A lupuslike condition induced by intraperitoneal administration of pristane(2,6,10,14 tetramethylpentadecane)in mice is widely used as a model of systemic lupus erythematosus(SLE).Due to their phylogenetic distance fr...A lupuslike condition induced by intraperitoneal administration of pristane(2,6,10,14 tetramethylpentadecane)in mice is widely used as a model of systemic lupus erythematosus(SLE).Due to their phylogenetic distance from humans,murine models are not always suitable tool for studying the specific activity of therapeutic agents and the pathogenesis of SLE.In order to overcome speciesspecific limitations of murine models,this approach was tested in nonhuman primates-cynomolgus monkeys(Macaca fascicularis).Two intraperitoneal injections at a dose of 3.5 mL/kg,administered at weeks 1 and 23,recapitulated SLE features,including:production of antinuclear autoantibodies(ANA),membranoproliferative glomerulonephritis with immune complex(IC)deposition in the glomeruli.However,from week 27 five of eight pristanetreated monkeys developed progressive respiratory failure.Two of these died at week 28 and the remaining were euthanized at week 32.The histology of the monkey lungs suggested exogenous lipoid pneumonia.Thus,while pristane induced serological autoimmunity and characteristic renal manifestations in Macaca fascicularis,the consequent lipoid pneumonia limited the observation period and prevented comprehensive evaluation of SLE manifestations beyond 32 weeks.展开更多
Traumatic brain injury can be categorized into primary and secondary injuries.Secondary injuries are the main cause of disability following traumatic brain injury,which involves a complex multicellular cascade.Microgl...Traumatic brain injury can be categorized into primary and secondary injuries.Secondary injuries are the main cause of disability following traumatic brain injury,which involves a complex multicellular cascade.Microglia play an important role in secondary injury and can be activated in response to traumatic brain injury.In this article,we review the origin and classification of microglia as well as the dynamic changes of microglia in traumatic brain injury.We also clarify the microglial polarization pathways and the therapeutic drugs targeting activated microglia.We found that regulating the signaling pathways involved in pro-inflammatory and anti-inflammatory microglia,such as the Toll-like receptor 4/nuclear factor-kappa B,mitogen-activated protein kinase,Janus kinase/signal transducer and activator of transcription,phosphoinositide 3-kinase/protein kinase B,Notch,and high mobility group box 1 pathways,can alleviate the inflammatory response triggered by microglia in traumatic brain injury,thereby exerting neuroprotective effects.We also reviewed the strategies developed on the basis of these pathways,such as drug and cell replacement therapies.Drugs that modulate inflammatory factors,such as rosuvastatin,have been shown to promote the polarization of antiinflammatory microglia and reduce the inflammatory response caused by traumatic brain injury.Mesenchymal stem cells possess anti-inflammatory properties,and clinical studies have confirmed their significant efficacy and safety in patients with traumatic brain injury.Additionally,advancements in mesenchymal stem cell-delivery methods—such as combinations of novel biomaterials,genetic engineering,and mesenchymal stem cell exosome therapy—have greatly enhanced the efficiency and therapeutic effects of mesenchymal stem cells in animal models.However,numerous challenges in the application of drug and mesenchymal stem cell treatment strategies remain to be addressed.In the future,new technologies,such as single-cell RNA sequencing and transcriptome analysis,can facilitate further experimental studies.Moreover,research involving non-human primates can help translate these treatment strategies to clinical practice.展开更多
Effective treatment methods for stroke,a common cerebrovascular disease with a high mortality rate,are still being sought.Exosome therapy,a form of acellular therapy,has demonstrated promising efficacy in various dise...Effective treatment methods for stroke,a common cerebrovascular disease with a high mortality rate,are still being sought.Exosome therapy,a form of acellular therapy,has demonstrated promising efficacy in various diseases in animal models;however,there is currently insufficient evidence to guide the clinical application of exosome in patients with stroke.This article reviews the progress of exosome applications in stroke treatment.It aims to elucidate the significant potential value of exosomes in stroke therapy and provide a reference for their clinical translation.At present,many studies on exosome-based therapies for stroke are actively underway.Regarding preclinical research,exosomes,as bioactive substances with diverse sources,currently favor stem cells as their origin.Due to their high plasticity,exosomes can be effectively modified through various physical,chemical,and genetic engineering methods to enhance their efficacy.In animal models of stroke,exosome therapy can reduce neuroinflammatory responses,alleviate oxidative stress damage,and inhibit programmed cell death.Additionally,exosomes can promote angiogenesis,repair and regenerate damaged white matter fiber bundles,and facilitate the migration and differentiation of neural stem cells,aiding the repair process.We also summarize new directions for the application of exosomes,specifically the exosome intervention through the ventricular-meningeal lymphatic system.The review findings suggest that the treatment paradigm for stroke is poised for transformation.展开更多
Although previous studies have demonstrated that transcranial focused ultrasound stimulation protects the ischemic brain,clear criteria for the stimulation time window and intensity are lacking.Electrical impedance to...Although previous studies have demonstrated that transcranial focused ultrasound stimulation protects the ischemic brain,clear criteria for the stimulation time window and intensity are lacking.Electrical impedance tomography enables real-time monitoring of changes in cerebral blood perfusion within the ischemic brain,but investigating the feasibility of using this method to assess post-stroke rehabilitation in vivo remains critical.In this study,ischemic stroke was induced in rats through middle cerebral artery occlusion surgery.Transcranial focused ultrasound stimulation was used to treat the rat model of ischemia,and electrical impedance tomography was used to measure impedance during both the acute stage of ischemia and the rehabilitation stage following the stimulation.Electrical impedance tomography results indicated that cerebral impedance increased after the onset of ischemia and decreased following transcranial focused ultrasound stimulation.Furthermore,the stimulation promoted motor function recovery,reduced cerebral infarction volume in the rat model of ischemic stroke,and induced the expression of brain-derived neurotrophic factor in the ischemic brain.Our results also revealed a significant correlation between the impedance of the ischemic brain post-intervention and improvements in behavioral scores and infarct volume.This study shows that daily administration of transcranial focused ultrasound stimulation for 20 minutes to the ischemic hemisphere 24 hours after cerebral ischemia enhanced motor recovery in a rat model of ischemia.Additionally,our findings indicate that electrical impedance tomography can serve as a valuable tool for quantitatively evaluating rehabilitation after ischemic stroke in vivo.These findings suggest the feasibility of using impedance data collected via electrical impedance tomography to clinically assess the effects of rehabilitatory interventions for patients with ischemic stroke.展开更多
Myasthenia gravis is a chronic autoimmune disorder that affects the neuromuscular junction leading to fluctuating skeletal muscle fatigability. The majority of myasthenia gravis patients have detectable antibodies in ...Myasthenia gravis is a chronic autoimmune disorder that affects the neuromuscular junction leading to fluctuating skeletal muscle fatigability. The majority of myasthenia gravis patients have detectable antibodies in their serum, targeting acetylcholine receptor, muscle-specific kinase, or related proteins. Current treatment for myasthenia gravis involves symptomatic therapy, immunosuppressive drugs such as corticosteroids, azathioprine, and mycophenolate mofetil, and thymectomy, which is primarily indicated in patients with thymoma or thymic hyperplasia. However, this condition continues to pose significant challenges including an unpredictable and variable disease progression, differing response to individual therapies, and substantial longterm side effects associated with standard treatments(including an increased risk of infections, osteoporosis, and diabetes), underscoring the necessity for a more personalized approach to treatment. Furthermore, about fifteen percent of patients, called “refractory myasthenia gravis patients”, do not respond adequately to standard therapies. In this context, the introduction of molecular therapies has marked a significant advance in myasthenia gravis management. Advances in understanding myasthenia gravis pathogenesis, especially the role of pathogenic antibodies, have driven the development of these biological drugs, which offer more selective, rapid, and safer alternatives to traditional immunosuppressants. This review aims to provide a comprehensive overview of emerging therapeutic strategies targeting specific immune pathways in myasthenia gravis, with a particular focus on preclinical evidence, therapeutic rationale, and clinical translation of B-cell depletion therapies, neonatal Fc receptor inhibitors, and complement inhibitors.展开更多
