There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis.Given that preclinical and clinical studies suggest benefits of dietary n-3 poly...There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis.Given that preclinical and clinical studies suggest benefits of dietary n-3 polyunsaturated fatty acids,such as docosahexaenoic acid,and exercise in Parkinson’s disease,we investigated whether both could synergistically interact to induce recovery of the dopaminergic pathway.First,mice received a unilateral stereotactic injection of 6-hydroxydopamine into the striatum to establish an animal model of nigrostriatal denervation.Four weeks after lesion,animals were fed a docosahexaenoic acid-enriched or a control diet for the next 8 weeks.During this period,the animals had access to a running wheel,which they could use or not.Docosahexaenoic acid treatment,voluntary exercise,or the combination of both had no effect on(i)distance traveled in the open field test,(ii)the percentage of contraversive rotations in the apomorphine-induction test or(iii)the number of tyrosine-hydroxylase-positive cells in the substantia nigra pars compacta.However,the docosahexaenoic acid diet increased the number of tyrosine-hydroxylase-positive terminals and induced a rise in dopamine concentrations in the lesioned striatum.Compared to docosahexaenoic acid treatment or exercise alone,the combination of docosahexaenoic acid and exercise(i)improved forelimb balance in the stepping test,(ii)decreased the striatal DOPAC/dopamine ratio and(iii)led to increased dopamine transporter levels in the lesioned striatum.The present results suggest that the combination of exercise and docosahexaenoic acid may act synergistically in the striatum of mice with a unilateral lesion of the dopaminergic system and provide support for clinical trials combining nutrition and physical exercise in the treatment of Parkinson’s disease.展开更多
Orally inhaled drug products(OIPs),such as corticosteroids and bronchodilators,are at the forefront of asthma and chronic obstructive pulmonary disease treatments,two diseases that afflict worldwide populations.Introd...Orally inhaled drug products(OIPs),such as corticosteroids and bronchodilators,are at the forefront of asthma and chronic obstructive pulmonary disease treatments,two diseases that afflict worldwide populations.Introducing generics of these products is essential,as the pricing of these medications remain a barrier to adequate patient care.Currently,there is no consensus between regulatory bodies as to the bioequivalence and equivalence requirements of OIPs that are intended for local action in the lungs.This manuscript critically reviews these requirements and presents future directions for clinicians,scientists,and regulators to consider to optimize the development and approval of OIPs.展开更多
BACKGROUND Benzylamine and methylamine activate glucose uptake in adipocytes.For tyramine,this effect has even been extended to cardiomyocytes.AIM To investigate the effects of catecholamines and other amines on gluco...BACKGROUND Benzylamine and methylamine activate glucose uptake in adipocytes.For tyramine,this effect has even been extended to cardiomyocytes.AIM To investigate the effects of catecholamines and other amines on glucose uptake.METHODS A screening compared 25 biogenic amines on 2-deoxyglucose(2-DG)uptake activation in rat adipocytes.Pharmacological approaches and transgenic mouse models were then used to decipher the mode of action of several hits.RESULTS In rat adipocytes,insulin stimulation of 2-DG uptake was reproduced with catecholamines.100μmol/L or 1 mmol/L adrenaline,noradrenaline,dopamine and deoxyepinephrine,maximally activated hexose transport only when sodium orthovanadate was added at 100μmol/L.Such activation was similar to that already reported for benzylamine,methylamine and tyramine,well-recognized substrates of semicarbazide-sensitive amine oxidase(SSAO)and monoamine oxidase(MAO).Several,but not all,tested agonists ofβ-adrenoreceptors(β-ARs)also activated glucose transport whileα-AR agonists were inactive.Lack of blockade byα-andβ-AR antagonists indicated that catecholamine-induced 2-DG uptake was not mediated by AR stimulation.Adipocytes from mice lackingβ1-,β2-andβ3-ARs(triple KO)also responded to millimolar doses of adrenaline or noradrenaline by activating hexose transport in the presence of 100μmol/L vanadate.The MAO blocker pargyline,and SSAO inhibitors did not block the effects of adrenaline or noradrenaline plus vanadate,which were blunted by antioxidants.CONCLUSION Catecholamines exert unexpected insulin-like actions in adipocytes when combined with vanadium.For limiting insulin resistance by activating glucose consumption at least in fat stores,we propose that catecholamine derivatives combined with vanadium can generate novel complexes that may have low toxicity and promising anti-diabetic properties.展开更多
Mornag Plain is a coastal area of the Mediterranean basin, which has undergone an agricultural industrial boom. The aim of this study was to investigate the different water qualities used for irrigation on heavy metal...Mornag Plain is a coastal area of the Mediterranean basin, which has undergone an agricultural industrial boom. The aim of this study was to investigate the different water qualities used for irrigation on heavy metal mobility in these polluted agricultural soils. The geo-accumulation indices for heavy metals (Ni, Cr, Pb, Cd, Cu, and Zn) revealed that industrial activities and used treated wastewater (TWW) contributed to soil pollution, and water irrigation always decreased this contamination. After long-term use of different water types, high perturbation of heavy metal redistribution has occurred. Groundwater use altered all heavy metal redistributions in the irrigated soil among various soil-solid and soil-solution fractions, as compared to the unirrigated soil. Slight acid water use transferred some metals from different solid phase components into water-soluble and exchangeable fractions. However, TWW use transformed some Ni, Cr, Cd, Cu, and Zn from water-soluble and exchangeable fractions to less labile fractions, particularly into organically bound fractions. Reuse of conventional water within the same soil decreased the whole soil redistribution index values, indicating tendency to return to the pattern of distribution of groundwater-irrigated soil.展开更多
