred faster in BV-treated mice than in the other groups, with a complete disappearance of nasal deviation two weeks after surgery. Morphologically, a normal fluorogold labeling of the facial motoneurons was restored 4 weeks after surgery in the BV-treated group, but no such restoration was ever observed in other groups. Our findings indicate the potential of the use of BV injections to enhance appropriate functional and neuronal outcomes after PNI.

Preventing falls: the use of machine learning for the prediction of future falls in individuals without history of fall.

Nowadays, it becomes of paramount societal importance to support many frail-prone groups in our society (elderly, patients with neurodegenerative diseases, etc.) to remain socially and physically active, maintain their quality of life, and avoid their loss of autonomy. Once older people enter the prefrail stage, they are already likely to experience falls whose consequences may accelerate the deterioration of their quality of life (injuries, fear of falling, reduction of physical activity). In that context, detecting frailty and high risk of fall at an early stage is the first line of defense against the detrimental consequences of fall. The second line of defense would be to develop original protocols to detect future fallers before any fall occur. This paper briefly summarizes the current advancements and perspectives that may arise from the combination of affordable and easy-to-use non-wearable systems (force platforms, 3D tracking motion systems), wearable systems (accelerometers, gyroscopes, inertial measurement units-IMUs) with appropriate machine learning analytics, as well as the efforts to address these challenges.

A New Sensitive Test Using Virtual Reality and Foam to Probe Postural Control in Vestibular Patients: The Unilateral Schwannoma Model.

Vestibular schwannomas (VS) are benign tumors of the vestibular nerve that may trigger hearing loss, tinnitus, rotatory vertigo, and dizziness in patients. Vestibular and auditory tests can determine the precise degree of impairment of the auditory nerve, and superior and inferior vestibular nerves. However, balance is often poorly quantified in patients with untreated vestibular schwannoma, for whom validated standardized assessments of balance are often lacking. Balance can be quantified with the EquiTest. However, this device was developed a long time ago and is expensive, specific, and not sensitive enough to detect early deficits because it assesses balance principally in the sagittal plane on a firm platform. In this study, we assessed postural performances in a well-defined group of VS patients. We used the Dizziness Handicap Inventory (DHI) and a customized device consisting of a smartphone, a mask delivering a fixed or moving visual scene, and foam rubber. Patients were tested in four successive sessions of 25 s each: eyes open (EO), eyes closed (EC), fixed visual scene (VR0), and visual moving scenes (VR1) delivered by the HTC VIVE mask. Postural oscillations were quantified with sensors from an android smartphone (Galaxy S9) fixed to the back. The results obtained were compared to those obtained with the EquiTest. Vestibulo-ocular deficits were also quantified with the caloric test and vHIT. The function of the utricle and saccule were assessed with ocular and cervical vestibular-evoked myogenic potentials (o-VEMPs and c-VEMPs), respectively. We found that falls and abnormal postural oscillations were frequently detected in the VS patients with the VR/Foam device. We detected no correlation between falls or abnormal postural movements and horizontal canal deficit or age. In conclusion, this new method provides a simpler, quicker, and cheaper method for quantifying balance. It will be very helpful for (1) determining balance deficits in VS patients; (2) optimizing the optimal therapy indications (active follow-up, surgery, or gamma therapy) and follow-up of VS patients before and after treatment; (3) developing new rehabilitation methods based on balance training in extreme conditions with disturbed visual and proprioceptive inputs.

Efficacy of LED Photobiomodulation for Functional and Axonal Regeneration After Facial Nerve Section-Suture.

