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Heart failure with preserved ejection fraction (HFpEF) is a global cardiovascular challenge, constituting nearly 50% of prevalent heart failure cases worldwide. Renal dysfunction is common in HFpEF and is linked to higher mortality. The interplay between HFpEF and chronic kidney disease, potentially through a bidirectional causative relationship, remains poorly understood. In our study, we explored renal abnormalities over time in an experimental rat model of HFpEF with multiple comorbidities. Obesity-prone (OP) and–resistant (OR) rats were fed a high fat diet (HFD) or a standard rat chow for 4 or 12 months (n= 10 rats/group). They underwent evaluation through echocardiography, cardiac catheterization, and renal histological analyses. After 12 months of HFD, OP rats developed HFpEF, featuring LV diastolic dysfunction, concentric LV hypertrophy, and fibrosis, while maintaining preserved LV ejection fraction—absent in the 4-month HFD group. HFpEF rats exhibited increased serum cystatin C levels and elevated renal expression of kidney injury molecule (KIM)-1, indicating renal dysfunction. Histological analysis revealed glomerular enlargement, sclerosis, and inflammatory infiltrates in 4-month HFD fed OP rats, intensified in HFpEF rats. Increased renal expression of inflammatory markers, adhesion molecules, and macrophage-specific marker CD68 was observed. Pro-inflammatory cytokines and indicators of renal apoptosis and sustained fibrosis were heightened in HFpEF rats, demonstrating matrix component upregulation and increased expression of pro-fibrotic factors. Our findings showed renal pathological alterations preceding HFpEF diagnosis in our experimental rat model, pointing out the intricate relationship between HFpEF and renal dysfunction., info:eu-repo/semantics/published

Résumé :La maladie d’Alzheimer (MA) est une maladie neurodégénérative, incurable, composée de deux lésions neuropathologiques :les plaques amyloïdes et les dégénérescences neurofibrillaires (DNF). Ces dernières sont composées de protéines tau hyperphosphorylées qui s’accumulent et s’agrègent dans le corps cellulaire des neurones en formant des filaments torsadés nommés « PHF » en anglais pour « Paired Helical Filaments ». Au cours de l’évolution de la maladie, la progression de la pathologie tau, mise en évidence par la présence des DNF dans le cerveau, semble être dépendante de voies neuroanatomiquement connectées. Cette observation a conduit à l’hypothèse que la protéine tau pourrait se comporter comme une protéine prion. Dans cette hypothèse, les protéines tau anormales doivent être internalisées par les cellules cibles pour opérer un changement physico-chimique des protéines tau endogènes (nucléation), qui, à leur tour acquièrent des caractéristiques pathologiques pouvant être transmises dans de nouvelles cellules (propagation). Néanmoins, contrairement aux prions, le caractère transmissible des protéines tau pathologiques n’a jamais été démontré.Des contaminations iatrogènes de protéines prions ont été reportées ou suspectées à la suite de transfusions sanguines ou de greffes de cornées. Afin d’évaluer les similitudes possibles entre les prions et la protéine tau, nous avons analysé la transmission éventuelle de la pathologie tau par le sang ou à la suite d’une chirurgie oculaire en procédant à des injections intravasculaires ou intraoculaires de PHF-tau, isolés de cerveaux de patients décédés de la MA, dans des souris sauvages (WT) ou transgéniques exprimant une protéine tau et/ou amyloïde humaine sauvage ou mutée.Les capacités de nucléation et de propagation des PHF-tau humains ont été validées in vitro à l’aide d’un modèle cellulaire de détection de l’activité de nucléation de la protéine tau et in vivo en utilisant des injections intracérébrales dans des so, Doctorat en Sciences biomédicales et pharmaceutiques (Médecine), info:eu-repo/semantics/nonPublished

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The flow diverter stent (FDS) has become a first-line treatment for numerous intra-cranial aneurysms (IAs) by promoting aneurysm thrombosis. However, the biological phenomena underlying its efficacy remain unknown. We proposed a method to collect in situ blood samples to explore the flow diversion effect within the aneurysm sac. In this feasibility study, we assessed the plasma levels of nucleotides within the aneurysm sac before and after flow diversion treatment., SCOPUS: ar.j, info:eu-repo/semantics/published