Polyprenylated acylphloroglucinols represent an important class of natural products found in many plants.Among them,the two related products oblongifolin C(Ob-C)and guttiferone K(Gt-K)isolated from Garcinia species(no...Polyprenylated acylphloroglucinols represent an important class of natural products found in many plants.Among them,the two related products oblongifolin C(Ob-C)and guttiferone K(Gt-K)isolated from Garcinia species(notably from edible fruits),have attracted attention due to their marked anticancer properties.The two compounds only differ by the nature of the C-6 side chain,prenyl(Gt-K)or geranyl(Ob-C)on the phloroglucinol core.Their origin,method of extraction and biological properties are presented here,with a focus on the targets and pathways implicated in their anticancer activities.Both compounds markedly reduce cancer cell proliferation in vitro,as well as tumor growth and metastasis in vivo.They are both potent inducer of tumor cell apoptosis,and regulation of autophagy flux is a hallmark of their mode of action.The distinct mechanism leading to autophagosome accumulation in cells and the implicated molecular targets are discussed.The specific role of the chaperone protein HSPA8,known to interact with Ob-C,is addressed.Molecular models of Gt-K and Ob-C bound to HSPA8 provide a structural basis to their common HSPA8-binding recognition capacity.The review shed light on the mechanism of action of these compounds,to encourage their studies and potential development.展开更多
Background: Genetically engineered animals are essential for gaining a proper understanding of the disease mechanisms of cystic fibrosis(CF). The rat is a relevant laboratory model for CF because of its zootechnical c...Background: Genetically engineered animals are essential for gaining a proper understanding of the disease mechanisms of cystic fibrosis(CF). The rat is a relevant laboratory model for CF because of its zootechnical capacity, size, and airway characteristics, including the presence of submucosal glands.Methods: We describe the generation of a CF rat model(F508 del) homozygous for the p.Phe508 del mutation in the transmembrane conductance regulator(Cftr) gene. This model was compared to new Cftr-/-rats(CFTR KO). Target organs in CF were examined by histological staining of tissue sections and tooth enamel was quantified by micro-computed tomography. The activity of CFTR was evaluated by nasal potential difference(NPD) and short-circuit current measurements. The effect of VX-809 and VX-770 was analyzed on nasal epithelial primary cell cultures from F508 del rats.Results: Both newborn F508 del and Knock out(KO) animals developed intestinal obstruction that could be partly compensated by special diet combined with an osmotic laxative. The two rat models exhibited CF phenotypic anomalies such as vas deferens agenesis and tooth enamel defects. Histology of the intestine, pancreas, liver, and lungs was normal. Absence of CFTR function in KO rats was confirmed ex vivo by short-circuit current measurements on colon mucosae and in vivo by NPD, whereas residual CFTR activity was observed in F508 del rats. Exposure of F508 del CFTR nasal primary cultures to a combination of VX-809 and VX-770 improved CFTR-mediated Cl-transport.Conclusions: The F508 del rats reproduce the phenotypes observed in CFTR KO animals and represent a novel resource to advance the development of CF therapeutics.展开更多
BACKGROUND When combined with vanadium salts,catecholamines strongly activate glucose uptake in rat and mouse adipocytes.AIM To test whether catecholamines activate glucose transport in human adipocytes.METHODS The up...BACKGROUND When combined with vanadium salts,catecholamines strongly activate glucose uptake in rat and mouse adipocytes.AIM To test whether catecholamines activate glucose transport in human adipocytes.METHODS The uptake of 2-deoxyglucose(2-DG)was measured in adipocytes isolated from pieces of abdominal subcutaneous tissue removed from women undergoing reconstructive surgery.Pharmacological approaches with amine oxidase inhibitors,adrenoreceptor agonists and antioxidants were performed to unravel the mechanisms of action of noradrenaline or adrenaline(also named epinephrine).RESULTS In human adipocytes,45-min incubation with 100μmol/L adrenaline or noradrenaline activated 2-DG uptake up to more than one-third of the maximal response to insulin.This stimulation was not reproduced with millimolar doses of dopamine or serotonin and was not enhanced by addition of vanadate to the incubation medium.Among various natural amines and adrenergic agonists tested,no other molecule was more efficient than adrenaline and noradrenaline in stimulating 2-DG uptake.The effect of the catecholamines was not impaired by pargyline and semicarbazide,contrarily to that of benzylamine or methylamine,which are recognized substrates of semicarbazide-sensitive amine oxidase.Hydrogen peroxide at 1 mmol/L activated hexose uptake but not pyrocatechol or benzoquinone,and only the former was potentiated by vanadate.Catalase and the phosphoinositide 3-kinase inhibitor wortmannin inhibited adrenaline-induced activation of 2-DG uptake.CONCLUSION High doses of catecholamines exert insulin-like actions on glucose transport in human adipocytes.At submillimolar doses,vanadium did not enhance this catecholamine activation of glucose transport.Consequently,this dismantles our previous suggestion to combine the metal ion with catecholamines to improve the benefit/risk ratio of vanadium-based antidiabetic approaches.展开更多
BACKGROUND There is recently a concern regarding the reinfection and reactivation of previously reCoVered coronavirus disease 2019(CoVID-19)patients.AIM To summarize the recent findings and reports of CoVID-19 reinfec...BACKGROUND There is recently a concern regarding the reinfection and reactivation of previously reCoVered coronavirus disease 2019(CoVID-19)patients.AIM To summarize the recent findings and reports of CoVID-19 reinfection in patients previously reCoVered from the disease.METHODS This study was a systematic review of current evidence conducted in August 2020.The authors studied the probable reinfection risk of novel coronavirus(CoVID-19).We performed a systematic search using the keywords in online databases.The investigation adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)checklist to ensure the reliability and validity of this study and results.RESULTS We reviewed 31 studies.Eight studies described reCoVered patients with reinfection.Only one study reported reinfected patients who died.In 26 studies,there was no information about the status of the patients.Several studies indicated that reinfection is not probable and that post-infection immunity is at least temporary and short.CONCLUSION Based on our review,we concluded that a positive polymerase chain reaction retest could be due to several reasons and should not always be considered as reinfection or reactivation of the disease.Most relevant studies in positive retest patients have shown relative and probably temporary immunity after the reCoVery of the disease.展开更多
