PD1/PD-L1 immune checkpoint as a potential target for preventing brain tumor progression.

Programmed death-1 (PD-1) is a cell surface receptor that functions as a T cell checkpoint and plays a central role in regulating T cell collapse. The binding of PD-1 to its ligand programmed death-ligand 1 (PD-L1) activates downstream signaling pathways and inhibits T cell activation in the perspective of immune system mechanism and regulation in tumor progression. It is well reported that tumors adopt certain immune-checkpoint pathways as a mechanism of resistance against immune cells such as T cells that are specific for tumor antigens. Indeed, the PD-1/PD-L1 pathway controls the induction and maintenance of immune tolerance within the tumor microenvironment. Thus, the PD-1/PD-L1 checkpoint regulation appears to be of extreme importance as well as the immunotherapy targeting that via and the using of PD-1/PD-L1 inhibitors that have changed the scenario of brain cancer treatment and survival. Here, we review the mechanism of action of PD-1 and PD-L1, the PD/PDL-1 signaling pathway involved in the progression of brain tumors, and its application as cancer immunotherapy counteracting tumor escape in central nervous system.

Protective effect of sodium propionate in Aß1-42 -induced neurotoxicity and spinal cord trauma.

Sodium propionate (SP) is one of the main short chain fatty acids (SCFA) that can be produced naturally through host metabolic pathways. SP have been documented and include the reduction of pro-inflammatory mediators in an in vivo model of colitis. The aim of this study is to evaluate the neuroprotective effects of SP in reducing inflammatory process associated to neurological disorders. We performed both in vitro model of Alzheimer's disease, induced by oligomeric Aß1-42 stimulation, and in in vivo model of spinal cord injury (SCI) in which neuroinflammation plays a crucial role. For in vitro model, the human neuroblastoma SH-SY5Y cell line was first differentiated with retinoic acid (100 µM) for 24 h and then stimulated by oligomeric Aß1-42 (1 µg/ml) and treated with SP at 0.1- 1-10 µM concentrations for another 24 h. Instead, the in vivo model of SCI was induced by extradural compression of the spinal cord at T6-T8 levels, and animals were treated with SP (10-30-100 mg/kg o.s) 1 and 6 h after SCI. Our results demonstrated that both in in vitro neuroinflammatory model and in vivo model of SCI the treatment with SP significantly reduced NF-κB nuclear translocation and IκBα degradation, as well as decreases COX-2 and iNOS expressions evaluated by Western blot analysis. Moreover, we showed that SP treatment significantly ameliorated histopathology changes and improved motor recovery in a dose-dependent manner. In conclusion, our results demonstrated that SP possesses neuroprotective effects, suggesting it could represent a target for therapeutic intervention in neuroinflammatory disorders.

Sodium Butyrate Exerts Neuroprotective Effects in Spinal Cord Injury.

Sodium butyrate (SB) is a dietary microbial fermentation product and serves as an important neuromodulator in the central nervous system. Recent experimental evidence has suggested potential therapeutic applications for butyrate, including its utility in treating metabolic and inflammatory diseases. The aim of the present study was to evaluate the potential beneficial effects of SB in a mouse model of spinal cord injury (SCI) and its possible mechanism of action. SCI was induced by extradural compression for 1 min of the spinal cord at the T6-7 level using an aneurysm clip, and SB (10-30-100 mg/kg) was administered by oral gavage 1 and 6 h after SCI. For locomotor activity, study mice were treated with SB once daily for 10 days. Morphological examination was performed by light microscopy through hematoxylin-eosin (H&E) staining. In addition, NF-κB, IκB-α, COX-2, and iNOS expressions were assayed by western blot analysis and IL-1ß and TNF-α levels by immunohistochemistry analysis. The results showed that SB treatment significantly ameliorated histopathology changes and improved recovery of motor function changes in spinal cord injury in a dose-dependent manner. Moreover, we demonstrated that SB modulated the NF-κB pathway showing a significant reduction in cytokine expression. Thus, this study showed that SB exerts neuroprotective effects anti-inflammatory properties following spinal cord injury suggesting that SB may serve as a potential candidate for future treatment of spinal cord injury.

PPAR-α Modulates the Anti-Inflammatory Effect of Melatonin in the Secondary Events of Spinal Cord Injury.

Melatonin is the principal secretory product of the pineal gland, and its role as an immunomodulator is well established. Recent evidence shows that melatonin is a scavenger of oxyradicals and peroxynitrite and reduces the development of inflammation and tissue injury events associated with spinal cord trauma. Previous results suggest that peroxisome proliferator-activated receptor α (PPAR-α), a nuclear receptor protein that functions as a transcription factor activated by fatty acids, plays a role in control of secondary inflammatory process associated with spinal cord injury (SCI).With the aim to characterize the role of PPAR-α in melatonin-mediated anti-inflammatory activity, we tested the efficacy of melatonin (30 mg/kg) in an experimental model of spinal cord trauma, induced in mice, by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy, and comparing mice lacking PPAR-α (PPAR-α KO) with wild-type (WT) mice.The results obtained indicate that melatonin-mediated anti-inflammatory activity is weakened in PPAR-α KO mice, as compared to WT controls. In particular, melatonin was less effective in PPAR-α KO, compared to WT mice, as evaluated by inhibition of the degree of spinal cord inflammation and tissue injury, neutrophil infiltration, pro-inflammatory cytokine expression, nuclear factor κB (NF-κB) activation, and inducible nitric oxide synthase (iNOS) expression. This study indicates that PPAR-α can contribute to the anti-inflammatory activity of melatonin in SCI.