Facial nerve damage can lead to partial or total facial nerve palsy. Photobiomodulation has been reported to improve and accelerate functional recovery following peripheral nerve lesion, depending on the type of lesion and the light exposure parameters used. The aim of this study was to investigate the effects of infrared exposure on functional and axonal regeneration after section-suture of the distal branches of the facial nerve: the buccal and marginal mandibular branches and the distal pes. The animals underwent surgery and were irradiated with infrared light at 850 nm twice daily from day 1 to day 16. The recovery of facial function was then studied at both the behavioral and morphological levels. Behavioral analyses were performed by videoscoring with a high-speed camera and using various devices to assess the recovery of whisker movement on the lesioned side from day 1 to day 30. We also assessed nasal deviation toward the intact side and the ability to close the ipsilateral eyelid completely from day 1 to day 38 and from day 1 to day 50, respectively. For morphological analyses, we assessed the re-establishment of facial motoneuron labeling with Fluorogold®, an immunofluorescent retrograde marker of axonal transport injected into the vibrissae, on D10, D14 and D30. We found that whisker movements recovery was significantly faster in treated than in control mice. A complete disappearance of nasal deviation was observed at 2 weeks in infrared-treated lesioned mice and at 5 weeks in controls. Complete eyelid closure was observed 3 weeks after surgery in treated animals and 6 weeks after surgery in controls. Finally, normal fluorogold labeling of the facial nuclei complex was restored 30 days after surgery in the treated animals, but no such restoration was ever observed in control animals. In conclusion, our data show that IR treatment at a distal site has a significant positive effect on facial nerve recovery. These findings pave the way for the clinical use of infrared photobiomodulation in patients with nerve lesions.

FVIII regulates the molecular profile of endothelial cells: functional impact on the blood barrier and macrophage behavior.

Hemophilia A is an inherited X-linked recessive bleeding disorder caused by deficient activity of blood coagulation factor VIII (FVIII). In addition, hemophilia patients show associated diseases including osteopenia, altered inflammation and vascular fragility which may represent the consequence of recurrent bleeding or may be related to the direct FVIII deficiency. Nowadays, recombinant FVIII is proposed to treat hemophilia patients with no circulating FVIII inhibitor. Initially described as a coenzyme to factor IXa for initiating thrombin generation, there is emerging evidence that FVIII is involved in multiple biological systems, including bone, vascular and immune systems. The present study investigated: (i) the functional activities of recombinant human FVIII (rFVIII) on endothelial cells, and (ii) the impact of rFVIII activities on the functional interactions of human monocytes and endothelial cells. We then investigated whether rFVIII had a direct effect on the adhesion of monocytes to the endothelium under physiological flow conditions. We observed that direct biological activities for rFVIII in endothelial cells were characterized by: (i) a decrease in endothelial cell adhesion to the underlying extracellular matrix; (ii) regulation of the transcriptomic and protein profiles of endothelial cells; (iii) an increase in the vascular tubes formed and vascular permeability in vitro; and (iv) an increase in monocyte adhesion activated endothelium and transendothelial migration. By regulating vascular permeability plus leukocyte adhesion and transendothelial migration, the present work highlights new biological functions for FVIII.

An opinion paper on the maintenance of robustness: Towards a multimodal and intergenerational approach using digital twins.

The increasing number of frail elderly people in our aging society is becoming problematic: about 11% of community-dwelling older persons are frail and another 42% are pre-frail. Consequently, a major challenge in the coming years will be to test people over the age of 60 years to detect pre-frailty at the earliest stage and to return them to robustness using the targeted interventions that are becoming increasingly available. This challenge requires individual longitudinal monitoring (ILM) or follow-up of community-dwelling older persons using quantitative approaches. This paper briefly describes an effort to tackle this challenge. Extending the detection of the pre-frail stages to other population groups is also suggested. Appropriate algorithms have been used to begin the tracing of faint physiological signals in order to detect transitions from robustness to pre-frailty states and from pre-frailty to frailty states. It is hoped that these studies will allow older adults to receive preventive treatment at the correct institutions and by the appropriate professionals as early as possible, which will prevent loss of autonomy. Altogether, ILM is conceived as an emerging property of databases ("digital twins") and not the reverse. Furthermore, ILM should facilitate a coordinated set of actions by the caregivers, which is a complex challenge in itself. This approach should be gradually extended to all ages, because frailty has no age, as is testified by overwork, burnout, and post-traumatic syndrome.

[Gender and health: what are we talking about?] / Genre et santé : de quoi parle-t-on ?

In terms of health, women and men are not on equal footing. Not only due to biological factors, but also in the social, cultural and economic realms. Gender bias influences medical practice, research, teaching and behaviour of both caregivers and patients. This bias results in situations of inequality as well as gender discrimination in access to health and medical care. Taking gender into account in matters of health is a major bioethical issue.

Targeting endothelial thioredoxin-interacting protein (TXNIP) protects from metabolic disorder-related impairment of vascular function and post-ischemic revascularisation.

