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.

Apolipoprotein E4 interferes with lipid metabolism to exacerbate depression-like behaviors in 5xFAD mice

Background:Apolipoprotein E4(ApoE4)allele is the strongest genetic risk factor for late-onset Alzheimer's disease,and it can aggravate depressive symptoms in non-AD patients.However,the impact of ApoE4 on AD-associated depression-l ike behaviors and its underlying pathogenic mechanisms remain unclear.Methods:This study developed a 5xFAD mouse model overexpressing human ApoE4(E4FAD).Behavioral assessments and synaptic function tests were conducted to explore the effects of ApoE4 on cognition and depression in 5xFAD mice.Changes in peripheral and central lipid metabolism,as well as the levels of serotonin(5-HT)andγ-aminobutyric acid(GABA)neurotransmitters in the prefrontal cortex,were examined.In addition,the protein levels of 24-dehydrocholesterol reductase/glycogen synthase kinase-3 beta/mammalian target of rapamycin(DHCR24/GSK3β/m TOR)and postsynaptic density protein 95/calmodulin-dependent protein kinase II/brain-derived neurotrophic factor(PSD95/CaMK-II/BDNF)were measured to investigate the molecular mechanism underlying the effects of ApoE4 on AD mice.Results:Compared with 5xFAD mice,E4FAD mice exhibited more severe depressionlike behaviors and cognitive impairments.These mice also exhibited increased amyloid-beta deposition in the hippocampus,increased astrocyte numbers,and decreased expression of depression-related neurotransmitters 5-HT and GABA in the prefrontal cortex.Furthermore,lipid metabolism disorders were observed in E4FAD,manifesting as elevated low-density lipoprotein cholesterol and reduced high-density lipoprotein cholesterol in peripheral blood,decreased cholesterol level in the prefrontal cortex,and reduced expression of key enzymes and proteins related to cholesterol synthesis and homeostasis.Abnormal expression of proteins related to the DHCR24/GSK3β/m TOR and PSD95/CaMK-II/BDNF pathways was also observed.Conclusion:This study found that ApoE4 overexpression exacerbates depressionlike behaviors in 5xFAD mice and confirmed that ApoE4 reduces cognitive function in these mice.The mechanism may involve the induction of central and peripheral lipid metabolism disorders.Therefore,modulating ApoE expression or function to restore cellular lipid homeostasis may be a promising therapeutic target for AD comorbid with depression.This study also provided a better animal model for studying AD comorbid with depression.

Hydrogen sulfide reduces oxidative stress in Huntington's disease via Nrf2

The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington's disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington's disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS(a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington's disease by activating nuclear factor erythroid 2-related factor 2,suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington's disease.

Hepatic transcriptome signatures in mice and humans with nonalcoholic fatty liver disease

Background:Nonalcoholic fatty liver disease(NAFLD)is the main reason for cirrhosis and hepatocellular carcinoma.As a starting point for NAFLD,the treatment of nonalcoholic fatty liver(NAFL)is receiving increasing attention.Mice fed a high-fat diet(HFD)and hereditary leptin deficiency(ob/ob)mice are important NAFL animal models.However,the comparison of these mouse models with human NAFL is still unclear.Methods:In this study,HFD-fed mice and ob/ob mice were used as NAFL animal models.Liver histopathological characteristics were compared,and liver transcriptome from both mouse models was performed using RNA sequencing(RNA-seq).RNAseq data obtained from the livers of NAFL patients was downloaded from the GEO database.Global gene expression profiles in the livers were further analyzed using functional enrichment analysis and the Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway.Results:Our results showed that the biochemical parameters of both mouse models and human NAFL were similar.Compared with HFD-fed mice,ob/ob mice were more similar in histologic appearance to NAFL patients.The liver transcriptome characteristics partly overlapped in mice and humans.Furthermore,in the NAFL pathway,most genes showed similar trends in mice and humans,thus demonstrating that both types of mice can be used as models for basic research on NAFL,considering the differences.Conclusion:Our findings show that HFD-fed mice and ob/ob mice can mimic human NAFL partly in pathophysiological process.The comparative analysis of liver transcriptome profile in mouse models and human NAFL presented here provides insights into the molecular characteristics across these NAFL models.

