Objectives:The five-year survival rate for pancreatic cancer is notably low,posing a significant challenge to patient health.The primary treatments are radiotherapy and chemotherapy,sometimes combined with targeted th...Objectives:The five-year survival rate for pancreatic cancer is notably low,posing a significant challenge to patient health.The primary treatments are radiotherapy and chemotherapy,sometimes combined with targeted therapy;however,their clinical benefits are limited.Therefore,developing new models to evaluate the therapeutic potential of novel molecules is essential.Fingolimod and Dimethyl Fumarate(DMF),currently used to treat multiple sclerosis,have recently been shown to have anti-cancer effects in several preclinical tumor models.This study aims to evaluate the therapeutic potential of Fingolimod and DMF in pancreatic cancer by investigating their respective in vitro cytotoxicity and in vivo antitumor effects.Methods:In this study,we evaluated for the first time these two drugs in pancreatic preclinical models in vitro using 3D spheroid tumor models and in vivo,which are compared to two standard-of-care consisting of Gemcitabine and Erlotinib.Results:In vitro,both Fingolimod and DMF induced cytotoxicity in spheroids from two pancreatic cell lines.Additionally,Fingolimod and DMF displayed anticancer effects in two subcutaneous xenograft models using PANC-1 and CFPAC-1 cells.Conclusions:Although the responses observed with Fingolimod and DMF were similar to those of Gemcitabine and Erlotinib,these findings indicate a potential emerging interest in Fingolimod and DMF for the treatment of pancreatic cancer.However,further work is still necessary to fully characterize how these drugs affect tumor progression.展开更多
Alzheimer’s disease(AD)remains an incurable neurodegenerative disorder with devastating societal and personal impacts.Despite decades of intensive research,therapeutic efforts targeting the clinical stages of AD have...Alzheimer’s disease(AD)remains an incurable neurodegenerative disorder with devastating societal and personal impacts.Despite decades of intensive research,therapeutic efforts targeting the clinical stages of AD have largely failed to halt or reverse disease progression.This has prompted a critical shift in focus toward the earlier,preclinical stages of AD,where interventions may hold greater promise for altering the disease trajectory.展开更多
Central poststroke pain(CPSP)is a medical complication that arises poststroke and significantly impacts the quality of life and social functioning of affected individuals.Despite ongoing research,the exact pathomechan...Central poststroke pain(CPSP)is a medical complication that arises poststroke and significantly impacts the quality of life and social functioning of affected individuals.Despite ongoing research,the exact pathomechanisms of CPSP remain unclear,and practical treatments are still unavailable.Our review aims to systematically analyse current clinical and preclinical studies on CPSP,which is critical for identifying gaps in knowledge and guiding the development of effective therapies.The review will clarify the clinical characteristics,evaluation scales and contemporary therapeutic approaches for CPSP based on clinical investigations.It will particularly emphasise the CPSP model initiated by stroke,shedding light on its underlying mechanisms and evaluating treatments validated in preclinical studies.Furthermore,the review will not only highlight methodological limitations in animal trials but also offer specific recommendations to researchers to improve the quality of future investigations and guide the development of effective therapies.This review is expected to provide valuable insights into the current knowledge regarding CPSP and can serve as a guide for future research and clinical practice.The review will contribute to the scientific understanding of CPSP and help develop effective clinical interventions.展开更多
Lymph node metastasis(LNM)is a crucial risk factor influencing an unfavorable prognosis in specific cancers.Fundamental research illuminates our understanding of tumor behavior and identifies valuable therapeutic targ...Lymph node metastasis(LNM)is a crucial risk factor influencing an unfavorable prognosis in specific cancers.Fundamental research illuminates our understanding of tumor behavior and identifies valuable therapeutic targets.Nevertheless,the exploration of fundamental theories and the validation of clinical therapies hinge on preclinical experiments.Preclinical models,in this context,serve as the conduit connecting fundamental theories to clinical outcomes.In vivo models established in animals offer a valuable platform for comprehensively observing interactions between tumor cells and organisms.Using various experimental animals,including mice,diverse methods,such as carcinogen-induced tumorigenesis,tumor cell line or human tumor transplantation,genetic engineering,and humanization,have been used effectively to construct numerous models for tumor LNM.Carcinogen-induced models simulate the entire process of tumorigenesis and metastasis.Transplantation models,using human tumor cell lines or patient-derived tumors,offer a research platform closely mirroring the histology and clinical behavior of human tumors.Genetically engineered models have been used to delve into the mechanisms of primary tumorigenesis within an intact microenvironment.Humanized models are used to overcome barriers between human and murine immune systems.Beyond mouse models,various other animal models have unique advantages and limitations,all contributing to exploring LNM.This review summarizes existing in vitro and animal preclinical models,identifies current bottlenecks in preclinical research,and offers an outlook on forthcoming preclinical models.展开更多
Cardamonin is a natural chalcone that has been extensively investigated for its anticancer activity.However,its clinical relevance is still not explicit,limiting its progression into clinical trials and highlighting a...Cardamonin is a natural chalcone that has been extensively investigated for its anticancer activity.However,its clinical relevance is still not explicit,limiting its progression into clinical trials and highlighting a persistent gap between preclinical evidence and practical application.This review aims to assess the readiness of cardamonin to progress from laboratory research to clinical application as an anticancer agent by examining both scientific evidence and translational challenges.Preclinical pharmacokinetic and pharmacodynamic data suggest that cardamonin’s therapeutic potential as an anticancer agent is hindered by its poor oral bioavailability.Although its molecular targets remain undefined,evidence indicates that cardamonin can inhibit various signaling pathways,including nuclear factor kappa-light-chain-enhancer of activated B cells,mammalian target of rapamycin,signal transducer and activator of transcription 3,and Wnt/β-catenin.The lack of in vivo toxicity studies creates uncertainty regarding the balance between its therapeutic benefits and potential adverse effects when moving from laboratory research to human trials.Despite these limitations,cardamonin has,however,demonstrated antiproliferative,anti-metastatic,and chemosensitizing effects,mainly against breast,colorectal,and ovarian cancers.Nevertheless,exploring its combination with standard chemotherapeutic agents may offer a promising foundation for advancing cardamonin into clinical trials.展开更多