INTRODUCTION: Although thioredoxin-interacting protein (TXNIP) is involved in a variety of biological functions, the contribution of endothelial TXNIP has not been well-defined in regards to endothelial and vascular function or in post-ischemic revascularisation. We postulated that inhibition of endothelial TXNIP with siRNA or in a Cre-LoxP system could be involved in protection from high fat, high protein, low carbohydrate (HFHPLC) diet-induced oxidative stress and endothelial dysfunction, leading to vascular damage and impaired revascularisation in vivo. METHODS AND RESULTS: To investigate the role of endothelial TXNIP, the TXNIP gene was deleted in endothelial cells using anti-TXNIP siRNA treatment or the Cre-LoxP system. Murine models were fed a HFHPLC diet, known to induce metabolic disorders. Endothelial TXNIP targeting resulted in protection against metabolic disorder-related endothelial oxidative stress and endothelial dysfunction. This protective effect mitigates media cell loss induced by metabolic disorders and hampered metabolic disorder-related vascular dysfunction assessed by aortic reactivity and distensibility. In aortic ring cultures, metabolic disorders impaired vessel sprouting and this alteration was alleviated by deletion of endothelial TXNIP. When subjected to ischemia, mice fed a HFHPLC diet exhibited defective post-ischemic angiogenesis and impaired blood flow recovery in hind limb ischemia. However, reducing endothelial TXNIP rescued metabolic disorder-related impairment of ischemia-induced revascularisation. CONCLUSION: Collectively, these results show that targeting endothelial TXNIP in metabolic disorders is essential to maintaining endothelial function, vascular function and improving ischemia-induced revascularisation, making TXNIP a potential therapeutic target for therapy of vascular complications related to metabolic disorders.

[GENDER IN THE BRAIN: BETWEEN SCIENCE AND IDEOLOGY]. / El sexo del cerebro: entre ciencia e ideología.

Despite tremendous advances in neurosciences, the idea that biology is a major determinant for gender differences in cognition and behavior, is still alive. Media and internet continue to feed the public with old clichés that claim that women are naturally good for empathy but unable to read a map, while men have a brain suited for maths and competition. These discourses suggest that at birth the intellectual abilities are wired differently in the brains of girls and boys. Such a view is in total contradiction with today's knowledge on cerebral plasticity, and on the role of the environment in re-shaping the brain through learning and expe-riences. The plasticity concept allows new insight to the question of the origin of brain differences and similarities between the sexes. Experience in the sociocultural context involves gender learning processes which interact with the biological processes. A major challenge is that of building an interdisciplinary dialogue across the biological, social, and human sciences to develop new approaches linking sex, gender and the brain.

Ceramide 1-Phosphate Protects Endothelial Colony-Forming Cells From Apoptosis and Increases Vasculogenesis In Vitro and In Vivo.

OBJECTIVE: Ceramide 1-phosphate (C1P) is a bioactive sphingolipid highly augmented in damaged tissues. Because of its abilities to stimulate migration of murine bone marrow-derived progenitor cells, it has been suggested that C1P might be involved in tissue regeneration. In the present study, we aimed to investigate whether C1P regulates survival and angiogenic activity of human progenitor cells with great therapeutic potential in regenerative medicine such as endothelial colony-orming cells (ECFCs). Approach and Results: C1P protected ECFC from TNFα (tumor necrosis factor-α)-induced and monosodium urate crystal-induced death and acted as a potent chemoattractant factor through the activation of ERK1/2 (extracellular signal-regulated kinases 1 and 2) and AKT pathways. C1P treatment enhanced ECFC adhesion to collagen type I, an effect that was prevented by ß1 integrin blockade, and to mature endothelial cells, which was mediated by the E-selectin/CD44 axis. ECFC proliferation and cord-like structure formation were also increased by C1P, as well as vascularization of gel plug implants loaded or not with ECFC. In a murine model of hindlimb ischemia, local administration of C1P alone promoted blood perfusion and reduced necrosis in the ischemic muscle. Additionally, the beneficial effects of ECFC infusion after ischemia were amplified by C1P pretreatment, resulting in a further and significant enhancement of leg reperfusion and muscle repair. CONCLUSIONS: Our findings suggest that C1P may have therapeutic relevance in ischemic disorders, improving tissue repair by itself, or priming ECFC angiogenic responses such as chemotaxis, adhesion, proliferation, and tubule formation, which result in a better outcome of ECFC-based therapy.

In vivo efficacy of endothelial growth medium stimulated mesenchymal stem cells derived from patients with critical limb ischemia.