Diabetes exacerbates inflammatory bowel disease in mice with dietinduced obesity

BACKGROUND The increased prevalence of inflammatory bowel disease(IBD)among patients with obesity and type 2 diabetes suggests a causal link between these diseases,potentially involving the effect of hyperglycemia to disrupt intestinal barrier integrity.AIM To investigate whether the deleterious impact of diabetes on the intestinal barrier is associated with increased IBD severity in a murine model of colitis in mice with and without diet-induced obesity.METHODS Mice were fed chow or a high-fat diet and subsequently received streptozotocin to induce diabetic-range hyperglycemia.Six weeks later,dextran sodium sulfate was given to induce colitis.In select experiments,a subset of diabetic mice was treated with the antidiabetic drug dapagliflozin prior to colitis onset.Endpoints included both clinical and histological measures of colitis activity as well as histochemical markers of colonic epithelial barrier integrity.RESULTS In mice given a high-fat diet,but not chow-fed animals,diabetes was associated with significantly increased clinical colitis activity and histopathologic markers of disease severity.Diabetes was also associated with a decrease in key components that regulate colonic epithelial barrier integrity(colonic mucin layer content and epithelial tight junction proteins)in diet-induced obese mice.Each of these effects of diabetes in diet-induced obese mice was ameliorated by restoring normoglycemia.CONCLUSION In obese mice,diabetes worsened clinical and pathologic outcomes of colitis via mechanisms that are reversible with treatment of hyperglycemia.Hyperglycemia-induced intestinal barrier dysfunction offers a plausible mechanism linking diabetes to increased colitis severity.These findings suggest that effective diabetes management may decrease the clinical severity of IBD.

Dexmedetomidine mediates the mechanism of action of ferroptosis in mice with Alzheimer’s disease by regulating the mTOR-TFR1 pathway

BACKGROUND Alzheimer’s disease(AD)is the most common neurodegenerative disorder,and there are currently no effective drugs to delay progression of the disease.Ferroptosis may play a vital part in AD,and is therefore receiving increasing attention by researchers.AIM To investigate the effects of dexmedetomidine(Dex)on ferroptosis in AD mouse hippocampus.METHODS Hippocampal neurons(HNs)HT22 were induced by amyloidβ-protein(Aβ)and both in vitro and in vivo AD mouse models were prepared via injections.The cellcounting kit-8 assay and immunofluorescence technique were adopted to determine cell proliferation activity and intracellular Fe2+levels,and the TBA method and microplate method were employed for malondialdehyde and glutathione measurements,respectively.Hippocampal tissue damage was determined using hematoxylin and eosin and Nissl staining.Mouse learning and memory ability in each group was assessed by the Morris water maze test,and the expression levels of mammalian target of rapamycin(mTOR)signal molecules and ferroptosis-related proteins transferrin receptor 1(TFR1),SLC7A11 and glutathione peroxidase 4 were examined by western blotting.RESULTS Dex enhanced lipid peroxidation and iron influx in mouse HNs in both in vitro and in vivo experiments,while inhibition of the mTOR axis blocked this process.These findings demonstrate that Dex can inhibit ferroptosis-induced damage in mouse HNs by activating mTOR-TFR1 signaling to regulate ferroptosis-associated proteins,thus alleviating cognitive dysfunction in AD mice.CONCLUSION Dex can activate the mTOR-TFR1 axis to inhibit ferroptosis in mouse HNs,thereby improving the learning and memory ability of mice.