Background:Developing a granulomatous liver injury preclinical model may pave the way to understanding hepatic-TB(tuberculosis)and autoimmune granulomatous liver diseases.Antitubercular(ATT)and other drugs'metabol...Background:Developing a granulomatous liver injury preclinical model may pave the way to understanding hepatic-TB(tuberculosis)and autoimmune granulomatous liver diseases.Antitubercular(ATT)and other drugs'metabolism in the presence of a specific type of liver injury is not well understood.The present study aimed to establish a preclinical model of granulomatous hepatitis by using the BCG(Bacillus CalmetteGuérin)vaccine,further studying it in the presence of ATT dosing,and analyze the pharmacokinetics of isoniazid,rifampicin,and their respective primary metabolites.Methods:We used 56 rats in seven equal groups.Group I functioned as a normal control(NC)receiving normal saline only.Groups II-IV received intravenous injections of low-,medium-,and high-dose BCG vaccine daily for 21 days.Groups V,VI,and VII received isoniazid(H)alone,rifampicin(R)alone,and isoniazid+rifampicin(HR)for a subsequent 15 days in addition to high dose BCG for the first 21 days,respectively.Liver function tests(LFT)were monitored on days 0,21,28,and 36.Rats were sacrificed later for oxidative stress and histopathological examination.Results:The study observed BCG dose-specific LFT derangements in groups II-IV compared to group I on day 21(p<0.05).Isoniazid,rifampicin,and combination intervention groups demonstrated normalization of the BCG-led LFT changes.Histology and oxidative stress parameters confirmed model development and biochemical changes.Isoniazid area under the curve(AUC)showed a reduction of 16.9%in BCG+HR group in comparison to the BCG+H group(p=0.01).Des-acetyl-rifampicin AUC and maximum-concentration value demonstrated a significant rise in BCG+HR group in comparison to the BCG+R group(p=0.001).Conclusion:A novel preclinical model of granulomatous liver injury was developed using the BCG vaccine strain and validated with ATT response.展开更多
With diabetes currently affecting 537 million people globally,innovative research approaches are urgently required.Zebrafish(Danio rerio)has emerged as a pivotal model organism in diabetes research,particularly valuab...With diabetes currently affecting 537 million people globally,innovative research approaches are urgently required.Zebrafish(Danio rerio)has emerged as a pivotal model organism in diabetes research,particularly valuable for developmental biology studies and preclinical therapeutic validation.Its rapid life cycle,optical transparency,and genetic tractability collectively enable efficient longitudinal observation of pathological progression and pharmacological responses.Utilizing zebrafish models,researchers have elucidated fundamental mechanisms governing islet development,β-cell dysfunction,and metabolic dysregulation.These experimental systems have significantly advanced our understanding of various diabetes subtypes,including type 1,type 2,gestational,and monogenic forms,while also facilitating mechanistic studies of diabetic complications such as retinopathy and nephropathy.Recent model refinements,particularly in simulating monogenic disorders and pregnancy-associated metabolic changes,promise to deepen our comprehension of disease pathophysiology and therapeutic interventions.Nevertheless,a persistent limitation lies in their incomplete recapitulation of human-specific physiological complexity and multi-organ metabolic interactions,factors that may influence translational applicability.Despite these constraints,zebrafish-based research continues to provide an indispensable platform for diabetes investigation,holding significant promise for alleviating the escalating global burden of this metabolic disorder.展开更多
Background:Multiple sclerosis(MS)is a chronic disease of the central nervous system(CNS),exhibiting hallmarks of both inflammation and neurodegeneration and with limited treatment options.The intricate nature of MS pa...Background:Multiple sclerosis(MS)is a chronic disease of the central nervous system(CNS),exhibiting hallmarks of both inflammation and neurodegeneration and with limited treatment options.The intricate nature of MS pathophysiology and its variable progression pose severe challenges for the development of effective therapies.The experimental autoimmune encephalomyelitis(EAE)MS model,in its most common form,is an aggressive disease,which is not representative of the MS course and offers a limited time window for drug evaluation.This study aimed to generate an attenuated EAE variant,which extends the clinical testing window while preserving the high incidence of the standard EAE model.Methods:Components of the EAE induction protocol were titrated to develop a milder disease profile.In a subsequent drug trial using the MS medication fingolimod hydrochloride(FTY,Gilenya),the new variant was validated under prophylactic and therapeutic treatment regimens.Results:The attenuated EAE variant retains the standard hallmarks of neuroinflammation and,crucially,significantly extends the time frame for clinical drug testing.Unlike the standard variant,where FTY efficacy could only be demonstrated by prophylactic treatment,the attenuated variant facilitated differentiation of drug effects by therapeutic treatment initiated early in the acute phase of disease.Conclusion:The new EAE variant is suitable for use in preclinical assessment of candidate therapeutics and the identification of targetable molecular mechanisms underpinning disease development and progression.This study illustrates the importance of optimizing and refining the experimental tool to enhance the translational success of the candidate therapeutics for MS.展开更多
Any new report on the anticancer properties of natural products always awakens new satisfaction and hope about the role of the international scientific community in its continuous contributions to human health,particu...Any new report on the anticancer properties of natural products always awakens new satisfaction and hope about the role of the international scientific community in its continuous contributions to human health,particularly when those reports contribute to both the understanding and therapeutics of cancer.For many de-cades,natural products have been pivotal in drug discovery programs because they offer a diverse array of anticancer therapeutic possibilities.Recently,two manuscripts published in the World Journal of Gastrointestinal Oncology added new data to the already extensive body of anticancer preclinical evidence for resvera-trol and senegenin,two compounds widely present in herbal preparations used in traditional Chinese medicine.The first one,with comprehensive and recognized anticancer properties,and the second one,shows a compelling body of evidence supporting its neuroprotective effects,but with emerging anticancer activities.Natural products have become key elements in the expanding and dynamic field of anticancer drug discovery.However,urgent and collective efforts are still needed to bridge the gap between preclinical and clinical research and thus bring new anticancer therapeutic breakthroughs.展开更多
Fibroblast activation protein(FAP)is overexpressed in cancer-associated fibroblasts across various cancer types.Numerous radiolabeled FAP inhibitors(FAPIs)(Fig.S1A)currently under clinical investigation have shown rem...Fibroblast activation protein(FAP)is overexpressed in cancer-associated fibroblasts across various cancer types.Numerous radiolabeled FAP inhibitors(FAPIs)(Fig.S1A)currently under clinical investigation have shown remarkable potential in cancer theranostics.展开更多
Oroxylin A(OA)is a natural flavonoid primarily derived from the plants Oroxylum indicum and Scutellaria baicalensis.Currently,OA is obtainable through chemical synthesis and exhibits polypharmacological properties,inc...Oroxylin A(OA)is a natural flavonoid primarily derived from the plants Oroxylum indicum and Scutellaria baicalensis.Currently,OA is obtainable through chemical synthesis and exhibits polypharmacological properties,including anti-cancer,anti-inflammatory,anti-microbial,and multi-organ protective effects.The first-in-class drug OA tablets are presently undergoing phase Ib/IIa clinical trials for hepatocellular carcinoma(HCC)treatment.Substantial evidence suggests that OA demonstrates therapeutic potential against various hepatic and gastrointestinal(GI)disorders,including HCC,hepatic fibrosis,fatty liver disease,hepatitis,liver injury,colitis,and colorectal cancer(CRC).OA exerts its therapeutic effects primarily by modulating several crucial signaling pathways,including those associated with apoptosis,oxidative stress,inflammation,glucolipid metabolism,and fibrosis activation.The oral pharmacokinetics of OA is characterized by phase II metabolism,hydrolysis,and enterohepatic recycling.This review provides a comprehensive overview of the critical stages involved in the development of OA tablets,presenting a holistic perspective on the progression of this first-in-class drug from preclinical to clinical phases.It encompasses the synthesis of active pharmaceutical ingredients,pharmacokinetics,pharmacological efficacy,toxicology,drug delivery,and recent advancements in clinical trials.Importantly,this review examines the potential mechanisms by which OA may influence the gut-liver axis,hypothesizing that these interactions may confer health benefits associated with OA that transcend the limitations posed by its poor bioavailability.展开更多
