Large animal models for Huntington's disease research

Huntington'sdisease(HD)isahereditary neurodegenerative disorder for which there is currently no effectivetreatmentavailable.Consequently,the development of appropriate disease models is critical to thoroughly investigate disease progression.The genetic basis of HD involves the abnormal expansion of CAG repeats in the huntingtin(HTT)gene,leading to the expansion of a polyglutamine repeat in the HTT protein.Mutant HTT carrying the expanded polyglutamine repeat undergoes misfolding and forms aggregates in the brain,which precipitate selective neuronal loss in specific brain regions.Animal models play an important role in elucidating the pathogenesis of neurodegenerative disorders such as HD and in identifying potential therapeutic targets.Due to the marked species differences between rodents and larger animals,substantial efforts have been directed toward establishing large animal models for HD research.These models are pivotal for advancing the discovery of novel therapeutic targets,enhancing effective drug delivery methods,and improving treatment outcomes.We have explored the advantages of utilizing large animal models,particularly pigs,in previous reviews.Since then,however,significant progress has been made in developing more sophisticated animal models that faithfully replicate the typical pathology of HD.In the current review,we provide a comprehensive overview of large animal models of HD,incorporating recent findings regarding the establishment of HD knock-in(KI)pigs and their genetic therapy.We also explore the utilization of large animal models in HD research,with a focus on sheep,non-human primates(NHPs),and pigs.Our objective is to provide valuable insights into the application of these large animal models for the investigation and treatment of neurodegenerative disorders.

Effects of mesenchymal stem cell on dopaminergic neurons,motor and memory functions in animal models of Parkinson's disease:a systematic review and meta-analysis

Parkinson’s disease is chara cterized by the loss of dopaminergic neurons in the substantia nigra pars com pacta,and although restoring striatal dopamine levels may improve symptoms,no treatment can cure or reve rse the disease itself.Stem cell therapy has a regenerative effect and is being actively studied as a candidate for the treatment of Parkinson’s disease.Mesenchymal stem cells are considered a promising option due to fewer ethical concerns,a lower risk of immune rejection,and a lower risk of teratogenicity.We performed a meta-analysis to evaluate the therapeutic effects of mesenchymal stem cells and their derivatives on motor function,memory,and preservation of dopamine rgic neurons in a Parkinson’s disease animal model.We searched bibliographic databases(PubMed/MEDLINE,Embase,CENTRAL,Scopus,and Web of Science)to identify articles and included only pee r-reviewed in vivo interve ntional animal studies published in any language through J une 28,2023.The study utilized the random-effect model to estimate the 95%confidence intervals(CI)of the standard mean differences(SMD)between the treatment and control groups.We use the systematic review center for laboratory animal expe rimentation’s risk of bias tool and the collaborative approach to meta-analysis and review of animal studies checklist for study quality assessment.A total of 33studies with data from 840 Parkinson’s disease model animals were included in the meta-analysis.Treatment with mesenchymal stem cells significantly improved motor function as assessed by the amphetamine-induced rotational test.Among the stem cell types,the bone marrow MSCs with neurotrophic factor group showed la rgest effect size(SMD[95%CI]=-6.21[-9.50 to-2.93],P=0.0001,I^(2)=0.0%).The stem cell treatment group had significantly more tyrosine hydroxylase positive dopamine rgic neurons in the striatum([95%CI]=1.04[0.59 to 1.49],P=0.0001,I^(2)=65.1%)and substantia nigra(SMD[95%CI]=1.38[0.89 to 1.87],P=0.0001,I^(2)=75.3%),indicating a protective effect on dopaminergic neurons.Subgroup analysis of the amphetamine-induced rotation test showed a significant reduction only in the intracranial-striatum route(SMD[95%CI]=-2.59[-3.25 to-1.94],P=0.0001,I^(2)=74.4%).The memory test showed significant improvement only in the intravenous route(SMD[95%CI]=4.80[1.84 to 7.76],P=0.027,I^(2)=79.6%).Mesenchymal stem cells have been shown to positively impact motor function and memory function and protect dopaminergic neurons in preclinical models of Parkinson’s disease.Further research is required to determine the optimal stem cell types,modifications,transplanted cell numbe rs,and delivery methods for these protocols.