Effects of Maxingloushi decoction on immune inflammation and programmed death markers in mice with chronic obstructive pulmonary disease

BACKGROUND: To investigate effects of Maxingloushi decoction on lung inflammation and programmed death markers(programmed death-1 [PD-1], programmed death-ligand 1 [PD-L1]) in the lung tissue, peripheral blood, and bronchoalveolar lavage fl uid(BLF) in a mouse model of chronic obstructive pulmonary disease(COPD).METHODS: Thirty-six mature male BALB/C mice were randomly divided into normal group(group A, n=6), COPD model group(group B, n=10), Maxingloushi decoction + COPD group(group C, n=10), and PD-1 inhibitor + COPD group(group D, n=10). The COPD model was established by smoke inhalation combined with lipopolysaccharide(LPS). Levels of PD-1 and PD-L1 in plasma and BLF were measured by enzyme-linked immunosorbent assay(ELISA). Histopathological techniques were used to semi-quantitatively analyze the immuno-fluorescence optical density(IOD) value of the lung tissue. RESULTS: In plasma and BLF, the expression of PD-1 in the group B was higher than that in the group A, and the expression of PD-L1 was lower than that in the group A. The expression of PD-1 and PD-L1 in the lung tissue was normalized in the group C in comparison with the group B(P<0.05) and the group D(P<0.05), and infl ammatory cell infiltration in the lung tissue was also improved.CONCLUSIONS: These findings reveal that COPD causes an immune imbalance in the peripheral blood and lung tissue, and that both Maxingloushi decoction and PD-1 inhibitor treatment can mitigate lung inflammation in COPD by reducing PD-1 expression and increasing PD-L1 expression. The treatment effect of Maxingloushi decoction may be superior to that of PD-1 inhibitor.

The role of mTOR signaling pathway in regulating autophagy in liver injury of TX mice with Wilson’s disease

Wilson disease(WD),known as hepatolenticular degeneration(HLD),is a treatable autosomal recessive disorder of copper metabolism.Because copper deposits in the liver first,the liver is not only the original defective organ but also the most affected organ.The liver injury is also one of the main causes of death throughout the course of the disease.Therefore,the treatment of liver injury is the main task of WD treatment,which is of great significance to improve the prognosis of patients.Autophagy is a process that promotes cell survival through degradation,recycling,and absorption in order to maintain the normal physiological function of cells,while excessive autophagy can aggravate cell death.In view of the abnormal damage of liver cells in patients with WD,which may be related to the change of autophagy level,in this study,we established an animal model of WD through toxic milk(TX)mice,observed the change of autophagy level in the liver,and observed the change of liver damage in mice after treatment with autophagy inhibitors.It was found that the mTOR signaling pathway was activated and autophagy was inhibited in Wilson mouse liver.After treatment with rapamycin,the autophagy level of mice liver was upregulated,and the copper content of mice liver was reduced,and the damage was alleviated.TX mouse hepatocytes were isolated,after using siRNA to interfere with mTOR expression,the copper accumulation was significantly reduced,which was the same with RAPA treatment.The results showed that in TX mice,the damage caused by copper accumulation in the liver may be related to the decrease of autophagy level caused by the activation of the mTOR signaling pathway.Our findings suggested that RAPA or the use of siRNA targeting mTOR may have potential applications in the treatment of Wilson’s disease.

Effect of Human Umbilical Cord Mesenchymal Stem Cells on GRP78/ATF4 Pathway in Alzheimer s Disease Model Mice