When teaching neurology students about epilepsy,selecting appropriate antiseizure medications(ASMs)based on seizure type is a fundamental objective.Carbamazepine(CBZ),a widely used first-line ASM,is effective against ...When teaching neurology students about epilepsy,selecting appropriate antiseizure medications(ASMs)based on seizure type is a fundamental objective.Carbamazepine(CBZ),a widely used first-line ASM,is effective against focal seizures,generalized tonic-clonic seizures,and mixed seizure patterns[1].However,CBZ paradoxically aggravates absence seizures,as demonstrated by increased 36 Hz spike-and-wave discharges(SWDs)in both patients and animal models[2,3].While prior studies implicated altered GABAA receptor function in the thalamic ventrobasal complex[4],the precise mechanisms remained unclear.Recently,an inspiring study published on PNAS by Jang et al.from Stanford University has highlighted the thalamic reticular nucleus(RT)as the key brain region responsible for CBZ's aggravating effect on absence seizures[5].The combination of transgenic mouse models,optogenetics,and detailed electrophysiology in the original study provided exceptional precision in probing mechanistic insights,which greatly strengthens the conclusions.展开更多
On the occasion of the New Year,I would like to extend my sincere gratitude and New Year greetings to the experts,scholars,author teams,and readers who have long supported the development of Animal Models and Experime...On the occasion of the New Year,I would like to extend my sincere gratitude and New Year greetings to the experts,scholars,author teams,and readers who have long supported the development of Animal Models and Experimental Medicine(AMEM).Over the past year,we have faced challenges together and achieved breakthroughs in academic influence,internationalization,and fulfilling social respon-sibilities.Looking ahead,we are filled with confidence as we strive to build an important bridge connecting laboratory animal science and technology with academic research.展开更多
Pathological scarring,manifested in the form of hypertrophic scars(HTS)and keloid scars(KS),represents a major clinical challenge due to its aesthetic and functional implications for patients.Understanding the molecul...Pathological scarring,manifested in the form of hypertrophic scars(HTS)and keloid scars(KS),represents a major clinical challenge due to its aesthetic and functional implications for patients.Understanding the molecular mechanisms involved in these types of scars and developing effective treatments requires the use of controlled ex-perimental models,especially animals,to overcome the limitations of clinical studies.The aim of this sistematic review is to critically analyze the animal models used in the last five years(2020-2025)for the study of pathological scars,highlighting their advantages,limitations and applicability in the development of new therapeutic strat-egies.Murine,rabbit and porcine models,as well as alternative models,offer varied perspectives on the formation and treatment of HTS and KS,with an emphasis on histological and molecular correlations with human pathology.By synthesizing recent data,the paper highlights the essential role of preclinical research in optimizing an-tifibrotic treatments and in advancing the translation of data into the clinical sphere.Overall,animal models remain essential for bridging mechanistic insights with clinical translation,supporting the development of more effective and personalized anti-scar therapies.展开更多
Background:The traditional method of heterotopic abdominal heart transplantation(HTx)involves crossclamping the inferior vena cava,which inevitably leads to bilateral lower limb ischemia(LI).This study first aimed to ...Background:The traditional method of heterotopic abdominal heart transplantation(HTx)involves crossclamping the inferior vena cava,which inevitably leads to bilateral lower limb ischemia(LI).This study first aimed to investigate the impact of LI on renal function in rats subjected to unilateral nephrectomy(UNx).Second,a modified method utilizing renal vessel-assisted anastomosis in rats with left UNx was compared with the traditional method for abdominal HTx.Methods:Male Sprague-Dawley rats were utilized as subjects for both experimental phases.In experiment 1,the animals were divided into four groups:sham operation group;LI group-rats undergoing occlusion of the abdominal aorta and vena cava below the renal vessels;UNx group-rats with left UNx;and LI+UNx group.All operated animals were monitored for up to 7 days for biochemical markers,renal histopathology,and survival rates.In experiment 2,we introduced the renal vessel-assisted method as the experimental group and compared it against the traditional method as the control within rat heterotopic HTx models.We assessed operative characteristics,echocardiography results,histological findings,and graft survival.Results:First,LI resulted in acute kidney dysfunction characterized by a decrease in 7day survival rates and creatinine clearance rates in both the LI and LI+UNx groups compared to the sham operation and UNx groups.Particularly,histopathological damage in the kidney and liver did not exhibit significant effects during this period.Second,the implementation of the renal vessel-assisted method significantly reduced bleeding volume at suture sites and enhanced the 7day survival rate compared to the traditional method.Conclusion:Acute kidney injury was induced by LI postoperation in treated rats.The renal vessel-assisted method demonstrated its effectiveness as a superior alternative that mitigates complications associated with the traditional method.展开更多
Cynomolgus macaques,a species of Old World primate native to southeastern and eastern Asia and the island of Mauritius,are one of the most important nonhuman primate models for infectious disease.Although the closely ...Cynomolgus macaques,a species of Old World primate native to southeastern and eastern Asia and the island of Mauritius,are one of the most important nonhuman primate models for infectious disease.Although the closely related rhesus macaque is classified into subspecies based on geographic origin,no such subdivision exists for cynomolgus macaques,and they continue to be used interchangeably in infectious disease research,reducing the comparability of data produced from these studies.Research into the population genetics of cynomolgus macaques has found significant differences between macaques native to different areas,including their genetic diversity,with macaques from insular populations such as Mauritius and the Philippines exhibiting highly restricted heterozygosity compared to mainland populations native to Indonesia or Cambodia.In the context of infectious disease studies,research into pathogens,including Ebola virus,Crimean-Congo hemorrhagic fever virus,and Mycobacterium tuberculosis have found differences in study outcomes,survival times,and immune cell responses between different populations of macaques.This review provides an overview of the differences between cynomolgus macaque populations in the context of genetic diversity,and in response to infection,and highlights the need for clear reporting of geographic origin of primates used in research.This will improve data comparison between studies and help to further refine this important animal model.展开更多
Background:The absence of effective animal models for sporadic Alzheimer's disease(AD)remains a pivotal barrier to therapy development.Because methanol metabolism produces endogenous formaldehyde,a neurotoxic agen...Background:The absence of effective animal models for sporadic Alzheimer's disease(AD)remains a pivotal barrier to therapy development.Because methanol metabolism produces endogenous formaldehyde,a neurotoxic agent linked to cognitive decline,this study investigated whether chronic,low-dose methanol exposure could recapitulate AD-like pathology and cognitive deficits in rhesus monkey,thereby establishing a nonhuman primate animal model driven by this environmental-metabolic insult.Methods:Adult rhesus monkeys received low-concentration methanol for 9 months.Behavioral tests for cognition,locomotion,sleep,and vision were conducted.Postmortem analyses involved histopathological examination,immunohistochemistry,immunofluorescence,and Western blot to evaluate neuronal integrity,microglial activation,and the expression of key proteins associated with AD(amyloid-β[Aβ],phosphorylated tau,TAR DNA-binding protein 43[TDP-43])and cellular stress(synaptic markers,mitochondrial fission,autophagy,and apoptosis-related proteins).Results:Chronic methanol exposure led to progressive cognitive and memory impairment without significant motor or visual deficits.Neuropathology revealed brain atrophy,neuronal loss,synaptic damage,microglial activation,and mitochondrial structural disorganization.Critically,the exposed animals exhibited hallmark AD-like molecular alterations,including increased Aβ deposition,tau hyperphosphorylation,and TDP-43 dysregulation.Furthermore,neurotoxicity was associated with elevated urinary formaldehyde,enhanced mitochondrial fission,increased autophagy,and elevated apoptosis.Conclusion:Chronic low-dose methanol exposure in rhesus monkeys recapitulates progressive cognitive deficits and AD-like neuropathological features.This model,driven by endogenous formaldehyde toxicity,effectively mimics key aspects of sporadic AD.Our findings shed light on the neurotoxic mechanisms of methanol and propose a reproducible and translationally relevant nonhuman primate model for studying AD pathogenesis and evaluating potential therapeutics.展开更多