Genetically modified pigs:Emerging animal models for hereditary hearing loss

Hereditary hearing loss(HHL),a genetic disorder that impairs auditory function,significantly affects quality of life and incurs substantial economic losses for society.To investigate the underlying causes of HHL and evaluate therapeutic outcomes,appropriate animal models are necessary.Pigs have been extensively used as valuable large animal models in biomedical research.In this review,we highlight the advantages of pig models in terms of ear anatomy,inner ear morphology,and electrophysiological characteristics,as well as recent advancements in the development of distinct genetically modified porcine models of hearing loss.Additionally,we discuss the prospects,challenges,and recommendations regarding the use pig models in HHL research.Overall,this review provides insights and perspectives for future studies on HHL using porcine models.

Neurophysiological, histological, and behavioral characterization of animal models of distraction spinal cord injury: a systematic review

Distraction spinal cord injury is caused by some degree of distraction or longitudinal tension on the spinal cord and commonly occurs in patients who undergo corrective operation for severe spinal deformity.With the increased degree and duration of distraction,spinal cord injuries become more serious in terms of their neurophysiology,histology,and behavior.Very few studies have been published on the specific characteristics of distraction spinal cord injury.In this study,we systematically review 22 related studies involving animal models of distraction spinal cord injury,focusing particularly on the neurophysiological,histological,and behavioral characteristics of this disease.In addition,we summarize the mechanisms underlying primary and secondary injuries caused by distraction spinal cord injury and clarify the effects of different degrees and durations of distraction on the primary injuries associated with spinal cord injury.We provide new concepts for the establishment of a model of distraction spinal cord injury and related basic research,and provide reference guidelines for the clinical diagnosis and treatment of this disease.

Immunobiology of COVID-19: Mechanistic and therapeutic insights from animal models

The distribution of the immune system throughout the body complicates in vitro assessments of coronavirus disease 2019(COVID-19)immunobiology,often resulting in a lack of reproducibility when extrapolated to the whole organism.Consequently,developing animal models is imperative for a comprehensive understanding of the pathology and immunology of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.This review summarizes current progress related to COVID-19 animal models,including non-human primates(NHPs),mice,and hamsters,with a focus on their roles in exploring the mechanisms of immunopathology,immune protection,and long-term effects of SARS-CoV-2 infection,as well as their application in immunoprevention and immunotherapy of SARS-CoV-2 infection.Differences among these animal models and their specific applications are also highlighted,as no single model can fully encapsulate all aspects of COVID-19.To effectively address the challenges posed by COVID-19,it is essential to select appropriate animal models that can accurately replicate both fatal and non-fatal infections with varying courses and severities.Optimizing animal model libraries and associated research tools is key to resolving the global COVID-19 pandemic,serving as a robust resource for future emerging infectious diseases.

How can we establish animal models of HIV-associated lymphoma?

Human immunodeficiency virus(HIV)infection is strongly associated with a height-ened incidence of lymphomas.To mirror the natural course of human HIV infection,animal models have been developed.These models serve as valuable tools to inves-tigate disease pathobiology,assess antiretroviral and immunomodulatory drugs,ex-plore viral reservoirs,and develop eradication strategies.However,there are currently no validated in vivo models of HIV-associated lymphoma(HAL),hampering progress in this crucial domain,and scant attention has been given to developing animal models dedicated to studying HAL,despite their pivotal role in advancing knowledge.This re-view provides a comprehensive overview of the existing animal models of HAL,which may enhance our understanding of the underlying pathogenesis and approaches for malignancies linked to HIV infection.