BACKGROUND Acute liver failure(ALF) has a high mortality varying from 80% to 85% with rapid progress in multi-organ system failure. Bioartificial liver(BAL) support systems have the potential to provide temporary supp...BACKGROUND Acute liver failure(ALF) has a high mortality varying from 80% to 85% with rapid progress in multi-organ system failure. Bioartificial liver(BAL) support systems have the potential to provide temporary support to bridge patients with ALF to liver transplantation or spontaneous recovery. In the past decades, several BAL support systems have been conducted in clinical trials. More recently,concerns have been raised on the renovation of high-quality cell sources and configuration of BAL support systems to provide more benefits to ALF models in preclinical experiments.AIM To investigate the characteristics of studies about BAL support systems for ALF,and to evaluate their effects on mortality.METHODS Eligible clinical trials and preclinical experiments on large animals were identified on Cochrane Library, PubMed, and EMbase up to March 6, 2019. Two reviewers independently extracted the necessary information, including key BAL indicators, survival and indicating outcomes, and adverse events during treatment. Descriptive analysis was used to identify the characteristics of the included studies, and a meta-analysis including only randomized controlled trial (RCT) studies was done to calculate the overall effect of BAL on mortality among humans and large animals, respectively.RESULTS Of the 30 selected studies, 18 were clinical trials and 12 were preclinical experiments. The meta-analysis result suggested that BAL might reduce mortality in ALF in large animals, probably due to the recent improvement of BAL, including the type, cell source, cell mass, and bioreactor, but seemed ineffective for humans (BAL vs control: relative risk(95% confidence interval),0.27(0.12-0.62) for animals and 0.72(0.48-1.08) for humans)Liver and renal functions, hematologic and coagulative parameters, encephalopathy index, and neurological indicators seemed to improve after BAL, with neither meaningful adverse events nor porcine endogenous retrovirus infection.CONCLUSION BAL may reduce the mortality of ALF by bridging the gap between preclinical experiments and clinical trials. Clinical trials using improved BAL must be designed scientifically and conducted in the future to provide evidence for transformation.展开更多
Hepatic encephalopathy(HE) is a major complication that is closely related to the progression of end-stage liver disease.Metabolic changes in advanced liver failure can promote cognition impairment,attention deficits ...Hepatic encephalopathy(HE) is a major complication that is closely related to the progression of end-stage liver disease.Metabolic changes in advanced liver failure can promote cognition impairment,attention deficits and motor dysfunction that may result in coma and death.HE can be subdivided according to the type of hepatic injury,namely,type A,which results from acute liver failure,type B,which is associated with a portosystemic shunting without intrinsic liver disease,and type C,which is due to chronic liver disease.Several studies have investigated the pathogenesis of the disease,and most of the mechanisms have been explored using animal models.This article aimed to review the use of preclinical models to investigate HE.The most used animal species are rats and mice.Experimental models of type A HE include surgical procedures and the administration of hepatotoxic medications,whereas models of types B and C HE are generally surgically induced lesions in liver tissue,which evolve to hepatic cirrhosis.Preclinical models have allowed the comprehension of the pathways related to HE.展开更多
Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's disease.These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced ...Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's disease.These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease.There is also evidence suppo rting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease,such as mood deflection,cognitive impairment,sleep disturbances,and fatigue.Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors,particularly glial cell line-derived neurotrophic factor,which suppo rt dopaminergic neurons.Besides,safinamide may interfere with neurodegenerative mechanisms,countera cting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity.Due to the dual mechanism of action,the new generation of type-B monoamine oxidase inhibitors,including safinamide,is gaining interest in other neurological pathologies,and many supporting preclinical studies are now available.The potential fields of application concern epilepsy,Duchenne muscular dystrophy,multiple scle rosis,and above all,ischemic brain injury.The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline,rasagiline,and safinamide in Parkinson's disease and beyond,focusing on possible future therapeutic applications.展开更多
Objective: Bergenia ciliata(Haw.) Sternb. is used in the Indian traditional system of medicine to treat various ailments including rheumatism and to heal wounds. The objective of the present study was to perform a pre...Objective: Bergenia ciliata(Haw.) Sternb. is used in the Indian traditional system of medicine to treat various ailments including rheumatism and to heal wounds. The objective of the present study was to perform a preclinical characterization of the B. ciliata-based botanical extract IIIM-160.Methods: ⅢM-160 was chemically standardized and analyzed for heavy metal content, aflatoxins,pesticides and microbial load. The in vitro and in vivo efficacies were determined in suitable models of inflammation, arthritis and nociception. An acute oral toxicity study was performed in Swiss albino mice.A suitable oral formulation was developed and characterized.Results: Bergenin was found to be the major component(9.1% w/w) of ⅢM-160. The botanical lead displayed inhibition of lipopolysaccharide-induced production of proinflammatory cytokines in THP-1 cells, with selectivity toward interleukin-6(IL-6) and had an excellent safety-window. It showed anti-inflammatory, anti-arthritic and antinociceptive activity in animal models and was not toxic at oral doses up to 2 g/kg in Swiss-albino mice. The gastroretentive, sustained-release capsule formulation showed sustained-release of the bergenin over the period of 24 h, resulting in improved plasma-exposure of bergenin in Sprague–Dawley rats.Conclusion: The dual-activity of IL-6 inhibition and antinociception marks the suitability of ⅢM-160 for treating rheumatoid arthritis. This study will serve as the benchmark for further research on this botanical formulation.展开更多
Despite the impressive efficacies demonstrated in preclinical research,hundreds of potentially neuroprotective drugs have failed to provide effective neuroprotec-tion for ischemic stroke in human clinical trials.Lack ...Despite the impressive efficacies demonstrated in preclinical research,hundreds of potentially neuroprotective drugs have failed to provide effective neuroprotec-tion for ischemic stroke in human clinical trials.Lack of a powerful animal model for human ischemic stroke could be a major reason for the failure to develop successful neuroprotective drugs for ischemic stroke.This review recapitulates the available cerebral ischemia animal models,provides an anatomical comparison of the circle of Willis of each species,and describes the functional assessment tests used in these ischemic stroke models.The distinct differences between human ischemic stroke and experimental stroke in available animal models is explored.Innovative animal models more closely resembling human strokes,better techniques in functional out-come assessment and better experimental designs generating clearer and stronger evidence may help realise the development of truly neuroprotective drugs that will benefit human ischemic stroke patients.This may involve use of newer molecules or revisiting earlier studies with new experimental designs.Translation of any resultant successes may then be tested in human clinical trials with greater confidence and optimism.展开更多
