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.

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.

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.

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.

Targeting autophagy in Alzheimer's disease:Animal models and mechanisms

Alzheimer's disease(AD)is an age-related progressive neurodegenerative disorder that leads to cognitive impairment and memory loss.Emerging evidence suggests that autophagy plays an important role in the pathogenesis of AD through the regulation of amyloid-beta(Aβ)and tau metabolism,and that autophagy dysfunction exacerbates amyloidosis and tau pathology.Therefore,targeting autophagy may be an effective approach for the treatment of AD.Animal models are considered useful tools for investigating the pathogenic mechanisms and therapeutic strategies of diseases.This review aims to summarize the pathological alterations in autophagy in representative AD animal models and to present recent studies on newly discovered autophagy-stimulating interventions in animal AD models.Finally,the opportunities,difficulties,and future directions of autophagy targeting in AD therapy are discussed.

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).

Animal models of eosinophilic esophagitis,review and perspectives

Eosinophilic oesophagitis(EoE)is an allergen/immune-mediated chronic esophageal disease characterized by esophageal mucosal eosinophilic infiltration and esophageal dysfunction.Although the disease was originally attributed to a delayed allergic reaction to allergens and a Th2-type immune response,the exact pathogenesis is complex,and the efficacy of existing treatments is unsatisfactory.Therefore,the study of the pathophysiological process of EOE has received increasing attention.Animal models have been used extensively to study the molecular mechanism of EOE pathogenesis and also provide a preclinical platform for human clinical intervention studies of novel therapeutic agents.To maximize the use of existing animal models of EOE,it is important to understand the advantages or limitations of each modeling approach.This paper systematically describes the selection of experimental animals,types of allergens,and methods of sensitization and excitation during the preparation of animal models of EoE.It also discusses the utility and shortcomings of each model with the aim of providing the latest perspectives on EoE models and leading to better choices of animal models.

Applications and advancements in animal models for antiviral research on mosquito-borne arboviruses

Vector-borne diseases caused by arthropod-borne viruses(arboviruses) are a considerable challenge to public health globally. Mosquito-borne arboviruses, such as Chikungunya, Dengue, and Zika viruses, cause a range of human illnesses and may be fatal. Currently, efforts to control these diseases still face challenges due to growing vector resistance towards insecticides, urbanization, and limited effective antiviral treatments and vaccines. Animal models are crucial in antiviral research on mosquito-borne arboviruses, playing a role in understanding disease mechanisms,vaccine development, and toxicity testing, but the application of animal models still faces the challenges of ethical considerations and animal-to-human translational success. Genetically engineered mouse models, hamster models and non-human primate(NHP) are currently used in arbovirus research, but new models such as tree shrews and novel humanized mice are emerging. In the context of Malaysian research, the use of long-tailed macaques as potential NHP models for arbovirus research is possible;however, it faces the ethical dilemma of using an endangered species for scientific purposes. Overall, animal models play a crucial role in advancing infectious disease research, but a balance between medical research and species conservation must be upheld.

A 10-year review and epidemiology of animal bite cases in Gerash city, south of Iran: A retrospective cross-sectional study

Objective:To determine the temporal trend and epidemiology of animal bite cases in Gerash City,Iran.Methods:This retrospective cross-sectional study analyzed 630 cases of people with animal bites between 2011 and 2021 in Gerash City.The collected data were analyzed using Chi-square test.Results:The mean age of victims was(30.9±17.5)years.80.54%Of victims were male,39.70%were self-employed,and 64.60%were adults(≥18 years).Most cases of bites occurred in 2019(91 cases),2020(74 cases)and 2021(87 cases),and most of the bites were related to the upper limbs(62.70%).Most of the wounds were superficial(78%),most of the biting animals were domestic animals(91.74%),and most of the victims had Iranian nationality(97.62%).Conclusions:Given the increasing trend of animal bites in Gerash City,health authorities should carry out basic measures such as education and awareness among the public,especially at-risk groups such as adult males.Additionally,since most cases of bites are due to dogs,it seems necessary to plan for vaccination of dogs,especially those with owners.

