Cutaneous exposure to food allergens through a disrupted skin barrier is recognized as an important cause of food allergy,and the cutaneous sensitized mouse model has been established to investigate relevant allergic ...Cutaneous exposure to food allergens through a disrupted skin barrier is recognized as an important cause of food allergy,and the cutaneous sensitized mouse model has been established to investigate relevant allergic disorders.However,the role of different genetic backgrounds of mice on immune responses to food allergens upon epicutaneous sensitization is largely unknown.In this study,two strains of mice,i.e.,the BALB/c and C57BL/6 mice,were epicutaneously sensitized with ovalbumin on atopic dermatitis(AD)-like skin lesions,followed by intragastric challenge to induce IgE-mediated food allergy.Allergic outcomes were measured as clinical signs,specific antibodies and cytokines,and immune cell subpopulations,as well as changes in intestinal barrier function and gut microbiota.Results showed that both strains of mice exhibited typical food-allergic symptoms with a Th2-skewed response.The C57BL/6 mice,rather than the BALB/c mice,were fitter for establishing an epicutaneously sensitized model of food allergy since a stronger Th2-biased response and severer disruptions in the intestinal barrier and gut homeostasis were observed.This study provides knowledge for selecting an appropriate mouse model to study food-allergic responses associated with AD-like skin lesions and highlights the role of genetic variations in the immune mechanism underlying pathogenesis of food allergy.展开更多
Anxiety disorder is a common mental disorder. It is necessary to establish a rapid, stable and specific anxiety model to provide a theoretical basis for further research on the pathogenesis of anxiety and drug develop...Anxiety disorder is a common mental disorder. It is necessary to establish a rapid, stable and specific anxiety model to provide a theoretical basis for further research on the pathogenesis of anxiety and drug development. A single intraperitoneal injection of m-chlorophenylpipera-zine (mCPP) (1, 2, 4 mg/kg) was given to male ICR mice to establish an anxiety model, and the effects of mCPP on anxiety behavior, pain, athletic ability, passive avoidance response ability and depressive behavior of male ICR mice were evaluated. A single intraperitoneal injection of mCPP shortened the time in open arms and decreased the percentage of time in open arms of mice in the elevated plus-maze test. mCPP also shortened center zone distance and reduced the number of entries to the central zone in the open field test. Moreover, mCPP reduced head-dip counts and increased the head-dip latency of mice in the hole-board test. After being administrated with a single intraperitoneal injection of mCPP for 24h, the mice showed no significant difference in the entry into the light side and the percentage of time in the light side of the light-dark box test. A single intraperitoneal injection of mCPP had no effects on tail flick latency, rotating time, number of errors and the step-down latency, the immobility time of mice in the tail-flick test, rotarod test, step-down test and TST respectively. In conclusion, we established a rapid and stable anxiety mouse model by single intraperitoneal injection of mCPP.展开更多
Epilepsy is a common and serious neurological disease that causes recurrent seizures. The brain damage caused by seizures can lead to depression, anxiety, cognitive impairment, or disability. In almost all cases chron...Epilepsy is a common and serious neurological disease that causes recurrent seizures. The brain damage caused by seizures can lead to depression, anxiety, cognitive impairment, or disability. In almost all cases chronic seizures are difficult to cure. MicroRNAs are widely expressed in the central nervous system and play important roles in the pathogenesis of several neurological disorders, including epilepsy. A variety of animals(mostly mice and rats) have been used to induce experimental epilepsy using different protocols and miRNA profiling performed. Most of the recent studies reviewed had performed miRNA profiling in hippocampal tissues and a large number of microRNAs were dysregulated when compared to controls. Most notably, miR-132-3p,-146a-5p,-10a-5p,-21a-3p,-27a-3p,-142a-5p,-212-3p,-431-5p, and-155 were upregulated in both the mouse and rat studies. Overexpression of miR-137 and miR-219 decreased seizure severity in a mouse epileptic model, and suppression of miR-451,-10a-5p,-21a-5p,-27a-5p,-142a-5p,-431-5p,-155, and-134 had a positive influence on seizure behavior. In the rat studies, overexpression of miR-139-5p decreased neuronal damage in drug-resistant rats and inhibition of miR-129-2-3p,-27a-3p,-155,-134,-181a, and-146a had a positive effect on seizure behavior and/or reduced the loss of neuronal cells. Further studies are warranted using adult female and immature male and female animals. It would also be helpful to test the ability of specific agomirs and antagomirs to control seizure activity in a subhuman primate model of epilepsy such as adult marmosets injected intraperitoneally with pilocarpine or cynomolgus monkeys given intrahippocampal injections of kainic acid.展开更多
