The Institut du Cerveau et de la Moelle epiniere - ICM （Brain ＆ Spine Institute） - is an international brain and spinal cord research center whose innovative concept and structure make ita unique institute of its k...The Institut du Cerveau et de la Moelle epiniere - ICM （Brain ＆ Spine Institute） - is an international brain and spinal cord research center whose innovative concept and structure make ita unique institute of its kind. The ICM brings patients, medics and researchers together with the aim of rapidly develop treatments for disorders of the nervous system and enable patients to benefit from them as quickly as possible. Scientists from different backgrounds and countries come together at the Institute to perform leading-edge research in this area.展开更多
Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal ce...Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal cells(MSCs)exhibited greater therapeutic efficacy than CD146-MSCs.These cells enhance epithelial repair through nuclear factor kappa B/cyclooxygenase-2-associated paracrine signaling and secretion of pro-angiogenic factors.We concur that MSCs hold significant promise for ARDS treatment;however,the heterogeneity of cell products is a translational barrier.Phenotype-aware strategies,such as CD146 enrichment,standardized potency assays,and extracellular vesicle profiling,are essential for improving the consistency of these studies.Further-more,advanced preclinical models,such as lung-on-a-chip systems,may provide more predictive insights into the therapeutic mechanisms.This article underscores the importance of CD146+MSCs in ARDS,emphasizes the need for precision in defining cell products,and discusses how integrating subset selection into translational pipelines could enhance the clinical impact of MSC-based therapies.展开更多
The variability of the sea surface salinity measurements provided by the Soil Moisture and Ocean Salinity mission reveals the presence of a local salinity maximum(a salty tongue)in the northwestern tropical Atlantic.T...The variability of the sea surface salinity measurements provided by the Soil Moisture and Ocean Salinity mission reveals the presence of a local salinity maximum(a salty tongue)in the northwestern tropical Atlantic.The sea surface salinity positive anomaly starts increasing in July,reaches its maximum in January,and then disappears.The local maximum of salinity appears in the late boreal autumn/winter,when the Amazon discharge is minimal and the salty water from the South Atlantic is transported by the North Brazil Current along the shelf break across the equator.The authors validate the satellite observations in this area and assess the vertical structure of the salinity maximum by using in situ measurements and an in situ-interpolated product.展开更多
Gastric and esophageal adenocarcinomas are one of the main causes of cancer-related death worldwide. While the incidence of gastric adenocarcinoma is decreasing, the incidence of gastroesophageal junction adenocarcino...Gastric and esophageal adenocarcinomas are one of the main causes of cancer-related death worldwide. While the incidence of gastric adenocarcinoma is decreasing, the incidence of gastroesophageal junction adenocarcinoma is rising rapidly in Western countries. Considering that surgical resection is currently the major curative treatment, and that the 5-year survival rate highly depends on the p TNM stage at diagnosis, gastroesophageal adenocarcinoma management is very challenging for oncologists. Several treatment strategies are being evaluated, and among them systemic chemotherapy, to decrease recurrences and improve overall survival. The MAGIC and FNCLCCFFCD trials showed a survival benefit of perioperative chemotherapy in patients with operable gastric and lower esophageal cancer, and these results had an impact on the European clinical practice. New strategies, including induction chemotherapy followed by preoperative chemoradiotherapy, targeted therapies in combination with perioperative chemotherapy and the new cytotoxic regimens, are currently assessed to improve current standards and help developing patienttailored therapeutic interventions.展开更多
Oral disintegrating tablets(ODTs) are a novel dosage form that can be dissolved on thetongue within 3 min or less especially for geriatric and pediatric patients. Current ODT for-mulation studies usually rely on the p...Oral disintegrating tablets(ODTs) are a novel dosage form that can be dissolved on thetongue within 3 min or less especially for geriatric and pediatric patients. Current ODT for-mulation studies usually rely on the personal experience of pharmaceutical experts andtrial-and-error in the laboratory, which is inefficient and time-consuming. The aim of cur-rent research was to establish the prediction model of ODT formulations with direct com-pression process by artificial neural network(ANN) and deep neural network(DNN) tech-niques. 