Background : Cynomolgus disease models that are similar to the preclinical stage of human type 2 diabetes mellitus(T2 DM) were established by feeding middle-aged cynomolgus monkeys different high energy diets to study...Background : Cynomolgus disease models that are similar to the preclinical stage of human type 2 diabetes mellitus(T2 DM) were established by feeding middle-aged cynomolgus monkeys different high energy diets to study the differential expression of diabetes-related genes. Methods : A total of 36 male monkeys were randomly divided into four groups and fed human diets with high sugar, high fat, double high sugar and fat, and a normal diet. The preclinical diabetes phase was determined by monitoring the metabolic characteristic indices and the results of oral glucose tolerance tests( OGTT). The mRNA expression of 45 diabetes-related genes in peripheral blood leukocytes was analyzed using real-time PCR. Results : A total of 22, 25, and 21 genes were significantly up-regulated( P < 0.05) and 5, 7, and 5 genes were significantly down-regulated( P < 0.05) in the above three induced groups, respectively, compared with the control group. Of the 45 tested genes, the expression profiles of 21 genes were consistent. Most of the expression levels in the double high sugar-and-fat individuals were slightly lower than those in the high glucose and high fat groups, although the expression patterns of the three groups were essentially similar. Conclusion : The different high energy diets all induced diabetes and shared some phenotypic properties with human T2 DM. Most of the expression patterns of the related genes were identical. The gene expression profiles could be used as references for the study of early diagnostic indicators and T2 DM pathogenesis.展开更多
Anodal transcranial direct current stimulation(AtDCS)has been shown to alleviate cognitive impairment in an APP/PS1 model of Alzheimer’s disease in the preclinical stage.However,this enhancement was only observed imm...Anodal transcranial direct current stimulation(AtDCS)has been shown to alleviate cognitive impairment in an APP/PS1 model of Alzheimer’s disease in the preclinical stage.However,this enhancement was only observed immediately after AtDCS,and the long-term effect of AtDCS remains unknown.In this study,we treated 26-week-old mouse models of Alzheimer’s disease in the preclinical stage with 10 AtDCS sessions or sham stimulation.The Morris water maze,novel object recognition task,and novel object location test were implemented to evaluate spatial learning memory and recognition memory of mice.Western blotting was used to detect the relevant protein content.Morphological changes were observed using immunohistochemistry and immunofluorescence staining.Six weeks after treatment,the mice subjected to AtDCS sessions had a shorter escape latency,a shorter path length,more platform area crossings,and spent more time in the target quadrant than sham-stimulated mice.The mice subjected to AtDCS sessions also performed better in the novel object recognition and novel object location tests than sham-stimulated mice.Furthermore,AtDCS reduced the levels of amyloid-β42 and glial fibrillary acidic protein,a marker of astrocyte activation,and increased the level of neuronal marker NeuN in hippocampal tissue.These findings suggest that AtDCS can improve the spatial learning and memory abilities and pathological state of an APP/PS1 mouse model of Alzheimer’s disease in the preclinical stage,with improvements that last for at least 6 weeks.展开更多
Pancreatic cancer carries a terrible prognosis,as the fourth most common cause of cancer death in the Western world.There is clearly a need for new therapies to treat this disease.One of the reasons no effective treat...Pancreatic cancer carries a terrible prognosis,as the fourth most common cause of cancer death in the Western world.There is clearly a need for new therapies to treat this disease.One of the reasons no effective treatment has been developed in the past decade may in part,be explained by the diverse influences exerted by the tumour microenvironment.The tumour stroma cross-talk in pancreatic cancer can influence chemotherapy delivery and response rate.Thus,appropriate preclinical in vitro models which can bridge simple 2D in vitro cell based assays and complex in vivo models are required to understand the biology of pancreatic cancer.Here we discuss the evolution of 3D organotypic models,which recapitulare the morphological and functional features of pancreatic ductal adenocarcinoma(PDAC).Organotypic cultures are a valid high throughput preclinical in vitro model that maybe a useful tool to help establish new therapies for PDAC.A huge advantage of the organotypic model system is that any component of the model can be easily modulated in a short timeframe.This allows new therapies that can target the cancer,the stromal compartment or both to be tested in a model that mirrors the in vivo situation.A major challenge for the future is to expand the cellular composition of the organotypic model to further develop a system that mimics the PDAC environment more precisely.We discuss how this challenge is being met to increase our understanding of this terrible disease and develop novel therapies that can improve the prognosis for patients.展开更多
AIM: To expand hematopoietic/progenitor stem cells (HS/PCs) from umbilical cord blood (UCB) and prepare the HS/PC product, and analyze preclinical transplantation and safety of HS/PC product. METHODS: Human bone marro...AIM: To expand hematopoietic/progenitor stem cells (HS/PCs) from umbilical cord blood (UCB) and prepare the HS/PC product, and analyze preclinical transplantation and safety of HS/PC product. METHODS: Human bone marrow-derived mesenchymal stem cells (MSCs) were used as feeder cells to expand HS/PCs from UCB in a serum-free culture system. The proliferation potential of HS/PCs was analyzed. The expanded HS/PCs were suspended in the L-15 medium to prepare the HS/PC product. The contamination of bacteria, fungi and mycoplasmas, the infection of exogenous virus, the concentration of bacterial endotoxin, and the SCF residual in HS/PC product were determined. Finally, cells from the HS/PC product with or without bone marrow-derived mesenchymal stem cells (BM-MSCs) were transplanted into the irradiated NOD/SCID mice to determine the in vivo engraftment potential. RESULTS: After co-culture for 10 d, the total nuclear cells (TNCs) increased 125-fold, and CD34 + cells increased 43-fold. The granulocyte-macrophage colonyforming cells (GM-CFCs) and erythroid colony-forming cells (E-CFCs) increased 3.3and 4.7-fold respectively. The expanded cells were collected and prepared as the expanded product of HS/PCs by re-suspending cells in L-15 medium. For preclinical safety, the HS/PC product was analysed for contamination by bacteria, fungi and mycoplasmas, the bacterial endotoxin concentration and the SCF content. The results showed that the HS/PC product contained no bacteria, fungi or mycoplasmas. The bacterial endotoxin concentration was less than the detection limit of 6 EU/mL, and residual SCF was 75 pg/mL. Based on clinical safety, the HS/PC product was qualified for clinical transplantation. Finally, the HS/PC product was transplanted the irradiated mice where it resulted in rapid engraftment of hematopoietic cells. CONCLUSION: HSPC product prepared from UCB in the serum-free culture system with hMSCs as feeder cells should be clinically safe and effective for clinical transplantation.展开更多
基金supported by Porsolt SAS,https://www.porsolt.com/.