BACKGROUND Non-erosive reflux disease(NERD),the main gastroesophageal reflux subtype,features reflux symptoms without mucosal damage.Anxiety links to visceral hypersensitivity in NERD,yet mechanisms and animal models ...BACKGROUND Non-erosive reflux disease(NERD),the main gastroesophageal reflux subtype,features reflux symptoms without mucosal damage.Anxiety links to visceral hypersensitivity in NERD,yet mechanisms and animal models are unclear.AIM To establish a translational NERD rat model with anxiety comorbidity via tail clamping and study corticotropin-releasing hormone(CRH)-mediated neuroimmune pathways in visceral hypersensitivity and esophageal injury.METHODS Sprague-Dawley(SD)and Wistar rats were grouped into sham,model,and modified groups(n=10 each).The treatments for the modified groups were as follows:SD rats received ovalbumin/aluminum hydroxide suspension+acid perfusion±tail clamping(40 minutes/day for 7 days),while Wistar rats received fructose water+tail clamping.Esophageal pathology,visceral sensitivity,and behavior were assessed.Serum CRH,calcitonin gene-related peptide(CGRP),5-hydroxytryptamine(5-HT),and mast cell tryptase(MCT)and central amygdala(CeA)CRH mRNA were measured via ELISA and qRT-PCR.RESULTS Tail clamping induced anxiety,worsening visceral hypersensitivity(lower abdominal withdrawal reflex thresholds,P<0.05)and esophageal injury(dilated intercellular spaces and mitochondrial edema).Both models showed raised serum CRH,CGRP,5-HT,and MCT(P<0.01)and CeA CRH mRNA expression(P<0.01).Behavioral tests confirmed anxiety-like phenotypes.NERD-anxiety rats showed clinical-like symptom severity without erosion.CONCLUSION Tail clamping induces anxiety in NERD models,worsening visceral hypersensitivity via CRH neuroimmune dysregulation,offering a translational model and highlighting CRH as a treatment target.展开更多
Background:The aim of the study was to develop a non-human primate model of metabolic dysfunction in Macaca fascicularis using chronic high-fat diet(HFD)to mimic clinical disease progression.Methods:Thirty-five male m...Background:The aim of the study was to develop a non-human primate model of metabolic dysfunction in Macaca fascicularis using chronic high-fat diet(HFD)to mimic clinical disease progression.Methods:Thirty-five male macaques aged 10-15 years underwent an 18-month HFD intervention.Physiological parameters(BMI,BP,hematology),liver fat fraction(evaluated by ultrasound/MRI),cardiac function(assessed by echocardiography),and histopathology(using liver biopsy)were measured before and after the intervention.Serum proteomics with KEGG/STRING analyses identified molecular mechanisms.Results:Within 6 months,HFD induced dyslipidemia(elevated TG,TCHO,HDL-C,LDL-C).After 18 months,metabolic dysfunction-associated steatohepatitis(MASH)was confirmed by histopathology in 57.14%(16/28)of macaques,diabetes(elevated FPG/HbA1c)in 17.86%(5/28),and myocardial hypertrophy(elevated LVMass/LAD)in 46.43%(13/28).Proteomics identified Bile acid-CoA:amino acid N-acyltransferase(BAAT)as a MASH hallmark protein,the level of which was inversely correlated with the degree of fibrosis.For diabetes,citrate synthase(CS)and malate dehydrogenase 1(MDH1)impaired glucose oxidation via the TCA cycle,while hexose-6-phosphate de-hydrogenase(H6PD)disrupted gluconeogenesis.Myocardial hypertrophy was associ-ated with the downregulation of SRC proto-oncogene,non-receptor tyrosine kinase(SRC),mitogen-activated protein kinase 14(MAPK14),emerin(EMD),and integrin subunit beta 1(ITGB1).Conclusions:An 18-month HFD successfully established a translational M.fascicula-ris model replicating key metabolic disorders(MASH,diabetes,cardiac hypertrophy).BAAT,CS/MDH1/H6PD,and SRC/MAPK14/EMD/ITGB1 were identified as mecha-nistic biomarkers for these conditions.展开更多
Background:This study aims to explore the establishment of an animal model of car-diac injury induced by trimethylamine-N-oxide(TMAO),a metabolite secreted by gut microorganisms,and to investigate its application in m...Background:This study aims to explore the establishment of an animal model of car-diac injury induced by trimethylamine-N-oxide(TMAO),a metabolite secreted by gut microorganisms,and to investigate its application in moderate-intensity continuous training(MICT)intervention.Methods:C57BL6/J mice were randomly divided into four groups:normal mice(Nor,n=15);mice administered TMAO(TMAO,n=15);mice undergoing(Nor+MICT,n=15);mice undergoing(MICT)and administered TMAO(TMAO+MICT,n=15).Mice in the TMAO and TMAO+MICT groups received daily gavage of high-dose TMAO for 8 weeks,whereas those in the Nor+MICT and TMAO+MICT groups underwent MICT for 8 weeks(60 min per session,5 days per week,at 50%maximal running capacity).Cardiac function was evaluated using ultrasound,myocardial histology was examined using hematoxylin and eosin(HE)staining,and nuclear magnetic resonance(NMR)-based metabolomics was employed for multivariate statistical and metabolic pathway analyses.Results:Relative to the Nor group,TMAO-treated mice exhibited significant weight loss,elevated heart rate,and reduced ejection fraction and left ventricular fractional shortening,indicating cardiac impairment.Importantly,the TMAO+MICT group dem-onstrated significant improvements in these parameters compared to the TMAO group,alongside distinct alterations in myocardial metabolic profiles.TMAO altered five metabolic pathways relative to controls,whereas MICT induced significant changes in three pathways in TMAO-treated mice.Conclusion:Eight weeks of high-dose TMAO administration induced significant cardiac dysfunction in mice,which was effectively mitigated by MICT intervention.Consequently,this animal model serves as a valuable tool for investigating the mecha-nisms underlying the impact of MICT on cardiovascular diseases.展开更多
Background:Healthy non-pharmacological lifestyle factors,such as regular physical exercise and dietary supplementation,have been shown to significantly improve cognitive outcomes over time compared to a more sedentary...Background:Healthy non-pharmacological lifestyle factors,such as regular physical exercise and dietary supplementation,have been shown to significantly improve cognitive outcomes over time compared to a more sedentary lifestyle and poor diet.Furthermore,exercise may serve as a potential protective factor in attenuating the effects associated with cognitive decline that are characteristic of neurodegenerative disorders,such as Alzheimer's disease(AD).Evidence indicates that certain dietary interventions can also attenuate the effects of neurodegeneration and positively impact longevity.Supplementation with polyphenols such as ellagic acid(EA),which is abundant in pomegranate juice,may help provide neuroprotective and longevity benefits.Methods:This study examined the potential protective potential of EA and exercise and provides insight into the combined use of a polyphenol-rich diet and exercise to enhance behavioral outcomes and lifespan in a transgenic Drosophila melanogaster(fruit fly)model of AD with the Aβ_(42) gene.Results:Fruit flies subjected to a 120-minute exercise regimen performed better on a climbing assay than flies that did not exercise.Conversely,flies that exercised for 30 min passed marginally more trials on a learning and memory assay using an aversive stimulus than flies that did not exercise,whereas both groups performed better than flies subjected to the more intense exercise condition.Conclusion:These results suggest a hormetic effect of exercise regarding memory performance.Finally,flies fed a low dose of dietary EA(0.24 mg/mL)lived significantly longer than flies fed the control diet or higher concentrations of EA,again suggesting a hormetic effect of EA on longevity.展开更多
The incidence of benign airway stenosis(BAS)is on the rise,and current treatment options are associated with a significant risk of restenosis.Therefore,there is an urgent need to explore new and effective prevention a...The incidence of benign airway stenosis(BAS)is on the rise,and current treatment options are associated with a significant risk of restenosis.Therefore,there is an urgent need to explore new and effective prevention and treatment methods.Animal models serve as essential tools for investigating disease mechanisms and assessing novel therapeutic strategies,and the scientific rigor of their construction and validation significantly impacts the reliability of research findings.This paper systematically reviews the research progress and evaluation systems of BAS animal models over the past decade,aiming to provide a robust foundation for the optimized construction of BAS models,intervention studies,and clinical translation.This effort is intended to facilitate the innovation and advancement in BAS prevention and treatment strategies.展开更多