Knee osteoarthritis:A review of animal models and intervention of traditional Chinese medicine

Background:Knee osteoarthritis(KOA)characterized by degeneration of knee cartilage and subsequent bone hyperplasia is a prevalent joint condition primarily affecting aging adults.The pathophysiology of KOA remains poorly understood,as it involves complex mechanisms that result in the same outcome.Consequently,researchers are interested in studying KOA and require appropriate animal models for basic research.Chinese herbal compounds,which consist of multiple herbs with diverse pharmacological properties,possess characteristics such as multicomponent,multipathway,and multitarget effects.The potential benefits in the treatment of KOA continue to attract attention.Purpose:This study aims to provide a comprehensive overview of the advantages,limitations,and specific considerations in selecting different species and methods for KOA animal models.This will help researchers make informed decisions when choosing an animal model.Methods:Online academic databases(e.g.,PubMed,Google Scholar,Web of Science,and CNKI)were searched using the search terms“knee osteoarthritis,”“animal models,”“traditional Chinese medicine,”and their combinations,primarily including KOA studies published from 2010 to 2023.Results:Based on literature retrieval,this review provides a comprehensive overview of the methods of establishing KOA animal models;introduces the current status of advantages and disadvantages of various animal models,including mice,rats,rabbits,dogs,and sheep/goats;and presents the current status of methods used to establish KOA animal models.Conclusion:This study provides a review of the animal models used in recent KOA research,discusses the common modeling methods,and emphasizes the role of traditional Chinese medicine compounds in the treatment of KOA.

Preliminary exploration of animal models of congenital choledochal cysts

BACKGROUND Various animal models have been used to explore the pathogenesis of choledochal cysts(CCs),but with little convincing results.Current surgical techniques can achieve satisfactory outcomes for treatment of CCs.Consequently,recent studies have focused more on clinical issues rather than basic research.Therefore,we need appropriate animal models to further basic research.AIM To establish an appropriate animal model that may contribute to the investigation of the pathogenesis of CCs.METHODS Eighty-four specific pathogen-free female Sprague-Dawley rats were randomly allocated to a surgical group,sham surgical group,or control group.A rat model of CC was established by partial ligation of the bile duct.The reliability of the model was confirmed by measurements of serum biochemical indices,morpho-logy of common bile ducts of the rats as well as molecular biology experiments in rat and human tissues.RESULTS Dilation classified as mild(diameter,≥1 mm to<3 mm),moderate(≥3 mm to<10 mm),and severe(≥10 mm)was observed in 17,17,and 2 rats in the surgical group,respectively,while no dilation was observed in the control and sham surgical groups.Serum levels of alanine aminotransferase,aspartate aminotrans-ferase,total bilirubin,direct bilirubin,and total bile acids were significantly elevated in the surgical group as compared to the control group 7 d after surgery,while direct bilirubin,total bilirubin,and gamma-glutamyltransferase were further increased 14 d after surgery.Most of the biochemical indices gradually decreased to normal ranges 28 d after surgery.The protein expression trend of signal transducer and activator of transcription 3 in rat model was consistent with the human CC tissues.CONCLUSION The model of partial ligation of the bile duct of juvenile rats could morphologically simulate the cystic or fusiform CC,which may contribute to investigating the pathogenesis of CC.

Advances in viral encephalitis:Viral transmission,host immunity,and experimental animal models

Viral infections have led to many public health crises and pandemics in the last few centuries.Neurotropic virus infection-induced viral encephalitis(VE),especially the symptomatic inflammation of the meninges and brain parenchyma,has attracted growing attention due to its high mortality and disability rates.Understanding the infectious routes of neurotropic viruses and the mechanism underlying the host immune response is critical to reduce viral spread and improve antiviral therapy outcomes.In this review,we summarize the common categories of neurotropic viruses,viral transmission routes in the body,host immune responses,and experimental animal models used for VE study to gain a deeper understanding of recent progress in the pathogenic and immunological mechanisms under neurotropic viral infection.This review should provide valuable resources and perspectives on how to cope with pandemic infections.

Large animal models of cardiac ischemia-reperfusion injury:Where are we now?