Severe acute respiratory syndrome coronavirus 2(SARSCo V-2)infection can result in more severe syndromes and poorer outcomes in patients with diabetes and obesity.However,the precise mechanisms responsible for the com...Severe acute respiratory syndrome coronavirus 2(SARSCo V-2)infection can result in more severe syndromes and poorer outcomes in patients with diabetes and obesity.However,the precise mechanisms responsible for the combined impact of coronavirus disease 2019(COVID-19)and diabetes have not yet been elucidated,and effective treatment options for SARS-Co V-2-infected diabetic patients remain limited.To investigate the disease pathogenesis,K18-h ACE2 transgenic(h ACE2^(Tg))mice with a leptin receptor deficiency(h ACE2-Lepr^(-/-))and high-fat diet(h ACE2-HFD)background were generated.The two mouse models were intranasally infected with a 5×10^(5) median tissue culture infectious dose(TCID_(50))of SARSCo V-2,with serum and lung tissue samples collected at 3days post-infection.The h ACE2-Lepr^(-/-)mice were then administered a combination of low-molecular-weight heparin(LMWH)(1 mg/kg or 5 mg/kg)and insulin via subcutaneous injection prior to intranasal infection with1×10^(4) TCID_(50)of SARS-Co V-2.Daily drug administration continued until the euthanasia of the mice.Analyses of viral RNA loads,histopathological changes in lung tissue,and inflammation factors were conducted.Results demonstrated similar SARS-Co V-2 susceptibility in h ACE2^(Tg)mice under both lean(chow diet)and obese(HFD)conditions.However,compared to the h ACE2-Lepr^(+/+)mice,h ACE2-Lepr^(-/-)mice exhibited more severe lung injury,enhanced expression of inflammatory cytokines and hypoxia-inducible factor-1α(HIF-1α),and increased apoptosis.Moreover,combined LMWH and insulin treatment effectively reduced disease progression and severity,attenuated lung pathological changes,and mitigated inflammatory responses.In conclusion,preexisting diabetes can lead to more severe lung damage upon SARS-Co V-2 infection,and LMWH may be a valuable therapeutic approach for managing COVID-19patients with diabetes.展开更多
Genetically engineered mouse(GEM)models are commonly used in biomedical research.Generating GEMs involve complex set of experimental procedures requiring sophisticated equipment and highly skilled technical staff.Beca...Genetically engineered mouse(GEM)models are commonly used in biomedical research.Generating GEMs involve complex set of experimental procedures requiring sophisticated equipment and highly skilled technical staff.Because of these reasons,most research institutes set up centralized core facilities where custom GEMs are created for research groups.Researchers,on the other hand,when they begin thinking about generating GEMs for their research,several questions arise in their minds.For example,what type of model(s)would be best useful for my research,how do I design them,what are the latest technologies and tools available for developing my model(s),and finally how to breed GEMs in my research.As there are several considerations and options in mouse designs,and as it is an expensive and time-consuming endeavor,careful planning upfront can ensure the highest chance of success.In this article,we provide brief answers to several frequently asked questions that arise when researchers begin thinking about generating mouse model(s)for their work.展开更多