Background:In preclinical research,tumor growth inhibition in subcutaneous models is frequently employed to evaluate therapeutic efficacy;however,such models often lack clinical translatability.Methods:To better appro...Background:In preclinical research,tumor growth inhibition in subcutaneous models is frequently employed to evaluate therapeutic efficacy;however,such models often lack clinical translatability.Methods:To better approximate clinical reality,taking the case of doxorubicin treatment,we utilized an orthotopic transplant and resection(OtR)strategy to systematically assess the effects of neoadjuvant chemotherapy,adjuvant chem-otherapy,and their combination on tumor growth,recurrence,and malignant progression.Results:Surprisingly,none of the treatments improved mouse survival,with adjuvant therapy even shortening it.Although neoadjuvant chemotherapy delayed preopera-tive tumor growth,and all regimens reduced recurrence rates,none effectively pre-vented metastasis.Furthermore,all treatment groups exhibited weight loss,indicative of chemotherapy-induced cachexia.Conclusions:Collectively,these findings demonstrate that reduced tumor growth in preclinical mouse models does not necessarily translate into overall survival benefit.Our results emphasize the critical importance of prioritizing metastasis prevention over tumor growth inhibition as a key efficacy endpoint in antitumor drug evaluation.展开更多
Background:Targeted delivery of biological macromolecules to the small intestine remains challenging due to their susceptibility to degradation in the hostile gastric environment.Methods:This study introduces a minima...Background:Targeted delivery of biological macromolecules to the small intestine remains challenging due to their susceptibility to degradation in the hostile gastric environment.Methods:This study introduces a minimally invasive,in situ injection technique for the murine small intestine that facilitates localized luminal delivery while circumventing gastric barriers.The procedure involves a small abdominal incision for direct injection into the duodenum near the pylorus.Postsurgical monitoring of physiological parameters,systemic inflammatory markers,liver function,and intestinal integrity was conducted over 72 h.Histopathological analysis was performed.The delivery of the functional protein TAT-EGFP(Tat protein fused to enhanced green fluorescent protein)to intestinal epithelial cells was evaluated and compared with oral gavage.As a proof of concept,single-cell RNA sequencing of the intestinal epithelium was performed after high-mobility group box 1 administration.Results:Postsurgical monitoring indicated only transient,anesthesia-related hypo-thermia and minor behavioral alterations.No significant changes were observed over 72 h in body weight,core temperature,clinical severity scores,systemic inflammatory markers(C-reactive protein and leukocytes),liver function(alanine aminotransferase),or intestinal integrity.Histopathological analysis confirmed preserved tissue architec-ture and normal digestive,absorptive,and barrier functions.The model successfully delivered TAT-EGFP to intestinal epithelial cells,an outcome not achievable via oral gavage due to gastric degradation.Single-cell RNA sequencing of the intestinal epi-thelium after high-mobility group box 1 administration revealed inflammatory gene expression patterns in specific epithelial subpopulations.Conclusions:Compared to traditional methods such as oral gavage or organoid cul-ture,this technique offers precise,degradation-resistant delivery of macromolecules in a physiological context.The model's versatility makes it a powerful platform for intestinal research,with applications in drug delivery assessment,gene therapy evalu-ation,and host-microbiota interaction studies.展开更多
Sympathetic nerve and vagus nerve remodeling play an important part in cardiac function post-myocardial infarction （MI）. Increasing evidence indicates that neuregulin-1 （NRG-1） improves cardiac function following ...Sympathetic nerve and vagus nerve remodeling play an important part in cardiac function post-myocardial infarction （MI）. Increasing evidence indicates that neuregulin-1 （NRG-1） improves cardiac function following heart failure. Since its impact on cardiac function and neural remodeling post-MI is poorly understood, we aimed to investigate the role of NRG-1 in autonomic nervous system remodeling post-MI. Forty-five Sprague-Dawley rats were equally randomized into three groups： sham （with the left anterior descending coronary artery exposed but without ligation）, MI （left anterior descending coronary artery ligation）, and MI plus NRG-1 （left anterior descending coronary artery ligation followed by intraperitoneal injection of NRG-1 （10 lag/kg, once daily for 7 days））. At 4 weeks after MI, echocardi- ography was used to detect the rat cardiac function by measuring the left ventricular end-systolic inner diameter, left ventricular diastolic diameter, left ventricular end-systolic volume, left ventricular end-diastolic volume, left ventricular ejection fraction, and left ventricular fractional shortening, mRNA and protein expression levels of tyrosine hydroxylase, growth associated protein-43 （neuronal specific pro- tein）, nerve growth factor, choline acetyltransferase （vagus nerve marker）, and vesicular acetylcholine transporter （cardiac vagal nerve fiber marker） in ischemic myocardia were detected by real-time PCR and western blot assay to assess autonomous nervous remodeling. After MI, the rat cardiac function deteriorated significantly, and it was significantly improved after NRG-1 injection. Compared with the MI group, mRNA and protein levels of tyrosine hydroxylase and growth associated protein-43, as well as choline acetyltransferase mRNA level significantly decreased in the MI plus NRG-1 group, while mRNA and protein levels of nerve growth factor and vesicular acetylcholine transporters, as well as choline acetyltransferase protein level slightly decreased. Our results indicate that NRG- 1 can improve cardiac function and regulate sympathetic and vagus nerve remodeling post-MI, thus reaching a new balance of the autonomic nervous system to protect the heart from injury.展开更多
Subcortical ischemic white matter injury(SIWMI),pathological correlate of white matter hyperintensities or leukoaraiosis on magnetic resonance imaging,is a common cause of cognitive decline in elderly.Despite its high...Subcortical ischemic white matter injury(SIWMI),pathological correlate of white matter hyperintensities or leukoaraiosis on magnetic resonance imaging,is a common cause of cognitive decline in elderly.Despite its high prevalence,it remains unknown how various components of the white matter degenerate in response to chronic ischemia.This incomplete knowledge is in part due to a lack of adequate animal model.The current review introduces various SIWMI animal models and aims to scrutinize their advantages and disadvantages primarily in regard to the pathological manifestations of white matter components.The SIWMI animal models are categorized into 1)chemically induced SIWMI models,2)vascular occlusive SIWMI models,and 3)SIWMI models with comorbid vascular risk factors.Chemically induced models display consistent lesions in predetermined areas of the white matter,but the abrupt evolution of lesions does not appropriately reflect the progressive pathological processes in human white matter hyperintensities.Vascular occlusive SIWMI models often do not exhibit white matter lesions that are sufficiently unequivocal to be quantified.When combined with comorbid vascular risk factors(specifically hypertension),however,they can produce progressive and definitive white matter lesions including diffuse rarefaction,demyelination,loss of oligodendrocytes,and glial activation,which are by far the closest to those found in human white matter hyperintensities lesions.However,considerable surgical mortality and unpredictable natural deaths during a follow-up period would necessitate further refinements in these models.In the meantime,in vitro SIWMI models that recapitulate myelinated white matter track may be utilized to study molecular mechanisms of the ischemic white matter injury.Appropriate in vivo and in vitro SIWMI models will contribute in a complementary manner to making a breakthrough in developing effective treatment to prevent progression of white matter hyperintensities.展开更多
文摘A lupuslike condition induced by intraperitoneal administration of pristane(2,6,10,14 tetramethylpentadecane)in mice is widely used as a model of systemic lupus erythematosus(SLE).Due to their phylogenetic distance from humans,murine models are not always suitable tool for studying the specific activity of therapeutic agents and the pathogenesis of SLE.In order to overcome speciesspecific limitations of murine models,this approach was tested in nonhuman primates-cynomolgus monkeys(Macaca fascicularis).Two intraperitoneal injections at a dose of 3.5 mL/kg,administered at weeks 1 and 23,recapitulated SLE features,including:production of antinuclear autoantibodies(ANA),membranoproliferative glomerulonephritis with immune complex(IC)deposition in the glomeruli.However,from week 27 five of eight pristanetreated monkeys developed progressive respiratory failure.Two of these died at week 28 and the remaining were euthanized at week 32.The histology of the monkey lungs suggested exogenous lipoid pneumonia.Thus,while pristane induced serological autoimmunity and characteristic renal manifestations in Macaca fascicularis,the consequent lipoid pneumonia limited the observation period and prevented comprehensive evaluation of SLE manifestations beyond 32 weeks.
