Type-B monoamine oxidase inhibitors in neurological diseases:clinical applications based on preclinical findings

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.

Bioartificial liver support systems for acute liver failure: A systematic review and meta-analysis of the clinical and preclinical literature

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.

Hepatic encephalopathy:Lessons from preclinical studies

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.

Anodal transcranial direct current stimulation alleviates cognitive impairment in an APP/PS1 model of Alzheimer’s disease in the preclinical stage

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.

Comparison of gene expression in cynomolgus monkeys with preclinical type Ⅱ diabetes induced by different high energy diets

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.

Preclinical animal studies in ischemic stroke:Challenges and some solutions

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.

Preclinical stem cell therapy in Chagas Disease: Perspectives for future research

Chagas cardiomyopathy still remains a challenging problem that is responsible for high morbidity and mortality in Central and Latin America. Chagas disease disrupts blood microcirculation via various autoimmune mechanisms, causing loss of cardiomyocytes and severe impairment of heart function. Different cell types and delivery approaches in Chagas Disease have been studied in both preclinical models and clinical trials. The main objective of this article is to clarify the reasons why the benefits that have been seen with cell therapy in preclinical models fail to translate to the clinical setting. This can be explained by crucial differences between the cellular types and pathophysiological mechanisms of the disease, as well as the differences between human patients and animal models. We discuss examples that demonstrate how the results from preclinical trials might have overestimated the efficacy of myocardial regeneration therapies. Future research should focus, not only on studying the best cell type to use but, very importantly, understanding the levels of safety and cellular interaction that can elicit efficient therapeutic effects in human tissue. Addressing the challenges associated with future research may ensure the success of stem cell therapy in improving preclinical models and the treatment of Chagas disease.

Importance of microenvironment in preclinical models of breast and prostate cancer

The majority of cancer drugs entering clinical trials fail to reach the market due to poor efficacy. Preclinicalefficacy has been traditionally tested using subcutaneous xenograft models that are cheap, fast and easy to perform. However, these models lack the correct tumor microenvironment, leading to poor clinical predictivity. Selecting compounds for clinical trials based on efficacy results obtained from subcutaneous xenograft models may therefore be one important reason for the high failure rates. In this review we concentrate in describing the role and importance of the tumor microenvironment in progression of breast and prostate cancer, and describe some breast and prostate cancer cell lines that are widely used in preclinical studies. We go through different preclinical efficacy models that incorporate the tissue microenvironment and should therefore be clinically more predictive than subcutaneous xenografts. These include three-dimensional cell culture models, orthotopic and metastasis models, humanized and transgenic mouse models, and patient-derived xenografts. Different endpoint measurements and applicable imaging techniques are also discussed. We conclude that models that incorporate the tissue microenvironment should be increasingly used in preclinical efficacy studies to reduce the current high attrition rates of cancer drugs in clinical trials.

Non-human primate pluripotent stem cells for the preclinical testing of regenerative therapies

Non-human primates play a key role in the preclinical validation of pluripotent stem cell-based cell replacement therapies.Pluripotent stem cells used as advanced therapy medical products boost the possibility to regenerate tissues and organs affected by degenerative diseases.Therefore,the methods to derive human induced pluripotent stem cell and embryonic stem cell lines following clinical standards have quickly developed in the last 15 years.For the preclinical validation of cell replacement therapies in non-human primates,it is necessary to generate non-human primate pluripotent stem cell with a homologous quality to their human counterparts.However,pluripotent stem cell technologies have developed at a slower pace in non-human primates in comparison with human cell systems.In recent years,however,relevant progress has also been made with non-human primate pluripotent stem cells.This review provides a systematic overview of the progress and remaining challenges for the generation of non-human primate induced pluripotent stem cells/embryonic stem cells for the preclinical testing and validation of cell replacement therapies.We focus on the critical domains of(1)reprogramming and embryonic stem cell line derivation,(2)cell line maintenance and characterization and,(3)application of non-human primate pluripotent stem cells in the context of selected preclinical studies to treat cardiovascular and neurodegenerative disorders performed in non-human primates.