Parkinson's disease,the most common movement disorder,has a strong neuroinflammatory aspect.This is evident by increased pro-inflammatory cytokines in the serum,and the presence of activated microglial cells,and i...Parkinson's disease,the most common movement disorder,has a strong neuroinflammatory aspect.This is evident by increased pro-inflammatory cytokines in the serum,and the presence of activated microglial cells,and inflammatory cytokines in the substantia nigra of post-mortem brains as well as cerebrospinal fluid of Parkinson's disease patients.The central and peripheral neuroinflammatory aspects of Parkinson's disease can be investigated in vivo via administration of the inflammagen lipopolysaccharide,a component of the cell wall of gram-negative bacteria.In this mini-review,we will critically evaluate different routes of lipopolysaccharide administration(including intranasal systemic and ste reotasic),their relevance to clinical Parkinson's disease as well as the recent findings in lipopolysaccharide mouse models.We will also share our own expe riences with systemic and intrastriatal lipopolysaccharide models in C57BL/6 mice and will discuss the usefulness of lipopolysaccharide mouse models for future research in the field.展开更多
Mitochondrial dysfunction is proposed to be substantially associated with ageing and ageing-related diseases like Alzheimer's disease(AD). However, it is unclear whether different mouse models with mitochondrialre...Mitochondrial dysfunction is proposed to be substantially associated with ageing and ageing-related diseases like Alzheimer's disease(AD). However, it is unclear whether different mouse models with mitochondrialrelated diseases have similar changes in mitochondrial morphology of the same tissues. Moreover, whether similarities in mitochondrial morphology can be a suitable marker for screening and/or discovering mitochondrial-protective substances remains unknown. Mitochondria morphology in different tissues of a novel mitochondrial outer membrane protein Slc25a46 knockout mouse and a traditional APP_(SWE)/PS1ΔE9 transgenic mouse were examined using transmission electron microscope(TEM). Both young Slc25a46 knockout mice and aged APP_(SWE)/PS1ΔE9 mice models showed similar mitochondrial damage in cerebellum tissues. The results indicated that different mitochondrial-related diseases shared similar alteration and defects in mitochondrial morphology. Furthermore, Lycium ruthenicum Murr. extract, a bioactive food substance with cognition-improving property, could effectively improve muscle strength and increase body weight in the Slc25a46 knockout mice. These findings suggest that mitochondrial morphology defects in mice models, particularly in the mitochondrial compartment, represent a unified and effective marker for screening and validating natural product-derived functional substances with mitochondrial protective properties. It also holds potential application in mitochondrial-impaired senile neurodegenerative diseases, especially in AD.展开更多
Background:Hepatocellular carcinoma(HCC)is the most common type of liver cancer.Recently,developments in radiotherapy technology have led to radiotherapy becoming one of the main therapeutics of HCC.Therefore,a suitab...Background:Hepatocellular carcinoma(HCC)is the most common type of liver cancer.Recently,developments in radiotherapy technology have led to radiotherapy becoming one of the main therapeutics of HCC.Therefore,a suitable animal model for radiotherapy of the orthotopic HCC mouse model is urgently needed.Methods:In the present study,Hepa1-6 cells were injected into the liver of C57BL/6 mice in situ to mimic the pathological characteristics of the original HCC.Tumor formation was monitored by applying magnetic resonance imaging techniques and verified by H&E histopathological staining,AFP staining,and Ki67 staining.A single dose of 10 Gy X-ray was applied to simulate clinical radiotherapy plans using image-guided radiotherapy(IGRT)equipment.The efficiency of radiotherapy was then assessed by examining tumor size and weight one week after radiation.Cleaved-caspase3 staining and TUNEL were used to assess apoptosis in tumor tissues.Results:Intrahepatic tumor development was detected in the liver according using MRI.A high-density shadow could be seen 10 days after cell injection,which indicated the formation of HCC in vivo.The tumors grew steadily bigger,and underwent precision radiotherapy 20 days after injection.The typical pathological characteristics of HCC,such as large,deeply stained nuclei and irregular cell size,were visible with H&E staining.After radiotherapy,significantly higher expression of the immunohistochemical markers Ki67 and AFP were detected in tumor tissue than in the nearby normal tissue.Compared with the control group,the tumor volume(p=0.05)and weight(p<0.05)of the irradiated group were significantly reduced.In addition,a higher frequency of apoptosis was identified in irradiated HCC tumor tissue using the TUNEL and cleaved-caspase3 staining assay.Conclusions:In a well-established orthotopic HCC model,MRI was utilized to monitor the formation of tumors,and IGRT was used to simulate clinical radiotherapy.The present study could provide a suitable preclinical system for HCC radiotherapyrelated studies.展开更多