基金supported by the Natural Science Foundation of Yunnan Province,No.202401AS070086(to ZW)the National Key Research and Development Program of China,No.2018YFA0801403(to ZW)+1 种基金Yunnan Science and Technology Talent and Platform Plan,No.202105AC160041(to ZW)the Natural Science Foundation of China,No.31960120(to ZW)。
文摘Traumatic brain injury can be categorized into primary and secondary injuries.Secondary injuries are the main cause of disability following traumatic brain injury,which involves a complex multicellular cascade.Microglia play an important role in secondary injury and can be activated in response to traumatic brain injury.In this article,we review the origin and classification of microglia as well as the dynamic changes of microglia in traumatic brain injury.We also clarify the microglial polarization pathways and the therapeutic drugs targeting activated microglia.We found that regulating the signaling pathways involved in pro-inflammatory and anti-inflammatory microglia,such as the Toll-like receptor 4/nuclear factor-kappa B,mitogen-activated protein kinase,Janus kinase/signal transducer and activator of transcription,phosphoinositide 3-kinase/protein kinase B,Notch,and high mobility group box 1 pathways,can alleviate the inflammatory response triggered by microglia in traumatic brain injury,thereby exerting neuroprotective effects.We also reviewed the strategies developed on the basis of these pathways,such as drug and cell replacement therapies.Drugs that modulate inflammatory factors,such as rosuvastatin,have been shown to promote the polarization of antiinflammatory microglia and reduce the inflammatory response caused by traumatic brain injury.Mesenchymal stem cells possess anti-inflammatory properties,and clinical studies have confirmed their significant efficacy and safety in patients with traumatic brain injury.Additionally,advancements in mesenchymal stem cell-delivery methods—such as combinations of novel biomaterials,genetic engineering,and mesenchymal stem cell exosome therapy—have greatly enhanced the efficiency and therapeutic effects of mesenchymal stem cells in animal models.However,numerous challenges in the application of drug and mesenchymal stem cell treatment strategies remain to be addressed.In the future,new technologies,such as single-cell RNA sequencing and transcriptome analysis,can facilitate further experimental studies.Moreover,research involving non-human primates can help translate these treatment strategies to clinical practice.
基金supported by the Natural Science Foundation of Chongqing,No.CSTB2023NSCQ-mSX0561(to WL).
文摘Effective treatment methods for stroke,a common cerebrovascular disease with a high mortality rate,are still being sought.Exosome therapy,a form of acellular therapy,has demonstrated promising efficacy in various diseases in animal models;however,there is currently insufficient evidence to guide the clinical application of exosome in patients with stroke.This article reviews the progress of exosome applications in stroke treatment.It aims to elucidate the significant potential value of exosomes in stroke therapy and provide a reference for their clinical translation.At present,many studies on exosome-based therapies for stroke are actively underway.Regarding preclinical research,exosomes,as bioactive substances with diverse sources,currently favor stem cells as their origin.Due to their high plasticity,exosomes can be effectively modified through various physical,chemical,and genetic engineering methods to enhance their efficacy.In animal models of stroke,exosome therapy can reduce neuroinflammatory responses,alleviate oxidative stress damage,and inhibit programmed cell death.Additionally,exosomes can promote angiogenesis,repair and regenerate damaged white matter fiber bundles,and facilitate the migration and differentiation of neural stem cells,aiding the repair process.We also summarize new directions for the application of exosomes,specifically the exosome intervention through the ventricular-meningeal lymphatic system.The review findings suggest that the treatment paradigm for stroke is poised for transformation.
基金supported by the Fundamental Research Funds for the Central Universities,Nos.G2021KY05107,G2021KY05101the National Natural Science Foundation of China,Nos.32071316,32211530049+1 种基金the Natural Science Foundation of Shaanxi Province,No.2022-JM482the Education and Teaching Reform Funds for the Central Universities,No.23GZ230102(all to LL and HH).
文摘Although previous studies have demonstrated that transcranial focused ultrasound stimulation protects the ischemic brain,clear criteria for the stimulation time window and intensity are lacking.Electrical impedance tomography enables real-time monitoring of changes in cerebral blood perfusion within the ischemic brain,but investigating the feasibility of using this method to assess post-stroke rehabilitation in vivo remains critical.In this study,ischemic stroke was induced in rats through middle cerebral artery occlusion surgery.Transcranial focused ultrasound stimulation was used to treat the rat model of ischemia,and electrical impedance tomography was used to measure impedance during both the acute stage of ischemia and the rehabilitation stage following the stimulation.Electrical impedance tomography results indicated that cerebral impedance increased after the onset of ischemia and decreased following transcranial focused ultrasound stimulation.Furthermore,the stimulation promoted motor function recovery,reduced cerebral infarction volume in the rat model of ischemic stroke,and induced the expression of brain-derived neurotrophic factor in the ischemic brain.Our results also revealed a significant correlation between the impedance of the ischemic brain post-intervention and improvements in behavioral scores and infarct volume.This study shows that daily administration of transcranial focused ultrasound stimulation for 20 minutes to the ischemic hemisphere 24 hours after cerebral ischemia enhanced motor recovery in a rat model of ischemia.Additionally,our findings indicate that electrical impedance tomography can serve as a valuable tool for quantitatively evaluating rehabilitation after ischemic stroke in vivo.These findings suggest the feasibility of using impedance data collected via electrical impedance tomography to clinically assess the effects of rehabilitatory interventions for patients with ischemic stroke.
文摘Myasthenia gravis is a chronic autoimmune disorder that affects the neuromuscular junction leading to fluctuating skeletal muscle fatigability. The majority of myasthenia gravis patients have detectable antibodies in their serum, targeting acetylcholine receptor, muscle-specific kinase, or related proteins. Current treatment for myasthenia gravis involves symptomatic therapy, immunosuppressive drugs such as corticosteroids, azathioprine, and mycophenolate mofetil, and thymectomy, which is primarily indicated in patients with thymoma or thymic hyperplasia. However, this condition continues to pose significant challenges including an unpredictable and variable disease progression, differing response to individual therapies, and substantial longterm side effects associated with standard treatments(including an increased risk of infections, osteoporosis, and diabetes), underscoring the necessity for a more personalized approach to treatment. Furthermore, about fifteen percent of patients, called “refractory myasthenia gravis patients”, do not respond adequately to standard therapies. In this context, the introduction of molecular therapies has marked a significant advance in myasthenia gravis management. Advances in understanding myasthenia gravis pathogenesis, especially the role of pathogenic antibodies, have driven the development of these biological drugs, which offer more selective, rapid, and safer alternatives to traditional immunosuppressants. This review aims to provide a comprehensive overview of emerging therapeutic strategies targeting specific immune pathways in myasthenia gravis, with a particular focus on preclinical evidence, therapeutic rationale, and clinical translation of B-cell depletion therapies, neonatal Fc receptor inhibitors, and complement inhibitors.