文摘Objectives:The five-year survival rate for pancreatic cancer is notably low,posing a significant challenge to patient health.The primary treatments are radiotherapy and chemotherapy,sometimes combined with targeted therapy;however,their clinical benefits are limited.Therefore,developing new models to evaluate the therapeutic potential of novel molecules is essential.Fingolimod and Dimethyl Fumarate(DMF),currently used to treat multiple sclerosis,have recently been shown to have anti-cancer effects in several preclinical tumor models.This study aims to evaluate the therapeutic potential of Fingolimod and DMF in pancreatic cancer by investigating their respective in vitro cytotoxicity and in vivo antitumor effects.Methods:In this study,we evaluated for the first time these two drugs in pancreatic preclinical models in vitro using 3D spheroid tumor models and in vivo,which are compared to two standard-of-care consisting of Gemcitabine and Erlotinib.Results:In vitro,both Fingolimod and DMF induced cytotoxicity in spheroids from two pancreatic cell lines.Additionally,Fingolimod and DMF displayed anticancer effects in two subcutaneous xenograft models using PANC-1 and CFPAC-1 cells.Conclusions:Although the responses observed with Fingolimod and DMF were similar to those of Gemcitabine and Erlotinib,these findings indicate a potential emerging interest in Fingolimod and DMF for the treatment of pancreatic cancer.However,further work is still necessary to fully characterize how these drugs affect tumor progression.
基金supported by the Canadian Institutes of Health Research Project grant (PJT-169197) to QYsupported by a CGS-M fellowship from the Canadian Institutes of Health Research
文摘Alzheimer’s disease(AD)remains an incurable neurodegenerative disorder with devastating societal and personal impacts.Despite decades of intensive research,therapeutic efforts targeting the clinical stages of AD have largely failed to halt or reverse disease progression.This has prompted a critical shift in focus toward the earlier,preclinical stages of AD,where interventions may hold greater promise for altering the disease trajectory.
基金supported by the National Natural Science Foundation of China(82371339 and U1704166)the Key Scientific Research Projects of Higher Education Institutions in Henan Province(24A320029).
文摘Central poststroke pain(CPSP)is a medical complication that arises poststroke and significantly impacts the quality of life and social functioning of affected individuals.Despite ongoing research,the exact pathomechanisms of CPSP remain unclear,and practical treatments are still unavailable.Our review aims to systematically analyse current clinical and preclinical studies on CPSP,which is critical for identifying gaps in knowledge and guiding the development of effective therapies.The review will clarify the clinical characteristics,evaluation scales and contemporary therapeutic approaches for CPSP based on clinical investigations.It will particularly emphasise the CPSP model initiated by stroke,shedding light on its underlying mechanisms and evaluating treatments validated in preclinical studies.Furthermore,the review will not only highlight methodological limitations in animal trials but also offer specific recommendations to researchers to improve the quality of future investigations and guide the development of effective therapies.This review is expected to provide valuable insights into the current knowledge regarding CPSP and can serve as a guide for future research and clinical practice.The review will contribute to the scientific understanding of CPSP and help develop effective clinical interventions.
基金supported by the Fundamental Research Funds for the Central Universities(Wuhan University,Clinical Medicine+X,No.2042024YXB017)the Hubei Province Chinese Medicine Research Project(No.ZY2023Q015)+2 种基金the National Natural Science Foundation of China(No.61904057)the Natural Science Foundation of Hubei Province(No.2023AFB665)the Medical Young Talents Program of Hubei Province,Wuhan Young Medical Talents Training Project,China.
文摘Lymph node metastasis(LNM)is a crucial risk factor influencing an unfavorable prognosis in specific cancers.Fundamental research illuminates our understanding of tumor behavior and identifies valuable therapeutic targets.Nevertheless,the exploration of fundamental theories and the validation of clinical therapies hinge on preclinical experiments.Preclinical models,in this context,serve as the conduit connecting fundamental theories to clinical outcomes.In vivo models established in animals offer a valuable platform for comprehensively observing interactions between tumor cells and organisms.Using various experimental animals,including mice,diverse methods,such as carcinogen-induced tumorigenesis,tumor cell line or human tumor transplantation,genetic engineering,and humanization,have been used effectively to construct numerous models for tumor LNM.Carcinogen-induced models simulate the entire process of tumorigenesis and metastasis.Transplantation models,using human tumor cell lines or patient-derived tumors,offer a research platform closely mirroring the histology and clinical behavior of human tumors.Genetically engineered models have been used to delve into the mechanisms of primary tumorigenesis within an intact microenvironment.Humanized models are used to overcome barriers between human and murine immune systems.Beyond mouse models,various other animal models have unique advantages and limitations,all contributing to exploring LNM.This review summarizes existing in vitro and animal preclinical models,identifies current bottlenecks in preclinical research,and offers an outlook on forthcoming preclinical models.
基金Supported by Malaysian Ministry of Higher Education through the Fundamental Research Grant Scheme,No.FP103-2019.
文摘Cardamonin is a natural chalcone that has been extensively investigated for its anticancer activity.However,its clinical relevance is still not explicit,limiting its progression into clinical trials and highlighting a persistent gap between preclinical evidence and practical application.This review aims to assess the readiness of cardamonin to progress from laboratory research to clinical application as an anticancer agent by examining both scientific evidence and translational challenges.Preclinical pharmacokinetic and pharmacodynamic data suggest that cardamonin’s therapeutic potential as an anticancer agent is hindered by its poor oral bioavailability.Although its molecular targets remain undefined,evidence indicates that cardamonin can inhibit various signaling pathways,including nuclear factor kappa-light-chain-enhancer of activated B cells,mammalian target of rapamycin,signal transducer and activator of transcription 3,and Wnt/β-catenin.The lack of in vivo toxicity studies creates uncertainty regarding the balance between its therapeutic benefits and potential adverse effects when moving from laboratory research to human trials.Despite these limitations,cardamonin has,however,demonstrated antiproliferative,anti-metastatic,and chemosensitizing effects,mainly against breast,colorectal,and ovarian cancers.Nevertheless,exploring its combination with standard chemotherapeutic agents may offer a promising foundation for advancing cardamonin into clinical trials.