Standard parenteral nutrition solutions are mixtures comprising interacting components that may degrade themselves over time.The objective of this study was to investigate the physicochemical and microbiological stabi...Standard parenteral nutrition solutions are mixtures comprising interacting components that may degrade themselves over time.The objective of this study was to investigate the physicochemical and microbiological stability of a hospital preparation for parenteral nutrition in neonatology.The analyses were performed throughout the storage of the preparations at 2–8°C(up to 4 months).The extent of stability was based on the determination of amino acids dosage,visual and physicochemical properties(glucose and electrolytes concentrations,pH and osmolality measurements,particle counting)and microbiological analysis(sterility test).A thermal degradation of ascorbic acid was conducted to evaluate the antioxidant properties of the parenteral mixture.Physicochemical and microbiological controls were found to comply with the specifications.Amino acids showed a good stability throughout the 4 months storage except for cysteine,which was progressively degraded to cystine,conferring a yellow coloration to parenteral solutions.Parenteral nutrition standards solutions remain stable for 4 months at 2–8°C,ensuring safe administration in preterm infants.展开更多
Nanomechanical heterogeneity is expected to have an effect on elasticity, injury and bone remodelling. In normal bone, we have two types of cells (osteoclasts and osteoblasts) working together to maintain existing bon...Nanomechanical heterogeneity is expected to have an effect on elasticity, injury and bone remodelling. In normal bone, we have two types of cells (osteoclasts and osteoblasts) working together to maintain existing bone. Bone cancers can produce factors that make the osteoclasts work harder. This means that more bone is destroyed than rebuilt, and leads to weakening of the affected bone. We report here the first demonstration of the nanoscale stiffness distribution in bone metastases before and after treatment of animals with the bisphosphonate Risedronate, a drug which is currently used for the treatment of bone metastases in patients with advanced cancers. The strategy used here is applicable to a wide class of biological tissues and may serve as a new reflection for biologically inspired scaffolds technologies.展开更多
BACKGROUND Despite overt insulin resistance,adipocytes of genetically obese Zucker rats accumulate the excess of calorie intake in the form of lipids.AIM To investigate whether factors can replace or reinforce insulin...BACKGROUND Despite overt insulin resistance,adipocytes of genetically obese Zucker rats accumulate the excess of calorie intake in the form of lipids.AIM To investigate whether factors can replace or reinforce insulin lipogenic action by exploring glucose uptake activation by hydrogen peroxide,since it is produced by monoamine oxidase(MAO)and semicarbazide-sensitive amine oxidase(SSAO)in adipocytes.METHODS 3H-2-deoxyglucose uptake(2-DG)was determined in adipocytes from obese and lean rats in response to insulin or MAO and SSAO substrates such as tyramine and benzylamine.14C-tyramine oxidation and binding of imidazolinic radioligands[3H-Idazoxan,3H-(2-benzofuranyl)-2-imidazoline]were studied in adipocytes,the liver,and muscle.The influence of in vivo administration of tyramine+vanadium on glucose handling was assessed in lean and obese rats.RESULTS 2-DG uptake and lipogenesis stimulation by insulin were dampened in adipocytes from obese rats,when compared to their lean littermates.Tyramine and benzylamine activation of hexose uptake was vanadate-dependent and was also limited,while MAO was increased and SSAO decreased.These changes were adipocyte-specific and accompanied by a greater number of imidazoline I2 binding sites in the obese rat,when compared to the lean.In vitro,tyramine precluded the binding to I2 sites,while in vivo,its administration together with vanadium lowered fasting plasma levels of glucose and triacylglycerols in obese CONCLUSION The adipocytes from obese Zucker rats exhibit increased MAO activity and imidazoline binding site number.However,probably as a consequence of SSAO down-regulation,the glucose transport stimulation by tyramine is decreased as much as that of insulin in these insulin-resistant adipocytes.The adipocyte amine oxidases deserve more studies with respect to their putative contribution to the management of glucose and lipid handling.展开更多
Introduction:Antibiotic resistance is a major global health challenge that disproportionately affects low-resource countries,particularly those in West Africa.E.coli,a major pathogen in childhood diarrhea,is both a pr...Introduction:Antibiotic resistance is a major global health challenge that disproportionately affects low-resource countries,particularly those in West Africa.E.coli,a major pathogen in childhood diarrhea,is both a prominent infectious agent and a reservoir of resistance genes,including resistance to lastresort antibiotics,such as carbapenems.Methodology:The study focused on 98 clinical E.coli isolates collected from stool samples of patients in a hospital setting in Bamako.The analyses included screening for DEC-specific virulence genes,detection of resistance genes across various classes of antibiotics(e.g.,beta-lactams,carbapenems,fluoroquinolones),and identification of class 1,2,and 3 integrons.The bla NDM gene was sequenced to identify mutations associated with carbapenem resistance.Results:Among the isolates,85.7%carried at least one virulence gene.Of these,half involved co-infections,commonly combining EPEC,EAEC,and ETEC strains.Regarding antibiotic resistance,94.9%of isolates harbored at least one resistance gene,and 50%were multidrug-resistant.The most frequently detected genes were bla TEM,qnrS1,and aphA3.Class 2 integrons were significantly associated with multidrug resistance(p=0.01).Sequencing of the bla NDM gene revealed point mutations likely to affect protein function,suggesting an evolution toward increased resistance to carbapenems.Conclusion:The high prevalence of multidrug-resistant diarrheagenic E.coli strains in this study highlights the local antibiotic pressure and the serious health threat it represents.This study shows that the newβ-lactamase bla NDM gene has disseminated in the hospital environment of Bamako.It should be noted that this will become a major challenge for clinicians.展开更多