Large animal models of cardiac ischemia-reperfusion are critical for evaluation of the efficacy of cardioprotective interventions prior to clinical translation.Nonetheless,current cardioprotective strategies/interventions formulated in preclinical cardiovascular research are often limited to small animal models,which are not transferable or reproducible in large animal models due to different factors such as:(i)complex and varied features of human ischemic cardiac disease(ICD),which are challenging to mimic in animal models,(ii)significant differences in surgical techniques applied,and(iii)differences in cardiovascular anatomy and physiology between small versus large animals.This article highlights the advantages and disadvantages of different large animal models of preclinical cardiac ischemic reperfusion injury(IRI),as well as the different methods used to induce and assess IRI,and the obstacles faced in using large animals for translational research in the settings of cardiac IR.

Establishment and evaluation of animal models of sepsis-associated encephalopathy

BACKGROUND:Sepsis-associated encephalopathy(SAE) is a critical disease caused by sepsis.In addition to high mortality,SAE can also adversely aff ect life quality and lead to significant socioeconomic costs.This review aims to explore the development of evaluation animal models of SAE,giving insight into the direction of future research in terms of its pathophysiology and therapy.METHODS:We performed a literature search from January 1,2000,to December 31,2022,in MEDLINE,PubMed,EMBASE,and Web of Science using related keywords.Two independent researchers screened all the accessible articles based on the inclusion and exclusion criteria and collected the relevant data of the studies.RESULTS:The animal models for sepsis are commonly induced through cecal ligation and puncture(CLP) or lipopolysaccharide(LPS) injection.SAE can be evaluated using nervous reflex scores and sepsis evaluation during the acute phase,or through Morris water maze(MWM),openfield test,fear condition(FC) test,inhibitory avoidance,and other tests during the late phase.CONCLUSION:CLP and LPS injection are the most common methods for establishing SAE animal models.Nervous reflexs cores,MWM,FC test,and inhibitory avoidance are widely used in SAE model analysis.Future research should focus on establishing a standardized system for SAE development and analysis.

Recent advances in anxiety disorders:Focus on animal models and pathological mechanisms

Anxiety disorders have become one of the most severe psychiatric disorders,and the incidence is increasing every year.They impose an extraordinary personal and socioeconomic burden.Anxiety disorders are influenced by multiple complex and interacting genetic,psychological,social,and environmental factors,which contribute to disruption or imbalance in homeostasis and eventually cause pathologic anxiety.The selection of a suitable animal model is important for the exploration of disease etiology and pathophysiology,and the development of new drugs.Therefore,a more comprehensive understanding of the advantages and limitations of existing animal models of anxiety disorders is helpful to further study the underlying pathological mechanisms of the disease.This review summarizes animal models and the pathogenesis of anxiety disorders,and discusses the current research status to provide insights for further study of anxiety disorders.

Research progress on animal models of corneal epithelial-stromal injury

A corneal epithelial-stromal defect is recognized as a major contributor to corneal scarring.Given the rising prevalence of blindness caused by corneal scarring,increasing attention has been focused on corneal epithelialstromal defects.Currently,the etiology and pathogenesis of these defects remain inadequately understood,necessitating further investigation through experimental research.Various modeling methods exist both domestically and internationally,each with distinct adaptive conditions,advantages,and disadvantages.This review primarily aims to summarize the techniques used to establish optimal animal models of corneal epithelial-stromal injury,including mechanical modeling,chemical alkali burns,post-refractive surgery infections,and genetic engineering.The intention is to provide valuable insights for studying the mechanisms underlying corneal epithelial-stromal injury and the development of corresponding therapeutic interventions.