文摘Background:Developing a granulomatous liver injury preclinical model may pave the way to understanding hepatic-TB(tuberculosis)and autoimmune granulomatous liver diseases.Antitubercular(ATT)and other drugs'metabolism in the presence of a specific type of liver injury is not well understood.The present study aimed to establish a preclinical model of granulomatous hepatitis by using the BCG(Bacillus CalmetteGuérin)vaccine,further studying it in the presence of ATT dosing,and analyze the pharmacokinetics of isoniazid,rifampicin,and their respective primary metabolites.Methods:We used 56 rats in seven equal groups.Group I functioned as a normal control(NC)receiving normal saline only.Groups II-IV received intravenous injections of low-,medium-,and high-dose BCG vaccine daily for 21 days.Groups V,VI,and VII received isoniazid(H)alone,rifampicin(R)alone,and isoniazid+rifampicin(HR)for a subsequent 15 days in addition to high dose BCG for the first 21 days,respectively.Liver function tests(LFT)were monitored on days 0,21,28,and 36.Rats were sacrificed later for oxidative stress and histopathological examination.Results:The study observed BCG dose-specific LFT derangements in groups II-IV compared to group I on day 21(p<0.05).Isoniazid,rifampicin,and combination intervention groups demonstrated normalization of the BCG-led LFT changes.Histology and oxidative stress parameters confirmed model development and biochemical changes.Isoniazid area under the curve(AUC)showed a reduction of 16.9%in BCG+HR group in comparison to the BCG+H group(p=0.01).Des-acetyl-rifampicin AUC and maximum-concentration value demonstrated a significant rise in BCG+HR group in comparison to the BCG+R group(p=0.001).Conclusion:A novel preclinical model of granulomatous liver injury was developed using the BCG vaccine strain and validated with ATT response.
基金Supported by Natural Science Foundation of Zhejiang Province,China,No.LQ24H070007。
文摘With diabetes currently affecting 537 million people globally,innovative research approaches are urgently required.Zebrafish(Danio rerio)has emerged as a pivotal model organism in diabetes research,particularly valuable for developmental biology studies and preclinical therapeutic validation.Its rapid life cycle,optical transparency,and genetic tractability collectively enable efficient longitudinal observation of pathological progression and pharmacological responses.Utilizing zebrafish models,researchers have elucidated fundamental mechanisms governing islet development,β-cell dysfunction,and metabolic dysregulation.These experimental systems have significantly advanced our understanding of various diabetes subtypes,including type 1,type 2,gestational,and monogenic forms,while also facilitating mechanistic studies of diabetic complications such as retinopathy and nephropathy.Recent model refinements,particularly in simulating monogenic disorders and pregnancy-associated metabolic changes,promise to deepen our comprehension of disease pathophysiology and therapeutic interventions.Nevertheless,a persistent limitation lies in their incomplete recapitulation of human-specific physiological complexity and multi-organ metabolic interactions,factors that may influence translational applicability.Despite these constraints,zebrafish-based research continues to provide an indispensable platform for diabetes investigation,holding significant promise for alleviating the escalating global burden of this metabolic disorder.
基金Private DonationLa Trobe Research Focus AreasMultiple Sclerosis Australia,Grant/Award Number:20-032。
文摘Background:Multiple sclerosis(MS)is a chronic disease of the central nervous system(CNS),exhibiting hallmarks of both inflammation and neurodegeneration and with limited treatment options.The intricate nature of MS pathophysiology and its variable progression pose severe challenges for the development of effective therapies.The experimental autoimmune encephalomyelitis(EAE)MS model,in its most common form,is an aggressive disease,which is not representative of the MS course and offers a limited time window for drug evaluation.This study aimed to generate an attenuated EAE variant,which extends the clinical testing window while preserving the high incidence of the standard EAE model.Methods:Components of the EAE induction protocol were titrated to develop a milder disease profile.In a subsequent drug trial using the MS medication fingolimod hydrochloride(FTY,Gilenya),the new variant was validated under prophylactic and therapeutic treatment regimens.Results:The attenuated EAE variant retains the standard hallmarks of neuroinflammation and,crucially,significantly extends the time frame for clinical drug testing.Unlike the standard variant,where FTY efficacy could only be demonstrated by prophylactic treatment,the attenuated variant facilitated differentiation of drug effects by therapeutic treatment initiated early in the acute phase of disease.Conclusion:The new EAE variant is suitable for use in preclinical assessment of candidate therapeutics and the identification of targetable molecular mechanisms underpinning disease development and progression.This study illustrates the importance of optimizing and refining the experimental tool to enhance the translational success of the candidate therapeutics for MS.
文摘Any new report on the anticancer properties of natural products always awakens new satisfaction and hope about the role of the international scientific community in its continuous contributions to human health,particularly when those reports contribute to both the understanding and therapeutics of cancer.For many de-cades,natural products have been pivotal in drug discovery programs because they offer a diverse array of anticancer therapeutic possibilities.Recently,two manuscripts published in the World Journal of Gastrointestinal Oncology added new data to the already extensive body of anticancer preclinical evidence for resvera-trol and senegenin,two compounds widely present in herbal preparations used in traditional Chinese medicine.The first one,with comprehensive and recognized anticancer properties,and the second one,shows a compelling body of evidence supporting its neuroprotective effects,but with emerging anticancer activities.Natural products have become key elements in the expanding and dynamic field of anticancer drug discovery.However,urgent and collective efforts are still needed to bridge the gap between preclinical and clinical research and thus bring new anticancer therapeutic breakthroughs.
基金supported by the grants provided by Zhuhai People's Hospital,China(Grant No.:2021KYQD-03)the National Natural Science Foundation of China(Grant No.:22176016).
文摘Fibroblast activation protein(FAP)is overexpressed in cancer-associated fibroblasts across various cancer types.Numerous radiolabeled FAP inhibitors(FAPIs)(Fig.S1A)currently under clinical investigation have shown remarkable potential in cancer theranostics.
基金supported by the National Natural Science Foundation of China(No.82174027)the Social Development Project of Jiangsu Provincial Key Research and Development Program(No.BE2021782)Qinglan Project of Jiangsu Province.