Organic anion-transporting polypeptides(OATP)transporter function,which mediates many drugs'liver uptake,was investigated as a molecular determinant of pharmacokinetic variability.Whole-body PET imaging using 11C-...Organic anion-transporting polypeptides(OATP)transporter function,which mediates many drugs'liver uptake,was investigated as a molecular determinant of pharmacokinetic variability.Whole-body PET imaging using 11C-glyburide,a metabolically stable OATP probe,was performed in 16 healthy humans.Ten subjects underwent another 11C-glyburide PET acquisition after OATP inhibition using rifampicin.Subjects were sorted according to age and sex:males<30y(24.0±3.2 y,n=7),males>50y(57.5±5.6 y,n=4),and females>50y(60.6±2.4 y,n=5).The blood-to-liver transfer rate(kuptake)was estimated to describe OATP function.Rifampicin decreased kuptake(−73±13%,P<0.001)and liver exposure(−50±10%,P<0.001)while increasing exposure in blood(+24±24%,P<0.01),myocardium,spleen,and brain(P<0.05).No evidence of extra-hepatic rifampicin-inhibitable transport of 11C-glyburide was found.Baseline liver exposure was 42.6±18.4%higher(P<0.05)in females>50y compared with males>50 y,consistent with higher kuptake values(P<0.05),with negligible impact on blood exposure(P<0.05).In males,neither liver exposure,blood exposure,nor kuptake were affected by aging(P<0.05).kuptake was positively and negatively correlated with liver(P<0.01,R^(2)=0.78)and blood(P<0.01,R2=0.40)exposures respectively.The impact of OATP function(kuptake)on liver exposure was 4-fold more pronounced than on blood exposure.OATP function may thus drive important sex-related differences in liver exposure,which were not discernible through conventional blood-based pharmacokinetics.展开更多
We have developed an efficient strategy for the non-covalent functionalization of multi-walled carbon nanotubes(MWCNTs)which allows a biomimetic presentation of carbohydrates on their surface byπ-πstacking interacti...We have developed an efficient strategy for the non-covalent functionalization of multi-walled carbon nanotubes(MWCNTs)which allows a biomimetic presentation of carbohydrates on their surface byπ-πstacking interactions.The strategy is based on the use of sugar-based amphiphiles functionalized with tetrabenzo[a,c,g,i]fluorene(Tbf),a polyaromatic compound with a topology that resembles a butterfly with open wings.The new carbohydrate-tethered Tbf amphiphiles have been synthesized in a straightforward manner using click chemistry.The reported method has been developed in order to improve the rather low ability of pyrene-based systems to exfoliate MWCNTs in water.By means of thermogravimetric analysis(TGA),ultraviolet(UV),infrared(IR),and fluorescence spectroscopies the interaction between MWCNTs and the Tbf group has been found to be stronger than those involving pyrene-based amphiphilic carbohydrates.The resulting aggregates with a multivalent sugar exposition on their surface are able to engage in specific ligand-lectin interactions similar to glycoconjugates on a cell membrane.展开更多
Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases.A natural fragment of serum albumin,named EPI-X4,has previously been identified as endogenous p...Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases.A natural fragment of serum albumin,named EPI-X4,has previously been identified as endogenous peptide antagonist and inverse agonist of CXCR4 and is a promising compound for the development of improved analogues for the therapy of CXCR4-associated diseases.To generate optimized EPI-X4 derivatives we here performed molecular docking analysis to identify key interaction motifs of EPI-X4/CXCR4.Subsequent rational drug design allowed to increase the anti-CXCR4 activity of EPI-X4.The EPI-X4 derivative JM#21 bound CXCR4 and suppressed CXCR4-tropic HIV-1 infection more efficiently than the clinically approved small molecule CXCR4 antagonist AMD3100.EPI-X4 JM#21 did not exert toxic effects in zebrafish embryos and suppressed allergen-induced infiltration of eosinophils and other immune cells into the airways of animals in an asthma mouse model.Moreover,topical administration of the optimized EPI-X4 derivative efficiently prevented inflammation of the skin in a mouse model of atopic dermatitis.Thus,rationally designed EPIX4 JM#21 is a novel potent antagonist of CXCR4 and the first CXCR4 inhibitor with therapeutic efficacy in atopic dermatitis.Further clinical development of this new class of CXCR4 antagonists for the therapy of atopic dermatitis,asthma and other CXCR4-associated diseases is highly warranted.展开更多
Objective: To investigate the anticancer activity of two diterpenes [palmonine F (C1) and palmonine D (C2)] and three steroids [cholesta-5,22-dien-3β-ol (C3), stigmasterol (C4) and 5α-cholest-5-en-3β-ol (C5)], isol...Objective: To investigate the anticancer activity of two diterpenes [palmonine F (C1) and palmonine D (C2)] and three steroids [cholesta-5,22-dien-3β-ol (C3), stigmasterol (C4) and 5α-cholest-5-en-3β-ol (C5)], isolated from the Mediterranean gorgonian Eunicella singularis, against MCF-7 breast cancer cell line. Methods: This study was performed on standard monolayer two-dimensional (2D) model to evaluate apoptosis by means of AnnexinV-FITC/PI flow cytometry and on three-dimensional (3D) spheroid model using Celigo imaging cytometer for spheroids size analysis. Results: Results indicated that both diterpenes and steroids exhibited an important apoptotic activity in a concentration-dependent manner with EC50 values of 13, 49, 30, 66 and 65 μg/mL for C1, C2, C3, C4 and C5, respectively. Treatment of MCF-73D cell model with C1–C5 induced growth regression of spheroids in a concentration-dependent manner similar to the clinical anti-breast cancer drug Taxol;over ten days of incubation, growth rates were < 1.5 at Day 10 with all tested compounds at 200 μg/mL. Conclusions: The present study indicates that the two diterpenes C1 and C2 and the three steroids C3, C4 and C5, isolated from Eunicella singularis, might be used as anti-breast cancer candidate drugs for further development.展开更多
Trivalent lanthanides in wide bandgap fluoride or phosphate hosts can present persistent luminescence between 200 nm and 1.7 μm after charging by X-rays.Mechanisms are reviewed and applications envisioned.
