Brain-derived gangliosides prime human platelet aggregation and induce platelet-leukocyte aggregate formation.

Background: Platelet activation and interaction with leukocytes are crucial in inflammation. Gangliosides, sialic acid-containing glycosphingolipids, have been linked to different inflammatory conditions related to cardio- and neurodegenerative disorders. The role of gangliosides in platelet and leukocyte function, although reported, still needs further investigation.

Brain-Periphery Interactions in Huntington's Disease: Mediators and Lifestyle Interventions.

Prominent pathological features of Huntington's disease (HD) are aggregations of mutated Huntingtin protein (mHtt) in the brain and neurodegeneration, which causes characteristic motor (such as chorea and dystonia) and non-motor symptoms. However, the numerous systemic and peripheral deficits in HD have gained increasing attention recently, since those factors likely modulate disease progression, including brain pathology. While whole-body metabolic abnormalities and organ-specific pathologies in HD have been relatively well described, the potential mediators of compromised inter-organ communication in HD have been insufficiently characterized.

Cohort analysis of novel variants in SPG4 patients and implementation of and studies to identify the pathogenic mechanism caused by splicing mutations.

Introduction: Pure hereditary spastic paraplegia (SPG) type 4 (SPG4) is caused by mutations of gene. This study aimed to analyze variants in SPG4 patients to highlight the occurrence of splicing mutations and combine functional studies to assess the relevance of these variants in the molecular mechanisms of the disease.

Methods: We performed an NGS panel in 105 patients, analysis for splicing mutations, and minigene assay.

Abnormal expression of sphingolipid-metabolizing enzymes in the heart of spontaneously hypertensive rat models.

Sphingolipids exert important roles within the cardiovascular system and related diseases. Perturbed sphingolipid metabolism was previously reported in cerebral and renal tissues of spontaneously hypertensive rats (SHR). Specific defects related to the synthesis of sphingolipids and to the metabolism of Sphingosine-1-Phospahte (S1P) were exclusively identified in the stroke-prone (SHRSP) with the respect to the stroke-resistant (SHRSR) strain.

Genome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity.

Huntington's disease (HD) is a neurodegenerative disorder caused by CAG-repeat expansions in the huntingtin (HTT) gene. The resulting mutant HTT (mHTT) protein induces toxicity and cell death via multiple mechanisms and no effective therapy is available. Here, we employ a genome-wide screening in pluripotent mouse embryonic stem cells (ESCs) to identify suppressors of mHTT toxicity.

Blood-Brain Barrier Integrity Is Perturbed in a -Null Mouse Model of Rett Syndrome.

Rett syndrome (RTT, online MIM 312750) is a devastating neurodevelopmental disorder characterized by motor and cognitive disabilities. It is mainly caused by pathogenetic variants in the X-linked gene, encoding an epigenetic factor crucial for brain functioning. Despite intensive studies, the RTT pathogenetic mechanism remains to be fully elucidated.

Treatment with the Glycosphingolipid Modulator THI Rescues Myelin Integrity in the Striatum of R6/2 HD Mice.

Huntington's disease is one of the most common dominantly inherited neurodegenerative disorders caused by an expansion of a polyglutamine (polyQ) stretch in the N-terminal region of huntingtin (Htt). Among all the molecular mechanisms, affected by the mutation, emerging evidence proposes glycosphingolipid dysfunction as one of the major determinants. High levels of sphingolipids have been found to localize in the myelin sheaths of oligodendrocytes, where they play an important role in myelination stability and functions.

Sphingolipids and impaired hypoxic stress responses in Huntington disease.

Huntington disease (HD) is a debilitating, currently incurable disease. Protein aggregation and metabolic deficits are pathological hallmarks but their link to neurodegeneration and symptoms remains debated. Here, we summarize alterations in the levels of different sphingolipids in an attempt to characterize sphingolipid patterns specific to HD, an additional molecular hallmark of the disease.

Treatment with THI, an inhibitor of sphingosine-1-phosphate lyase, modulates glycosphingolipid metabolism and results therapeutically effective in experimental models of Huntington's disease.

Huntington's disease (HD) is a fatal neurodegenerative disorder with no effective cure currently available. Over the past few years our research has shown that alterations in sphingolipid metabolism represent a critical determinant in HD pathogenesis. In particular, aberrant metabolism of sphingosine-1-phosphate (S1P) has been reported in multiple disease settings, including human postmortem brains from HD patients.

Decipher non-canonical SPAST splicing mutations with the help of functional assays in patients affected by spastic paraplegia 4 (SPG4).

Flowchart showing the molecular approach used to decipher the non-canonical splicing mutations.

Brain Region and Cell Compartment Dependent Regulation of Electron Transport System Components in Huntington's Disease Model Mice.

Huntington's disease (HD) is a rare hereditary neurodegenerative disorder characterized by multiple metabolic dysfunctions including defects in mitochondrial homeostasis and functions. Although we have recently reported age-related changes in the respiratory capacities in different brain areas in HD mice, the precise mechanisms of how mitochondria become compromised in HD are still poorly understood. In this study, we investigated mRNA and protein levels of selected subunits of electron transport system (ETS) complexes and ATP-synthase in the cortex and striatum of symptomatic R6/2 mice.