Acute liver failure:A systematic review and network meta-analysis of optimal type of stem cells in animal models

BACKGROUND The therapeutic effects of various stem cells in acute liver failure(ALF)have been demonstrated in preclinical studies.However,the specific type of stem cells with the highest therapeutic potential has not been determined.AIM To validate the efficacy of stem cells in ALF model and to identify the most promising stem cells.METHODS A search was conducted on the PubMed,Web of Science,Embase,Scopus,and Cochrane databases from inception to May 3,2022,and updated on November 16,2022 to identify relevant studies.Two independent reviewers performed the literature search,identification,screening,quality assessment,and data extraction.RESULTS A total of 89 animal studies were included in the analysis.The results of traditional meta-analysis showed that stem cell therapy could significantly reduce the serum levels of alanine aminotransferase[weighted mean difference(WMD)=-181.05(-191.71,-170.39)],aspartate aminotransferase[WMD=-309.04(-328.45,-289.63)],tumor necrosis factor-alpha[WMD=-8.75(-9.93,-7.56)],and interleukin-6[WMD=-10.43(-12.11,-8.76)]in animal models of ALF.Further subgroup analysis and network meta-analysis showed that although mesenchymal stem cells are the current research hotspot,the effect of liver stem cells(LSCs)on improving liver function is significantly better than that of the other five types of stem cells.In addition,the ranking results showed that the possibility of LSCs improving liver function ranked first.This fully proves the great therapeutic potential of LSCs,which needs to be paid more attention in the future.CONCLUSION LSCs may have a higher therapeutic potential.Further high-quality animal experiments are needed to explore the most effective stem cells for ALF.

Genome-edited rabbits:Unleashing the potential of a promising experimental animal model across diverse diseases

Animal models are extensively used in all aspects of biomedical research,with substantial contributions to our understanding of diseases,the development of pharmaceuticals,and the exploration of gene functions.The field of genome modification in rabbits has progressed slowly.However,recent advancements,particularly in CRISPR/Cas9-related technologies,have catalyzed the successful development of various genome-edited rabbit models to mimic diverse diseases,including cardiovascular disorders,immunodeficiencies,agingrelated ailments,neurological diseases,and ophthalmic pathologies.These models hold great promise in advancing biomedical research due to their closer physiological and biochemical resemblance to humans compared to mice.This review aims to summarize the novel gene-editing approaches currently available for rabbits and present the applications and prospects of such models in biomedicine,underscoring their impact and future potential in translational medicine.

Optimizing diabetic kidney disease animal models:Insights from a meta-analytic approach

Diabetic kidney disease(DKD)is a prevalent complication of diabetes,often leading to end-stage renal disease.Animal models have been widely used to study the pathogenesis of DKD and evaluate potential therapies.However,current animal models often fail to fully capture the pathological characteristics of renal injury observed in clinical patients with DKD.Additionally,modeling DKD is often a time-consuming,costly,and labor-intensive process.The current review aims to summarize modeling strategies in the establishment of DKD animal models by utilizing meta-analysis related methods and to aid in the optimization of these models for future research.A total of 1215 articles were retrieved with the keywords of“diabetic kidney disease”and“animal experiment”in the past 10 years.Following screening,84 articles were selected for inclusion in the meta-analysis.Review manager 5.4.1 was employed to analyze the changes in blood glucose,glycosylated hemoglobin,total cholesterol,triglyceride,serum creatinine,blood urea nitrogen,and urinary albumin excretion rate in each model.Renal lesions shown in different models that were not suitable to be included in the metaanalysis were also extensively discussed.The above analysis suggested that combining various stimuli or introducing additional renal injuries to current models would be a promising avenue to overcome existing challenges and limitations.In conclusion,our review article provides an in-depth analysis of the limitations in current DKD animal models and proposes strategies for improving the accuracy and reliability of these models that will inspire future research efforts in the DKD research field.

Fundus photography,fluorescein angiography,optical coherence tomography and electroretinography of preclinical animal models of ocular diseases

The eye is an immune-privileged and sensory organ in humans and animals.Anatomical,physiological,and pathobiological features share significant similarities across divergent species(1).Each compartment of the eye has a unique structure and function.The anterior and posterior compartments of the eye contain endothelium(cornea),epithelium(cornea,ciliary body,iris),muscle(ciliary body),vitreous and neuronal(retina)tissues,which make the eye suitable to evaluate efficacy and safety of tissue specific drugs(2).