Selective adenosine A(2a) receptor agonists reduce the apoptosis in an experimental model of spinal cord trauma.

Adenosine is an important regulator of inflammatory mechanisms. Functional studies indicate a protective effect of adenosine A2A receptor agonists in spinal cord injury (SCI). The basic molecular mechanisms accounting for their protective effects from spinal cord injury have to be fully elucidated. The aim of this study is to evaluate in vivo protection by two selective A2A receptor agonists, 2-[p-(2-carboxyethyl)phenylethylamino]-50-ethylcarboxamidoadenosine (CGS 21680, 100 microg/kg) and (4-[3-(6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydro-furan-2-yl)-9H-purin-2-yl)prop-2-ynyl] piperidine-1-carboxylic acid methyl ester) (ATL 313, 3 microg/kg) on the degree of apoptosis, in the experimental model of spinal cord injury. Spinal cord trauma was induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. Spinal cord trauma in mice was characterised by edema, neutrophilic infiltration and apoptosis. ATL 313, administered by subcutaneously implanted osmotic minipumps after SCI, clearly reduced motor deficit for up to 19 days after operation. The selective A2A receptor agonists ATL 313 and CGS 21680 administered after SCI, reduced tissue damage, TUNEL staining, cytokine (TNF-alpha) expression, Bax, Fas-L and Caspase-3 expression, Annexin-V staining, while increasing Bcl-2 expression. In conclusion, our results demonstrate that treatment with adenosine A2A receptor agonists prevents the apoptotic process that is an important step of secondary damage after SCI.

GW0742, a high affinity PPAR-ß/δ agonist reduces lung inflammation induced by bleomycin instillation in mice.

Peroxisome Proliferator-Activated Receptor ß/δ belongs to a family of ligand-activated transcription factors. Recent data have clarified its metabolic roles and enhanced the potential role of this receptor as a pharmacological target. Moreover, although its role in acute inflammation remains unclear, being the nuclear receptor PPAR ß/δ widely expressed in many tissues, including the vascular endothelium, we assume that the infiltration of PMNs into tissues, a prominent feature in inflammation, may also be related to PPAR ß/δ. Mice subjected to intratracheal instillation of bleomycin (BLEO, 1 mg/kg), a glycopeptide produced by the bacterium Streptomyces verticillus, develop lung inflammation and injury characterized by a significant neutrophil infiltration and tissue oedema. Therefore, the aim of this study is to investigate the effects of GW0742, a synthetic high affinity PPAR ß/δ agonist, and its possible role in preventing the advance of inflammatory and apoptotic processes induced by bleomycin, that long-term leads to the appearance of pulmonary fibrosis. Our data showed that GW0742-treatment (0.3 mg/Kg, 10 percent DMSO, i.p.) has therapeutic effects on pulmonary damage, decreasing many inflammatory and apoptotic parameters detected by measurement of: 1) cytokine production; 2) leukocyte accumulation, indirectly measured as decrease of myeloperoxidase (MPO) activity; 3) IkBα degradation and NF-kB nuclear translocation; 4) ERK phosphorylation; 5) stress oxidative by NO formation due to iNOS expression; 6) nitrotyrosine and PAR localization; 7) the degree of apoptosis, evaluated by Bax and Bcl-2 balance, FAS ligand expression and TUNEL staining. Taken together, our results clearly show that GW0742 reduces the lung injury and inflammation due to the intratracheal BLEO--instillation in mice.

Effect of PD98059, a selective MAPK3/MAPK1 inhibitor, on acute lung injury in mice.

The aim of the present study is to evaluate the contribution of mitogen-activated protein kinase 1-3 MAPK3/MAPK1) in a model of acute lung inflammation in mice. Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by: accumulation of fluid containing a large number of neutrophils (PMNs) in the pleural cavity, infiltration of PMNs in lung tissues and subsequent adhesion molecule expression (I-CAM and P-selectin), lipid peroxidation, and increased production of tumour necrosis factor-alpha, (TNF-alpha) and interleukin-1beta (IL-1beta). Furthermore, carrageenan induced lung apoptosis (Bax and Bcl-2 expression) as well as nitrotyrosine formation, NF-kB activation, and pJNK expression, as determined by immunohistochemical analysis of lung tissues and the degree of lung inflammation and tissue injury (histological score). Administration of PD98059, an inhibitor of MAPK3/MAPK1 (10 mg/kg) 1 h after carrageenan caused a reduction in all the parameters of inflammation measured. Thus, based on these findings we propose that inhibitors of the MAPK3/MAPK1 signaling pathways, such as PD98059, may be useful in the treatment of various inflammatory diseases.