Diabetic foot ulcers(DFUs)are a serious and prevalent complication of diabetes.Current diagnostic options are limited to macroscopic wound analysis such as wound size,depth,and infection.Molecular diagnostics promise ...Diabetic foot ulcers(DFUs)are a serious and prevalent complication of diabetes.Current diagnostic options are limited to macroscopic wound analysis such as wound size,depth,and infection.Molecular diagnostics promise to improve DFU diagnosis,staging,and assessment of treatment response.Here,we developed a rapid and easy-to-use fluorescent pH-sensing bandage for wound diagnostics.In a fluorescent dye screen,we identified pyranine as the lead compound due to its suitable pH-sensing properties in the clinically relevant pH range of 6-9.To minimize the release of this dye into the wound bed,we screened a library of ionic microparticles and found a strong adhesion of the anionic dye to a cationic polymeric microparticle.These dye-loaded microparticles showed a strong fluorescence response in the clinically relevant pH range of 6-9 and a dye release below 1%after 1 day in biological media.The dye-loaded microparticles were subsequently encapsulated in a calcium alginate hydrogel to minimize the interaction of the microparticles with the wound tissue.This pH-sensing diagnostic wound dressing was tested on full thickness dorsal wounds of mice,and a linear fluorescence response(R^(2)=0.9909)to clinically relevant pH values was observed.These findings encourage further development of this pH-sensing system for molecular diagnostics in DFUs.展开更多
基金supported by funding from Parkinson Canadafunded by a scholarship from Parkinson Canadaa scholarship from Fonds d’Enseignement et de Recherche (FER) (Faculty of Pharmacy, Université Laval)
文摘There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis.Given that preclinical and clinical studies suggest benefits of dietary n-3 polyunsaturated fatty acids,such as docosahexaenoic acid,and exercise in Parkinson’s disease,we investigated whether both could synergistically interact to induce recovery of the dopaminergic pathway.First,mice received a unilateral stereotactic injection of 6-hydroxydopamine into the striatum to establish an animal model of nigrostriatal denervation.Four weeks after lesion,animals were fed a docosahexaenoic acid-enriched or a control diet for the next 8 weeks.During this period,the animals had access to a running wheel,which they could use or not.Docosahexaenoic acid treatment,voluntary exercise,or the combination of both had no effect on(i)distance traveled in the open field test,(ii)the percentage of contraversive rotations in the apomorphine-induction test or(iii)the number of tyrosine-hydroxylase-positive cells in the substantia nigra pars compacta.However,the docosahexaenoic acid diet increased the number of tyrosine-hydroxylase-positive terminals and induced a rise in dopamine concentrations in the lesioned striatum.Compared to docosahexaenoic acid treatment or exercise alone,the combination of docosahexaenoic acid and exercise(i)improved forelimb balance in the stepping test,(ii)decreased the striatal DOPAC/dopamine ratio and(iii)led to increased dopamine transporter levels in the lesioned striatum.The present results suggest that the combination of exercise and docosahexaenoic acid may act synergistically in the striatum of mice with a unilateral lesion of the dopaminergic system and provide support for clinical trials combining nutrition and physical exercise in the treatment of Parkinson’s disease.
文摘Orally inhaled drug products(OIPs),such as corticosteroids and bronchodilators,are at the forefront of asthma and chronic obstructive pulmonary disease treatments,two diseases that afflict worldwide populations.Introducing generics of these products is essential,as the pricing of these medications remain a barrier to adequate patient care.Currently,there is no consensus between regulatory bodies as to the bioequivalence and equivalence requirements of OIPs that are intended for local action in the lungs.This manuscript critically reviews these requirements and presents future directions for clinicians,scientists,and regulators to consider to optimize the development and approval of OIPs.
基金We thank the staff of animal unit CREFRE, currently headed by Xavier Collet, andespecially its Rangueil satellite for housing wild type and transgenic rodents, andAnne Bouloumié for helpful discussions.
文摘BACKGROUND Benzylamine and methylamine activate glucose uptake in adipocytes.For tyramine,this effect has even been extended to cardiomyocytes.AIM To investigate the effects of catecholamines and other amines on glucose uptake.METHODS A screening compared 25 biogenic amines on 2-deoxyglucose(2-DG)uptake activation in rat adipocytes.Pharmacological approaches and transgenic mouse models were then used to decipher the mode of action of several hits.RESULTS In rat adipocytes,insulin stimulation of 2-DG uptake was reproduced with catecholamines.100μmol/L or 1 mmol/L adrenaline,noradrenaline,dopamine and deoxyepinephrine,maximally activated hexose transport only when sodium orthovanadate was added at 100μmol/L.Such activation was similar to that already reported for benzylamine,methylamine and tyramine,well-recognized substrates of semicarbazide-sensitive amine oxidase(SSAO)and monoamine oxidase(MAO).Several,but not all,tested agonists ofβ-adrenoreceptors(β-ARs)also activated glucose transport whileα-AR agonists were inactive.Lack of blockade byα-andβ-AR antagonists indicated that catecholamine-induced 2-DG uptake was not mediated by AR stimulation.Adipocytes from mice lackingβ1-,β2-andβ3-ARs(triple KO)also responded to millimolar doses of adrenaline or noradrenaline by activating hexose transport in the presence of 100μmol/L vanadate.The MAO blocker pargyline,and SSAO inhibitors did not block the effects of adrenaline or noradrenaline plus vanadate,which were blunted by antioxidants.CONCLUSION Catecholamines exert unexpected insulin-like actions in adipocytes when combined with vanadium.For limiting insulin resistance by activating glucose consumption at least in fat stores,we propose that catecholamine derivatives combined with vanadium can generate novel complexes that may have low toxicity and promising anti-diabetic properties.
文摘Mornag Plain is a coastal area of the Mediterranean basin, which has undergone an agricultural industrial boom. The aim of this study was to investigate the different water qualities used for irrigation on heavy metal mobility in these polluted agricultural soils. The geo-accumulation indices for heavy metals (Ni, Cr, Pb, Cd, Cu, and Zn) revealed that industrial activities and used treated wastewater (TWW) contributed to soil pollution, and water irrigation always decreased this contamination. After long-term use of different water types, high perturbation of heavy metal redistribution has occurred. Groundwater use altered all heavy metal redistributions in the irrigated soil among various soil-solid and soil-solution fractions, as compared to the unirrigated soil. Slight acid water use transferred some metals from different solid phase components into water-soluble and exchangeable fractions. However, TWW use transformed some Ni, Cr, Cd, Cu, and Zn from water-soluble and exchangeable fractions to less labile fractions, particularly into organically bound fractions. Reuse of conventional water within the same soil decreased the whole soil redistribution index values, indicating tendency to return to the pattern of distribution of groundwater-irrigated soil.
