Role of lysophosphatidic acid and its receptors in health and disease: novel therapeutic strategies.

Lysophosphatidic acid (LPA) is an abundant bioactive phospholipid, with multiple functions both in development and in pathological conditions. Here, we review the literature about the differential signaling of LPA through its specific receptors, which makes this lipid a versatile signaling molecule. This differential signaling is important for understanding how this molecule can have such diverse effects during central nervous system development and angiogenesis; and also, how it can act as a powerful mediator of pathological conditions, such as neuropathic pain, neurodegenerative diseases, and cancer progression. Ultimately, we review the preclinical and clinical uses of Autotaxin, LPA, and its receptors as therapeutic targets, approaching the most recent data of promising molecules modulating both LPA production and signaling. This review aims to summarize the most update knowledge about the mechanisms of LPA production and signaling in order to understand its biological functions in the central nervous system both in health and disease.

The multiple functions of the co-chaperone stress inducible protein 1.

Stress inducible protein 1 (STI1) is a co-chaperone acting with Hsp70 and Hsp90 for the correct client proteins' folding and therefore for the maintenance of cellular homeostasis. Besides being expressed in the cytosol, STI1 can also be found both in the cell membrane and the extracellular medium playing several relevant roles in the central nervous system (CNS) and tumor microenvironment. During CNS development, in association with cellular prion protein (PrPc), STI1 regulates crucial events such as neuroprotection, neuritogenesis, astrocyte differentiation and survival. In cancer, STI1 is involved with tumor growth and invasion, is undoubtedly a pro-tumor factor, being considered as a biomarker and possibly therapeutic target for several malignancies. In this review, we discuss current knowledge and new findings on STI1 function as well as its role in tissue homeostasis, CNS and tumor progression.

Anatomy and function of the vertebral column lymphatic network in mice.

Cranial lymphatic vessels (LVs) are involved in the transport of fluids, macromolecules and central nervous system (CNS) immune responses. Little information about spinal LVs is available, because these delicate structures are embedded within vertebral tissues and difficult to visualize using traditional histology. Here we show an extended vertebral column LV network using three-dimensional imaging of decalcified iDISCO+-clarified spine segments. Vertebral LVs connect to peripheral sensory and sympathetic ganglia and form metameric vertebral circuits connecting to lymph nodes and the thoracic duct. They drain the epidural space and the dura mater around the spinal cord and associate with leukocytes. Vertebral LVs remodel extensively after spinal cord injury and VEGF-C-induced vertebral lymphangiogenesis exacerbates the inflammatory responses, T cell infiltration and demyelination following focal spinal cord lesion. Therefore, vertebral LVs add to skull meningeal LVs as gatekeepers of CNS immunity and may be potential targets to improve the maintenance and repair of spinal tissues.

Glioblastoma Therapy in the Age of Molecular Medicine.

Glioblastoma (GBM) is the most common and fatal primary malignant brain tumor. Despite advances in the understanding of the biology of gliomas, little has changed in the treatment of these tumors in the past decade. Phase III clinical trials showed no benefit for the use of bevacizumab in newly diagnosed patients, leading to a renewed search for new antiangiogenic drugs, as well as immunotherapeutic approaches, including checkpoint inhibitors, chimeric antigen receptor T cells, and intracerebral CpG-oligodeoxynucleotides. The emerging role of infiltrating microglia and macrophages, and of metabolic alterations, is also being taken into account in preclinical research and drug development. In this review, we discuss progress in the search for new therapeutic strategies, particularly approaches focusing on the tumor microenvironment.

Combination Therapy with Sulfasalazine and Valproic Acid Promotes Human Glioblastoma Cell Death Through Imbalance of the Intracellular Oxidative Response.

Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor and still lacks effective therapeutic strategies. It has already been shown that old drugs like sulfasalazine (SAS) and valproic acid (VPA) present antitumoral activities in glioma cell lines. SAS has also been associated with a decrease of intracellular glutathione (GSH) levels through a potent inhibition of xc- glutamate/cystine exchanger leading to an antioxidant deprotection. In the same way, VPA was recently identified as a histone deacetylase (HDAT) inhibitor capable of activating tumor suppression genes. As both drugs are widely used in clinical practice and their profile of adverse effects is well known, the aim of our study was to investigate the effects of the combined treatment with SAS and VPA in GBM cell lines. We observed that both drugs were able to reduce cell viability in a dose-dependent manner and the combined treatment potentiated these effects. Combined treatment also increased cell death and inhibited proliferation of GBM cells, while having no effect on human and rat cultured astrocytes. Also, we observed high protein expression of the catalytic subunit of xc- in all the examined GBM cell lines, and treatment with SAS blocked its activity and decreased intracellular GSH levels. Noteworthy, SAS but not VPA was also able to reduce the [14C]-ascorbate uptake. Together, these data indicate that SAS and VPA exhibit a substantial effect on GBM cell's death related to an intracellular oxidative response imbalance, making this combination of drugs a promising therapeutic strategy.