[Objectives]To study the effect of human umbilical cord mesenchymal stem cells(hUC-MSCs)on GRP78/ATF4 pathway in APP/PS1 mice.[Methods]Twelve 6-month-old female APP/PS1 mice were randomly divided into model group(MOD,n=6)and human umbilical cord mesenchymal stem cell treatment group(MSC,n=6);six 6-month-old C57BL/6N mice were used as control group(CON,n=6).The mice in each group were treated with the fourth generation of human umbilical cord mesenchymal stem cells through tail vein.Four weeks later,the mice in each group were killed.The expression of GFP78 and ATF4 in the cortex of mice in each group was detected by Western blotting and real-time fluorescence quantitative PCR.[Results]The results of immunoblotting and real-time fluorescence quantitative PCR showed that the expression of GRP78 in MOD group was lower than that in CON group and the expression of ATF4 increased.The expression of GRP78 protein in MSC group was higher than that in MOD group,but the expression of ATF4 protein was lower.The results of real-time fluorescence quantitative PCR showed that the mRNA level of GRP78 decreased and the mRNA level of ATF4 increased in MOD group compared with CON group.The mRNA level of GRP78 in MSC group was higher than that in MOD group,while the mRNA level of ATF4 in MSC group was lower than that in MOD group.[Conclusions]Human umbilical cord mesenchymal stem cells can regulate the expression of GRP78/ATF4 pathway in APP/PSI mice,which may be related to the stress level of endoplasmic reticulum in the brain of APP/PS1 mice mediated by human umbilical cord mesenchymal stem cells.

Investigating Müller glia reprogramming in mice: a retrospective of the last decade, and a look to the future

Müller glia,as prominent glial cells within the retina,plays a significant role in maintaining retinal homeostasis in both healthy and diseased states.In lower vertebrates like zebrafish,these cells assume responsibility for spontaneous retinal regeneration,wherein endogenous Müller glia undergo proliferation,transform into Müller glia-derived progenitor cells,and subsequently regenerate the entire retina with restored functionality.Conversely,Müller glia in the mouse and human retina exhibit limited neural reprogramming.Müller glia reprogramming is thus a promising strategy for treating neurodegenerative ocular disorders.Müller glia reprogramming in mice has been accomplished with remarkable success,through various technologies.Advancements in molecular,genetic,epigenetic,morphological,and physiological evaluations have made it easier to document and investigate the Müller glia programming process in mice.Nevertheless,there remain issues that hinder improving reprogramming efficiency and maturity.Thus,understanding the reprogramming mechanism is crucial toward exploring factors that will improve Müller glia reprogramming efficiency,and for developing novel Müller glia reprogramming strategies.This review describes recent progress in relatively successful Müller glia reprogramming strategies.It also provides a basis for developing new Müller glia reprogramming strategies in mice,including epigenetic remodeling,metabolic modulation,immune regulation,chemical small-molecules regulation,extracellular matrix remodeling,and cell-cell fusion,to achieve Müller glia reprogramming in mice.

Changes of biochemical indices in brain, liver tissue and serum in mice with Alzheimer disease after Chinese medicine treatment