Head and neck squamous cell cancer(HNSCC)is a leading global malignancy.Every year,More than 830000 people are diagnosed with HNSCC globally,with more than 430000 fatalities.HNSCC is a deadly diverse malignancy with m...Head and neck squamous cell cancer(HNSCC)is a leading global malignancy.Every year,More than 830000 people are diagnosed with HNSCC globally,with more than 430000 fatalities.HNSCC is a deadly diverse malignancy with many tumor locations and biological characteristics.It originates from the squamous epithelium of the oral cavity,oropharynx,nasopharynx,larynx,and hypopharynx.The most frequently impacted regions are the tongue and larynx.Previous investigations have demonstrated the critical role of host genetic susceptibility in the progression of HNSCC.Despite the advances in our knowledge,the improved survival rate of HNSCC patients over the last 40 years has been limited.Failure to identify the molecular origins of development of HNSCC and the genetic basis of the disease and its biological heterogeneity impedes the development of new therapeutic methods.These results indicate a need to identify more genetic factors underlying this complex disease,which can be better used in early detection and prevention strategies.The lack of reliable animal models to investigate the underlying molecular processes is one of the most significant barriers to understanding HNSCC tumors.In this report,we explore and discuss potential research prospects utilizing the Collaborative Cross mouse model and crossing it to mice carrying single or double knockout genes(e.g.Smad 4 and P53 genes)to identify genetic factors affecting the development of this complex disease using genome-wide association studies,epigenetics,micro RNA,long noncoding RNA,lnc RNA,histone modifications,methylation,phosphorylation,and proteomics.展开更多
The current animal models of stroke primarily model a single intracerebral hemorrhage(ICH)attack,and there is a lack of a reliable model of recurrent ICH.In this study,we established 16-month-old C57 B L/6 male mouse ...The current animal models of stroke primarily model a single intracerebral hemorrhage(ICH)attack,and there is a lack of a reliable model of recurrent ICH.In this study,we established 16-month-old C57 B L/6 male mouse models of ICH by injecting collagenaseⅦ-S into the left striatum.Twenty-one days later,we injected collagenaseⅦ-S into the right striatum to simulate recurrent ICH.Our results showed that mice subjected to bilateral striatal hemorrhage had poorer neurological function at the early stage of hemorrhage,delayed recovery in locomotor function,motor coordination,and movement speed,and more obvious emotional and cognitive dysfunction than mice subjected to unilate ral striatal hemorrhage.These findings indicate that mouse models of bilateral striatal hemorrhage can well simulate clinically common recurrent ICH.These models should be used as a novel tool for investigating the pathogenesis and treatment targets of recurrent ICH.展开更多
Patients with potential spinal stenosis are susceptible to central cord syndrome induced by blunt trauma.Suitable animal models are helpful for studying the pathogenesis and treatment of such injuries.In this study,we...Patients with potential spinal stenosis are susceptible to central cord syndrome induced by blunt trauma.Suitable animal models are helpful for studying the pathogenesis and treatment of such injuries.In this study,we established a mouse model of acute blunt traumatic spinal cord injury by compressing the C6 spinal cord with 5 and 10 g/mm~2 compression weights to simulate cervical central cord syndrome.Behavioral testing confirmed that this model exhibited the characteristics of central cord syndrome because motor function in the front paws was impaired,whereas basic motor and sensory functions of the lower extremities were retained.Hematoxylin-eosin staining showed that the diseased region of the spinal cord in this mouse model was restricted to the gray matter of the central cord,whereas the white matter was rarely affected.Magnetic resonance imaging showed a hypointense signal in the lesion after mild and severe injury.In addition,immunofluorescence staining showed that the degree of nerve tract injury in the spinal cord white matter was mild,and that there was a chronic inflammation reaction.These findings suggest that this mouse model of central cord syndrome can be used as a model for preclinical research,and that gray matter is most vulnerable to injury in central cord syndrome,leading to impaired motor function.展开更多