Despite advances in targeted therapies and immunotherapy in lung cancer, chemotherapy remains the backbone of treatment in most patients at different stages of the disease. Inhaled chemotherapy is a promising strategy to target lung tumours and to limit the induced severe systemic toxicities. Cisplatin dry powder for inhalation (CIS-DPI) was tested as an innovative way to deliver cisplatin locally via the pulmonary route with minimal systemic toxicities. In vivo, CIS-DPI demonstrated a dose-dependent antiproliferative activity in the M109 orthotopic murine lung tumour model and upregulated the immune checkpoint PD-L1 on lung tumour cells. Combination of CIS-DPI with the immune checkpoint inhibitor anti-PD1 showed significantly reduced tumour size, increased the number of responders and prolonged median survival over time in comparison to the anti-PD1 monotherapy. Furthermore, the CIS-DPI and anti-PD1 combination induced an intra-tumour recruitment of conventional dendritic cells and tumour infiltrating lymphocytes, highlighting an anti-tumour immune response. This study demonstrates that combining CIS-DPI with anti-PD1 is a promising strategy to improve lung cancer therapy., SCOPUS: ar.j, info:eu-repo/semantics/published

Among genetic susceptibility loci associated with late-onset Alzheimer disease (LOAD), genetic polymorphisms identified in genes encoding lipid carriers led to the hypothesis that a disruption of lipid metabolism could promote disease progression. We previously reported that amyloid precursor protein (APP) involved in Alzheimer disease (AD) physiopathology impairs lipid synthesis needed for cortical networks' activity and that activation of peroxisome proliferator-activated receptor α (PPARα), a metabolic regulator involved in lipid metabolism, improves synaptic plasticity in an AD mouse model. These observations led us to investigate a possible correlation between PPARα function and full-length APP expression. Here, we report that PPARα expression and activation were inversely related to APP expression both in LOAD brains and in early-onset AD cases with a duplication of the APP gene, but not in control human brains. Moreover, human APP expression decreased PPARA expression and its related target genes in transgenic mice and in cultured cortical cells, while opposite results were observed in APP-silenced cortical networks. In cultured neurons, APP-mediated decrease or increase in synaptic activity was corrected by a PPARα-specific agonist and antagonist, respectively. APP-mediated control of synaptic activity was abolished following PPARα deficiency, indicating a key function of PPARα in this process., info:eu-repo/semantics/published

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JNK1 (c-Jun N-terminal kinase 1) has been studied in numerous biological phenomena, but its role in skin inflammation diseases has not been fully defined yet. We therefore evaluated the role of JNK1 in imiquimod-induced dermatitis, a classical model that shares many features with human psoriasis. We showed that JNK1 was necessary for the expression of inflammatory markers and for acanthosis induced by imiquimod. We demonstrated that the loss of JNK1 in dendritic cells or myeloid cells reduced inflammatory markers but did not affect acanthosis induced by imiquimod. In vitro experiments in bone marrow-derived macrophages (BMMs) supported the role of JNK1 in the activation of the inflammasome pathway by the Aldara® cream. Next, we observed that the loss of JNK1 in keratinocytes did not reduce imiquimod-induced expression of most inflammatory markers but acanthosis and proliferation of epidermal cells was decreased. To better understand the role of JNK1 in keratinocytes, we evaluated the transcriptome and the epigenomic landscape of JNK1-deficient epidermal cells from mice treated with imiquimod. These data highlighted the potential role of JNK1 downstream of the EGFR pathway. We further observed that the inhibition of the EGFR pathway decreased imiquimod-induced acanthosis. Our work shows the dual role of JNK1 in skin inflammation induced by imiquimod. On one hand, JNK1 influences the expression of inflammatory mediators by myeloid cells, probably through the inflammasome pathway. On the other hand, JNK1 modulates the response of keratinocytes to EGFR ligands. Taken together, these data suggest that JNK1 could represent a valuable therapeutic target for the management of psoriasis., Doctorat en Sciences médicales (Médecine), info:eu-repo/semantics/nonPublished

