Molecular targeting of retinoic acid metabolism in neuroblastoma: the role of the CYP26 inhibitor R116010 in vitro and in vivo

Isomerisation to all-trans-retinoic acid (ATRA) is widely accepted as the key mechanism underlying the favourable clinical properties of 13-cis-retinoic acid (13cisRA). As intracellular metabolism of ATRA by CYP26 may result in clinical resistance to 13cisRA, an increase in efficacy may be achieved through modulation of this metabolic pathway. We have evaluated the effect of the CYP26 inhibitor R116010 on retinoid metabolism in neuroblastoma cell lines and a xenograft model. In neuroblastoma cells, which showed a high level of CYP26 induction in response to ATRA, R116010 selectively inhibited ATRA metabolism. In addition, siRNA-mediated knockdown of CYP26 selectively increased ATRA levels and the expression of retinoid-responsive marker genes was potentiated by R116010. Treatment of mice bearing SH-SY5Y xenografts with 13cisRA (100 mg kg−1) revealed substantial levels (16%) of intratumoral ATRA after 6 h, despite plasma ATRA levels representing only 1% total retinoids under these conditions. Co-administration of R116010 with 13cisRA in this mouse model resulted in significant increases in plasma ATRA and 13cisRA concentrations. Furthermore, R116010 induced significant decreases in levels of 4-oxo metabolites in hepatic tissue after co-administration with either ATRA or 13cisRA. These data suggest considerable potential for CYP26 inhibitors in the future treatment of neuroblastoma with 13cisRA

Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)

Background: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods: CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results: This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion: CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic

A Novel Sesquiterpene Lactone Xanthatin-13-(pyrrolidine-2-carboxylic acid) Isolated from Burdock Leaf Up-Regulates Cells’ Oxidative Stress Defense Pathway

The aim of our study was to identify novel molecules able to induce an adaptative response against oxidative stress during the first stages of metabolic syndrome. A cellular survival in vitro test against H2O2-based test was applied after pretreatment with various natural bitter Asteraceae extracts. This screening revealed potent protection from burdock leaf extract. Using chromatography and LC-MS—RMN, we then isolated and identified an original sesquiterpene lactone bioactive molecule: the Xanthatin-13-(pyrrolidine-2-carboxylic acid) (XPc). A real-time RT-qPCR experiment was carried out on three essential genes involved in oxidative stress protection: GPx, SOD, and G6PD. In presence of XPc, an over-expression of the G6PD gene was recorded, whereas no modification of the two others genes could be observed. A biochemical docking approach demonstrated that XPc had a high probability to directly interact with G6PD at different positions. One of the most probable docking sites corresponds precisely to the binding site of AG1, known to stabilize the G6PD dimeric form and enhance its activity. In conclusion, this novel sesquiterpene lactone XPc might be a promising prophylactic bioactive agent against oxidative stress and inflammation in chronic diseases such as metabolic syndrome or type 2 diabetes.</jats:p

An Original Asteraceae Based Infused Drink Prevents Metabolic Syndrome in Fructose-Rat Model

Metabolic syndrome (METS) is a complex disorder that predisposes an affected person to an increased risk of diabetes and cardiovascular disease. Bitter Asteraceae plants contain several compounds active against METS that can be used as an alternative preventive therapy. Our previous work showed that a natural chicory extract (NCRAE) containing chicoric acid (CRA) and chlorogenic acid (CGA) in a molar ratio of 70/30 exhibited an antioxidant, insulin sensitization and anti-hyperglycemic effect. The present study was designed to evaluate the preventive effects of an NCRAE-like extract against METS in a complementary natural pharmacotherapeutic approach. An original Asteraceae infused drink containing the NCRAE CRA/CGA molecular ratio equivalent was prepared from dandelion (Taraxacum officinale L.) and burdock (Arctium lappa L.). The anti-METS effect of this drink was evaluated on the fructose-rat model for 8 weeks. Body weight, blood biochemistry, hepatic glucose-6-phosphatase, arterial blood pressure glucose and insulin tolerance were evaluated after 8 weeks. Our results show that daily oral intake of the Asteraceae infused drink led to a reduction of body weight gain, hyperglycemia, hypertriglyceridemia, insulin resistance and hypertension. Moreover, rat-by-rat analysis of the insulinemia measures revealed two types of responders. One sub-group of subjects demonstrated normal insulinemia and the other subgroup demonstrated hyperinsulinemia. This hyperinsulinemia, associated with the inhibition of the glucose-6-phosphatase activity in the liver tissue, may suggest an insulin release caused by CGA. The present study suggests that this original infusion of dandelion leaves and burdock roots may be used as an adjuvant therapy to prevent metabolic syndrome

An Original Asteraceae Based Infused Drink Prevents Metabolic Syndrome in Fructose-Rat Model