145 formulation data were extracted from Web of Science. All datasets were dividedinto three parts: training set(105 data), validation set(20) and testing set(20). ANN andDNN were compared for the prediction of the disintegrating time. The accuracy of the ANNmodel have reached 85.60%, 80.00% and 75.00% on the training set, validation set and testingset respectively, whereas that of the DNN model were 85.60%, 85.00% and 80.00%, respec-tively. Compared with the ANN, DNN showed the better prediction for ODT formulations.It is the first time that deep neural network with the improved dataset selection algorithmis applied to formulation prediction on small data. The proposed predictive approach couldevaluate the critical parameters about quality control of formulation, and guide researchand process development. The implementation of this prediction model could effectivelyreduce drug product development timeline and material usage, and proactively facilitatethe development of a robust drug product.展开更多
Background: There is currently no drug or therapy that cures COVID-19, a highly contagious and life-threatening disease.Objective: This systematic review and meta-analysis summarized contemporary studies that report t...Background: There is currently no drug or therapy that cures COVID-19, a highly contagious and life-threatening disease.Objective: This systematic review and meta-analysis summarized contemporary studies that report the use of Chinese herbal medicine(CHM) to treat COVID-19.Search strategy: Six electronic databases(PubMed/MEDLINE, Cochrane Library, ScienceDirect, Google Scholar, Wanfang Data and China National Knowledge Infrastructure) were searched from their beginning to May 15, 2020 with the following search terms: traditional Chinese medicine, Chinese medicine,Chinese herbal medicine, COVID-19, new coronavirus pneumonia, SARS-CoV-2, and randomized controlled trial.Inclusion criteria: Randomized controlled trials(RCTs) from peer-reviewed journals and non-reviewed publications were included. Further, included RCTs had a control group that was given standard care(SC;such as conventional Western medicine treatments or routine medical care), and a treatment group that was given SC plus CHM.Data extraction and analysis: Two evaluators screened and collected literature independently;information on participants, study design, interventions, follow-up and adverse events were extracted, and risk of bias was assessed. The primary outcomes included scores that represented changes in symptoms and signs over the course of treatment. Secondary outcomes included the level of inflammatory markers, improvement of pneumonia confirmed by computed tomography(CT), and adverse events. Dichotomous data were expressed as risk ratio or hazard ratio with 95% confidence interval(CI);where time-to-event analysis was used, outcomes were expressed as odds ratio with 95% CI. Continuous data were expressed as difference in means(MD) with 95% CI, and standardized mean difference(SMD) was used when different outcome scales were pooled.Results: Seven original studies, comprising a total of 732 adults, were included in this meta-analysis.Compared to SC alone, CHM plus SC had a superior effect on the change of symptom and sign score(-1.30 by SMD, 95% CI [-2.43, -0.16];3 studies;n = 261, P = 0.03), on inflammatory marker C-reactive protein(CRP, mg/L;-11.82 by MD, 95% CI [-17.95, -5.69];5 studies;n = 325, P = 0.0002),on number of patients with improved lung CT scans(1.34 by risk ratio, 95% CI [1.19, 1.51];4 studies;n = 489, P < 0.00001). No significant adverse events were recorded in the included RCTs.Conclusion: Current evidence shows that CHM, as an adjunct treatment with standard care, helps to improve treatment outcomes in COVID-19 cases.展开更多
In this paper,the combined addition of copper or iron and sulphate ions onto TiO_(2) prepared by a simple sol-gel method is studied for formic acid photocatalytic conversion.A wide structural and morphological charact...In this paper,the combined addition of copper or iron and sulphate ions onto TiO_(2) prepared by a simple sol-gel method is studied for formic acid photocatalytic conversion.A wide structural and morphological characterization of the different photocatalysts was performed by X-ray diffraction(XRD),N_(2)-physisorption for BET surface area measurements,scanning and transmission electronic microscopies(SEM and TEM),UV-Vis diffuse spectroscopy(DRS)and X-ray photoelectron spectroscopy(XPS),in order to correlate the physico-chemical properties of the materials to their photocatalytic efficiencies for formic acid oxidation.Results have shown important differences among the catalysts depending on the metal added.Sulphated TiO_(2)/Cu(1%Cu)was the best photocatalyst obtaining about 100% formic acid conversion in only 5 min.The appropriate physico-chemical features of this photocatalyst,given by the addition of combined copper and sulphate ions,explain its excellence in photocatalytic reaction.展开更多