Transcatheter mitral valve implantation using a novel system:preclinical results

Background This preclinical study in sheep sought to demonstrate the initial safety and feasibility of a novel transcatheter mitral valve system(Mi-thos valve)composed of a self-expanding frame and a bovine pericardial tissue bioprosthesis.Methods The valve was implanted in 26 sheep using a transapical approach for short-and long-term evaluation.The technical feasibility,safety,durability,and valve function were evaluated during and 6 months after the procedure using intracardiac and transthoracic echocardiography,multisliced computed tomography,histological analysis,and electron microscopy.Results The success rate of valve implantation was 100%,and the immediate survival rate after surgery was 84%.Five animals died within 90 min after the development of the prosthetic valve due to an acute left ventricular outflow tract obstruction(n=2)and sudden intraoperative ventricular fibrillation(n=3).Twelve animals died within 1 month due to acute left heart dysfunction.Mild(n=5)and moderate(n=2)paravalvular leakage occurred in seven animals,and two moderate PVL animals died of chronic heart failure within three months.Multimodality imaging studies of the remaining seven animals showed excellent function and alignment of the valves,with no coronary artery obstruction,no left ventricular outflow tract obstruction,no severe transvalvular gradients and no paravalvular leakage.Macroscopic evaluation demonstrated stable,secure positioning of the valve,with full endothelialization of the valve leaflets without injury to the ventricular or atrial walls.Histological and electron microscopic examinations at six months showed no obvious macro-or microcalcification in the leaflets.Conclusions Preclinical studies indicate that transcatheter implantation of the Mi-thos valve is technically safe and feasible.The durability,functionality,and lack of leaflet calcification were all verified in animal experiments.The information from these preclinical studies will be applied to patient selection criteria and the first-in-human studies.

Update on the preclinical and clinical assessment of Withania somnifera: from ancient Rasayana to modern perspectives

The Rasayana plant Withania somnifera(W.somnifera)Dunal,also known as“Ashwagandha”,has been mentioned in various classical Ayurvedic texts,such as Charaka Samhita,Sushruta Samhita,and Nighantus.This Ayurvedic drug has been referred to as a tonic that renews the body,provides physical and mental vigor in weakened states,and promotes endurance and longevity.W.somnifera possesses notable biological activity in many ailments,such as diabetes,conjunctivitis,insomnia,senile dementia,Parkinson’s disease,nervous system disorders,rheumatism,and arthritis.These pharmacological activities are due to the presence of diverse active components and their derivatives.Some lead compounds are found to be effective against anxiety and other central nervous system disorders.W.somnifera has been proven to be effective and safe for a wide range of ailments from ancient to modern times.Its reported properties represent the traditional use of W.somnifera as indicated in the literature;furthermore,W.somnifera is one of the most important prescribed drugs in Ayurveda for its multimodal effects.This current review highlights the bioactive present and provides an overview of the toxicological and pharmacological studies on W.somnifera,including preclinical and clinical studies.From its earliest utilization to its current application,W.somnifera has been recognized to be effective at clinical levels for human health and welfare.Greater attention to the safety and efficacy of W.somnifera would provide more scientific evidence,promoting global acceptance of the Ayurvedic plant.

Preclinical models in ophthalmic oncology-a narrative review

Objective:This review serves as a comprehensive description and summary of currently available preclinical models of three tumors in ophthalmic oncology:conjunctival melanoma(CM),uveal melanoma(UM),and retinoblastoma.Background:Malignant melanomas are the most common tumors of the eye in adults,most often localized in the uvea and conjunctiva.Although the primary tumor can be successfully eliminated in many cases,nearly one in two UMs-and one in three CMs-are fatal to the patient due to metastasis.Effective therapies for metastatic uveal and CMs are unfortunately still not available,so there is an urgent need for new therapeutic strategies to improve prognosis quoad vitam and prolong the survival of melanoma patients.Another widely known tumor of the eye is retinoblastoma,which is the most common pediatric ocular malignancy,occurring in approximately 1 in 15,000-18,000 live births.Overall,it is considered well treatable,with a survival rate of approximately 90%at 3 years,although fatal if untreated.For a long time,enucleation was also considered the treatment of choice,with bilateral cases having one eye irradiated and the eye with the more advanced tumor removed.Since the 1990s,however,systemic chemotherapy has been predominantly used to preserve the quality of life and vision of young patients,although the cellular activity of the retinoblastoma often remains after treatment with chemotherapeutic agents.Prognosis of the disease is immensely depending on the stage and time of diagnosis and is varying between countries due to different developmental status of health care systems.Methods:We review recent advances in the available literature on established preclinical models in CM,UM,and retinoblastoma.In addition,we discuss the advantages and limitations of these models and provide an overview of current alternatives to animal testing in preclinical studies.Conclusions:In the case of all three diseases,further research is needed for improved therapeutic options.Animal models in particular are indispensable for cancer research in order to mimic the extremely complex processes of human carcinogenesis,physiology and progression.Certainly,animal studies do not easily translate to human diseases due to biological differences and limitations.However,they continue to serve as the primary source and link between in vitro testing and clinical studies in patients.In order to minimize animal experiments and possibly even replace them in the future,alternatives such as 3D cell cultures and in silico predictions are useful and insightful additions and require further development.Still,no currently available preclinical model can be fully translated to some of here described diseases.Nevertheless,they all provide essential insights and knowledge that should be of use in the future for better understanding and pursuit of new therapeutic strategies.