Epithelial ovarian cancer(EOC) is the leading cause of gynecological cancer-related mortality in the developed world. EOC is a heterogeneous disease represented by several histological and molecular subtypes. Therefor...Epithelial ovarian cancer(EOC) is the leading cause of gynecological cancer-related mortality in the developed world. EOC is a heterogeneous disease represented by several histological and molecular subtypes. Therefore, exploration of relevant preclinical animal models that consider the heterogenic nature of EOC is of great importance for the development of novel therapeutic strategies that can be translated clinically to combat this devastating disease. In this review, we discuss recent progress in the development of preclinical mouse models for EOC study as well as their advantages and limitations.展开更多
Fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling plays essential roles in bone development and diseases. Missense mutations in FGFs and FGFRs in humans can cause various congenital...Fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling plays essential roles in bone development and diseases. Missense mutations in FGFs and FGFRs in humans can cause various congenital bone diseases, including chondrodysplasia syndromes, craniosynostosis syndromes and syndromes with dysregulated phosphate metabolism. FGF/FGFR signaling is also an important pathway involved in the maintenance of adult bone homeostasis. Multiple kinds of mouse models, mimicking human skeleton diseases caused by missense mutations in FGFs and FGFRs, have been established by knock-m/out and transgenic technologies. These genetically modified mice provide good models for studying the role of FGF/FGFR signaling in skeleton development and homeostasis. In this review, we summarize the mouse models of FGF signaling-related skeleton diseases and recent progresses regarding the molecular mechanisms, underlying the role of FGFs/FGFRs in the regulation of bone development and homeostasis. This review also provides a perspective view on future works to explore the roles of FGF signaling in skeletal development and homeostasis.展开更多
AIM To establish an inducible liver injury mouse model and transplant human hepatocytes to obtain liverhumanized mice.METHODS We crossed three mouse strains,including albumin(Alb)-cre transgenic mice,inducible diphthe...AIM To establish an inducible liver injury mouse model and transplant human hepatocytes to obtain liverhumanized mice.METHODS We crossed three mouse strains,including albumin(Alb)-cre transgenic mice,inducible diphtheria toxin receptor(DTR) transgenic mice and severe combined immune deficient(SCID)-beige mice,to create Alb-cre/DTR/SCID-beige(ADSB) mice,which coincidentally harbor Alb-cre and DTR transgenes and are immunodeficient. As the Cre expression is driven by the liver-specific promoter Alb(encoding ALB),the DTR stop signal flanked by two lox P sites can be deleted in the ADSB mice,resulting in DTR expression in the liver. ADSB mice aged 8-10 wk were injected intraperitoneally(i.p.) with diphtheria toxin(DT) and liver damage was assessed by serum alanine aminotransferase(ALT) level. Two days later,mouse livers were sampled for histological analysis,and human hepatocytes were transplanted into the livers on the same day. A human ALB enzyme-linked immunosorbent assay was performed 7,14,21 and 28 d after transplantation. Human CD68 immunohistochemistry was performed 30 and 90 d after transplantation.RESULTS We crossed Alb-cre with DTR and SCID-beige mice to obtain ADSB mice. These mice were found to have liver damage 4 d after i.p. injection of 2.5 ng/g bodyweight DT. Bodyweight began to decrease on day 2,increased on day 7,and was lowest on day 4(range,10.5%-13.4%). Serum ALT activity began to increase on day 2 and reached a peak value of 289.7 ± 16.2 IU/m L on day 4,then returned to background values on day 7. After transplantation of human liver cells,peripheral blood human ALB level was 1580 ± 454.8 ng/m L(range,750.2-3064.9 ng/m L) after 28 d and Kupffer cells were present in the liver at 30 d in ADSB mice.CONCLUSION Human hepatocytes were successfully repopulated in the livers of ADSB mice. The inducible mouse model of humanized liver in ADSB mice may have functional applications,such as hepatocyte transplantation,hepatic regeneration and drug metabolism.展开更多