Cyclodextrin complexation is a wise strategy to enhance aqueous solubility of waterinsoluble drugs.However,the aggregation mechanism of drug-cyclodextrin complexes is still unclear.This research aimed to investigate t...Cyclodextrin complexation is a wise strategy to enhance aqueous solubility of waterinsoluble drugs.However,the aggregation mechanism of drug-cyclodextrin complexes is still unclear.This research aimed to investigate the molecular aggregation mechanism of glipizide/cyclodextrin complexation by the combination of experimental and modeling methods.Binding free energies between glipizide and cyclodextrins from modeling calculations were higher than those by the phase solubility diagram method.Both experimental and modeling results showed that methylated-β-cyclodextrin exhibited the best solubilizing capability to glipizide.Size-measurement results confirmed the aggregation between glipizide and all four cyclodextrins in high concentrations.Glipizide/γ-cyclodextrin and glipizide/β-cyclodextrin complexes showed stronger aggregation trend than HP-β-cyclodextrin and methylated-β-cyclodextrin.The substituted groups in the rim of HP-β-cyclodextrin and methylated-β-cyclodextrin lead to weak aggregation.This research provided us a clear molecular mechanism of glipizide/cyclodextrin complexation and aggregation.This research will also benefit the formulation development of cyclodextrin solubilization.展开更多
Current formulation development strongly relies on trial-and-error experiments in the laboratory by pharmaceutical scientists,which is time-consuming,high cost and waste materials.This research aims to integrate vario...Current formulation development strongly relies on trial-and-error experiments in the laboratory by pharmaceutical scientists,which is time-consuming,high cost and waste materials.This research aims to integrate various computational tools,including machine learning,molecular dynamic simulation and physiologically based absorption modeling(PBAM),to enhance andrographolide(AG)/cyclodextrins(CDs)formulation design.The light GBM prediction model we built before was utilized to predict AG/CDs inclusion's binding free energy.AG/γ-CD inclusion complexes showed the strongest binding affinity,which was experimentally validated by the phase solubility study.The molecular dynamic simulation was used to investigate the inclusion mechanism between AG andγ-CD,which was experimentally characterized by DSC,FTIR and NMR techniques.PBAM was applied to simulate the in vivo behavior of the formulations,which were validated by cell and animal experiments.Cell experiments revealed that the presence of D-α-Tocopherol polyethylene glycol succinate(TPGS)significantly increased the intracellular uptake of AG in MDCKMDR1 cells and the absorptive transport of AG in MDCK-MDR1 monolayers.The relative bioavailability of the AG-CD-TPGS ternary system in rats was increased to 2.6-fold and 1.59-fold compared with crude AG and commercial dropping pills,respectively.In conclusion,this is the first time to integrate various computational tools to develop a new AG-CD-TPGS ternary formulation with significant improvement of aqueous solubility,dissolution rate and bioavailability.The integrated computational tool is a novel and robust methodology to facilitate pharmaceutical formulation design.展开更多
Inflammatory bowel disease (IBD) is a refractory chronic intestinal inflammatory disease caused by a malfunction of immune system. As the key immune cells in the intestine, macrophages play an important role in mainta...Inflammatory bowel disease (IBD) is a refractory chronic intestinal inflammatory disease caused by a malfunction of immune system. As the key immune cells in the intestine, macrophages play an important role in maintaining intestinal homeostasis and tissue repair of the IBD. Pharmacological modulation of macrophage function exhibits the promising therapeutic effect for IBD. In this study, mannose-modified liposomes (MAN-LPs) are prepared for macrophage targeting to improve therapeutic efficiency. Rosiglitazone (ROSI) as an agonist of peroxisome proliferators-activated receptor γ (PPAR-γ) is used as the model drug to fabricate different sized liposomes. The impacts of mannose modification and particle size for macrophage targeting are investigated in cells, zebrafish, and mouse models and the therapeutic effects of the MAN-LPs are evaluated on dextran sulfate sodium (DSS)-induced IBD mouse. Compared to unmodified liposome, MAN-LPs display higher uptake by RAW 264.7 cells and better co-localization with macrophage in zebrafish model. Furthermore, MAN-LPs could effectively accumulate in the inflammatory intestinal sites in IBD mouse model. Most importantly, the targeting ability of MAN-LPs is obviously enhanced with the increasing of particle size, whereas the largest MAN-LPs particles achieve the best anti-inflammatory effect in cells, and a higher therapeutic efficiency in IBD mouse model. Therefore, mannose-modified liposome is a promising strategy for macrophage-targeting in IBD treatment. Particle size of MAN-LPs will affect macrophage targeting ability, as well as the therapeutic effect in-vivo.展开更多