BACKGROUND： Alzheimer disease is a main type of dementia, and the important clinical characteristic is the rapid declines of memory and cognitive ability. OBJECTIVE： To study changes of biochemical indices in brain, liver tissue and serum, as well as memory of mice with Alzheimer disease after Chinese medicine treatment. DESIGN： A comparative animal experimental observation. SETTING： Haierfu Research Center of Youjiang Medical College for Nationalities. MATERIALS： Forty-eight healthy Kunming mice （24 males and 24 females）, 3 months old, were provided by the animal room of Youjiang Medical College for Nationalities. The animals were divided into four groups according to sex and body mass： control group, model group, Wuyuan Buxue treated group, Haierfu treated group, and 12 mice in each group. Wuyuan Buxue oral liquid was extracted from Polygonum multiflorum Thunb （red, radix） and longan meat （country medicine quasi- word B20020828）. Haierfu oral liquid was extracted from Yinhua, poriacocos, licorice, etc （Q/452600RYYLC01-92）. METHODS： The experiment was completed in Haierfu Research Center and Institute of Heavy Metal and Fluorosis-Arsenism of Youjiang Medical College for Nationalities from May 2006 to December 2006. ① All animals except those in the control group were given feed which was mixed with AlCl3 （12 g/L）, and they could freely drink 3 g/L Al（NO3）3. The mice in the control group were given normal feed. Wuyuan Buxue oral liquid and Haierfu oral liquid were distilled by distilled water for one time respectively. Five months after model establishment, mice in the Wuyuan Buxue treated group and Haierfu treated group were given intrapastric perfusion of Wuyuan Buxue oral liquid and Haierfu oral liquid respectively, and those in the model group and control group were given intrapastric perfusion of distilled water of the same volume. All the mice were treated for 45 days. ② The swimming time （s） and error times were determined with Y-shape water maze before and after experiment; Hemoglobin was determined by method of HICN. After treatment, serum was isolated from eyeballs to determine the activities of glutathione peroxidase （GSH-PX）, urea and cholesterol. The animals were executed to remove brain and liver, then 10% homogenate was prepared to determine the activity of acetylcholinesterase （AChE）, clearance of O2-·, content of malondialdehyde （MDA）, activities of superoxide dismutase （SOD） and GSH-PX. MAIN OUTCOME MEASURES： ① Swimming time and error times in the water maze, and the content of hemoglobin; ② alanine aminotransferase （ALT） activity and contents of urea and cholesterol in serum after treatment; ③ Activities of GSH-PX, AChE and SOD, and MDA content in liver, and AChE activity in brain after treatment. RESULTS： Totally 48 mice were used, and some of them died due to unknown reasons, finally 32 mice （8 in each group） were involved in the analysis of results. ① Content of hemoglobin before and after treatment： There were obvious changes in the groups （P 〈 0.05）. ② Comparison of ALT, cholesterol and urea in serum： The contents of urea in the Wuyuan Buxue treated group and Haierfu treated group were obviously higher than those in the control group and model group （P 〈 0.05, 0.01）; ALT and cholesterol had no significant differences among the groups （P 〉 0.05）. ③ Comparisons of the activities of AChE, GSH-PX and SOD in brain homogenate： The activity of AChE was significantly higher in the control group than the model group and Haierfu treated group, also higher in the Wuyuan Buxue treated group than in the model group （P 〈 0.05）. The activity of GSH-PX in the model group was significantly higher than those in the treated groups （P 〈 0.01）. The activity of SOD in the control group was significantly higher than those in the treated groups （P 〈 0.05, P 〈 0.01）. ④ Comparison of activities of GSH-PX and SOD, and MDA content in liver homogenate： The activities of GSH-PX and SOD in the model group were obviously lower than those in the Wuyuan Buxue treated group （P 〈 0.05）. MDA content had no obvious differencesamong the groups （P 〉 0.05）. ⑤ Comparison of MDA content, and clearance of O2-· in brain and liver： The MDA content in brain in the model group was significantly higher than those in the treated groups; The clearances of O2-· in liver in the treated groups were significantly higher than those in the control group and model group （P 〈 0.01）. ⑥ Swimming time and error rate in water maze： Before treatment, the swimming speed had no obvious difference among the groups, while the error rate was obviously different. After treatment, there was no obvious difference in the control group; The swimming time was prolonged as compared with that before treatment in the other three groups, and there were no obvious differences among the three group; The error rate was the highest in the model group （25%）, and the lowest in the Wuyuan Buxue treated group （8.3%）. CONCLUSION： Both the Chinese medicines of Wuyuan Buxue oral liquid and Haierfu oral liquid can improve the biochemical indices in serum, liver and brain, and the memory ability of mice with Alzheimer disease.

AAV mediated carboxyl terminus of Hsp70 interacting protein overexpression mitigates the cognitive and pathological phenotypes of APP/PS1 mice

The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer’s disease.We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain.CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests,reduced amyloid-βplaques,and decreased the expression of both amyloid-βand phosphorylated tau.CHIP also alleviated the concentration of microglia and astrocytes around plaques.In APP/PS1 mice of a younger age,CHIP overexpression promoted an increase in ADAM10 expression and inhibitedβ-site APP cleaving enzyme 1,insulin degrading enzyme,and neprilysin expression.Levels of HSP70 and HSP40,which have functional relevance to CHIP,were also increased.Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated,which may also reflect a potential mechanism for the neuroprotective effect of CHIP.Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice.Indeed,overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer’s disease.

Gamma-glutamyl transferase 5 overexpression in cerebrovascular endothelial cells improves brain pathology,cognition,and behavior in APP/PS1 mice

In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.