文摘Polyprenylated acylphloroglucinols represent an important class of natural products found in many plants.Among them,the two related products oblongifolin C(Ob-C)and guttiferone K(Gt-K)isolated from Garcinia species(notably from edible fruits),have attracted attention due to their marked anticancer properties.The two compounds only differ by the nature of the C-6 side chain,prenyl(Gt-K)or geranyl(Ob-C)on the phloroglucinol core.Their origin,method of extraction and biological properties are presented here,with a focus on the targets and pathways implicated in their anticancer activities.Both compounds markedly reduce cancer cell proliferation in vitro,as well as tumor growth and metastasis in vivo.They are both potent inducer of tumor cell apoptosis,and regulation of autophagy flux is a hallmark of their mode of action.The distinct mechanism leading to autophagosome accumulation in cells and the implicated molecular targets are discussed.The specific role of the chaperone protein HSPA8,known to interact with Ob-C,is addressed.Molecular models of Gt-K and Ob-C bound to HSPA8 provide a structural basis to their common HSPA8-binding recognition capacity.The review shed light on the mechanism of action of these compounds,to encourage their studies and potential development.
基金TEFOR,Grant/Award Number:RIIINSB-0014France Life Imaging,Grant/Award Number:ANR-11-INBS-0006+6 种基金Swiss Cystic Fibrosis Foundation CFCHFondation Maladies RaresInfrastructures Biologie-SantéIHU-CESTI,Grant/Award Number:ANR-10-IBHU-005IRSR Pays de la LoireVaincre la MucoviscidoseSwiss National Foundation,Grant/Award Number:310030_172909
文摘Background: Genetically engineered animals are essential for gaining a proper understanding of the disease mechanisms of cystic fibrosis(CF). The rat is a relevant laboratory model for CF because of its zootechnical capacity, size, and airway characteristics, including the presence of submucosal glands.Methods: We describe the generation of a CF rat model(F508 del) homozygous for the p.Phe508 del mutation in the transmembrane conductance regulator(Cftr) gene. This model was compared to new Cftr-/-rats(CFTR KO). Target organs in CF were examined by histological staining of tissue sections and tooth enamel was quantified by micro-computed tomography. The activity of CFTR was evaluated by nasal potential difference(NPD) and short-circuit current measurements. The effect of VX-809 and VX-770 was analyzed on nasal epithelial primary cell cultures from F508 del rats.Results: Both newborn F508 del and Knock out(KO) animals developed intestinal obstruction that could be partly compensated by special diet combined with an osmotic laxative. The two rat models exhibited CF phenotypic anomalies such as vas deferens agenesis and tooth enamel defects. Histology of the intestine, pancreas, liver, and lungs was normal. Absence of CFTR function in KO rats was confirmed ex vivo by short-circuit current measurements on colon mucosae and in vivo by NPD, whereas residual CFTR activity was observed in F508 del rats. Exposure of F508 del CFTR nasal primary cultures to a combination of VX-809 and VX-770 improved CFTR-mediated Cl-transport.Conclusions: The F508 del rats reproduce the phenotypes observed in CFTR KO animals and represent a novel resource to advance the development of CF therapeutics.
文摘BACKGROUND When combined with vanadium salts,catecholamines strongly activate glucose uptake in rat and mouse adipocytes.AIM To test whether catecholamines activate glucose transport in human adipocytes.METHODS The uptake of 2-deoxyglucose(2-DG)was measured in adipocytes isolated from pieces of abdominal subcutaneous tissue removed from women undergoing reconstructive surgery.Pharmacological approaches with amine oxidase inhibitors,adrenoreceptor agonists and antioxidants were performed to unravel the mechanisms of action of noradrenaline or adrenaline(also named epinephrine).RESULTS In human adipocytes,45-min incubation with 100μmol/L adrenaline or noradrenaline activated 2-DG uptake up to more than one-third of the maximal response to insulin.This stimulation was not reproduced with millimolar doses of dopamine or serotonin and was not enhanced by addition of vanadate to the incubation medium.Among various natural amines and adrenergic agonists tested,no other molecule was more efficient than adrenaline and noradrenaline in stimulating 2-DG uptake.The effect of the catecholamines was not impaired by pargyline and semicarbazide,contrarily to that of benzylamine or methylamine,which are recognized substrates of semicarbazide-sensitive amine oxidase.Hydrogen peroxide at 1 mmol/L activated hexose uptake but not pyrocatechol or benzoquinone,and only the former was potentiated by vanadate.Catalase and the phosphoinositide 3-kinase inhibitor wortmannin inhibited adrenaline-induced activation of 2-DG uptake.CONCLUSION High doses of catecholamines exert insulin-like actions on glucose transport in human adipocytes.At submillimolar doses,vanadium did not enhance this catecholamine activation of glucose transport.Consequently,this dismantles our previous suggestion to combine the metal ion with catecholamines to improve the benefit/risk ratio of vanadium-based antidiabetic approaches.
文摘BACKGROUND There is recently a concern regarding the reinfection and reactivation of previously reCoVered coronavirus disease 2019(CoVID-19)patients.AIM To summarize the recent findings and reports of CoVID-19 reinfection in patients previously reCoVered from the disease.METHODS This study was a systematic review of current evidence conducted in August 2020.The authors studied the probable reinfection risk of novel coronavirus(CoVID-19).We performed a systematic search using the keywords in online databases.The investigation adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)checklist to ensure the reliability and validity of this study and results.RESULTS We reviewed 31 studies.Eight studies described reCoVered patients with reinfection.Only one study reported reinfected patients who died.In 26 studies,there was no information about the status of the patients.Several studies indicated that reinfection is not probable and that post-infection immunity is at least temporary and short.CONCLUSION Based on our review,we concluded that a positive polymerase chain reaction retest could be due to several reasons and should not always be considered as reinfection or reactivation of the disease.Most relevant studies in positive retest patients have shown relative and probably temporary immunity after the reCoVery of the disease.
文摘Standard parenteral nutrition solutions are mixtures comprising interacting components that may degrade themselves over time.The objective of this study was to investigate the physicochemical and microbiological stability of a hospital preparation for parenteral nutrition in neonatology.The analyses were performed throughout the storage of the preparations at 2–8°C(up to 4 months).The extent of stability was based on the determination of amino acids dosage,visual and physicochemical properties(glucose and electrolytes concentrations,pH and osmolality measurements,particle counting)and microbiological analysis(sterility test).A thermal degradation of ascorbic acid was conducted to evaluate the antioxidant properties of the parenteral mixture.Physicochemical and microbiological controls were found to comply with the specifications.Amino acids showed a good stability throughout the 4 months storage except for cysteine,which was progressively degraded to cystine,conferring a yellow coloration to parenteral solutions.Parenteral nutrition standards solutions remain stable for 4 months at 2–8°C,ensuring safe administration in preterm infants.