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Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental psychiatric disorder affecting 5-7% of children and ≈2.5% of adults worldwide, characterized by inattention, by a combination of hyperactivity and impulsivity, or by the three components. Individuals diagnosed with ADHD have an increased risk of educational and occupational failure, accidents, criminality, social disability and developing other psychiatric disorders, being an important burden for the patient and for society.Despite years of research, the etiology of ADHD remains unknown. However, neuroimaging studies demonstrated that ADHD patients display consistent abnormalities in the striatum, the main input nucleus of the basal ganglia, while the precise implication is poorly characterized. The most common pharmacological treatment in ADHD relies on psychostimulants such as amphetamine (Adderall) and methylphenidate (Ritalin). Importantly, in healthy individuals, these drugs stimulate behavioral arousal by increasing the brain efflux of monoamines, while they paradoxically serve to attenuate hyperactivity/impulsivity and improve focus and cognitive performances in ADHD patients. The goals of this thesis are to investigate the implication of one striatal neuronal population in ADHD symptomatology in a transgenic mouse line and to dissect the implication of each monoaminergic system in the paradoxical effects of psychostimulants. First, we developed a new valid mouse model of ADHD characterized by hyperactivity, inattention and motor impulsivity, that displays an ablation of the indirect pathway spiny projection neurons (iSPNs) of the striatum. In addition, in these mice, amphetamine induces a paradoxical reduction of locomotion, which mirrors the calming effect of amphetamine in ADHD patients. In this work, we thus show for the first time the implication of iSPN in attention and impulsivity and suggest a possible role of these neurons in ADHD symptomatology. Further, by using a chemogenetic, Doctorat en Sciences biomédicales et pharmaceutiques (Médecine), info:eu-repo/semantics/nonPublished

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Résumé Responsable de près de 7 millions de décès prématurés par an à travers le monde, la pollution atmosphérique représente un problème sanitaire mondial majeur. L’exposition humaine à la pollution particulaire dont les émissions de diesel représentent la principale source, est responsable d’une élévation de la mortalité et de l’incidence d’événements cardiovasculaires. Les mécanismes physiopathologiques sous-tendant cette toxicité aigue restent à ce jour largement méconnus. A l’aide d’une méthodologie d’exposition standardisée aux émissions de diesel, nous avons exploré les effets vasculaires périphériques et pulmonaires ainsi que les effets hémostatiques et plaquettaires secondaires à l’inhalation particulaire chez des sujets sains. L’étude dynamique de la microcirculation périphérique par Laser Doppler Imager nous a permis de démontrer une altération de la vasomotricité endothélium-dépendante induite par l’exposition aux émissions de diesel. La dysfonction observée est associée à une diminution de la biodisponibilité locale du NO ainsi qu’à une production radicalaire accrue au sein de la cellule endothéliale. Au cours d’une épreuve dynamique d’élévation du débit cardiaque par infusion de dobutamine, l’exposition aiguë aux émissions de diesel entraîne une élévation de la résistance vasculaire pulmonaire et une diminution de la distensibilité vasculaire pulmonaire mesurées par échocardiographie. Enfin, l’expression de surface des marqueurs d’activation plaquettaire CD62p (P-selectine) et CD63 est augmentée après exposition aux émissions de diesel, en corrélation avec la quantité de particules inhalées et constitue ainsi un état d’activation plaquettaire accru sans toutefois de modification de l’agrégation plaquettaire. A travers ces effets vasculaires systémiques et pulmonaires ainsi que ces effets hémostatiques, l’exposition aux émissions de diesel entraîne une toxicité cardiovasculaire aiguë, agissant en synergie, capable de déclencher la survenue d’événements, Doctorat en Sciences médicales (Médecine), info:eu-repo/semantics/nonPublished