Impacts of exercise interventions on different diseases and organ functions in mice

Background'. In recent years, much evidence has emerged to indicate that exercise can benefit people when performed properly. This reviewsummarizes the exercise interventions used in studies involving mice as they are related to special diseases or physiological status. To furtherunderstand the effects of exercise interventions in treating or preventing diseases, it is important to establish a template for exercise interventionsthat can be used in future exercise-related studies.Methods'. PubMed was used as the data resource for articles. To identify studies related to the effectiveness of exercise interventions for treatingvarious diseases and organ functions in mice, we used the following search language: (exercise [Title] OR training [Title] OR physical activity[Title]) AND (mice [title/abstract] OR mouse [title/abstract] OR mus [title/abstract]). To limit the range of search results, we included 2 filters:one that limited publication dates to "in 10 years,^ and one that sorted the results as "best match^^. Then we grouped the commonly used exercisemethods according to their similarities and differences. We then evaluated the effectiveness of the exercise interventions for their impact on diseasesand organ functions in 8 different systems.Results'. A total of 331 articles were included in the analysis procedure. The articles were then segmented into 8 systems for which the exerciseinterventions were used in targeting and treating disorders: motor system (60 studies), metabolic system (45 studies), cardio-cerebral vascularsystem (58 studies), nervous system (74 studies), immune system (32 studies), respiratory system (7 studies), digestive system (1 study), and thesystem related to the development of cancer (54 studies). The methods of exercise interventions mainly involved the use of treadmills, voluntarywheel-running, forced wheel-running, swimming, and resistance training. It was found that regardless of the specific exercise method used, mostof them demonstrated positive effects on various systemic diseases and organ functions. Most diseases were remitted with exercise regardless ofthe exercise method used, although some diseases showed the best remission effects when a specific method was used.Conclusion-. Our review strongly suggests that exercise intervention is a cornerstone in disease prevention and treatment in mice. Because exerciseinterventions in humans typically focus on chronic diseases, national fitness, and body weight loss, and typically have low intervention com・pliance rates, it is important to use mice models to investigate the molecular mechanisms underlying the health benefits from exerciseinterventions in humans.

Efficacy of Sailuotong(塞络通)on neurovascular unit in amyloid precursor protein/presenilin-1 transgenic mice with Alzheimer's disease

OBJECTIVE:To discuss the influence of Sailuotong(塞络通,SLT)on the Neurovascular Unit(NVUs)of amyloid precursor protein(APP)/presenilin-1(PS1)mice and evaluate the role of gas supplementation in activating blood circulation during the progression of Alzheimer's disease(AD).METHODS:The mice were allocated into the following nine groups:(a)the C57 Black(C57BL)sham-operated group(control group),(b)ischaemic treatment in C57BL mice(the C57 ischaemic group),(c)the APP/PS1 sham surgery group(APP/PS1 model group),(d)ischaemic treatment in APP/PS1 mice(APP/PS1 ischaemic group),(e)C57BL mice treated with aspirin following ischaemic treatment(C57BL ischaemic+aspirin group),(f)C57BL mice treated with SLT following ischaemic treatment(C57BL ischaemic+SLT group),(g)APP/PS1 mice treated with SLT(APP/PS1+SLT group),(h)APP/PS1 mice treated with donepezil hydrochloride following ischaemic treatment(APP/PS1 ischaemic+donepezil hydrochloride group)and(i)APP/PS1 mice treated with SLT following ischaemic treatment(APP/PS1 ischaemic+SLT group).The ischaemic model was established by operating on the bilateral common carotid arteries and creating a microembolism.The Morris water maze and step-down tests were used to detect the spatial behaviour and memory ability of mice.The hippocampus of each mouse was observed by haematoxylin and eosin(HE)and Congo red staining.The ultrastructure of NVUs in each group was observed by electron microscopy,and various biochemical indicators were detected by enzymelinked immunosorbent assay(ELISA).The protein expression level was detected by Western blot.The mRNA expression was detected by quantitative real-time polymerase chain reaction(qRT-PCR).RESULTS:The results of the Morris water maze and step-down tests showed that ischemia reduced learning and memory in the mice,which were restored by SLT.The results of HE staining showed that SLT restored the pathological changes of the NVUs.The Congo red staining results revealed that SLT also improved the scattered orange-red sediments in the upper cortex and hippocampus of the APP/PS1 and APP/PS1 ischaemic mice.Furthermore,SLT significantly reduced the content of Aβ,improved the vascular endothelium and repaired the mitochondrial structures.The ELISA detection,western blot detection and qRT-PCR showed that SLT significantly increased the vascular endothelial growth factor(VEGF),angiopoietin and basic fibroblast growth factor,as well as the levels of gene and protein expression of low-density lipoprotein receptor-related protein-1(LRP-1)and VEGF in brain tissue.CONCLUSIONS:By increasing the expression of VEGF,SLT can promote vascular proliferation,up-regulate the expression of LRP-1,promote the clearance of Aβand improve the cognitive impairment of APP/PS1 mice.These results confirm that SLT can improve AD by promoting vascular proliferation and Aβclearance to protect the function of NVUs.