文摘Oroxylin A(OA)is a natural flavonoid primarily derived from the plants Oroxylum indicum and Scutellaria baicalensis.Currently,OA is obtainable through chemical synthesis and exhibits polypharmacological properties,including anti-cancer,anti-inflammatory,anti-microbial,and multi-organ protective effects.The first-in-class drug OA tablets are presently undergoing phase Ib/IIa clinical trials for hepatocellular carcinoma(HCC)treatment.Substantial evidence suggests that OA demonstrates therapeutic potential against various hepatic and gastrointestinal(GI)disorders,including HCC,hepatic fibrosis,fatty liver disease,hepatitis,liver injury,colitis,and colorectal cancer(CRC).OA exerts its therapeutic effects primarily by modulating several crucial signaling pathways,including those associated with apoptosis,oxidative stress,inflammation,glucolipid metabolism,and fibrosis activation.The oral pharmacokinetics of OA is characterized by phase II metabolism,hydrolysis,and enterohepatic recycling.This review provides a comprehensive overview of the critical stages involved in the development of OA tablets,presenting a holistic perspective on the progression of this first-in-class drug from preclinical to clinical phases.It encompasses the synthesis of active pharmaceutical ingredients,pharmacokinetics,pharmacological efficacy,toxicology,drug delivery,and recent advancements in clinical trials.Importantly,this review examines the potential mechanisms by which OA may influence the gut-liver axis,hypothesizing that these interactions may confer health benefits associated with OA that transcend the limitations posed by its poor bioavailability.
文摘BACKGROUND Acute liver failure(ALF) has a high mortality varying from 80% to 85% with rapid progress in multi-organ system failure. Bioartificial liver(BAL) support systems have the potential to provide temporary support to bridge patients with ALF to liver transplantation or spontaneous recovery. In the past decades, several BAL support systems have been conducted in clinical trials. More recently,concerns have been raised on the renovation of high-quality cell sources and configuration of BAL support systems to provide more benefits to ALF models in preclinical experiments.AIM To investigate the characteristics of studies about BAL support systems for ALF,and to evaluate their effects on mortality.METHODS Eligible clinical trials and preclinical experiments on large animals were identified on Cochrane Library, PubMed, and EMbase up to March 6, 2019. Two reviewers independently extracted the necessary information, including key BAL indicators, survival and indicating outcomes, and adverse events during treatment. Descriptive analysis was used to identify the characteristics of the included studies, and a meta-analysis including only randomized controlled trial (RCT) studies was done to calculate the overall effect of BAL on mortality among humans and large animals, respectively.RESULTS Of the 30 selected studies, 18 were clinical trials and 12 were preclinical experiments. The meta-analysis result suggested that BAL might reduce mortality in ALF in large animals, probably due to the recent improvement of BAL, including the type, cell source, cell mass, and bioreactor, but seemed ineffective for humans (BAL vs control: relative risk(95% confidence interval),0.27(0.12-0.62) for animals and 0.72(0.48-1.08) for humans)Liver and renal functions, hematologic and coagulative parameters, encephalopathy index, and neurological indicators seemed to improve after BAL, with neither meaningful adverse events nor porcine endogenous retrovirus infection.CONCLUSION BAL may reduce the mortality of ALF by bridging the gap between preclinical experiments and clinical trials. Clinical trials using improved BAL must be designed scientifically and conducted in the future to provide evidence for transformation.
文摘Hepatic encephalopathy(HE) is a major complication that is closely related to the progression of end-stage liver disease.Metabolic changes in advanced liver failure can promote cognition impairment,attention deficits and motor dysfunction that may result in coma and death.HE can be subdivided according to the type of hepatic injury,namely,type A,which results from acute liver failure,type B,which is associated with a portosystemic shunting without intrinsic liver disease,and type C,which is due to chronic liver disease.Several studies have investigated the pathogenesis of the disease,and most of the mechanisms have been explored using animal models.This article aimed to review the use of preclinical models to investigate HE.The most used animal species are rats and mice.Experimental models of type A HE include surgical procedures and the administration of hepatotoxic medications,whereas models of types B and C HE are generally surgically induced lesions in liver tissue,which evolve to hepatic cirrhosis.Preclinical models have allowed the comprehension of the pathways related to HE.
文摘Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's disease.These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease.There is also evidence suppo rting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease,such as mood deflection,cognitive impairment,sleep disturbances,and fatigue.Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors,particularly glial cell line-derived neurotrophic factor,which suppo rt dopaminergic neurons.Besides,safinamide may interfere with neurodegenerative mechanisms,countera cting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity.Due to the dual mechanism of action,the new generation of type-B monoamine oxidase inhibitors,including safinamide,is gaining interest in other neurological pathologies,and many supporting preclinical studies are now available.The potential fields of application concern epilepsy,Duchenne muscular dystrophy,multiple scle rosis,and above all,ischemic brain injury.The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline,rasagiline,and safinamide in Parkinson's disease and beyond,focusing on possible future therapeutic applications.
基金financially supported by CSIR 12th Five Year Plan project BSC-0205CSIR-Phytopharmaceutical Mission Project HCP010+1 种基金CSIR-YSA (Young Scientist Award,P90807) Research Grantthe fellowship from Department of Biotechnology,India (GAP-2158).IIIM publication number: ⅢM/2222/2018
文摘Objective: Bergenia ciliata(Haw.) Sternb. is used in the Indian traditional system of medicine to treat various ailments including rheumatism and to heal wounds. The objective of the present study was to perform a preclinical characterization of the B. ciliata-based botanical extract IIIM-160.Methods: ⅢM-160 was chemically standardized and analyzed for heavy metal content, aflatoxins,pesticides and microbial load. The in vitro and in vivo efficacies were determined in suitable models of inflammation, arthritis and nociception. An acute oral toxicity study was performed in Swiss albino mice.A suitable oral formulation was developed and characterized.Results: Bergenin was found to be the major component(9.1% w/w) of ⅢM-160. The botanical lead displayed inhibition of lipopolysaccharide-induced production of proinflammatory cytokines in THP-1 cells, with selectivity toward interleukin-6(IL-6) and had an excellent safety-window. It showed anti-inflammatory, anti-arthritic and antinociceptive activity in animal models and was not toxic at oral doses up to 2 g/kg in Swiss-albino mice. The gastroretentive, sustained-release capsule formulation showed sustained-release of the bergenin over the period of 24 h, resulting in improved plasma-exposure of bergenin in Sprague–Dawley rats.Conclusion: The dual-activity of IL-6 inhibition and antinociception marks the suitability of ⅢM-160 for treating rheumatoid arthritis. This study will serve as the benchmark for further research on this botanical formulation.
基金Science and Engineering Research Board,Grant/Award Number:CRG/2019/002076Council of Scientific and Industrial Research,Grant/Award Number:09/805(0012)/2019-EMR-I。
文摘Despite the impressive efficacies demonstrated in preclinical research,hundreds of potentially neuroprotective drugs have failed to provide effective neuroprotec-tion for ischemic stroke in human clinical trials.Lack of a powerful animal model for human ischemic stroke could be a major reason for the failure to develop successful neuroprotective drugs for ischemic stroke.This review recapitulates the available cerebral ischemia animal models,provides an anatomical comparison of the circle of Willis of each species,and describes the functional assessment tests used in these ischemic stroke models.The distinct differences between human ischemic stroke and experimental stroke in available animal models is explored.Innovative animal models more closely resembling human strokes,better techniques in functional out-come assessment and better experimental designs generating clearer and stronger evidence may help realise the development of truly neuroprotective drugs that will benefit human ischemic stroke patients.This may involve use of newer molecules or revisiting earlier studies with new experimental designs.Translation of any resultant successes may then be tested in human clinical trials with greater confidence and optimism.
