An interesting example for spectral invariants

In "Illinois J. of Math. {\bf 38} (1994) 653--678", the heat operator of a Bismut superconnection for a family of generalized Dirac operators is defined along the leaves of a foliation with Hausdorff groupoid. The Novikov-Shubin invariants of the Dirac operators were assumed greater than three times the codimension of the foliation. It was then showed that the associated heat operator converges to the Chern character of the index bundle of the operator. In "J. K-Theory {\bf 1} (2008) 305--356", we improved this result by reducing the requirement on the Novikov-Shubin invariants to one half of the codimension. In this paper, we construct examples which show that this is the best possible result.Comment: Third author added. Some typos corrected and some material added. Appeared in Journal of K Theory, Volume 13, in 2014, pages 305 to 31

Exosomes and their Cargo as a New Avenue for Brain and Treatment of CNSRelated Diseases

Extracellular Vesicles (EVs), which belong to nanoscale vesicles, including microvesicles (MVs) and exosomes, are now considered a new important tool for intercellular neuronal communication in the Central Nervous System (CNS) under physiological and pathological conditions. EVs are shed into blood, peripheral body fluids and cerebrospinal fluid (CSF) by a large variety of cells. EVs can act locally on neighboring and distant cells. EVs represent the fingerprints of the originating cells and can carry a variety of molecular constituents of their cell of origin, including protein, lipids, DNA and microRNAs (miRNAs). The most studied EVs are the exosomes because they are ubiquitous and have the capacity to transfer cell-derived components and bioactive molecules to target cells. In this minireview, we focused on cell-cell communication in CNS mediated by exosomes and their important cargo as an innovative way to treat or follow up with CNS diseases. © 2022 Benameur et al

Extracellular vesicles miRNA cargo for microglia polarization in traumatic brain injury

Traumatic brain injury (TBI) is one of the major causes of death and disability worldwide, and despite its high dissemination, effective pharmacotherapies are lacking. TBI can be divided into two phases: the instantaneous primary mechanical injury, which occurs at the moment of insult, and the delayed secondary injury, which involves a cascade of biological processes that lead to neuroinflammation. Neuroinflammation is a hallmark of both acute and chronic TBI, and it is considered to be one of the major determinants of the outcome and progression of disease. In TBI one of the emerging mechanisms for cell–cell communication involved in the immune response regulation is represented by Extracellular Vesicles (EVs). These latter are produced by all cell types and are considered a fingerprint of their generating cells. Exosomes are the most studied nanosized vesicles and can carry a variety of molecular constituents of their cell of origin, including microRNAs (miRNAs). Several miRNAs have been shown to target key neuropathophysiological pathways involved in TBI. The focus of this review is to analyze exosomes and their miRNA cargo to modulate TBI neuroinflammation providing new strategies for prevent long‐term progression of disease

Sonic Hedgehog Pathway as a Target for Therapy in Angiogenesis-Related Diseases

Hedgehog (Hh) proteins belong to a class of morphogens involved in many biological processes during embryonic development; they are relatively silent during normal adult life although they may be recruited postnatally in response to tissue injury. Three secreted proteins have been identified: Sonic hedgehog (Shh), Desert hedgehog and Indian hedgehog. The interaction of Hh ligand with its receptor Patched-1 triggers the activation of smoothened and initiates transduction events that lead to the regulation of transcriptional factors belonging to the Gli family. Hh pathway orchestrates both coronary development and adult coronary neovascularisation by controlling the expression of multiple proangiogenic genes and anti-apoptotic cytokines. Shh pathway enhances the recruitment of endothelial progenitor cells in addition to the mechanisms described for other Hh and concurs to its myocardial protection. In cerebral ischemia, Hh mimicking molecules has been reported to limit damages caused by vessel occlusion. Besides, Shh carried by microparticles corrects endothelial injury through nitric oxide release. Anomalous activations of Hh pathway are implicated in various types of tumours including medulloblastoma, carcinoma of esophagus, stomach, pancreas and colon. Hh can influence angiogenesis in both positive and negative manner and they may have implication for therapeutic strategies to treat either ischemic or cancer diseases