AIM: To investigate the effects of periocular injection of propranolol and celecoxib on ocular levels of vascular endothelial growth factor (VEGF) in a diabetic mouse model. METHODS: Forty 4-6wk BALB-C male mice ...AIM: To investigate the effects of periocular injection of propranolol and celecoxib on ocular levels of vascular endothelial growth factor (VEGF) in a diabetic mouse model. METHODS: Forty 4-6wk BALB-C male mice weighing 20-25 g were used. The study groups included: nondiabetic control (group 1), diabetic control (group 2), diabetic propranolol (group 3), and diabetic celecoxib (group 4). After induction of type 1 diabetes by streptozotocin, propranolol (10 μg) and celecoxib (200 μg dissolved in carboxymethylcellulose 0.5%) were injected periocularly. The ocular level of VEGF was measured in all the study groups using enzyme-linked immuno sorbent assay (ELISA) method. RESULTS: Ocular VEGF level was significantly increased (1.25 fold) in the diabetic control group when compared to the non-diabetic group one week after induction with streptozotocin (P=0.002). Both periocular propranolol and celecoxib significantly reduced ocular VEGF levels (P=0.047 and P〈0.001, respectively). The effect was more pronounced with celecoxib, CONCLUSION: The periocular administration of propranolol and celecoxib can significantly reduce ocular VEGF levels in a diabetic mouse model.展开更多
Background:Alzheimer's disease(AD)is an incurable and irreversible neurodegen-erative disease,without a clear pathogenesis.Therefore,identification of candidates before amyloid-βplaque(Aβ)deposition proceeds is ...Background:Alzheimer's disease(AD)is an incurable and irreversible neurodegen-erative disease,without a clear pathogenesis.Therefore,identification of candidates before amyloid-βplaque(Aβ)deposition proceeds is of major significance for earlier intervention in AD.Methods:To explore the potential noninvasive earlier biomarkers of AD in a 5XFAD mouse model,microRNAs(miRNAs)from urinary exosomes in 1-month-old pre-Aβaccumulation 5XFAD mice models and their littermate controls were profiled by mi-croarray analysis.The differentially expressed miRNAs were further analyzed via droplet digital PCR(ddPCR).Results:Microarray analysis demonstrated that 48 differentially expressed miRNAs(18 upregulated and 30 downregulated),of which six miRNAs-miR-196b-5p,miR-339-3p,miR-34a-5p,miR-376b-3p,miR-677-5p,and miR-721-were predicted to display gene targets and important signaling pathways closely associated with AD pathogenesis and verified by ddPCR.Conclusions:Urinary exosomal miRNAs showing differences in expression prior to Aβ-plaque deposition were identified.These exosomal miRNAs represent potential noninvasive biomarkers that may be used to prevent AD in clinical applications.展开更多
The spread of an advantageous mutation through a population is of fundamental interest in population genetics. While the classical Moran model is formulated for a well-mixed population, it has long been recognized tha...The spread of an advantageous mutation through a population is of fundamental interest in population genetics. While the classical Moran model is formulated for a well-mixed population, it has long been recognized that in real-world applications, the population usually has an explicit spatial structure which can significantly influence the dynamics. In the context of cancer initiation in epithelial tissue, several recent works have analyzed the dynamics of advantageous mutant spread on integer lattices, using the biased voter model from particle systems theory. In this spatial version of the Moran model, individuals first reproduce according to their fitness and then replace a neighboring individual. From a biological standpoint, the opposite dynamics, where individuals first die and are then replaced by a neighboring individual according to its fitness, are equally relevant. Here, we investigate this death-birth analogue of the biased voter model. We construct the process mathematically, derive the associated dual process, establish bounds on the survival probability of a single mutant, and prove that the process has an asymptotic shape. We also briefly discuss alternative birth-death and death-birth dynamics, depending on how the mutant fitness advantage affects the dynamics. We show that birth-death and death-birth formulations of the biased voter model are equivalent when fitness affects the former event of each update of the model, whereas the birth-death model is fundamentally different from the death-birth model when fitness affects the latter event.展开更多