The World Health Organization has predicted that neurodegenerative diseases affecting the motor function will become the second most prevalent cause of death in the next 20 years.New therapies can result from three ma...The World Health Organization has predicted that neurodegenerative diseases affecting the motor function will become the second most prevalent cause of death in the next 20 years.New therapies can result from three main sources:synthetic compounds,natural products,and existing drugs.Parkinson’s disease(PD)is a common neurodegenerative disease affecting 1–3%of the adult population over 50 years of age worldwide.It is initially characterized by the death of dopaminergic neurons in the substantia nigra pars compact and later by the widespread loss of nondopaminergic neurons,including those in the cortex.展开更多
Intracerebral injections of tracers or viral constructs in rodents are now commonly used in the neurosciences and must be executed perfectly. The purpose of this article is to update existing protocols for intracerebr...Intracerebral injections of tracers or viral constructs in rodents are now commonly used in the neurosciences and must be executed perfectly. The purpose of this article is to update existing protocols for intracerebral injections in adult and neonatal mice. Our procedure for stereotaxic injections in adult mice allows the investigator to improve the effectiveness and safety, and save time. Furthermore, for the first time, we describe a two-handed procedure for intracerebral injections in neonatal mice that can be performed by a single operator in a very short time. Our technique using the stereotaxic arm allows a higher precision than freehand techniques previously described. Stereotaxic injections in adult mice can be performed in 20 min and have 〉90% efficacy in targeting the injection site. Injections in neonatal mice can be performed in 5 min. Efficacy depends on the difficulty of precisely localizing the injection sites, due to the small size of the animal. We describe an innovative, effortless, and reproducible surgical protocol for intracerebral injections in adult and neonatal mice.展开更多
文摘The Institut du Cerveau et de la Moelle epiniere - ICM （Brain ＆ Spine Institute） - is an international brain and spinal cord research center whose innovative concept and structure make ita unique institute of its kind. The ICM brings patients, medics and researchers together with the aim of rapidly develop treatments for disorders of the nervous system and enable patients to benefit from them as quickly as possible. Scientists from different backgrounds and countries come together at the Institute to perform leading-edge research in this area.
基金the Scientific and Technological Research Council of Türkiye(TÜBİTAK)Under the International Postdoctoral Research Fellowship Program(2219),No.1059B192400980the National Postdoctoral Research Fellowship Program(2218),No.122C158.
文摘Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal cells(MSCs)exhibited greater therapeutic efficacy than CD146-MSCs.These cells enhance epithelial repair through nuclear factor kappa B/cyclooxygenase-2-associated paracrine signaling and secretion of pro-angiogenic factors.We concur that MSCs hold significant promise for ARDS treatment;however,the heterogeneity of cell products is a translational barrier.Phenotype-aware strategies,such as CD146 enrichment,standardized potency assays,and extracellular vesicle profiling,are essential for improving the consistency of these studies.Further-more,advanced preclinical models,such as lung-on-a-chip systems,may provide more predictive insights into the therapeutic mechanisms.This article underscores the importance of CD146+MSCs in ARDS,emphasizes the need for precision in defining cell products,and discusses how integrating subset selection into translational pipelines could enhance the clinical impact of MSC-based therapies.
基金financed by the Funda?ao para a Ciencia e a Tecnologia(FCT)through the project UIDP/04292/2020(https://doi.org/10.54499/UIDP/04292/2020)UIDB/04292/2020(https://doi.org/10.54499/UIDB/04292/2020)+2 种基金awarded to MARE and through project LA/P/0069/2020(https://doi.org/10.54499/LA/P/0069/2020)granted to the Associate Laboratory ARNETfunded by the European Space Agency through the SMOS Expert Support Laboratory(ESL)for SMOS Level 2 over land,ocean,ice[4000130567/20/I-BG]MCIN/AEI/10.13039/501,100,011,033 through the project INTERACT[PID2020-114623RB-C31]。
文摘The variability of the sea surface salinity measurements provided by the Soil Moisture and Ocean Salinity mission reveals the presence of a local salinity maximum(a salty tongue)in the northwestern tropical Atlantic.The sea surface salinity positive anomaly starts increasing in July,reaches its maximum in January,and then disappears.The local maximum of salinity appears in the late boreal autumn/winter,when the Amazon discharge is minimal and the salty water from the South Atlantic is transported by the North Brazil Current along the shelf break across the equator.The authors validate the satellite observations in this area and assess the vertical structure of the salinity maximum by using in situ measurements and an in situ-interpolated product.