基金supported by the National Natural Science Foundation of China(82173796)the Research Project of Zhejiang Chinese Medical University(2023JKZDZC04).
文摘When teaching neurology students about epilepsy,selecting appropriate antiseizure medications(ASMs)based on seizure type is a fundamental objective.Carbamazepine(CBZ),a widely used first-line ASM,is effective against focal seizures,generalized tonic-clonic seizures,and mixed seizure patterns[1].However,CBZ paradoxically aggravates absence seizures,as demonstrated by increased 36 Hz spike-and-wave discharges(SWDs)in both patients and animal models[2,3].While prior studies implicated altered GABAA receptor function in the thalamic ventrobasal complex[4],the precise mechanisms remained unclear.Recently,an inspiring study published on PNAS by Jang et al.from Stanford University has highlighted the thalamic reticular nucleus(RT)as the key brain region responsible for CBZ's aggravating effect on absence seizures[5].The combination of transgenic mouse models,optogenetics,and detailed electrophysiology in the original study provided exceptional precision in probing mechanistic insights,which greatly strengthens the conclusions.
文摘On the occasion of the New Year,I would like to extend my sincere gratitude and New Year greetings to the experts,scholars,author teams,and readers who have long supported the development of Animal Models and Experimental Medicine(AMEM).Over the past year,we have faced challenges together and achieved breakthroughs in academic influence,internationalization,and fulfilling social respon-sibilities.Looking ahead,we are filled with confidence as we strive to build an important bridge connecting laboratory animal science and technology with academic research.
基金Ministry of Research,Innovation and Digitization,CCCDI-UEFISCDI,Grant/Award Number:PN-IV-P7-7.1-PED-2024-1578,within PNCDI Ⅳ.
文摘Pathological scarring,manifested in the form of hypertrophic scars(HTS)and keloid scars(KS),represents a major clinical challenge due to its aesthetic and functional implications for patients.Understanding the molecular mechanisms involved in these types of scars and developing effective treatments requires the use of controlled ex-perimental models,especially animals,to overcome the limitations of clinical studies.The aim of this sistematic review is to critically analyze the animal models used in the last five years(2020-2025)for the study of pathological scars,highlighting their advantages,limitations and applicability in the development of new therapeutic strat-egies.Murine,rabbit and porcine models,as well as alternative models,offer varied perspectives on the formation and treatment of HTS and KS,with an emphasis on histological and molecular correlations with human pathology.By synthesizing recent data,the paper highlights the essential role of preclinical research in optimizing an-tifibrotic treatments and in advancing the translation of data into the clinical sphere.Overall,animal models remain essential for bridging mechanistic insights with clinical translation,supporting the development of more effective and personalized anti-scar therapies.
基金The Youth Project of Tianjin Natural Science Foundation,Grant/Award Number:23JCQNJC01380。
文摘Background:The traditional method of heterotopic abdominal heart transplantation(HTx)involves crossclamping the inferior vena cava,which inevitably leads to bilateral lower limb ischemia(LI).This study first aimed to investigate the impact of LI on renal function in rats subjected to unilateral nephrectomy(UNx).Second,a modified method utilizing renal vessel-assisted anastomosis in rats with left UNx was compared with the traditional method for abdominal HTx.Methods:Male Sprague-Dawley rats were utilized as subjects for both experimental phases.In experiment 1,the animals were divided into four groups:sham operation group;LI group-rats undergoing occlusion of the abdominal aorta and vena cava below the renal vessels;UNx group-rats with left UNx;and LI+UNx group.All operated animals were monitored for up to 7 days for biochemical markers,renal histopathology,and survival rates.In experiment 2,we introduced the renal vessel-assisted method as the experimental group and compared it against the traditional method as the control within rat heterotopic HTx models.We assessed operative characteristics,echocardiography results,histological findings,and graft survival.Results:First,LI resulted in acute kidney dysfunction characterized by a decrease in 7day survival rates and creatinine clearance rates in both the LI and LI+UNx groups compared to the sham operation and UNx groups.Particularly,histopathological damage in the kidney and liver did not exhibit significant effects during this period.Second,the implementation of the renal vessel-assisted method significantly reduced bleeding volume at suture sites and enhanced the 7day survival rate compared to the traditional method.Conclusion:Acute kidney injury was induced by LI postoperation in treated rats.The renal vessel-assisted method demonstrated its effectiveness as a superior alternative that mitigates complications associated with the traditional method.
文摘Cynomolgus macaques,a species of Old World primate native to southeastern and eastern Asia and the island of Mauritius,are one of the most important nonhuman primate models for infectious disease.Although the closely related rhesus macaque is classified into subspecies based on geographic origin,no such subdivision exists for cynomolgus macaques,and they continue to be used interchangeably in infectious disease research,reducing the comparability of data produced from these studies.Research into the population genetics of cynomolgus macaques has found significant differences between macaques native to different areas,including their genetic diversity,with macaques from insular populations such as Mauritius and the Philippines exhibiting highly restricted heterozygosity compared to mainland populations native to Indonesia or Cambodia.In the context of infectious disease studies,research into pathogens,including Ebola virus,Crimean-Congo hemorrhagic fever virus,and Mycobacterium tuberculosis have found differences in study outcomes,survival times,and immune cell responses between different populations of macaques.This review provides an overview of the differences between cynomolgus macaque populations in the context of genetic diversity,and in response to infection,and highlights the need for clear reporting of geographic origin of primates used in research.This will improve data comparison between studies and help to further refine this important animal model.
基金Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences,Grant/Award Number:2021-I2M-1-034Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences,Grant/Award Number:2023-PT180-01+1 种基金PUMC Innovation Fund for Graduate Students,Grant/Award Number:2017-1001-07National Natural Science Foundation of China,Grant/Award Number:82161138027。
文摘Background:The absence of effective animal models for sporadic Alzheimer's disease(AD)remains a pivotal barrier to therapy development.Because methanol metabolism produces endogenous formaldehyde,a neurotoxic agent linked to cognitive decline,this study investigated whether chronic,low-dose methanol exposure could recapitulate AD-like pathology and cognitive deficits in rhesus monkey,thereby establishing a nonhuman primate animal model driven by this environmental-metabolic insult.Methods:Adult rhesus monkeys received low-concentration methanol for 9 months.Behavioral tests for cognition,locomotion,sleep,and vision were conducted.Postmortem analyses involved histopathological examination,immunohistochemistry,immunofluorescence,and Western blot to evaluate neuronal integrity,microglial activation,and the expression of key proteins associated with AD(amyloid-β[Aβ],phosphorylated tau,TAR DNA-binding protein 43[TDP-43])and cellular stress(synaptic markers,mitochondrial fission,autophagy,and apoptosis-related proteins).Results:Chronic methanol exposure led to progressive cognitive and memory impairment without significant motor or visual deficits.Neuropathology revealed brain atrophy,neuronal loss,synaptic damage,microglial activation,and mitochondrial structural disorganization.Critically,the exposed animals exhibited hallmark AD-like molecular alterations,including increased Aβ deposition,tau hyperphosphorylation,and TDP-43 dysregulation.Furthermore,neurotoxicity was associated with elevated urinary formaldehyde,enhanced mitochondrial fission,increased autophagy,and elevated apoptosis.Conclusion:Chronic low-dose methanol exposure in rhesus monkeys recapitulates progressive cognitive deficits and AD-like neuropathological features.This model,driven by endogenous formaldehyde toxicity,effectively mimics key aspects of sporadic AD.Our findings shed light on the neurotoxic mechanisms of methanol and propose a reproducible and translationally relevant nonhuman primate model for studying AD pathogenesis and evaluating potential therapeutics.