基金This work was supported by the NanoOSCAR ANR project from the“Agence Natiionale la Recherche”,the“Fondation Avenir”,the“Ligue contre le Cancer du Haut-Rhin,Région Alsace”and“Cancéropôle du Grand Est”.
文摘Nanomechanical heterogeneity is expected to have an effect on elasticity, injury and bone remodelling. In normal bone, we have two types of cells (osteoclasts and osteoblasts) working together to maintain existing bone. Bone cancers can produce factors that make the osteoclasts work harder. This means that more bone is destroyed than rebuilt, and leads to weakening of the affected bone. We report here the first demonstration of the nanoscale stiffness distribution in bone metastases before and after treatment of animals with the bisphosphonate Risedronate, a drug which is currently used for the treatment of bone metastases in patients with advanced cancers. The strategy used here is applicable to a wide class of biological tissues and may serve as a new reflection for biologically inspired scaffolds technologies.
基金Supported by Recurrent Grants from Institut National de la Santéet de la Recherche Médicale to the INSERM U1048.
文摘BACKGROUND Despite overt insulin resistance,adipocytes of genetically obese Zucker rats accumulate the excess of calorie intake in the form of lipids.AIM To investigate whether factors can replace or reinforce insulin lipogenic action by exploring glucose uptake activation by hydrogen peroxide,since it is produced by monoamine oxidase(MAO)and semicarbazide-sensitive amine oxidase(SSAO)in adipocytes.METHODS 3H-2-deoxyglucose uptake(2-DG)was determined in adipocytes from obese and lean rats in response to insulin or MAO and SSAO substrates such as tyramine and benzylamine.14C-tyramine oxidation and binding of imidazolinic radioligands[3H-Idazoxan,3H-(2-benzofuranyl)-2-imidazoline]were studied in adipocytes,the liver,and muscle.The influence of in vivo administration of tyramine+vanadium on glucose handling was assessed in lean and obese rats.RESULTS 2-DG uptake and lipogenesis stimulation by insulin were dampened in adipocytes from obese rats,when compared to their lean littermates.Tyramine and benzylamine activation of hexose uptake was vanadate-dependent and was also limited,while MAO was increased and SSAO decreased.These changes were adipocyte-specific and accompanied by a greater number of imidazoline I2 binding sites in the obese rat,when compared to the lean.In vitro,tyramine precluded the binding to I2 sites,while in vivo,its administration together with vanadium lowered fasting plasma levels of glucose and triacylglycerols in obese CONCLUSION The adipocytes from obese Zucker rats exhibit increased MAO activity and imidazoline binding site number.However,probably as a consequence of SSAO down-regulation,the glucose transport stimulation by tyramine is decreased as much as that of insulin in these insulin-resistant adipocytes.The adipocyte amine oxidases deserve more studies with respect to their putative contribution to the management of glucose and lipid handling.
文摘Introduction:Antibiotic resistance is a major global health challenge that disproportionately affects low-resource countries,particularly those in West Africa.E.coli,a major pathogen in childhood diarrhea,is both a prominent infectious agent and a reservoir of resistance genes,including resistance to lastresort antibiotics,such as carbapenems.Methodology:The study focused on 98 clinical E.coli isolates collected from stool samples of patients in a hospital setting in Bamako.The analyses included screening for DEC-specific virulence genes,detection of resistance genes across various classes of antibiotics(e.g.,beta-lactams,carbapenems,fluoroquinolones),and identification of class 1,2,and 3 integrons.The bla NDM gene was sequenced to identify mutations associated with carbapenem resistance.Results:Among the isolates,85.7%carried at least one virulence gene.Of these,half involved co-infections,commonly combining EPEC,EAEC,and ETEC strains.Regarding antibiotic resistance,94.9%of isolates harbored at least one resistance gene,and 50%were multidrug-resistant.The most frequently detected genes were bla TEM,qnrS1,and aphA3.Class 2 integrons were significantly associated with multidrug resistance(p=0.01).Sequencing of the bla NDM gene revealed point mutations likely to affect protein function,suggesting an evolution toward increased resistance to carbapenems.Conclusion:The high prevalence of multidrug-resistant diarrheagenic E.coli strains in this study highlights the local antibiotic pressure and the serious health threat it represents.This study shows that the newβ-lactamase bla NDM gene has disseminated in the hospital environment of Bamako.It should be noted that this will become a major challenge for clinicians.
基金funded by grant ANR-16-CE17-0011(France)and performed on a platform member of the France Life Imaging network(grant ANR-11-INBS-0006,France).
文摘Organic anion-transporting polypeptides(OATP)transporter function,which mediates many drugs'liver uptake,was investigated as a molecular determinant of pharmacokinetic variability.Whole-body PET imaging using 11C-glyburide,a metabolically stable OATP probe,was performed in 16 healthy humans.Ten subjects underwent another 11C-glyburide PET acquisition after OATP inhibition using rifampicin.Subjects were sorted according to age and sex:males<30y(24.0±3.2 y,n=7),males>50y(57.5±5.6 y,n=4),and females>50y(60.6±2.4 y,n=5).The blood-to-liver transfer rate(kuptake)was estimated to describe OATP function.Rifampicin decreased kuptake(−73±13%,P<0.001)and liver exposure(−50±10%,P<0.001)while increasing exposure in blood(+24±24%,P<0.01),myocardium,spleen,and brain(P<0.05).No evidence of extra-hepatic rifampicin-inhibitable transport of 11C-glyburide was found.Baseline liver exposure was 42.6±18.4%higher(P<0.05)in females>50y compared with males>50 y,consistent with higher kuptake values(P<0.05),with negligible impact on blood exposure(P<0.05).In males,neither liver exposure,blood exposure,nor kuptake were affected by aging(P<0.05).kuptake was positively and negatively correlated with liver(P<0.01,R^(2)=0.78)and blood(P<0.01,R2=0.40)exposures respectively.The impact of OATP function(kuptake)on liver exposure was 4-fold more pronounced than on blood exposure.OATP function may thus drive important sex-related differences in liver exposure,which were not discernible through conventional blood-based pharmacokinetics.