文摘Gastric and esophageal adenocarcinomas are one of the main causes of cancer-related death worldwide. While the incidence of gastric adenocarcinoma is decreasing, the incidence of gastroesophageal junction adenocarcinoma is rising rapidly in Western countries. Considering that surgical resection is currently the major curative treatment, and that the 5-year survival rate highly depends on the p TNM stage at diagnosis, gastroesophageal adenocarcinoma management is very challenging for oncologists. Several treatment strategies are being evaluated, and among them systemic chemotherapy, to decrease recurrences and improve overall survival. The MAGIC and FNCLCCFFCD trials showed a survival benefit of perioperative chemotherapy in patients with operable gastric and lower esophageal cancer, and these results had an impact on the European clinical practice. New strategies, including induction chemotherapy followed by preoperative chemoradiotherapy, targeted therapies in combination with perioperative chemotherapy and the new cytotoxic regimens, are currently assessed to improve current standards and help developing patienttailored therapeutic interventions.
基金financially supported by the Universityof Macao Research Grant (MYRG2016-00038-ICMS-QRCM &MYRG2016-00040-ICMS-QRCM)Macao Science and Technology Development Fund (FDCT) (Grant No. 103/2015/A3)the National Natural Science Foundation of China (Grant No. 61562011 )
文摘Oral disintegrating tablets(ODTs) are a novel dosage form that can be dissolved on thetongue within 3 min or less especially for geriatric and pediatric patients. Current ODT for-mulation studies usually rely on the personal experience of pharmaceutical experts andtrial-and-error in the laboratory, which is inefficient and time-consuming. The aim of cur-rent research was to establish the prediction model of ODT formulations with direct com-pression process by artificial neural network(ANN) and deep neural network(DNN) tech-niques. 145 formulation data were extracted from Web of Science. All datasets were dividedinto three parts: training set(105 data), validation set(20) and testing set(20). ANN andDNN were compared for the prediction of the disintegrating time. The accuracy of the ANNmodel have reached 85.60%, 80.00% and 75.00% on the training set, validation set and testingset respectively, whereas that of the DNN model were 85.60%, 85.00% and 80.00%, respec-tively. Compared with the ANN, DNN showed the better prediction for ODT formulations.It is the first time that deep neural network with the improved dataset selection algorithmis applied to formulation prediction on small data. The proposed predictive approach couldevaluate the critical parameters about quality control of formulation, and guide researchand process development. The implementation of this prediction model could effectivelyreduce drug product development timeline and material usage, and proactively facilitatethe development of a robust drug product.
文摘Background: There is currently no drug or therapy that cures COVID-19, a highly contagious and life-threatening disease.Objective: This systematic review and meta-analysis summarized contemporary studies that report the use of Chinese herbal medicine(CHM) to treat COVID-19.Search strategy: Six electronic databases(PubMed/MEDLINE, Cochrane Library, ScienceDirect, Google Scholar, Wanfang Data and China National Knowledge Infrastructure) were searched from their beginning to May 15, 2020 with the following search terms: traditional Chinese medicine, Chinese medicine,Chinese herbal medicine, COVID-19, new coronavirus pneumonia, SARS-CoV-2, and randomized controlled trial.Inclusion criteria: Randomized controlled trials(RCTs) from peer-reviewed journals and non-reviewed publications were included. Further, included RCTs had a control group that was given standard care(SC;such as conventional Western medicine treatments or routine medical care), and a treatment group that was given SC plus CHM.Data extraction and analysis: Two evaluators screened and collected literature independently;information on participants, study design, interventions, follow-up and adverse events were extracted, and risk of bias was assessed. The primary outcomes included scores that represented changes in symptoms and signs over the course of treatment. Secondary outcomes included the level of inflammatory markers, improvement of pneumonia confirmed by computed tomography(CT), and adverse events. Dichotomous data were expressed as risk ratio or hazard ratio with 95% confidence interval(CI);where time-to-event analysis was used, outcomes were expressed as odds ratio with 95% CI. Continuous data were expressed as difference in means(MD) with 95% CI, and standardized mean difference(SMD) was used when different outcome scales were pooled.Results: Seven original studies, comprising a total of 732 adults, were included in this meta-analysis.Compared to SC alone, CHM plus SC had a superior effect on the change of symptom and sign score(-1.30 by SMD, 95% CI [-2.43, -0.16];3 studies;n = 261, P = 0.03), on inflammatory marker C-reactive protein(CRP, mg/L;-11.82 by MD, 95% CI [-17.95, -5.69];5 studies;n = 325, P = 0.0002),on number of patients with improved lung CT scans(1.34 by risk ratio, 95% CI [1.19, 1.51];4 studies;n = 489, P < 0.00001). No significant adverse events were recorded in the included RCTs.Conclusion: Current evidence shows that CHM, as an adjunct treatment with standard care, helps to improve treatment outcomes in COVID-19 cases.