Metastatic human hepatocellular carcinoma models in nude mice and cell line with metastatic potential

Metastatic human HCC model is needed for the studies on mechanism and intervention of metastatic recurrence. By using orthotopic implantation of histologically intact tissues of 30 surgical specimens, a patient-like metastatic model of human HCC in nude mice (LCI-D20) and a low metastatic model of human HCC in nude mice (LCI-D35) have been established. All mice with transplanted LCI-D20 tumors exhibited extremely high metastatic ability including spontaneous metastasis to liver, lungs, lymph nodes and peritoneal seeding. Remarkable difference was also found in expression of some of the invasiveness related genes and growth factors between the LCI-D20 and LCI-D35 tumors. PAI-1 increased gradually following tumor progression in LCI-D20 model, and correlated with tumor size and AFP level. Phasic expression of tissue intercellular adhesion molecule-1 in this model was also observed. Using corneal micropocket model, it was demonstrated that the vascular response induced by LCI-D20 tumor was stronger than that induced by LCI-D35 tumor. Similar report on metastatic human HCC model in nude mice and human HCC cell line with metastatic potential was rarely found in the literature. This LCI-D20 model has been widely used for the studies on intervention of metastasis, including anti-angiogenesis,antisense approach, metalloproteinase inhibitor, differentiation inducer, etc. It is concluded that the establishment of metastatic human HCC model in nude mice and human HCC cell line with metastatic potential will provide important models for the in vitro and in vitro study of HCC invasiveness, angiogenesis as well as intervention of HCC recurrence.

T cells promote the regeneration of neural precursor cells in the hippocampus of Alzheimer's disease mice

Alzheimer＇s disease is closely associated with disorders of neurogenesis in the brain, and growing evidence supports the involvement of immunological mechanisms in the development of the disease. However, at present, the role of T cells in neuronal regeneration in the brain is unknown. We injected amyloid-beta 1-42 peptide into the hippocampus of six BALB/c wild-type mice and six BALB/c-nude mice with T-cell immunodeficiency to establish an animal model of Alzhei- mer＇s disease. A further six mice of each genotype were injected with same volume of normal saline. Immunohistochemistry revealed that the number of regenerated neural progenitor cells in the hippocampus of BALB/c wild-type mice was significantly higher than that in BALB/c-nude mice. Quantitative fluorescence PCR assay showed that the expression levels of peripheral T cell-associated cytokines （interleukin-2, interferon-y） and hippocampal microglia-related cyto- kines （interleukin-113, tumor necrosis factor-a） correlated with the number of regenerated neural progenitor cells in the hippocampus. These results indicate that T cells promote hippocampal neurogenesis in Alzheimer＇s disease and T-cell immunodeficiency restricts neuronal regeneration in the hippocampus. The mechanism underlying the promotion of neuronal regeneration by T cells is mediated by an increased expression of peripheral T cells and central microglial cytokines in Alzheimer＇s disease mice. Our findings provide an experimental basis for understanding the role of T cells in Alzheimer＇s disease.