基金This work was supported by the Ministerio de Ciencia e Innovación(grant No.CTQ2010-21755-CO2-00)the Junta de Andalucía(grant Nos.P06-FQM-01852 and P07-FQM-2774)the Centre National de la Recherche Scientifique(France)and the Consejo Superior de Investigaciones Científicas(Egide Picasso 09543XA and Projets Internationaux de Cooperation Scientifiques Program 2008-2010).
文摘We have developed an efficient strategy for the non-covalent functionalization of multi-walled carbon nanotubes(MWCNTs)which allows a biomimetic presentation of carbohydrates on their surface byπ-πstacking interactions.The strategy is based on the use of sugar-based amphiphiles functionalized with tetrabenzo[a,c,g,i]fluorene(Tbf),a polyaromatic compound with a topology that resembles a butterfly with open wings.The new carbohydrate-tethered Tbf amphiphiles have been synthesized in a straightforward manner using click chemistry.The reported method has been developed in order to improve the rather low ability of pyrene-based systems to exfoliate MWCNTs in water.By means of thermogravimetric analysis(TGA),ultraviolet(UV),infrared(IR),and fluorescence spectroscopies the interaction between MWCNTs and the Tbf group has been found to be stronger than those involving pyrene-based amphiphilic carbohydrates.The resulting aggregates with a multivalent sugar exposition on their surface are able to engage in specific ligand-lectin interactions similar to glycoconjugates on a cell membrane.
基金supported by the German Research Foundation(DFG)through the CRC1279supported by the DFG under Germany’s Excellence Strategy-EXC 2033-390677874-RESOLVby the Boehringer Ingelheim Foundation(Plus-3 Program)
文摘Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases.A natural fragment of serum albumin,named EPI-X4,has previously been identified as endogenous peptide antagonist and inverse agonist of CXCR4 and is a promising compound for the development of improved analogues for the therapy of CXCR4-associated diseases.To generate optimized EPI-X4 derivatives we here performed molecular docking analysis to identify key interaction motifs of EPI-X4/CXCR4.Subsequent rational drug design allowed to increase the anti-CXCR4 activity of EPI-X4.The EPI-X4 derivative JM#21 bound CXCR4 and suppressed CXCR4-tropic HIV-1 infection more efficiently than the clinically approved small molecule CXCR4 antagonist AMD3100.EPI-X4 JM#21 did not exert toxic effects in zebrafish embryos and suppressed allergen-induced infiltration of eosinophils and other immune cells into the airways of animals in an asthma mouse model.Moreover,topical administration of the optimized EPI-X4 derivative efficiently prevented inflammation of the skin in a mouse model of atopic dermatitis.Thus,rationally designed EPIX4 JM#21 is a novel potent antagonist of CXCR4 and the first CXCR4 inhibitor with therapeutic efficacy in atopic dermatitis.Further clinical development of this new class of CXCR4 antagonists for the therapy of atopic dermatitis,asthma and other CXCR4-associated diseases is highly warranted.
基金Ministry of Higher Education,Scientific Research and Technology,Tunisia,MHSSR of Tunisia(Grant No.11/TM06).
文摘Objective: To investigate the anticancer activity of two diterpenes [palmonine F (C1) and palmonine D (C2)] and three steroids [cholesta-5,22-dien-3β-ol (C3), stigmasterol (C4) and 5α-cholest-5-en-3β-ol (C5)], isolated from the Mediterranean gorgonian Eunicella singularis, against MCF-7 breast cancer cell line. Methods: This study was performed on standard monolayer two-dimensional (2D) model to evaluate apoptosis by means of AnnexinV-FITC/PI flow cytometry and on three-dimensional (3D) spheroid model using Celigo imaging cytometer for spheroids size analysis. Results: Results indicated that both diterpenes and steroids exhibited an important apoptotic activity in a concentration-dependent manner with EC50 values of 13, 49, 30, 66 and 65 μg/mL for C1, C2, C3, C4 and C5, respectively. Treatment of MCF-73D cell model with C1–C5 induced growth regression of spheroids in a concentration-dependent manner similar to the clinical anti-breast cancer drug Taxol;over ten days of incubation, growth rates were < 1.5 at Day 10 with all tested compounds at 200 μg/mL. Conclusions: The present study indicates that the two diterpenes C1 and C2 and the three steroids C3, C4 and C5, isolated from Eunicella singularis, might be used as anti-breast cancer candidate drugs for further development.
文摘Trivalent lanthanides in wide bandgap fluoride or phosphate hosts can present persistent luminescence between 200 nm and 1.7 μm after charging by X-rays.Mechanisms are reviewed and applications envisioned.
基金Natural Sciences and Engineering Research Council of Canada,Grant/Award Number:RGPIN-2022-04384Canada Foundation for Innovation,Grant/Award Number:42712Fonds de recherche du Québec–Nature et technologies,Grant/Award Number:330153。
文摘Diabetic foot ulcers(DFUs)are a serious and prevalent complication of diabetes.Current diagnostic options are limited to macroscopic wound analysis such as wound size,depth,and infection.Molecular diagnostics promise to improve DFU diagnosis,staging,and assessment of treatment response.Here,we developed a rapid and easy-to-use fluorescent pH-sensing bandage for wound diagnostics.In a fluorescent dye screen,we identified pyranine as the lead compound due to its suitable pH-sensing properties in the clinically relevant pH range of 6-9.To minimize the release of this dye into the wound bed,we screened a library of ionic microparticles and found a strong adhesion of the anionic dye to a cationic polymeric microparticle.These dye-loaded microparticles showed a strong fluorescence response in the clinically relevant pH range of 6-9 and a dye release below 1%after 1 day in biological media.The dye-loaded microparticles were subsequently encapsulated in a calcium alginate hydrogel to minimize the interaction of the microparticles with the wound tissue.This pH-sensing diagnostic wound dressing was tested on full thickness dorsal wounds of mice,and a linear fluorescence response(R^(2)=0.9909)to clinically relevant pH values was observed.These findings encourage further development of this pH-sensing system for molecular diagnostics in DFUs.