The etiology of renal dysfunction in sepsis is currently attributed to altered perfusion, microcirculatory abnormalities and cellular alterations. To clarify these mechanisms, we characterized the changes in renal perfusion and cortex metabolism in a large animal model of sepsis. In this model, sepsis was associated with metabolic alterations that may reflect early induction of cortical glycolysis. Septic shock was associated with reduced renal perfusion and decreased cortical and medullary blood flow, followed by signs of anaerobic metabolism in the cortex when flow reductions became critical. Attempts to correct renal hypoperfusion and alleviate the associated perfusion/metabolism mismatch with fenoldopam or renal denervation were unsuccessful. In the final study we focussed on the role of renal autoregulation in experimental sepsis and septic shock. Evidence suggests that higher blood pressure targets are needed in patients with impaired renal autoregulation and septic shock, but the effects of vasopressors should also be considered. We therefore investigated the effects of arginine vasopressin and norepinephrine on renal autoregulation in ovine septic shock. In experimental septic shock, arginine vasopressin was associated with a lower autoregulatory threshold than norepinephrine. As vasopressors may have different effects on renal autoregulation, individualized therapy of blood pressure management in patients with septic shock should take into account drug-specific effects., Doctorat en Sciences médicales (Médecine), info:eu-repo/semantics/nonPublished

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Ce travail de thèse vise à l’identification des voies de signalisation cellulaires responsables de la régulation de l’expression des gènes humains DUOX dans la thyroïde. Les protéines DUOX1 et DUOX2 sont exprimées à la membrane apicale du thyrocyte, grâce à leur facteur de maturation DUOXA, et participent à la synthèse des hormones thyroïdiennes à travers la génération de peroxyde d’hydrogène. Les voies de signalisation et les facteurs de transcription contrôlant l’expression des gènes DUOX ne sont pas clairement définis dans les thyroïdes humaines et murines mais plusieurs études ont démontré une augmentation de leur expression via des cytokines inflammatoires dans des lignées cellulaires humaines. L’existence de cytokines susceptibles de réguler positivement l’expression des DUOX dans les thyrocytes a grandement suscité notre intérêt. En effet, il importe de comprendre les mécanismes responsables de leur expression car les protéines DUOX sont de plus en plus associées à des cancers et des maladies inflammatoires chroniques. Dans ce travail de recherche, il a été mis en évidence que les cytokines de type Th2 interleukine-4 et interleukine-13 augmentent la production de peroxyde d’hydrogène dans les thyrocytes humains en culture primaire suite à une induction des protéines DUOX2 et DUOXA2. L’interleukine-4 augmente aussi l’expression des couples de gènes Duox1/Duoxa1 et Duox2/Duoxa2 dans les thyrocytes murins, générant ainsi plus de peroxyde d’hydrogène. La stimulation par l’interleukine-4 et l’interleukine-13 dans les thyrocytes humains est dépendante du récepteur IL4RII et de l’activation de la voie de signalisation JAK1/STAT6. L’effet de l’interleukine-4 est contrecarré par la cytokine de type Th1 interféron-ɣ et est associée à une augmentation de l’expression de la protéine SOCS-1 qui bloque la fonction du facteur de transcription STAT6. L’induction de l’expression des gènes DUOX2/DUOXA2 dans des thyroïdes provenant de patients atteints de la maladie de Graves o, Doctorat en Sciences biomédicales et pharmaceutiques (Médecine), info:eu-repo/semantics/nonPublished