Characteristics of a primate model of focal motor cortical seizures suitable for preclinical testing of therapies like DBS

Background and objective: Generating and characterizing primate models of epileptic seizures are important for understanding pathophysiology of diseases and establishing preclinical efficacy of novel therapies like Deep Brain Stimulation. A focal motor epilepsy model is described here. Method: Seizures were obtained after intracortical penicillin injection into the motor strip through a cannula in two awake monkeys and electrocorticograms were recorded by epidural screws. Seizures were analyzed and compared for number, average duration of each seizure and total duration of ictal activity. Pharmaco-resistance for antiepileptic drug was tested by administration of Diazepam during seizures. Results: A motor status with seizures mimicking those seen in Kojevnikov’s syndrome was easily generated several minutes after penicillin injection and lasted 24 h on an average. The model thus characterized appears stable and consistent. There is no significant variation between experiments in individual primate as well as between two specimens. Diazepam though reduced the total duration of seizures, failed to abolish behavioural seizures. Conclusion: This model represents a good alternative model for preclinical research aiming at testing novel therapies because seizures are obtained on demand, last up to 24 h after a single penicillin injection, are stable and resistant to Diazepam.

X-ray photon counting detectors for preclinical and clinical applications

Photon counting detectors(PCDs) have attained w ide use in X-ray imaging for various preclinical and clinical applications in the past decade. This paper briefly review s the preclinical and clinical applications of PCDs based X-ray imaging systems.Starting with an introduction of X-ray single photon detection mechanism,the brief review first describes tw o major advantages of utilizing PCDs: photon energy resolving capability and electronic noise elimination. Compared to energy integrating detectors(EIDs),the aforementioned advantages make PCDs more favorable in X-ray imaging with profound benefits such as enhanced tissue contrast,decreased image noise,increased signal to noise ratio,decreased radiation dose to the small animals and patients,and more accurate material decomposition. The utilizations of PCDs in X-ray projection radiography and computed tomography(CT)including micro-CT,dedicated breast CT,K-edge CT,and clinical CT are then review ed for the imaging applications ranging from phantoms to small animals and humans. In addition,optimization methods aiming to improve the imaging performance using PCDs are briefly review ed. PCDs are not flaw less though,and their limitations are also discussed in this review. Nevertheless,PCDs may continuously contribute to the advancement of X-ray imaging techniques in future preclinical and clinical applications.

Revolutionizing preclinical research for pancreatic cancer:the potential of 3D bioprinting technology for personalized therapy

Pancreatic cancer(PC)is a prevalent digestive malignancy worldwide and ranks as the fourth leading cause of cancer-related deaths globally.The incidence and mortality rates have been increasing annually,and due to its insidious onset and high malignancy,most patients are diagnosed at an advanced stage,with a 5-year survival rate of less than 8%(1).PC can be classified into endocrine and exocrine tumors,with over 95% of pancreatic malignant tumors originating from the exocrine portion of the pancreas.

Interplay between mesenchymal stromal cells and the immune system after transplantation: implications for advanced cell therapy in the retina

Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models.Mesenchymal stromal cells are well positioned as therapeutics because they address the underlying mechanisms of neurodegeneration,namely trophic factor deprivation and neuroinflammation.Most studies have focused on the beneficial effects of mesenchymal stromal cell transplantation on neuronal survival or functional improvement.However,little attention has been paid to the interaction between mesenchymal stromal cells and the host immune system due to the immunomodulatory properties of mesenchymal stromal cells and the long-held belief of the immunoprivileged status of the central nervous system.Here,we review the crosstalk between mesenchymal stromal cells and the immune system in general and in the context of the central nervous system,focusing on recent work in the retina and the importance of the type of transplantation.