A Rationale for Hypoxic and Chemical Conditioning in Huntington's Disease.

Neurodegenerative diseases are characterized by adverse cellular environments and pathological alterations causing neurodegeneration in distinct brain regions. This development is triggered or facilitated by conditions such as hypoxia, ischemia or inflammation and is associated with disruptions of fundamental cellular functions, including metabolic and ion homeostasis. Targeting intracellular downstream consequences to specifically reverse these pathological changes proved difficult to translate to clinical settings.

Curcumin-Loaded Nanoparticles Based on Amphiphilic Hyaluronan-Conjugate Explored as Targeting Delivery System for Neurodegenerative Disorders.

Identification of molecules able to promote neuroprotective mechanisms can represent a promising therapeutic approach to neurodegenerative disorders including Huntington's disease. Curcumin is an antioxidant and neuroprotective agent, even though its efficacy is limited by its poor absorption, rapid metabolism, systemic elimination, and limited blood-brain barrier (BBB) permeability. Herein, we report on novel biodegradable curcumin-containing nanoparticles to favor the compound delivery and potentially enhance its brain bioavailability.

Mitochondrial Respiration Changes in R6/2 Huntington's Disease Model Mice during Aging in a Brain Region Specific Manner.

Mitochondrial dysfunction is crucially involved in aging and neurodegenerative diseases, such as Huntington's Disease (HD). How mitochondria become compromised in HD is poorly understood but instrumental for the development of treatments to prevent or reverse resulting deficits. In this paper, we investigate whether oxidative phosphorylation (OXPHOS) differs across brain regions in juvenile as compared to adult mice and whether such developmental changes might be compromised in the R6/2 mouse model of HD.

The longevity-associated variant of BPIFB4 improves a CXCR4-mediated striatum-microglia crosstalk preventing disease progression in a mouse model of Huntington's disease.

The longevity-associated variant (LAV) of the bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) has been found significantly enriched in long-living individuals. Neuroinflammation is a key player in Huntington's disease (HD), a neurodegenerative disorder caused by neural death due to expanded CAG repeats encoding a long polyglutamine tract in the huntingtin protein (Htt). Herein, we showed that striatal-derived cell lines with expanded Htt (STHdh Q) expressed and secreted lower levels of BPIFB4, when compared with Htt expressing cells (STHdh Q), which correlated with a defective stress response to proteasome inhibition.

Mutant huntingtin interacts with the sterol regulatory element-binding proteins and impairs their nuclear import.

Brain cholesterol homeostasis is altered in Huntington's disease (HD), a neurodegenerative disorder caused by the expansion of a CAG nucleotide repeat in the HTT gene. Genes involved in the synthesis of cholesterol and fatty acids were shown to be downregulated shortly after the expression of mutant huntingtin (mHTT) in inducible HD cells. Nuclear levels of the transcription factors that regulate lipid biogenesis, the sterol regulatory element-binding proteins (SREBP1 and SREBP2), were found to be decreased in HD models compared to wild-type, but the underlying causes were not known.

Curcumin C3 complex®/Bioperine® has antineoplastic activity in mesothelioma: an in vitro and in vivo analysis.

Background: A major limitation in the treatment for malignant mesothelioma is related to serious side effects caused by chemotherapeutics and to the development of cancer-resistance. Advances in cancer therapies have been reached thanks to the introduction of alternative approaches, such as the use of phytochemicals. Curcumin-C3complex®/Bioperine® is a commercially standardized extract containing a ratio-defined mixture of three curcuminoids and piperine that greatly increase its bioavailability.

Stimulation of Sphingosine Kinase 1 (SPHK1) Is Beneficial in a Huntington's Disease Pre-clinical Model.

Although several agents have been identified to provide therapeutic benefits in Huntington disease (HD), the number of conventionally used treatments remains limited and only symptomatic. Thus, it is plausible that the need to identify new therapeutic targets for the development of alternative and more effective treatments is becoming increasingly urgent. Recently, the sphingosine-1-phosphate (S1P) axis has been reported to be a valid potential novel molecular target for therapy development in HD.

Positive Effects against UV-A Induced Damage and Oxidative Stress on an Cell Model Using a Hyaluronic Acid Based Formulation Containing Amino Acids, Vitamins, and Minerals.

Ultraviolet (UV) radiations are responsible for skin photoaging inducing alteration of the molecular and cellular pathways resulting in dryness and reduction of skin elasticity. In this study, we investigated, , the antiaging and antioxidant effects of hyaluronan formulations based hydrogel. Skinkò E, an intradermic formulation composed of hyaluronic acid (HA), minerals, amino acids, and vitamins, was compared with the sole HA of the same size.

Author Correction: Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington's disease.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Sphingolipid Metabolism: A New Therapeutic Opportunity for Brain Degenerative Disorders.

Neurodegenerative diseases represent a class of fatal brain disorders for which the number of effective therapeutic options remains limited with only symptomatic treatment accessible. Multiple studies show that defects in sphingolipid pathways are shared among different brain disorders including neurodegenerative diseases and may contribute to their complex pathogenesis. In this mini review, we discuss the hypothesis that modulation of sphingolipid metabolism and their related signaling pathways may represent a potential therapeutic approach for those devastating conditions.