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As many chemotherapy regimens induce follicular depletion, fertility preservation became a major concern in young cancer patients. By maintaining follicles at the resting stage, gonadotropin-releasing hormone analogues (GnRHa) were proposed as an ovarian-protective option during chemotherapy. However, their efficacy and mechanisms of action remain to be elucidated. Mice were dosed with cyclophosphamide (Cy, 100-500mg/kg i.p) to quantify follicular depletion and evaluate apoptosis at different times. We observed a dose-dependent depletion of the follicular reserve within 24 hours after Cy injection with a mean follicular loss of 45% at the dose of 200mg/kg. Apoptosis occurs in the granulosa cells of growing follicles within 12 hours after Cy treatment, while no apoptosis was detected in resting follicles suggesting that chemotherapy acutely affects both resting and growing follicles through different mechanisms. We further tested the ability of both GnRH agonist and antagonist to inhibit oestrus cycles, follicular growth and FSH secretion in mice and to protect ovarian reserve against chemotherapy. Although GnRHa were efficient to disrupt oestrus cycles, they failed to inhibit follicular development, irrespective of the doses and injection sites (sc or im). Around 20% of healthy growing follicles were still observed during GnRHa treatment and serum FSH levels were not reduced either by antagonist or agonist. GnRHa had no effect on Cy-induced follicular damages. Thus, we showed that GnRHa were not as efficient at inhibiting the pituitary-gonadal axis in mice as in human. Furthermore, the acute depletion of primordial follicles observed after chemotherapy does not support the hypothesis that the ovary may be protected by gonadotropin suppression., SCOPUS: ar.j, info:eu-repo/semantics/published

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Active immunization using tau phospho-peptides in tauopathy mouse models has been observed to reduce tau pathology, especially when given prior to the onset of pathology. Since tau aggregates in these models and in human tauopathies are composed of full-length tau with many post-translational modifications, and are composed of several tau isoforms in many of them, pathological tau proteins bearing all these post-translational modifications might prove to be optimal tau conformers to use as immunogens, especially in models with advanced tau pathology. To this aim, we immunized aged wild-type and mutant tau mice with preparations containing human paired helical filaments (PHF) emulsified in Alum-adjuvant. This immunization protocol with fibrillar PHF-tau was well tolerated and did not induce an inflammatory reaction in the brain or adverse effect in these aged mice. Mice immunized with four repeated injections developed anti-PHF-tau antibodies with rising titers that labeled human neurofibrillary tangles in situ. Immunized mutant tau mice had a lower density of hippocampal Gallyas-positive neurons. Brain levels of Sarkosyl-insoluble tau were also reduced in immunized mice. These results indicate that an immunization protocol using fibrillar PHF-tau proteins is an efficient and tolerated approach to reduce tau pathology in an aged tauopathy animal model., Journal Article, SCOPUS: ar.j, info:eu-repo/semantics/published

A major portion of spinal cord injury (SCI) cases affect midcervical levels, the location of the phrenic motor neuron (PhMN) pool that innervates the diaphragm. While initial trauma is uncontrollable, a valuable opportunity exists in the hours to days following SCI for preventing PhMN loss and consequent respiratory dysfunction that occurs during secondary degeneration. One of the primary causes of secondary injury is excitotoxic cell death due to dysregulation of extracellular glutamate homeostasis. GLT1, mainly expressed by astrocytes, is responsible for the vast majority of functional uptake of extracellular glutamate in the CNS, particularly in spinal cord. We found that, in bacterial artificial chromosome-GLT1-enhanced green fluorescent protein reporter mice following unilateral midcervical (C4) contusion SCI, numbers of GLT1-expressing astrocytes in ventral horn and total intraspinal GLT1 protein expression were reduced soon after injury and the decrease persisted for ≥6 weeks. We used intraspinal delivery of adeno-associated virus type 8 (AAV8)-Gfa2 vector to rat cervical spinal cord ventral horn for targeting focal astrocyte GLT1 overexpression in areas of PhMN loss. Intraspinal delivery of AAV8-Gfa2-GLT1 resulted in transduction primarily of GFAP(+) astrocytes that persisted for ≥6 weeks postinjury, as well as increased intraspinal GLT1 protein expression. Surprisingly, we found that astrocyte-targeted GLT1 overexpression increased lesion size, PhMN loss, phrenic nerve axonal degeneration, and diaphragm neuromuscular junction denervation, and resulted in reduced functional diaphragm innervation as assessed by phrenic nerve-diaphragm compound muscle action potential recordings. These results demonstrate that GLT1 overexpression via intraspinal AAV-Gfa2-GLT1 delivery exacerbates neuronal damage and increases respiratory impairment following cervical SCI., Journal Article, SCOPUS: ar.j, info:eu-repo/semantics/published