Understanding the spectrum of non-motor symptoms in multiple sclerosis:insights from animal models

Multiple sclerosis is a chronic autoimmune disease of the central nervous system and is generally considered to be a non-traumatic,physically debilitating neurological disorder.In addition to experiencing motor disability,patients with multiple sclerosis also experience a variety of nonmotor symptoms,including cognitive deficits,anxiety,depression,sensory impairments,and pain.However,the pathogenesis and treatment of such non-motor symptoms in multiple scle rosis are still under research.Preclinical studies for multiple sclerosis benefit from the use of disease-appropriate animal models,including experimental autoimmune encephalomyelitis.Prior to understanding the pathophysiology and developing treatments for non-motor symptoms,it is critical to chara cterize the animal model in terms of its ability to replicate certain non-motor features of multiple sclerosis.As such,no single animal model can mimic the entire spectrum of symptoms.This review focuses on the non-motor symptoms that have been investigated in animal models of multiple sclerosis as well as possible underlying mechanisms.Further,we highlighted gaps in the literature to explain the nonmotor aspects of multiple sclerosis in expe rimental animal models,which will serve as the basis for future studies.

Progress,implications,and challenges in using humanized immune system mice in CAR-T therapy-Application evaluation and improvement

In recent years,humanized immune system(HIS)mice have been gradually used as models for preclinical research in pharmacotherapies and cell therapies with major breakthroughs in tumor and other fields,better mimicking the human immune system and the tumor immune microenvironment,compared to traditional immunodeficient mice.To better promote the application of HIS mice in preclinical research,we se-lectively summarize the current prevalent and breakthrough research and evaluation of chimeric antigen receptor(CAR)-T cells in various antiviral and antitumor treat-ments.By exploring its application in preclinical research,we find that it can better reflect the actual clinical patient condition,with the advantages of providing high-efficiency detection indicators,even for progressive research and development.We believe that it has better clinical patient simulation and promotion for the updated design of CAR-T cell therapy than directly transplanted immunodeficient mice.The characteristics of the main models are proposed to improve the use defects of the existing models by reducing the limitation of antihost reaction,combining multiple models,and unifying sources and organoid substitution.Strategy study of relapse and toxicity after CAR-T treatment also provides more possibilities for application and development.

Understanding wound healing in obesity

Obesity has become more prevalent in the global population.It is associated with the development of several diseases including diabetes mellitus,coronary heart disease,and metabolic syndrome.There are a multitude of factors impacted by obesity that may contribute to poor wound healing outcomes.With millions worldwide classified as obese,it is imperative to understand wound healing in these patients.Despite advances in the understanding of wound healing in both healthy and diabetic populations,much is unknown about wound healing in obese patients.This review examines the impact of obesity on wound healing and several animal models that may be used to broaden our understanding in this area.As a growing portion of the population identifies as obese,understanding the underlying mechanisms and how to overcome poor wound healing is of the utmost importance.

Advances in preclinical evaluation of experimental antibody-drug conjugates

The ability to chemically modify monoclonal antibodies with the attachment of specific functional groups has opened up an enormous range of possibilities for the targeted treatment and diagnosis of cancer in the clinic.As the number of such antibody-based drug candidates has increased,so too has the need for more stringent and robust preclinical evaluation of their in vivo performance to maximize the likelihood that time,research effort,and money are only spent developing the most effective and promising candidate molecules for translation to the clinic.Concurrent with the development of antibody-drug conjugate(ADC)technology,several recent advances in preclinical research stand to greatly increase the experimental rigor by which promising candidate molecules can be evaluated.These include advances in preclinical tumor modeling with the development of patient-derived tumor organoid models that far better recapitulate many aspects of the human disease than conventional subcutaneous xenograft models.Such models are amenable to genetic manipulation,which will greatly improve our understanding of the relationship between ADC and antigen and stringently evaluate mechanisms of therapeutic response.Finally,tumor development is often not visible in these in vivo models.We discuss how the application of several preclinical molecular imaging techniques will greatly enhance the quality of experimental data,enabling quantitative pre-and post-treatment tumor measurements or the precise assessment of ADCs as effective diagnostics.In our opinion,when taken together,these advances in preclinical cancer research will greatly improve the identification of effective candidate ADC molecules with the best chance of clinical translation and cancer patient benefit.