Fluorinated apelin-13 mediates neuroprotective effects in multiple sclerosis models.

Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease leading to demyelination and axonal loss. Current treatments are immunomodulatory or immunosuppressive drugs acting on the inflammatory component. However, these treatments do not adequately address the crucial aspect of neuroprotection. Recently, an association between an altered balance of adipokines and MS has been proposed as both a risk factor for developing MS and a chronic disease aggravating factor. Specifically, a decrease of apelin plasma levels in MS patients compared to controls correlates with the number of relapses and disease severity. Here we report a dramatic downregulation of apelin levels in the CNS of EAE mice which is also detected in MS patients brain samples compared to controls. Exploiting innovative design and synthesis techniques, we engineered a novel fluorinated apelin-13 peptide characterized by enhanced plasmatic stability compared to its native counterpart. With this peptide, we assessed the potential therapeutic benefits of apelin preventive supplementation in the EAE mouse model. We show that the fluorinated Apelin-13 peptide ameliorates EAE clinical score and preserves myelin content in the EAE MOG model recapitulating the progressive form of disease. These results combined with ex-vivo experiments in brain organotypic slices and in vitro studies in neurons and primary microglia and macrophages suggest that apelin has neuroprotective effects and influences the microglia/macrophages function.

Toward a Combination of Biomarkers for Molecular Characterization of Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system associated with chronic inflammation, demyelination, and axonal damage. MS is a highly heterogeneous disease that leads to discrepancies regarding the clinical appearance, progression, and therapy response of patients. Therefore, there is a strong unmet need for clinically relevant biomarkers capable of recapitulating the features of the disease. Experimental autoimmune encephalomyelitis (EAE) is a valuable model for studying the pathophysiology of MS as it recapitulates the main hallmarks of the disease: inflammation, blood-brain barrier (BBB) disruption, gliosis, myelin damage, and repair mechanisms. In this study, we used the EAE-PLP animal model and established a molecular RNA signature for each phase of the disease (onset, peak, remission). We compared variances of expression of known biomarkers by RT-qPCR in the brain and spinal cord of sham and EAE animals monitoring each of the five hallmarks of the disease. Using magnetic cell isolation technology, we isolated microglia and oligodendrocytes of mice of each category, and we compared the RNA expression variations. We identify genes deregulated during a restricted time frame, and we provide insight into the timing and interrelationships of pathological disease processes at the organ and cell levels.

Handheld Fluorescence Spectrometer Enabling Sensitive Aflatoxin Detection in Maize.

Aflatoxins are among the main carcinogens threatening food and feed safety while imposing major detection challenges to the agrifood industry. Today, aflatoxins are typically detected using destructive and sample-based chemical analysis that are not optimally suited to sense their local presence in the food chain. Therefore, we pursued the development of a non-destructive optical sensing technique based on fluorescence spectroscopy. We present a novel compact fluorescence sensing unit, comprising both ultraviolet excitation and fluorescence detection in a single handheld device. First, the sensing unit was benchmarked against a validated research-grade fluorescence setup and demonstrated high sensitivity by spectrally separating contaminated maize powder samples with aflatoxin concentrations of 6.6 µg/kg and 11.6 µg/kg. Next, we successfully classified a batch of naturally contaminated maize kernels within three subsamples showing a total aflatoxin concentration of 0 µg/kg, 0.6 µg/kg and 1647.8 µg/kg. Consequently, our novel sensing methodology presents good sensitivity and high potential for integration along the food chain, paving the way toward improved food safety.

Implication of the Transmembrane Domain in the Interleukin 10 Receptor Platform Oligomerisation.

Interleukin 10 (IL-10) exerts anti-inflammatory and immune regulatory roles through its fixation to the IL-10 receptor (IL-10R). The two subunits (IL-10Rα and IL-10Rß) organise themselves to form a hetero-tetramer to induce the activation of the transcription factor STAT3. We analysed the activation patterns of the IL-10R, especially the contribution of the transmembrane (TM) domain of the IL-10Rα and IL-10Rß subunits, as evidence accumulates that this short domain has tremendous implications in receptor oligomerisation and activation. We also addressed whether targeting the TM domain of IL-10R with peptides mimicking the TM sequences of the subunits translates into biological consequences. The results illustrate the involvement of the TM domains from both subunits in receptor activation and feature a distinctive amino acid crucial for the interaction. The TM peptide targeting approach also appears to be suitable for modulating the activation of the receptor through its action on the dimerization capabilities of the TM domains and thereby constitutes a potential new strategy for the modulation of the inflammation in pathologic contexts.

Manipulating Macrophage/Microglia Polarization to Treat Glioblastoma or Multiple Sclerosis.

Macrophages and microglia are implicated in several diseases with divergent roles in physiopathology. This discrepancy can be explained by their capacity to endorse different polarization states. Theoretical extremes of these states are called M1 and M2. M1 are pro-inflammatory, microbicidal, and cytotoxic whereas M2 are anti-inflammatory, immunoregulatory cells in favor of tumor progression. In pathological states, these polarizations are dysregulated, thus restoring phenotypes could be an interesting treatment approach against diseases. In this review, we will focus on compounds targeting macrophages and microglia polarization in two very distinctive pathologies: multiple sclerosis and glioblastoma. Multiple sclerosis is an inflammatory disease characterized by demyelination and axon degradation. In this case, macrophages and microglia endorse a M1-like phenotype inducing inflammation. Promoting the opposite M2-like polarization could be an interesting treatment strategy. Glioblastoma is a brain tumor in which macrophages and microglia facilitate tumor progression, spreading, and angiogenesis. They are part of the tumor associated macrophages displaying an anti-inflammatory phenotype, thereby inhibiting anti-tumoral immunity. Re-activating them could be a method to limit and reduce tumor progression. These two pathologies will be used to exemplify that targeting the polarization of macrophages and microglia is a promising approach with a broad spectrum of applications deserving more attention.