文摘In this paper,the combined addition of copper or iron and sulphate ions onto TiO_(2) prepared by a simple sol-gel method is studied for formic acid photocatalytic conversion.A wide structural and morphological characterization of the different photocatalysts was performed by X-ray diffraction(XRD),N_(2)-physisorption for BET surface area measurements,scanning and transmission electronic microscopies(SEM and TEM),UV-Vis diffuse spectroscopy(DRS)and X-ray photoelectron spectroscopy(XPS),in order to correlate the physico-chemical properties of the materials to their photocatalytic efficiencies for formic acid oxidation.Results have shown important differences among the catalysts depending on the metal added.Sulphated TiO_(2)/Cu(1%Cu)was the best photocatalyst obtaining about 100% formic acid conversion in only 5 min.The appropriate physico-chemical features of this photocatalyst,given by the addition of combined copper and sulphate ions,explain its excellence in photocatalytic reaction.
基金supported by the University of Macao Research Grants(MYRG2016-00038-ICMS-QRCM and MYRG2016-00040-ICMS-QRCM)in part at the High-Performance Computing Cluster(HPCC)which is supported by Information and Communication Technology Office(ICTO)of the University of Macao
文摘Cyclodextrin complexation is a wise strategy to enhance aqueous solubility of waterinsoluble drugs.However,the aggregation mechanism of drug-cyclodextrin complexes is still unclear.This research aimed to investigate the molecular aggregation mechanism of glipizide/cyclodextrin complexation by the combination of experimental and modeling methods.Binding free energies between glipizide and cyclodextrins from modeling calculations were higher than those by the phase solubility diagram method.Both experimental and modeling results showed that methylated-β-cyclodextrin exhibited the best solubilizing capability to glipizide.Size-measurement results confirmed the aggregation between glipizide and all four cyclodextrins in high concentrations.Glipizide/γ-cyclodextrin and glipizide/β-cyclodextrin complexes showed stronger aggregation trend than HP-β-cyclodextrin and methylated-β-cyclodextrin.The substituted groups in the rim of HP-β-cyclodextrin and methylated-β-cyclodextrin lead to weak aggregation.This research provided us a clear molecular mechanism of glipizide/cyclodextrin complexation and aggregation.This research will also benefit the formulation development of cyclodextrin solubilization.
基金financially supported by the FDCT Project 0029/2018/A1the University of Macao Research Grants(MYRG2019-00041-ICMS)performed in part at the High-Performance Computing Cluster(HPCC)which is supported by Information and Communication Technology Office(ICTO)of the University of Macao。
文摘Current formulation development strongly relies on trial-and-error experiments in the laboratory by pharmaceutical scientists,which is time-consuming,high cost and waste materials.This research aims to integrate various computational tools,including machine learning,molecular dynamic simulation and physiologically based absorption modeling(PBAM),to enhance andrographolide(AG)/cyclodextrins(CDs)formulation design.The light GBM prediction model we built before was utilized to predict AG/CDs inclusion's binding free energy.AG/γ-CD inclusion complexes showed the strongest binding affinity,which was experimentally validated by the phase solubility study.The molecular dynamic simulation was used to investigate the inclusion mechanism between AG andγ-CD,which was experimentally characterized by DSC,FTIR and NMR techniques.PBAM was applied to simulate the in vivo behavior of the formulations,which were validated by cell and animal experiments.Cell experiments revealed that the presence of D-α-Tocopherol polyethylene glycol succinate(TPGS)significantly increased the intracellular uptake of AG in MDCKMDR1 cells and the absorptive transport of AG in MDCK-MDR1 monolayers.The relative bioavailability of the AG-CD-TPGS ternary system in rats was increased to 2.6-fold and 1.59-fold compared with crude AG and commercial dropping pills,respectively.In conclusion,this is the first time to integrate various computational tools to develop a new AG-CD-TPGS ternary formulation with significant improvement of aqueous solubility,dissolution rate and bioavailability.The integrated computational tool is a novel and robust methodology to facilitate pharmaceutical formulation design.
