Excitotoxicity in a chronic model of multiple sclerosis: Neuroprotective effects of cannabinoids through CB1 and CB2 receptor activation

Inflammation, autoimmune response, demyelination and axonal damage are thought to participate in the pathogenesis of multiple sclerosis (MS). Understanding whether axonal damage causes or originates from demyelination is a crucial issue. Excitotoxic processes may be responsible for white matter and axonal damage. Experimental and clinical studies indicate that cannabinoids could prove efficient in the treatment of MS. Using a chronic model of MS in mice, we show here that clinical signs and axonal damage in the spinal cord were reduced by the AMPA antagonist, NBQX. Amelioration of symptomatology by the synthetic cannabinoid HU210 was also accompanied by a reduction of axonal damage in this model. Moreover, HU210 reduced AMPA-induced excitotoxicity both in vivo and in vitro through the obligatory activation of both CB1 and CB2 cannabinoid receptors. Together, these data underline the implication of excitotoxic processes in demyelinating pathologies such as MS and the potential therapeutic properties of cannabinoids.     

Cell Damage,Antioxidant Status,and Cortisol Levels Related to Nutrition in Ski Mountaineering During a Two-Day Race

The aim of this study was to measure the effect of nutrition on cell damage, antioxidant enzymes, and cortisol during a two-day ski mountaineering competition. Twenty-one male skiers participated in the study. Creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (AP), cortisol and C-reactive protein (CRP), glutathione peroxidase (GPx) and reductase activities (GR) and C-reactive protein (CRP) levels, total antioxidant status, and cortisol levels were measured in serum the day before and immediately after the race. Their diet was also analysed during the competition. Enzymes and cortisol levels significantly increased after the competition. CK and LDH and cortisol levels were negatively correlated to total energy, protein, and fat intake. Intake of vitamin A, B1, B2, B6 and niacin was negatively correlated to LDH and AP. A negative correlation was also found between CK activity and Na, Fe, and Zn intake. Cortisol levels were negatively correlated to the intake of vitamins C, B1 and B2, and niacin. A positive correlation was found between serum GPx and intake of energy, carbohydrates, proteins, A and B vitamins, and folic acid. Skiers with the lowest nutrient intake during the competition were the ones who showed greater cell damage and lower antioxidant enzyme activity and cortisol levels, which may impair performance and also cause injuries and accidents. Particularly, skiers should have high intakes of total energy, macronutrients, vitamins A and B, Na, Zn, and Fe in order to decrease the deleterious effect of strenuous exercise.

Key points

• A two-day ski mountaineering race produced muscle cell damage and oxidative stress and an increase in cortisol levels.
• There was a marked insufficient intake of carbohydrates which has been shown to affect performance
• Those skiers with lowest nutrient intake showed greater cell damage, lower antioxidant activity and higher cortisol levels.
• Nutrition should be carefully monitored and assessed in order to minimize the mentioned blood changes to avoid fatigue, injuries and also accidents in this type of sport; particularly when skiers must carry their own food.

Key words: Energy intake, micronutrients, muscle damage, antioxidant enzymes, skiing     

The US Approach to Biosimilars

In the US, the Biologics Price Competition and Innovation Act (BPCI Act, 2009) provided the pathway to create an abbreviated licensure procedure for biologic products that are demonstrated to be biosimilar to or interchangeable with a Food and Drug Administration (FDA) licensed biologic product. In February 2012, the FDA issued three guidelines that list the requirements for biosimilar registration. The topics covered include scientific and quality considerations to demonstrate biosimilarity to a reference product and a guidance that clarifies the BPCI Act implementation. The sponsor application for the biosimilar approval must contain biosimilarity information based on data derived from analytical, animal, and clinical studies. Clinical studies should include an assessment of immunogenicity, pharmacokinetics, pharmacodynamics, and address one or more indications licensed for the reference product. To demonstrate biosimilarity the applicant is allowed to use comparative animal or clinical data with a non-US-licensed product. According to these guidelines, the FDA will consider different aspects when evaluating biosimilarity, such as product formulation, complexity, and stability which will have a risk-based approach and will depend on the degree of knowledge of the product characteristics, as well as clinical experience with the reference one. The FDA intends to use a risk-based and facts-focused approach for review of applications of biosimilars, although it faces several challenges. Once a biologic medicine has been demonstrated to be biosimilar to the reference product, an abridged development program for the biosimilar medicine can be carried out in a similar way to that established by the European Medicines Agency (EMA). In addition, FDA legislation goes a step further than the EMA, offering the possibility to adopt full interchangeability for biosimilars.     