BACKGROUND: Cell therapy has been proposed for patients with critical limb ischemia (CLI). Autologous bone marrow derived cells (BMCs) have been mostly used, mesenchymal stem cells (MSCs) being an alternative. The aim of this study was to characterize two types of MSCs and evaluate their efficacy. METHODS: MSCs were obtained from CLI-patients BMCs. Stimulated- (S-) MSCs were cultured in endothelial growth medium. Cells were characterized by the expression of cell surface markers, the relative expression of 6 genes, the secretion of 10 cytokines and the ability to form vessel-like structures. The cell proangiogenic properties was analysed in vivo, in a hindlimb ischemia model. Perfusion of lower limbs and functional tests were assessed for 28 days after cell infusion. Muscle histological analysis (neoangiogenesis, arteriogenesis and muscle repair) was performed. RESULTS: S-MSCs can be obtained from CLI-patients BMCs. They do not express endothelial specific markers but can be distinguished from MSCs by their secretome. S-MSCs have the ability to form tube-like structures and, in vivo, to induce blood flow recovery. No amputation was observed in S-MSCs treated mice. Functional tests showed improvement in treated groups with a superiority of MSCs and S-MSCs. In muscles, CD31+ and αSMA+ labelling were the highest in S-MSCs treated mice. S-MSCs induced the highest muscle repair. CONCLUSIONS: S-MSCs exert angiogenic potential probably mediated by a paracrine mechanism. Their administration is associated with flow recovery, limb salvage and muscle repair. The secretome from S-MSCs or secretome-derived products may have a strong potential in vessel regeneration and muscle repair. Trial registration NCT00533104.

Corrigendum: An Initial Passive Phase That Limits the Time to Recover and Emphasizes the Role of Proprioceptive Information.

[This corrects the article DOI: 10.3389/fneur.2018.00986.].

In vitro and in vivo evaluation of a dextran-graft-polybutylmethacrylate copolymer coated on CoCr metallic stent.

Introduction: The major complications of stent implantation are restenosis and late stent thrombosis. PBMA polymers are used for stent coating because of their mechanical properties. We previously synthesized and characterized Dextrangraft-polybutylmethacrylate copolymer (Dex-PBMA) as a potential stent coating. In this study, we evaluated the haemocompatibility and biocompatibility properties of Dex-PBMA in vitro and in vivo. Methods: Here, we investigated: (1) the effectiveness of polymer coating under physiological conditions and its ability to release Tacrolimus®, (2) the capacity of Dex-PBMA to inhibit Staphylococcus aureus adhesion, (3) the thrombin generation and the human platelet adhesion in static and dynamic conditions, (4) the biocompatibility properties in vitro on human endothelial colony forming cells ( ECFC) and on mesenchymal stem cells (MSC) and in vivo in rat models, and (5) we implanted Dex-PBMA and Dex-PBMATAC coated stents in neointimal hyperplasia restenosis rabbit model. Results: Dex-PBMA coating efficiently prevented bacterial adhesion and release Tacrolimus®. Dex-PBMA exhibit haemocompatibility properties under flow and ECFC and MSC compatibility. In vivo, no pathological foreign body reaction was observed neither after intramuscular nor intravascular aortic implantation. After Dex-PBMA and Dex-PBMATAC coated stents 30 days implantation in a restenosis rabbit model, an endothelial cell coverage was observed and the lumen patency was preserved. Conclusion: Based on our findings, Dex-PBMA exhibited vascular compatibility and can potentially be used as a coating for metallic coronary stents.

Arterial Stiffening with Ultrafast Ultrasound Imaging Gives New Insight into Arterial Phenotype of Vascular Ehlers-Danlos Mouse Models.