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Human induced pluripotent stem cells (iPSCs) offer hope for personalized regenerative cell therapy in amyotrophic lateral sclerosis (ALS). We analyzed the fate of human iPSC-derived neural progenitors transplanted into the spinal cord of wild-type and transgenic rats carrying a human mutated SOD1(G93A) gene. The aim was to follow survival and differentiation of human neural progenitors until day 60 post-transplantation in two different in vivo environments, one being ALS-like. iPSCderived neural progenitors efficiently engrafted in the adult spinal cord and survived at high numbers. Different neural progenitor, astroglial, and neuronal markers indicated that, over time, the transplanted nestin-positive cells differentiated into cells displaying a neuronal phenotype in both wild-type and transgenic SOD1 rats. Although a transient microglial phenotype was detected at day 15, astroglial staining was negative in engrafted cells from day 1 to day 60. At day 30, differentiation toward a neuronal phenotype was identified, which was further established at day 60 by the expression of the neuronal marker MAP2. A specification process into motoneuron-like structures was evidenced in the ventral horns in both wild-type and SOD1 rats. Our results demonstrate proof-ofprinciple of survival and differentiation of human iPSC-derived neural progenitors in in vivo ALS environment, offering perspectives for the use of iPSC-based therapy in ALS. © AlphaMed Press., SCOPUS: ar.j, info:eu-repo/semantics/published

Erythropoiesis is affected during deep saturation dives. The mechanism should be related to a downregulation of serum Erythropoietin (s-EPO) concentration or to a toxic effect of the hyperbaric hyperoxia. We evaluated s-EPO and other haematological parameters in 6 scuba divers before, during and after a 14-days guinness saturation dive (8-10 m). Athletes were breathing air at 1.8-2 ATA, under the control of a team of physicians. Serum parameters were measured before diving (T0) and: 7 days (T1), 14 days (T2) after the beginning of the dive and 2 h (T3) and 24 h (T4) after resurfacing. Hgb, and many other haematological parameters did not change whereas Ht, s-EPO, the ratio between s-EPO predicted and that observed and reticulocytes (absolute, percent) declined progressively from T0 to T3. At T4 a significant rise in s-EPO was observed. Hgb did not vary but erythropoiesis seemed to be affected as s-EPO and reticulocyte counts showed. All these changes were statistically significant. The experiment, conducted in realistic conditions of dive length, oxygen concentration and pressure, allows us to formulate some hypotheses about the role of prolonged hyperbarism on erythropoiesis. The s-EPO rise, 24 h after resurfacing, is clearly documented and related to the "Normobaric Oxygen Paradox". This evidence suggests interesting hypotheses for new clinical applications such as modulation of s-EPO production and Hgb content triggered by appropriate O2 administration in pre-surgical patients or in some anemic disease., JOURNAL ARTICLE, info:eu-repo/semantics/published

Scuba and breath-hold divers are compared to investigate whether endothelial response changes are similar despite different exposure(s) to hyperoxia., Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

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By definition, rest tremor is an involuntary oscillation occurring while the body segment is maintained at rest, fully supported against gravity. To look for a rest tremor, the patient is seated with the upper limbs relaxed and the forearms on the thighs, or the patient is lying horizontally in complete repose. Rest tremor is typically in the 3–6 Hz frequency range (Fig. 7.1) and may reach high levels of severity. Rest tremor is usually asymmetrical, in general starting distally in the arms and legs. Typically, tremor in the upper limbs reminds the “pill rolling” movement. Lips and jaw can be affected, with a rhythmic clicking of teeth. Head and trunk are usually spared. Rest tremor may disappear or subside with action (posture, movement, maintaining an isometric force, exerting a specific task) and is associated with reciprocal activation in antagonistic muscles. In some cases, patients can reduce the tremor by holding one hand with the other or crossing the legs. Rest tremor often increases with mental stress (i.e. counting backwards) or contralateral motion (Froment manoeuvre). However, this feature is not specific. Rest tremor disappears during sleep, as most tremulous disorders., SCOPUS: ch.b, info:eu-repo/semantics/published

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