基金Science and Technology Planning Project of Guangdong Province,Grant/Award Number:2016A030303037 and 2017A070702014Natural Science Foundation of Guangdong Province,(2018A030313307)+1 种基金National Natural Science Foundation of China,Grant/Award Number:81102358GDAS Special Project of Science and Technology Development,Grant/Award Number:2017GDASCX-0107
文摘Background : Cynomolgus disease models that are similar to the preclinical stage of human type 2 diabetes mellitus(T2 DM) were established by feeding middle-aged cynomolgus monkeys different high energy diets to study the differential expression of diabetes-related genes. Methods : A total of 36 male monkeys were randomly divided into four groups and fed human diets with high sugar, high fat, double high sugar and fat, and a normal diet. The preclinical diabetes phase was determined by monitoring the metabolic characteristic indices and the results of oral glucose tolerance tests( OGTT). The mRNA expression of 45 diabetes-related genes in peripheral blood leukocytes was analyzed using real-time PCR. Results : A total of 22, 25, and 21 genes were significantly up-regulated( P < 0.05) and 5, 7, and 5 genes were significantly down-regulated( P < 0.05) in the above three induced groups, respectively, compared with the control group. Of the 45 tested genes, the expression profiles of 21 genes were consistent. Most of the expression levels in the double high sugar-and-fat individuals were slightly lower than those in the high glucose and high fat groups, although the expression patterns of the three groups were essentially similar. Conclusion : The different high energy diets all induced diabetes and shared some phenotypic properties with human T2 DM. Most of the expression patterns of the related genes were identical. The gene expression profiles could be used as references for the study of early diagnostic indicators and T2 DM pathogenesis.
基金supported by the National Natural Science Foundation of China,No.31971287(to XYW)the Advanced Interdisciplinary Studies Foundation of School of Basic Medical Science,Army Medical University of China,No.2018JCQY07(to HZW).
文摘Anodal transcranial direct current stimulation(AtDCS)has been shown to alleviate cognitive impairment in an APP/PS1 model of Alzheimer’s disease in the preclinical stage.However,this enhancement was only observed immediately after AtDCS,and the long-term effect of AtDCS remains unknown.In this study,we treated 26-week-old mouse models of Alzheimer’s disease in the preclinical stage with 10 AtDCS sessions or sham stimulation.The Morris water maze,novel object recognition task,and novel object location test were implemented to evaluate spatial learning memory and recognition memory of mice.Western blotting was used to detect the relevant protein content.Morphological changes were observed using immunohistochemistry and immunofluorescence staining.Six weeks after treatment,the mice subjected to AtDCS sessions had a shorter escape latency,a shorter path length,more platform area crossings,and spent more time in the target quadrant than sham-stimulated mice.The mice subjected to AtDCS sessions also performed better in the novel object recognition and novel object location tests than sham-stimulated mice.Furthermore,AtDCS reduced the levels of amyloid-β42 and glial fibrillary acidic protein,a marker of astrocyte activation,and increased the level of neuronal marker NeuN in hippocampal tissue.These findings suggest that AtDCS can improve the spatial learning and memory abilities and pathological state of an APP/PS1 mouse model of Alzheimer’s disease in the preclinical stage,with improvements that last for at least 6 weeks.
文摘Pancreatic cancer carries a terrible prognosis,as the fourth most common cause of cancer death in the Western world.There is clearly a need for new therapies to treat this disease.One of the reasons no effective treatment has been developed in the past decade may in part,be explained by the diverse influences exerted by the tumour microenvironment.The tumour stroma cross-talk in pancreatic cancer can influence chemotherapy delivery and response rate.Thus,appropriate preclinical in vitro models which can bridge simple 2D in vitro cell based assays and complex in vivo models are required to understand the biology of pancreatic cancer.Here we discuss the evolution of 3D organotypic models,which recapitulare the morphological and functional features of pancreatic ductal adenocarcinoma(PDAC).Organotypic cultures are a valid high throughput preclinical in vitro model that maybe a useful tool to help establish new therapies for PDAC.A huge advantage of the organotypic model system is that any component of the model can be easily modulated in a short timeframe.This allows new therapies that can target the cancer,the stromal compartment or both to be tested in a model that mirrors the in vivo situation.A major challenge for the future is to expand the cellular composition of the organotypic model to further develop a system that mimics the PDAC environment more precisely.We discuss how this challenge is being met to increase our understanding of this terrible disease and develop novel therapies that can improve the prognosis for patients.
基金Supported by Scientific Foundation of Zhejiang (2009C13020)National Natural Science Foundation of China, No. 30971460
文摘AIM: To expand hematopoietic/progenitor stem cells (HS/PCs) from umbilical cord blood (UCB) and prepare the HS/PC product, and analyze preclinical transplantation and safety of HS/PC product. METHODS: Human bone marrow-derived mesenchymal stem cells (MSCs) were used as feeder cells to expand HS/PCs from UCB in a serum-free culture system. The proliferation potential of HS/PCs was analyzed. The expanded HS/PCs were suspended in the L-15 medium to prepare the HS/PC product. The contamination of bacteria, fungi and mycoplasmas, the infection of exogenous virus, the concentration of bacterial endotoxin, and the SCF residual in HS/PC product were determined. Finally, cells from the HS/PC product with or without bone marrow-derived mesenchymal stem cells (BM-MSCs) were transplanted into the irradiated NOD/SCID mice to determine the in vivo engraftment potential. RESULTS: After co-culture for 10 d, the total nuclear cells (TNCs) increased 125-fold, and CD34 + cells increased 43-fold. The granulocyte-macrophage colonyforming cells (GM-CFCs) and erythroid colony-forming cells (E-CFCs) increased 3.3and 4.7-fold respectively. The expanded cells were collected and prepared as the expanded product of HS/PCs by re-suspending cells in L-15 medium. For preclinical safety, the HS/PC product was analysed for contamination by bacteria, fungi and mycoplasmas, the bacterial endotoxin concentration and the SCF content. The results showed that the HS/PC product contained no bacteria, fungi or mycoplasmas. The bacterial endotoxin concentration was less than the detection limit of 6 EU/mL, and residual SCF was 75 pg/mL. Based on clinical safety, the HS/PC product was qualified for clinical transplantation. Finally, the HS/PC product was transplanted the irradiated mice where it resulted in rapid engraftment of hematopoietic cells. CONCLUSION: HSPC product prepared from UCB in the serum-free culture system with hMSCs as feeder cells should be clinically safe and effective for clinical transplantation.