基金Supported by the National Key Specialty of Traditional Chinese Medicine(Spleen and Stomach Diseases),No.0500004National Natural Science Foundation of China,No.82205104 and No.82104850+1 种基金Hospital Capability Enhancement Project of Xiyuan Hospital,CACMS,No.XYZX0303-07the Fundamental Research Funds for the Central Public Welfare Research Institutes,Excellent Young Scientists Training Program of China Academy of Chinese Medical Sciences,No.ZZ16-YQ-002.
文摘BACKGROUND Non-erosive reflux disease(NERD),the main gastroesophageal reflux subtype,features reflux symptoms without mucosal damage.Anxiety links to visceral hypersensitivity in NERD,yet mechanisms and animal models are unclear.AIM To establish a translational NERD rat model with anxiety comorbidity via tail clamping and study corticotropin-releasing hormone(CRH)-mediated neuroimmune pathways in visceral hypersensitivity and esophageal injury.METHODS Sprague-Dawley(SD)and Wistar rats were grouped into sham,model,and modified groups(n=10 each).The treatments for the modified groups were as follows:SD rats received ovalbumin/aluminum hydroxide suspension+acid perfusion±tail clamping(40 minutes/day for 7 days),while Wistar rats received fructose water+tail clamping.Esophageal pathology,visceral sensitivity,and behavior were assessed.Serum CRH,calcitonin gene-related peptide(CGRP),5-hydroxytryptamine(5-HT),and mast cell tryptase(MCT)and central amygdala(CeA)CRH mRNA were measured via ELISA and qRT-PCR.RESULTS Tail clamping induced anxiety,worsening visceral hypersensitivity(lower abdominal withdrawal reflex thresholds,P<0.05)and esophageal injury(dilated intercellular spaces and mitochondrial edema).Both models showed raised serum CRH,CGRP,5-HT,and MCT(P<0.01)and CeA CRH mRNA expression(P<0.01).Behavioral tests confirmed anxiety-like phenotypes.NERD-anxiety rats showed clinical-like symptom severity without erosion.CONCLUSION Tail clamping induces anxiety in NERD models,worsening visceral hypersensitivity via CRH neuroimmune dysregulation,offering a translational model and highlighting CRH as a treatment target.
基金National Key Research and Development Program of China,Grant/Award Number:2021YFF0702200Science and Technology Projects in Guangzhou,Grant/Award Number:202206010084,202206010197 and 202206060002+1 种基金Guangdong S&T programme,Grant/Award Number:2009A081000002 and 2023B0303040004Technology Planning Project of Linzhi,Grant/Award Number:2023-YZ-01。
文摘Background:The aim of the study was to develop a non-human primate model of metabolic dysfunction in Macaca fascicularis using chronic high-fat diet(HFD)to mimic clinical disease progression.Methods:Thirty-five male macaques aged 10-15 years underwent an 18-month HFD intervention.Physiological parameters(BMI,BP,hematology),liver fat fraction(evaluated by ultrasound/MRI),cardiac function(assessed by echocardiography),and histopathology(using liver biopsy)were measured before and after the intervention.Serum proteomics with KEGG/STRING analyses identified molecular mechanisms.Results:Within 6 months,HFD induced dyslipidemia(elevated TG,TCHO,HDL-C,LDL-C).After 18 months,metabolic dysfunction-associated steatohepatitis(MASH)was confirmed by histopathology in 57.14%(16/28)of macaques,diabetes(elevated FPG/HbA1c)in 17.86%(5/28),and myocardial hypertrophy(elevated LVMass/LAD)in 46.43%(13/28).Proteomics identified Bile acid-CoA:amino acid N-acyltransferase(BAAT)as a MASH hallmark protein,the level of which was inversely correlated with the degree of fibrosis.For diabetes,citrate synthase(CS)and malate dehydrogenase 1(MDH1)impaired glucose oxidation via the TCA cycle,while hexose-6-phosphate de-hydrogenase(H6PD)disrupted gluconeogenesis.Myocardial hypertrophy was associ-ated with the downregulation of SRC proto-oncogene,non-receptor tyrosine kinase(SRC),mitogen-activated protein kinase 14(MAPK14),emerin(EMD),and integrin subunit beta 1(ITGB1).Conclusions:An 18-month HFD successfully established a translational M.fascicula-ris model replicating key metabolic disorders(MASH,diabetes,cardiac hypertrophy).BAAT,CS/MDH1/H6PD,and SRC/MAPK14/EMD/ITGB1 were identified as mecha-nistic biomarkers for these conditions.
基金National Natural Science Foundation of China,Grant/Award Number:32271496China Fundamental Research Funds for the Central Universities(Bejing Sport University)Grant/Award Number:2024TZJK001。
文摘Background:This study aims to explore the establishment of an animal model of car-diac injury induced by trimethylamine-N-oxide(TMAO),a metabolite secreted by gut microorganisms,and to investigate its application in moderate-intensity continuous training(MICT)intervention.Methods:C57BL6/J mice were randomly divided into four groups:normal mice(Nor,n=15);mice administered TMAO(TMAO,n=15);mice undergoing(Nor+MICT,n=15);mice undergoing(MICT)and administered TMAO(TMAO+MICT,n=15).Mice in the TMAO and TMAO+MICT groups received daily gavage of high-dose TMAO for 8 weeks,whereas those in the Nor+MICT and TMAO+MICT groups underwent MICT for 8 weeks(60 min per session,5 days per week,at 50%maximal running capacity).Cardiac function was evaluated using ultrasound,myocardial histology was examined using hematoxylin and eosin(HE)staining,and nuclear magnetic resonance(NMR)-based metabolomics was employed for multivariate statistical and metabolic pathway analyses.Results:Relative to the Nor group,TMAO-treated mice exhibited significant weight loss,elevated heart rate,and reduced ejection fraction and left ventricular fractional shortening,indicating cardiac impairment.Importantly,the TMAO+MICT group dem-onstrated significant improvements in these parameters compared to the TMAO group,alongside distinct alterations in myocardial metabolic profiles.TMAO altered five metabolic pathways relative to controls,whereas MICT induced significant changes in three pathways in TMAO-treated mice.Conclusion:Eight weeks of high-dose TMAO administration induced significant cardiac dysfunction in mice,which was effectively mitigated by MICT intervention.Consequently,this animal model serves as a valuable tool for investigating the mecha-nisms underlying the impact of MICT on cardiovascular diseases.
基金supported by the Hartman Behavioral Neuroscience Laboratory.
文摘Background:Healthy non-pharmacological lifestyle factors,such as regular physical exercise and dietary supplementation,have been shown to significantly improve cognitive outcomes over time compared to a more sedentary lifestyle and poor diet.Furthermore,exercise may serve as a potential protective factor in attenuating the effects associated with cognitive decline that are characteristic of neurodegenerative disorders,such as Alzheimer's disease(AD).Evidence indicates that certain dietary interventions can also attenuate the effects of neurodegeneration and positively impact longevity.Supplementation with polyphenols such as ellagic acid(EA),which is abundant in pomegranate juice,may help provide neuroprotective and longevity benefits.Methods:This study examined the potential protective potential of EA and exercise and provides insight into the combined use of a polyphenol-rich diet and exercise to enhance behavioral outcomes and lifespan in a transgenic Drosophila melanogaster(fruit fly)model of AD with the Aβ_(42) gene.Results:Fruit flies subjected to a 120-minute exercise regimen performed better on a climbing assay than flies that did not exercise.Conversely,flies that exercised for 30 min passed marginally more trials on a learning and memory assay using an aversive stimulus than flies that did not exercise,whereas both groups performed better than flies subjected to the more intense exercise condition.Conclusion:These results suggest a hormetic effect of exercise regarding memory performance.Finally,flies fed a low dose of dietary EA(0.24 mg/mL)lived significantly longer than flies fed the control diet or higher concentrations of EA,again suggesting a hormetic effect of EA on longevity.