Spatial analysis of animal bites in Iran(2015-2020):A cross-sectional study

Objective:To investigate the distribution pattern of animal bites in Mirjaveh,Iran from 2015 to 2020.Methods:The data on animal bites were collected from the Department of Infectious Diseases,the provincial health center.Monthly climatic data on precipitation and temperature during the study period were also collected.The correlation between incidence and temperature,precipitation rate,land type,and altitude was also analyzed.Results:The results showed that men were more affected by animal bites than women(76.4%,P<0.001),and the highest incidence rate occurred in the age group of 5-19 years.The incidence rate of animal bites was found to be correlated with temperature and altitude.An increase in temperature was associated with a rise in the incidence rate of animal bites.The number of animal bites increased until 2019,possibly due to an increase in the number of dogs in the area.Conclusions:Targeted interventions should be implemented to reduce the incidence of animal bites,particularly among children,housewives,and students.Improving access to appropriate treatments,increasing public awareness of the hazards of animal bites,and increasing the number of vaccinated dogs in the area are essential strategies to be considered.

Tree shrew (Tupaia belangeri)as a novel laboratory disease animal model

The tree shrew （Tupaia belangeri） is a promising laboratory animal that possesses a closer genetic relationship to primates than to rodents. In addition, advantages such as small size, easy breeding, and rapid reproduction make the tree shrew an ideal subject for the study of human disease. Numerous tree shrew disease models have been generated in biological and medical studies in recent years. Here we summarize current tree shrew disease models, including models of infectious diseases, cancers, depressive disorders, drug addiction, myopia, metabolic diseases, and immune-related diseases. With the success of tree shrew transgenic technology, this species will be increasingly used in biological and medical studies in the future.

Challenges in animal modelling of mesenchymal stromal cell therapy for inflammatory bowel disease

Utilization of mesenchymal stromal cells(MSCs) for the treatment of Crohn's disease and ulcerative colitis is of translational interest.Safety of MSC therapy has been well demonstrated in early phase clinical trials but efficacy in randomized clinical trials needs to be demonstrated.Understanding MSC mechanisms of action to reduce gut injury and inflammation is necessary to improve current ongoing and future clinical trials.However, two major hurdles impede the direct translation of data derived from animal experiments to the clinical situation:(1) limitations of the currently available animal models of colitis that reflect human inflammatory bowel diseases(IBD).The etiology and progression of human IBD are multifactorial and hence a challenge to mimic in animal models; and(2) Species specific differences in the functionality of MSCs derived from mice versus humans.MSCs derived from mice and humans are not identical in their mechanisms of action in suppressing inflammation.Thus, preclinical animal studies with murine derived MSCs cannot be considered as an exact replica of human MSC based clinical trials.In the present review, we discuss the therapeutic properties of MSCs in preclinical and clinical studies of IBD.We also discuss the challenges and approaches of using appropriate animal models of colitis, not only to study putative MSC therapeutic efficacy and their mechanisms of action, but also the suitability of translating findings derived from such studies to the clinic.

Amelioration of Alzheimer's disease pathology and cognitive deficits by immunomodulatory agents in animal models of Alzheimer's disease

The most common age-related neurodegenerative disease is Alzheimer's disease(AD) characterized by aggregated amyloid-β(Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles,together with loss of cholinergic neurons,synaptic alterations,and chronic inflammation within the brain.These lead to progressive impairment of cognitive function.There is evidence of innate immune activation in AD with microgliosis.Classically-activated microglia(M1 state) secrete inflammatory and neurotoxic mediators,and peripheral immune cells are recruited to inflammation sites in the brain.The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects.Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials.Treatment with immunomodulatory/anti-inflammatory agents early in the disease process,while not preventive,is able to inhibit the inflammatory consequences of both Aβ and tau aggregation.The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD.The majority of the animal studies reviewed had used transgenic models of early-onset AD.More effort needs to be given to creat models of late-onset AD.The effects of a combinational therapy involving two or more of the tested pharmaceutical agents,or one of these agents given in conjunction with one of the cell-based therapies,in an aged animal model of AD would warrant investigation.