Beta 2-adrenergic receptor activation enhances neurogenesis in Alzheimer's disease mice

Impaired hippocampal neurogenesis is one of the early pathological features of Alzheimer＇s disease. Enhancing adult hippocampal neuro- genesis has been pursued as a potential therapeutic strategy for Alzheimer＇s disease. Recent studies have demonstrated that environmental novelty activates β2-adrenergic signaling and prevents the memory impairment induced by amyloid-β oligomers. Here, we hypothesized that β2-adrenoceptor activation would enhance neurogenesis and ameliorate memory deficits in Alzheimer＇s disease. To test this hypothe- sis, we investigated the effects and mechanisms of action of β2-adrenoceptor activation on neurogenesis and memory in amyloid precursor protein/presenilin 1 （APP/PS1） mice using the agonist clenbuterol （intraperitoneal injection, 2 mg/kg）. We found that β2-adrenoceptor ac- tivation enhanced hippocampal neurogenesis, ameliorated memory deficits, and increased dendritic branching and the density of dendritic spines, lhese effects were associated with the upregulation of postsynaptic density 95, synapsin 1 and synaptophysin in APP/PS1 mice. Furthermore, β2-adrenoceptor activation decreased cerebral amyloid plaques by decreasing APP phosphorylation at Thr668. These findings suggest that β2-adrenoceptor activation enhances neurogenesis and ameliorates memory deficits in APP/PS 1 mice.

D-Tyr-tRNA^(Tyr) Deacylase,a New Role in Alzheimer's-associated Disease in SAMP8 Mice

Objective To assess the expression level of D-Tyr-tRNATyr deacylase(DTD) in SAMP8 mice and speculate the function of DTD in disorders associated with Alzheimer's disease(AD).Methods Altogether 12 SAMP8 mice and 12 SAMR1 mice were used in this study.Semi-quantita-tive reverse transcription-polymerase chain reaction(RT-PCR) and Western blot were performed to detect the mRNA and protein levels of DTD in the mice.Purified DTD protein was injected into lateral ventricle to investigate the function of DTD in SAMP mice.The behavior of the mice was tested by using a Step-through Test System.Results Both mRNA and protein levels of DTD were found to be significantly lower in SAMP8 mice compared with those in SAMR1 mice(P<0.05).In vivo injection of DTD protein did not lead to an obvious change in behavior of SAM mice.Conclusions DTD might function in the process of AD-associated pathology and could possibly participate in physiology process in a long-term manner to orchestrate with other regulators in order to maintain the balance of organism.

Shuanghuanglian injection downregulates nuclear factor-kappa B expression in mice with viral encephalitis

A mouse model of viral encephalitis was induced by intracranial injection of a Coxsackie virus B3 suspension. Quantitative real-time reverse transcription-PCR and western blot assay were applied to detect mRNA and protein expression of intelectin-2 and nuclear factor-kappa B in the viral encephalitis and control groups. Nuclear factor-kappa B and intelectin-2 mRNA and protein expression were significantly increased in mice with viral encephalitis. After intraperitoneal injection of Shuanghuanglian at a dose of 1.5 mg/kg for 5 successive days, intelectin-2 and nuclear factor-kappa B protein and mRNA expression were significantly decreased. To elucidate the relationship between intelectin-2 and nuclear factor-kappa B, mice with viral encephalitis were administered an intracerebral injection of 107 pfu recombinant lentivirus expressing intelectin shRNA. Both protein and mRNA levels of intelectin and nuclear factor-kappa B in brain tissue of mice were significantly decreased. Experimental findings suggest that Shuanghuanglian injection may downregulate nuclear factor-kappa B production via suppression of intelectin production, thus inhibiting inflammation associated with viral encephalitis.