First evidence of sphingosine 1-phosphate lyase protein expression and activity downregulation in human neoplasm: implication for resistance to therapeutics in prostate cancer

This is the first report of sphingosine 1-phosphate lyase (SPL) protein expression and enzymatic activity in human neoplasm. This enzyme drives irreversible degradation of sphingosine 1-phosphate (S1P), a bioactive lipid associated with resistance to therapeutics in various cancers, including prostate adenocarcinoma. In fresh human prostatectomy specimens, a remarkable decrease in SPL enzymatic activity was found in tumor samples, as compared with normal adjacent tissues. A significant relationship between loss of SPL expression and higher Gleason score was confirmed in tissue microarray (TMA) analysis. Moreover, SPL protein expression and activity were inversely correlated with those of sphingosine kinase-1 (SphK1), the enzyme producing S1P. SPL and SphK1 expressions were independently predictive of aggressive cancer on TMA, supporting the relevance of S1P in prostate cancer. In human C4-2B and PC-3 cell lines, silencing SPL enhanced survival after irradiation or chemotherapy by decreasing expression of proteins involved in sensing and repairing DNA damage or apoptosis, respectively. In contrast, enforced expression of SPL sensitized cancer cells to irradiation or docetaxel by tilting the ceramide/S1P balance toward cell death. Interestingly, the S1P degradation products failed to sensitize to chemo- and radiotherapy, supporting the crucial role of ceramide/S1P balance in cancer. Of note, the combination of SPL enforced expression with a SphK1 silencing strategy by further decreasing S1P content made prostate cancer cells even more sensitive to anticancer therapies, suggesting that a dual strategy aimed at stimulating SPL, and inhibiting SphK1 could represent a future approach to sensitize cancer cells to cancer treatments. Mol Cancer Ther; 11(9); 1841-51. ?2012 AACR.     

Platelet CLEC-2 and podoplanin in cancer metastasis

It has long been recognised that the function of platelets in health and disease span far beyond their roles in haemostasis and thrombosis. The observation that tumour cells induce platelet aggregation was followed by extensive experimental evidence linking platelets to cancer progression. Aggregated platelets coat tumour cells during their transit through the bloodstream and mediate adherence to vascular endothelium, protection from shear stresses, evasion from immune molecules, and release of an array of bioactive molecules that facilitate tumour cell extravasation and growth at metastatic sites. The sialyated membrane glycoprotein podoplanin is found on the leading edge of tumour cells and is thought to influence their migratory and invasive properties. Podoplanin elicits powerful platelet aggregation and is the endogenous ligand for the platelet C-type lectin receptor, CLEC-2, which itself regulates podoplanin signalling. Here, the bidirectional relationship between CLEC-2 and podoplanin is described and considered in the context of tumour growth and metastasis.     

Relative telomere length impact on mortality of COVID-19: Sex differences

Increasing age is associated with severity and higher mortality of COVID-19. Telomere shortening is associated with higher risk of infections and may be used to identify those patients who are more likely to die. We evaluated the association between relative telomere length (RTL) and COVID-19 mortality. RTL was measured in patients hospitalized because of COVID-19. We used Kaplan–Meier method to analyze survival probabilities, and Cox regression to investigate the association between RTL and mortality (30 and 90 days). Six hundred and eight patients were included in the analysis (mean age =72.5 years, 41.1% women, and 53.8% Caucasic). During the study period, 75 people died from COVID-19 and 533 survived. Lower RTL was associated with a higher risk of death in women either at 30 (adjusted hazard ratio [HR] (aHR) = 3.33; 95% confidence interval [CI] = 1.05–10.00; p = 0.040) and at 90 days (aHR = 3.57; 95%CI = 1.23–11.11; p = 0.019). Lower RTL was associated with a higher risk of dying of COVID-19 in women. This finding suggests that RTL has an essential role in the prognosis of this subset of the population.