Neuroprotection by immunomodulatory agents in animal models of Parkinson's disease

Parkinson’s disease（PD） is an age-related neurodegenerative disease for which the characteristic motor symptoms emerge after an extensive loss of dopamine containing neurons.The cell bodies of these neurons are present in the substantia nigra,with the nerve terminals being in the striatum.Both innate and adaptive immune responses may contribute to dopaminergic neurodegeneration and disease progression is potentially linked to these.Studies in the last twenty years have indicated an important role for neuroinflammation in PD through degeneration of the nigrostriatal dopaminergic pathway.Characteristic of neuroinflammation is the activation of brain glial cells,principally microglia and astrocytes that release various soluble factors.Many of these factors are proinflammatory and neurotoxic and harmful to nigral dopaminergic neurons.Recent studies have identified several different agents with immunomodulatory properties that protected dopaminergic neurons from degeneration and death in animal models of PD.All of the agents were effective in reducing the motor deficit and alleviating dopaminergic neurotoxicity and,when measured,preventing the decrease of dopamine upon being administered therapeutically after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,6-hydroxydopamine,rotenone-lesioning or delivery of adeno-associated virus-α-synuclein to the ventral midbrain of animals.Some of these agents were shown to exert an anti-inflammatory action,decrease oxidative stress,and reduce lipid peroxidation products.Activation of microglia and astrocytes was also decreased,as well as infiltration of T cells into the substantia nigra.Pretreatment with fingolimod,tanshinoine I,dimethyl fumarate,thalidomide,or cocaine-and amphetamine-regulated transcript peptide as a preventive strategy ameliorated motor deficits and nigral dopaminergic neurotoxicity in brain-lesioned animals.Immunomodulatory agents could be used to treat patients with early clinical signs of the disease or potentially even prior to disease onset in those identified as having pre-disposing risk,including genetic factors.

Animal models of Alzheimer’s disease: Applications, evaluation, and perspectives

Although great advances in elucidating the molecular basis and pathogenesis of Alzheimer’s disease(AD)have been made and multifarious novel therapeutic approaches have been developed,AD remains an incurable disease.Evidence shows that AD neuropathology occurs decades before clinical presentation.AD is divided into three stages:preclinical stage,mild cognitive impairment(MCI),and AD dementia.In the natural world,some animals,such as non-human primates(NHPs)and canines,can develop spontaneous AD-like dementia.However,most animals do not develop AD.With the development of transgenic techniques,both invertebrate and vertebrate animals have been employed to uncover the mechanisms of AD and study treatment methods.Most AD research focuses on early-onset familial AD(FAD)because FAD is associated with specific genetic mutations.However,there are no well-established late-onset sporadic AD(SAD)animal models because SAD is not directly linked to any genetic mutation,and multiple environmental factors are involved.Moreover,the widely used animal models are not able to sufficiently recapitulate the pathological events that occur in the MCI or preclinical stages.This review summarizes the common models used to study AD,from yeast to NHP models,and discusses the different applications,evaluation methods,and challenges related to AD animal models,as well as prospects for the evolution of future studies.