Rifaximin on epigenetics and autophagy in animal model of hepatocellular carcinoma secondary to metabolic-dysfunction associated steatotic liver disease

BACKGROUND Prevalence of hepatocellular carcinoma(HCC)is increasing,especially in patients with metabolic dysfunctionassociated steatotic liver disease(MASLD).AIM To investigate rifaximin(RIF)effects on epigenetic/autophagy markers in animals.METHODS Adult Sprague-Dawley rats were randomly assigned(n=8,each)and treated from 5-16 wk:Control[standard diet,water plus gavage with vehicle(Veh)],HCC[high-fat choline deficient diet(HFCD),diethylnitrosamine(DEN)in drinking water and Veh gavage],and RIF[HFCD,DEN and RIF(50 mg/kg/d)gavage].Gene expression of epigenetic/autophagy markers and circulating miRNAs were obtained.RESULTS All HCC and RIF animals developed metabolic-dysfunction associated steatohepatitis fibrosis,and cirrhosis,but three RIF-group did not develop HCC.Comparing animals who developed HCC with those who did not,miR-122,miR-34a,tubulin alpha-1c(Tuba-1c),metalloproteinases-2(Mmp2),and metalloproteinases-9(Mmp9)were significantly higher in the HCC-group.The opposite occurred with Becn1,coactivator associated arginine methyltransferase-1(Carm1),enhancer of zeste homolog-2(Ezh2),autophagy-related factor LC3A/B(Map1 Lc3b),and p62/sequestosome-1(p62/SQSTM1)-protein.Comparing with controls,Map1 Lc3b,Becn1 and Ezh2 were lower in HCC and RIF-groups(P<0.05).Carm1 was lower in HCC compared to RIF(P<0.05).Hepatic expression of Mmp9 was higher in HCC in relation to the control;the opposite was observed for p62/Sqstm1(P<0.05).Expression of p62/SQSTM1 protein was lower in the RIF-group compared to the control(P=0.024).There was no difference among groups for Tuba-1c,Aldolase-B,alpha-fetoprotein,and Mmp2(P>0.05).miR-122 was higher in HCC,and miR-34a in RIF compared to controls(P<0.05).miR-26b was lower in HCC compared to RIF,and the inverse was observed for miR-224(P<0.05).There was no difference among groups regarding miR-33a,miR-143,miR-155,miR-375 and miR-21(P>0.05).CONCLUSION RIF might have a possible beneficial effect on preventing/delaying liver carcinogenesis through epigenetic modulation in a rat model of MASLD-HCC.

Establishing of the Transplanted Animal Models for Human Lung Cancer

Lung cancer is the leading cause of cancer mortality worldwide.Even with the applications of excision, radiotherapy, chemotherapy, and gene therapy, the 5 year survival rate is only 15% in the USA. Clinically relevant laboratory animal models of the disease could greatly facilitate understanding of the pathogenesis of lung cancer, its progression, invasion and metastasis. Transplanted lung cancer models are of special interest and are widely used today. Such models are essential tools in accelerating development of new therapies for lung cancer. In this communication we will present a brief overview of the hosts, sites and pathways used to establish transplanted animal lung tumor models.

Large animal ischemic stroke models: replicating human stroke pathophysiology

The high morbidity and mortality rate of ischemic stroke in humans has led to the development of numerous animal models that replicate human stroke to further understand the underlying pathophysiology and to explore potential therapeutic interventions.Although promising therapeutics have been identified using these animal models,with most undergoing significant testing in rodent models,the vast majority of these interventions have failed in human clinical trials.This failure of preclinical translation highlights the critical need for better therapeutic assessment in more clinically relevant ischemic stroke animal models.Large animal models such as non-human primates,sheep,pigs,and dogs are likely more predictive of human responses and outcomes due to brain anatomy and physiology that are more similar to humans-potentially making large animal testing a key step in the stroke therapy translational pipeline.The objective of this review is to highlight key characteristics that potentially make these gyrencephalic,large animal ischemic stroke models more predictive by comparing pathophysiological responses,tissue-level changes,and model limitations.