OBJECTIVE: Vascular Ehlers-Danlos syndrome (vEDS) is associated with arterial ruptures due to a mutant gene encoding collagen type III (Col-III). To better understand the role of Col-III, we aimed at evaluating aortic stiffness and dynamic stiffening in vEDS mouse models, with either a quantitative (col3KO mice) or a qualitative Col-III defect (col3KI mice). MATERIALS AND METHODS: Abdominal aortic wall pulse wave velocities (PWV) in col3KO and col3KI mice were compared to their respective wild type (WT) littermates using a 15 MHz ultrafast ultrasonic transducer. A carotid catheter continuously monitored pressure changes due to phenylephrine injections. PWV1, generated at diastolic blood pressure (DBP), and PWV2, at systolic blood pressure (SBP) were recorded. Difference between PWV2 and PWV1 (Delta-PWV) normalized by the pulse pressure (PP), corresponding to the aortic stiffening over the cardiac cycle, were compared between mutant and WT mice, as well as the regression slope of PWV as a function of pressure. RESULTS: Delta-PWV/PP was lower in col3KO (p = 0.033) and col3KI mice (p < 0.001) vs. WT-mice regardless of the pressure level. The slope of PWV1 with DBP increase showed a lower arterial stiffness in mutant mice vs. controls in both models. This difference was amplified when evaluating stiffness at systolic blood pressure levels with PWV2. CONCLUSION: In both vEDS mouse models, aortic stiffening was reduced, mainly driven by a lower stiffness at systolic blood pressure. Defective Col-III may be responsible for this, as it is utilized when pressure rises. These pre-clinical data could explain vascular fragility observed in vEDS patients.

Downregulation of Microparticle Release and Pro-Inflammatory Properties of Activated Human Polymorphonuclear Neutrophils by LMW Fucoidan.

Exposition of neutrophils (polymorphonuclear neutrophils, PMNs) to bacterial products triggers exacerbated activation of these cells, increasing their harmful effects on host tissues. We evaluated the possibility of interfering with the classic immune innate responses of human PMNs exposed to bacterial endotoxin (lipopolysaccharide, LPS), and further stimulated with bacterial formyl peptide (N-formyl-methionine-leucine-phenylalanine, fMLP). We showed that the low- molecular-weight fucoidan (LMW-Fuc), a polysaccharide extracted from brown algae, attenuated the exacerbated activation induced by fMLP on LPS-primed PMNs, in vitro, impairing chemotaxis, NET formation, and the pro-survival and pro-oxidative effects. LMW-Fuc also inhibited the activation of canonical signaling pathways, AKT, bad, p47phox and MLC, activated by the exposition of PMN to bacterial products. The activation of PMN by sequential exposure to LPS and fMLP induced the release of L-selectin+ microparticles, which were able to trigger extracellular reactive oxygen species production by fresh PMNs and macrophages. Furthermore, we observed that LMW-Fuc inhibited microparticle release from activated PMN. In vivo experiments showed that circulating PMN-derived microparticles could be detected in mice exposed to bacterial products (LPS/fMLP), being downregulated in animals treated with LMW-Fuc. The data highlight the autocrine and paracrine role of pro-inflammatory microparticles derived from activated PMN and demonstrate the anti-inflammatory effects of LMW-Fuc on these cells.

An Initial Passive Phase That Limits the Time to Recover and Emphasizes the Role of Proprioceptive Information.

In the present experiments, multiple balance perturbations were provided by unpredictable support-surface translations in various directions and velocities. The aim of this study was to distinguish the passive and the active phases during the pre-impact period of a fall. It was hypothesized that it should be feasible if one uses a specific quantitative kinematic analysis to evaluate the dispersion of the body segments trajectories across trials. Moreover, a multi-joint kinematical model was created for each subject, based on a new 3-D minimally invasive stereoradiographic X-ray images to assess subject-specific geometry and inertial parameters. The simulations allowed discriminating between the contributions of the passive (inertia-induced properties) and the active (neuromuscular response) components during falls. Our data show that there is limited time to adjust the way one fall from a standing position. We showed that the pre-impact period is truncated of 200 ms. During the initial part of a fall, the observed trajectory results from the interaction between the destabilizing external force and the body: inertial properties intrinsic to joints, ligaments and musculotendinous system have then a major contribution, as suggested for the regulation of static upright stance. This passive phase is later followed by an active phase, which consists of a corrective response to the postural perturbation. We believe that during a fall from standing height, it takes about 300 ms for postural responses to start correcting the body trajectory, while the impact is expected to occur around 700 ms. It has been argued that this time is sufficient to change the way one falls and that this makes it possible to apply safer ways of falling, for example by using martial arts fall techniques. Also, our results imply visual and vestibular information are not congruent with the beginning of the on-going fall. This consequence is to be noted as subjects prepare to the impact on the basis of sensory information, which would be uniquely mainly of proprioceptive origin at the fall onset. One limitation of the present analysis is that no EMG was included so far but these data are the subject of a future study.