基金the Macao Science and Technology Development Fund(No.0086/2021/A2)Shenzhen Fundamental Research Program(No.SGDX20210823103804030)+1 种基金the 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund(Guangdong-Hong Kong-Macao Joint Lab,No.2020B1212030006)Guangdong Basic and Applied Basic Research Foundation(No.2022A1515012416).
文摘Inflammatory bowel disease (IBD) is a refractory chronic intestinal inflammatory disease caused by a malfunction of immune system. As the key immune cells in the intestine, macrophages play an important role in maintaining intestinal homeostasis and tissue repair of the IBD. Pharmacological modulation of macrophage function exhibits the promising therapeutic effect for IBD. In this study, mannose-modified liposomes (MAN-LPs) are prepared for macrophage targeting to improve therapeutic efficiency. Rosiglitazone (ROSI) as an agonist of peroxisome proliferators-activated receptor γ (PPAR-γ) is used as the model drug to fabricate different sized liposomes. The impacts of mannose modification and particle size for macrophage targeting are investigated in cells, zebrafish, and mouse models and the therapeutic effects of the MAN-LPs are evaluated on dextran sulfate sodium (DSS)-induced IBD mouse. Compared to unmodified liposome, MAN-LPs display higher uptake by RAW 264.7 cells and better co-localization with macrophage in zebrafish model. Furthermore, MAN-LPs could effectively accumulate in the inflammatory intestinal sites in IBD mouse model. Most importantly, the targeting ability of MAN-LPs is obviously enhanced with the increasing of particle size, whereas the largest MAN-LPs particles achieve the best anti-inflammatory effect in cells, and a higher therapeutic efficiency in IBD mouse model. Therefore, mannose-modified liposome is a promising strategy for macrophage-targeting in IBD treatment. Particle size of MAN-LPs will affect macrophage targeting ability, as well as the therapeutic effect in-vivo.
基金supported by Grants PIP 0906CO from CONICETPICT 3776 from Agencia Nacional de Promoción Científica y Tecnológica(ANPCyT)CIUNSa 2530/0 from Universidad Nacional de Salta and PIUNT D641/1(all to LA)
文摘The World Health Organization has predicted that neurodegenerative diseases affecting the motor function will become the second most prevalent cause of death in the next 20 years.New therapies can result from three main sources:synthetic compounds,natural products,and existing drugs.Parkinson’s disease(PD)is a common neurodegenerative disease affecting 1–3%of the adult population over 50 years of age worldwide.It is initially characterized by the death of dopaminergic neurons in the substantia nigra pars compact and later by the widespread loss of nondopaminergic neurons,including those in the cortex.
基金supported by the French Society of Neurosurgery (B.M.)by an ANR Grant JCJC R10206DD (D.F.)
文摘Intracerebral injections of tracers or viral constructs in rodents are now commonly used in the neurosciences and must be executed perfectly. The purpose of this article is to update existing protocols for intracerebral injections in adult and neonatal mice. Our procedure for stereotaxic injections in adult mice allows the investigator to improve the effectiveness and safety, and save time. Furthermore, for the first time, we describe a two-handed procedure for intracerebral injections in neonatal mice that can be performed by a single operator in a very short time. Our technique using the stereotaxic arm allows a higher precision than freehand techniques previously described. Stereotaxic injections in adult mice can be performed in 20 min and have 〉90% efficacy in targeting the injection site. Injections in neonatal mice can be performed in 5 min. Efficacy depends on the difficulty of precisely localizing the injection sites, due to the small size of the animal. We describe an innovative, effortless, and reproducible surgical protocol for intracerebral injections in adult and neonatal mice.