Natural stilbenes effects in animal models of Alzheimer’s disease

Alzheimer’s disease is one of the most frequent neurodegenerative diseases.This pathology is characterized by protein aggregates,mainly constituted by amyloid peptide and tau,leading to neuronal death and cognitive impairments.Drugs currently proposed to treat this pathology do not prevent neurodegenerative processes and are mainly symptomatic therapies.However,stilbenes presenting multiple pharmacological effects could be good potential therapeutic candidates.The aim of this review is to gather the more significant papers among the broad literature on this topic,concerning the beneficial effects of stilbenes (resveratrol derivatives) in animal models of Alzheimer’s disease.Indeed,numerous studies focus on cellular models,but an in vivo approach remains of primary importance since in animals (mice or rats,generally),bioavailability and metabolism are taken into account,which is not the case in in vitro studies.Furthermore,examination of memory ability is feasible in animal models,which strengthens the relevance of a compound with a view to future therapy in humans.This paper is addressed to any researcher who needs to study untested natural stilbenes or who wants to experiment the most effective natural stilbenes in largest animals or in humans.This review shows that resveratrol,the reference polyphenol,is largely studied and seems to have interesting properties on amyloid plaques,and cognitive impairment.However,some resveratrol derivatives such as gnetin C,trans-piceid,or astringin have never been tested on animals.Furthermore,pterostilbene is of particular interest,by its improvement of cognitive disorders and its neuroprotective role.It could be relevant to evaluate this molecule in clinical trials.

Animal models in the study of Alzheimer's disease and Parkinson's disease:A historical perspective

Alzheimer's disease and Parkinson's disease are two of the most prevalent and disabling neurodegenerative diseases globally.Both are proteinopathic conditions and while occasionally inherited,are largely sporadic in nature.Although the advances in our understanding of the two have been significant,they are far from complete and neither diagnosis nor the current practices in treatment and rehabilitation is adequately helpful.Animal models have historically found application as testing beds for novel therapeutics and continue to be valuable aids in pharmacological research.This review chronicles the development of those models in the context of Alzheimer's and Parkinson's disease,and highlights the shifting paradigms in studying two humanspecific conditions in non-human organisms.

Choosing the right animal model for infectious disease research

A complex biological system is often required to study the myriad of host-pathogen interactions associated with infectious diseases, especially since the current basis of biology has reached the molecular level. The use of animal models is important for understanding the very complex temporal relationships that occur in infectious disease involving the body, its neuroendocrine and immune systems and the infectious organism. Because of these complex interactions, the choice of animal model must be a thoughtful and clearly defined process in order to provide relevant, translatable scientific data and to ensure the most beneficial use of the animals. While many animals respond similarly to humans from physiological, pathological, and therapeutic perspectives, there are also significant species-by-species differences. A welldesigned animal model requires a thorough understanding of similarities and differences in the responses between humans and animals and incorporates that knowledge into the goals of the study. Determining the intrinsic and extrinsic factors associated with the disease and creating a biological information matrix to compare the animal model and human disease courses is a useful tool to help choose the appropriate animal model. Confidence in the correlation of results from a model to the human disease can be achieved only if the relationship of the model to the human disease is well understood.

Research Survey of Animal Model of Hepatic Fibro-sis Integrated with Western Medicine Diseases and Traditional Chinese Medicine^TCM~)Syndrome

Although the animal models of hepatic fibrosis developed by former researchers have pathological changes of hepatic fibrosis, they do not include charac- teristics of important TCM syndromes such as stagnation of qi, deficiency of qi, liver depression, phlegm-dampness and blood stasis because of single-factor model- ing. Animal models of hepatic fibrosis and animal models integrated disease and syndrome were reviewed, and several new types of integrated disease and syndrome animal models constructed by multiple-factor modeling method were evaluated, under the guidance of etiological theory of TCM. This kind of hepatic fibrosis model animals has dual characteristics of disease and syndrome. It is consistent with pathological characteristics of hepatic fibrosis in western medicine when replicating the basic characteristics accorded with TCM syndrome. Thus, the pathogenesis and pathogenic process of clinical disease and syndrome formation is simulated more ac- curately, providing a new platform and pathway for studying hepatic fibrosis disease with integrated traditional Chinese and western medicine.