Metabolic syndrome (METS) is a complex disorder that predisposes an affected person to an increased risk of diabetes and cardiovascular disease. Bitter Asteraceae plants contain several compounds active against METS that can be used as an alternative preventive therapy. Our previous work showed that a natural chicory extract (NCRAE) containing chicoric acid (CRA) and chlorogenic acid (CGA) in a molar ratio of 70/30 exhibited an antioxidant, insulin sensitization and anti-hyperglycemic effect. The present study was designed to evaluate the preventive effects of an NCRAE-like extract against METS in a complementary natural pharmacotherapeutic approach. An original Asteraceae infused drink containing the NCRAE CRA/CGA molecular ratio equivalent was prepared from dandelion (Taraxacum officinale L.) and burdock (Arctium lappa L.). The anti-METS effect of this drink was evaluated on the fructose-rat model for 8 weeks. Body weight, blood biochemistry, hepatic glucose-6-phosphatase, arterial blood pressure glucose and insulin tolerance were evaluated after 8 weeks. Our results show that daily oral intake of the Asteraceae infused drink led to a reduction of body weight gain, hyperglycemia, hypertriglyceridemia, insulin resistance and hypertension. Moreover, rat-by-rat analysis of the insulinemia measures revealed two types of responders. One sub-group of subjects demonstrated normal insulinemia and the other subgroup demonstrated hyperinsulinemia. This hyperinsulinemia, associated with the inhibition of the glucose-6-phosphatase activity in the liver tissue, may suggest an insulin release caused by CGA. The present study suggests that this original infusion of dandelion leaves and burdock roots may be used as an adjuvant therapy to prevent metabolic syndrome

In Vitro Tests for a Rapid Evaluation of Antidiabetic Potential of Plant Species Containing Caffeic Acid Derivatives: A Validation by Two Well-Known Antidiabetic Plants, Ocimum gratissimum L. Leaf and Musanga cecropioides R. Br. ex Tedlie (Mu) Stem Bark

Plant bioactive extracts represent a major resource for identifying drugs and adjuvant therapy for type 2 diabetes. To promote early screening of plants’ antidiabetic potential, we designed a four in vitro tests strategy to anticipate in vivo bioactivity. Two antidiabetic plants were studied: Ocimum gratissimum L. (Oc) leaf extract and Musanga cecropoides R. Br. ex Tedlie (Mu) stem bark extract. Chemical compositions were analyzed by LCMS and HPLC. Antidiabetic properties were measured based on (1) INS-1 cells for insulin secretion, (2) L6 myoblast cells for insulin sensitization (Glut-4 translocation), (3) L6 myoblast cells for protection against hydrogen peroxide (H2O2) oxidative stress (cell mortality), and (4) liver microsomial fraction for glucose-6-phosphastase activity (G6P). Oc extract increased insulin secretion and insulin sensitivity, whereas it decreased oxidative stress-induced cell mortality and G6P activity. Mu extract decreased insulin secretion and had no effect on insulin sensitivity or G6P activity, but it increased oxidative stress-induced cell mortality. Results were compared with NCRAE, an antidiabetic plant extract used as reference, previously characterized and reported with increased insulin secretion and insulin sensitivity, protection against oxidative stress, and decreased G6P activity. The proposed set of four in vitro tests combined with chemical analysis provided insight into the interest in rapid early screening of plant extract antidiabetic potential to anticipate pharmaco-toxicological in vivo effects.</jats:p

ATLAS Tracking Detector Upgrade studies using the Fast Simulation Engine

The successful physics program Run-1 of the LHC has put a strong emphasis on design studies for future upgrades of the existing LHC detectors. In ATLAS, testing alternative layouts through the full simulation and reconstruction chain is a work-intensive program, which can only be carried out for a few concept layouts. To facilitate layout prototyping, we have established a novel technique based on the ATLAS reconstruction geometry and a fast simulation engine that allows fast layout iterations and a realistic but fast Monte Carlo simulation. This approach is extended by a fast digitisation and reconstruction module

An Original Asteraceae Based Infused Drink Prevents Metabolic Syndrome in Fructose-Rat Model

Metabolic syndrome (METS) is a complex disorder that predisposes an affected person to an increased risk of diabetes and cardiovascular disease. Bitter Asteraceae plants contain several compounds active against METS that can be used as an alternative preventive therapy. Our previous work showed that a natural chicory extract (NCRAE) containing chicoric acid (CRA) and chlorogenic acid (CGA) in a molar ratio of 70/30 exhibited an antioxidant, insulin sensitization and anti-hyperglycemic effect. The present study was designed to evaluate the preventive effects of an NCRAE-like extract against METS in a complementary natural pharmacotherapeutic approach. An original Asteraceae infused drink containing the NCRAE CRA/CGA molecular ratio equivalent was prepared from dandelion (Taraxacum officinale L.) and burdock (Arctium lappa L.). The anti-METS effect of this drink was evaluated on the fructose-rat model for 8 weeks. Body weight, blood biochemistry, hepatic glucose-6-phosphatase, arterial blood pressure glucose and insulin tolerance were evaluated after 8 weeks. Our results show that daily oral intake of the Asteraceae infused drink led to a reduction of body weight gain, hyperglycemia, hypertriglyceridemia, insulin resistance and hypertension. Moreover, rat-by-rat analysis of the insulinemia measures revealed two types of responders. One sub-group of subjects demonstrated normal insulinemia and the other subgroup demonstrated hyperinsulinemia. This hyperinsulinemia, associated with the inhibition of the glucose-6-phosphatase activity in the liver tissue, may suggest an insulin release caused by CGA. The present study suggests that this original infusion of dandelion leaves and burdock roots may be used as an adjuvant therapy to prevent metabolic syndrome.</jats:p