基金National Natural Science Foundation of China,Grant/Award Number:82000102 and 82270112。
文摘The incidence of benign airway stenosis(BAS)is on the rise,and current treatment options are associated with a significant risk of restenosis.Therefore,there is an urgent need to explore new and effective prevention and treatment methods.Animal models serve as essential tools for investigating disease mechanisms and assessing novel therapeutic strategies,and the scientific rigor of their construction and validation significantly impacts the reliability of research findings.This paper systematically reviews the research progress and evaluation systems of BAS animal models over the past decade,aiming to provide a robust foundation for the optimized construction of BAS models,intervention studies,and clinical translation.This effort is intended to facilitate the innovation and advancement in BAS prevention and treatment strategies.
文摘Background:In preclinical research,tumor growth inhibition in subcutaneous models is frequently employed to evaluate therapeutic efficacy;however,such models often lack clinical translatability.Methods:To better approximate clinical reality,taking the case of doxorubicin treatment,we utilized an orthotopic transplant and resection(OtR)strategy to systematically assess the effects of neoadjuvant chemotherapy,adjuvant chem-otherapy,and their combination on tumor growth,recurrence,and malignant progression.Results:Surprisingly,none of the treatments improved mouse survival,with adjuvant therapy even shortening it.Although neoadjuvant chemotherapy delayed preopera-tive tumor growth,and all regimens reduced recurrence rates,none effectively pre-vented metastasis.Furthermore,all treatment groups exhibited weight loss,indicative of chemotherapy-induced cachexia.Conclusions:Collectively,these findings demonstrate that reduced tumor growth in preclinical mouse models does not necessarily translate into overall survival benefit.Our results emphasize the critical importance of prioritizing metastasis prevention over tumor growth inhibition as a key efficacy endpoint in antitumor drug evaluation.
基金National Natural Science Foundation of China,Grant/Award Number:82172140。
文摘Background:Targeted delivery of biological macromolecules to the small intestine remains challenging due to their susceptibility to degradation in the hostile gastric environment.Methods:This study introduces a minimally invasive,in situ injection technique for the murine small intestine that facilitates localized luminal delivery while circumventing gastric barriers.The procedure involves a small abdominal incision for direct injection into the duodenum near the pylorus.Postsurgical monitoring of physiological parameters,systemic inflammatory markers,liver function,and intestinal integrity was conducted over 72 h.Histopathological analysis was performed.The delivery of the functional protein TAT-EGFP(Tat protein fused to enhanced green fluorescent protein)to intestinal epithelial cells was evaluated and compared with oral gavage.As a proof of concept,single-cell RNA sequencing of the intestinal epithelium was performed after high-mobility group box 1 administration.Results:Postsurgical monitoring indicated only transient,anesthesia-related hypo-thermia and minor behavioral alterations.No significant changes were observed over 72 h in body weight,core temperature,clinical severity scores,systemic inflammatory markers(C-reactive protein and leukocytes),liver function(alanine aminotransferase),or intestinal integrity.Histopathological analysis confirmed preserved tissue architec-ture and normal digestive,absorptive,and barrier functions.The model successfully delivered TAT-EGFP to intestinal epithelial cells,an outcome not achievable via oral gavage due to gastric degradation.Single-cell RNA sequencing of the intestinal epi-thelium after high-mobility group box 1 administration revealed inflammatory gene expression patterns in specific epithelial subpopulations.Conclusions:Compared to traditional methods such as oral gavage or organoid cul-ture,this technique offers precise,degradation-resistant delivery of macromolecules in a physiological context.The model's versatility makes it a powerful platform for intestinal research,with applications in drug delivery assessment,gene therapy evalu-ation,and host-microbiota interaction studies.
基金supported by a grant from the National Key Basic Research Development Program,the“973”Program,No.2012CB518604the National Natural Science Foundation of China,No.81260052+1 种基金the Natural Science Foundation of Hubei Province,No.2014CKB497,2014BKB075,and 2015BKA339the Natural Science Foundation of Henan Province of China,No.201602262
文摘Sympathetic nerve and vagus nerve remodeling play an important part in cardiac function post-myocardial infarction （MI）. Increasing evidence indicates that neuregulin-1 （NRG-1） improves cardiac function following heart failure. Since its impact on cardiac function and neural remodeling post-MI is poorly understood, we aimed to investigate the role of NRG-1 in autonomic nervous system remodeling post-MI. Forty-five Sprague-Dawley rats were equally randomized into three groups： sham （with the left anterior descending coronary artery exposed but without ligation）, MI （left anterior descending coronary artery ligation）, and MI plus NRG-1 （left anterior descending coronary artery ligation followed by intraperitoneal injection of NRG-1 （10 lag/kg, once daily for 7 days））. At 4 weeks after MI, echocardi- ography was used to detect the rat cardiac function by measuring the left ventricular end-systolic inner diameter, left ventricular diastolic diameter, left ventricular end-systolic volume, left ventricular end-diastolic volume, left ventricular ejection fraction, and left ventricular fractional shortening, mRNA and protein expression levels of tyrosine hydroxylase, growth associated protein-43 （neuronal specific pro- tein）, nerve growth factor, choline acetyltransferase （vagus nerve marker）, and vesicular acetylcholine transporter （cardiac vagal nerve fiber marker） in ischemic myocardia were detected by real-time PCR and western blot assay to assess autonomous nervous remodeling. After MI, the rat cardiac function deteriorated significantly, and it was significantly improved after NRG-1 injection. Compared with the MI group, mRNA and protein levels of tyrosine hydroxylase and growth associated protein-43, as well as choline acetyltransferase mRNA level significantly decreased in the MI plus NRG-1 group, while mRNA and protein levels of nerve growth factor and vesicular acetylcholine transporters, as well as choline acetyltransferase protein level slightly decreased. Our results indicate that NRG- 1 can improve cardiac function and regulate sympathetic and vagus nerve remodeling post-MI, thus reaching a new balance of the autonomic nervous system to protect the heart from injury.
基金This work was supported by the National Research Foundation of Korea(NRF)grants funded by the Korea government(MSIT,Ministry of Science and ICT)(NRF-2018M3A9E8023853(to JYC)NRF-2018R1C1B6006145(to JYC)NRF-2018R1A2A1A05020292(to BGK)and NRF-2019R1A5A2026045(to JYC and BGK).
文摘Subcortical ischemic white matter injury(SIWMI),pathological correlate of white matter hyperintensities or leukoaraiosis on magnetic resonance imaging,is a common cause of cognitive decline in elderly.Despite its high prevalence,it remains unknown how various components of the white matter degenerate in response to chronic ischemia.This incomplete knowledge is in part due to a lack of adequate animal model.The current review introduces various SIWMI animal models and aims to scrutinize their advantages and disadvantages primarily in regard to the pathological manifestations of white matter components.The SIWMI animal models are categorized into 1)chemically induced SIWMI models,2)vascular occlusive SIWMI models,and 3)SIWMI models with comorbid vascular risk factors.Chemically induced models display consistent lesions in predetermined areas of the white matter,but the abrupt evolution of lesions does not appropriately reflect the progressive pathological processes in human white matter hyperintensities.Vascular occlusive SIWMI models often do not exhibit white matter lesions that are sufficiently unequivocal to be quantified.When combined with comorbid vascular risk factors(specifically hypertension),however,they can produce progressive and definitive white matter lesions including diffuse rarefaction,demyelination,loss of oligodendrocytes,and glial activation,which are by far the closest to those found in human white matter hyperintensities lesions.However,considerable surgical mortality and unpredictable natural deaths during a follow-up period would necessitate further refinements in these models.In the meantime,in vitro SIWMI models that recapitulate myelinated white matter track may be utilized to study molecular mechanisms of the ischemic white matter injury.Appropriate in vivo and in vitro SIWMI models will contribute in a complementary manner to making a breakthrough in developing effective treatment to prevent progression of white matter hyperintensities.