Therapeutic potential of plasma membrane-derived microparticles

In the past, plasma membrane-derived microparticles were considered "cellular dust." According to the literature, circulating levels of microparticles are increased in several cardiovascular diseases associated with inflammation, suggesting that microparticles are linked to deleterious effects such as endothelial dysfunction or thrombosis. However, very recent studies have shown that under several conditions microparticles can transfer biological messages between cells. Indeed, microparticles act as vectors of key information to maintain cell homeostasis or to favor cell repair and induce angiogenesis. For instance, microparticles of platelet origin are able to repair myocardial injury after myocardial infarction. Also, we have shown that engineered microparticles generated from human activated/apoptotic T cells promote angiogenesis through the up-regulation of adhesion proteins and pro-angiogenic factors in human endothelial cells. Interestingly, the effects induced by these microparticles on the formation of capillary-like structures, expression of adhesion molecules, and pro-angiogenic factors are reversed after silencing of the Sonic Hedgehog (Shh) morphogen pathway. In addition, the same type of microparticles is able to induce neo-vascularization in an ischemic hindlimb model. These effects are, at least in part, mediated by Shh and nitric oxide production. Taking into consideration these results and the most recent data concerning the ability of microparticles to transmit genetic information between cells through mRNA transfer, it is plausible that plasma membrane-derived microparticles could serve as tools with veritable therapeutic potential

The emerging role of curcumin in the modulation of TLR-4 signaling pathway: Focus on neuroprotective and anti-rheumatic properties

Natural products have been used in medicine for thousands of years. Given their potential health benefits, they have gained significant popularity in recent times. The administration of phytochemicals existed shown to regulate differential gene expression and modulate various cellular pathways implicated in cell protection. Curcumin is a natural dietary polyphenol extracted from Curcuma Longa Linn with different biological and pharmacological effects. One of the important targets of curcumin is Toll-like receptor-4 (TLR-4), the receptor which plays a key role in the modulation of the immune responses and the stimulation of inflammatory chemokines and cytokines production. Different studies have demonstrated that curcumin attenuates inflammatory response via TLR-4 acting directly on receptor, or by its downstream pathway. Curcumin bioavailability is low, so the use of exosomes, as nano drug delivery, could improve the efficacy of curcumin in inflammatory diseases. The focus of this review is to explore the therapeutic effect of curcumin interacting with TLR-4 receptor and how this modulation could improve the prognosis of neuroinflammatory and rheumatic diseases

Plasma cells release membrane microparticles in a mouse model of multiple myeloma.

Microparticles (MPs) released from the plasma membrane play a role in tumor progression. Involvement of MPs in myeloma (MM) has been poorly investigated. Because of the strong interaction of MM cells with bone microenvironment, we hypothesized an implication of MPs in MM using a murine model. Forty-four mice were injected with 5THL-MM cells and compared with 14 non-injected mice. Blood was collected at the early and end stages of MM development (EMM and LMM) to characterize the circulating MPs. At LMM, MPs were isolated from bone marrow (BM) of long bones of 22 mice, after centrifugation. Electron microscopy immunohistochemistry and Western blotting using CD138 were performed on BM-derived MPs. At EMM, MPs circulating level was significantly lower versus controls. In LMM, a significant increase of the total MP number from plasma was observed versus controls. Characterization of circulating MPs showed an increase of leukocyte- and erythrocyte-derived MPs. In LMM, serum M-protein was correlated with circulating MP number. BM-derived MPs increased in LMM and expressed CD138. Anti-CD138 coupled with nanobeads localized at the MP surface. There is evidence of an association between increase of MPs and MM development; the results underscore the participation of plasma cell-derived MPs originating from BM