Osteoarthritis (OA) is a degenerative joint disease and a major cause of pain and disability in older adults. We have previously identified epidermal growth factor receptor (EGFR) signaling as an important regulat...Osteoarthritis (OA) is a degenerative joint disease and a major cause of pain and disability in older adults. We have previously identified epidermal growth factor receptor (EGFR) signaling as an important regulator of cartilage matrix degradation during epiphyseal cartilage development. To study its function in OA progression, we performed surgical destabilization of the medial meniscus (DMM) to induce OA in two mouse models with reduced EGFR activity, one with genetic modification (, was/+ mice) and the other one with pharmacological inhibition (gefitinib treatment). Histological analyses and scoring at 3 months post-surgery revealed increased cartilage destruction and accelerated OA progression in both mouse models. TUNEL staining demonstrated that EGFR signaling protects chondrocytes from OA-induced apoptosis, which was further confirmed in primary chondrocyte culture. Immunohistochemistry showed increased aggrecan degradation in these mouse models, which coincides with elevated amounts of ADAMTS5 and matrix metalloproteinase 13 (MMP13), the principle proteinases responsible for aggrecan degradation, in the articular cartilage after DMM surgery. Furthermore, hypoxia-inducible factor 2α (HIF2α), a critical catabolic transcription factor stimulating MMP13 expression during OA, was also upregulated in mice with reduced EGFR signaling. Taken together, our findings demonstrate a primarily protective role of EGFR during OA progression by regulating chondrocyte survival and cartilage degradation.展开更多
AIM: To choose appropriate concentration of sodium hydroxide(Na OH) solution to establish a stable and consistent corneal alkali burn mouse model in grade II.·METHODS: The mice(n =60) were randomly divided ...AIM: To choose appropriate concentration of sodium hydroxide(Na OH) solution to establish a stable and consistent corneal alkali burn mouse model in grade II.·METHODS: The mice(n =60) were randomly divided into four groups and 15 mice each group. Corneal alkali burns were induced by placing circle filter paper soaked with Na OH solutions on the right central cornea for 30 s.The concentrations of Na OH solutions of groups A, B, C,and D were 0.1 mol/L, 0.15 mol/L, 0.2 mol/L, and 1.0 mol/L respectively. Then these corneas were irrigated with 20 m L physiological saline(0.9% Na Cl). On day 7 postburn, slit lamp microscope was used to observe corneal opacity,corneal epithelial sodium fluorescein staining positive rate, incidence of corneal ulcer and corneal neovascularization, meanwhile pictures of the anterior eyes were taken. Cirrus spectral domain optical coherence tomography was used to scan cornea to observe corneal epithelial defect and corneal ulcer.·RESULTS: Corneal opacity scores( x ±s) were not significantly different between the group A and group B(P =0.097). Incidence of corneal ulcer in group B was significantly higher than that in group A(P =0.035).Incidence of corneal ulcer and perforation rate in group B was lower than that in group C. Groups C and D had corneal neovascularization, and incidence of corneal neovascularization in group D was significantly higher than that in group C(P =0.000).·CONCLUSION: Using 0.15 mol/L Na OH can establish grade II mouse model of corneal alkali burns.展开更多
Colorectal cancer is a worldwide health burden,with high incidence and mortality,especially in the advanced stages of the disease.Preclinical models are very important and valuable to discover and validate early and s...Colorectal cancer is a worldwide health burden,with high incidence and mortality,especially in the advanced stages of the disease.Preclinical models are very important and valuable to discover and validate early and specific biomarkers as well as new therapeutic targets.In order to accomplish that,the animal models must replicate the clinical evolution of the disease in all of its phases.In this article,we review the existent mouse models,with their strengths and weaknesses in the replication of human cancer disease progression,with major focus on orthotopic models.展开更多
基金the financial support received from the Natural Science Foundation of China(32202202 and 31871735)the Zhejiang Provincial Natural Science Foundation of China(LGN22C200027)the Open Fund of the Key Laboratory of Biosafety Detection for Zhejiang Market Regulation(2022BS004)。
文摘Cutaneous exposure to food allergens through a disrupted skin barrier is recognized as an important cause of food allergy,and the cutaneous sensitized mouse model has been established to investigate relevant allergic disorders.However,the role of different genetic backgrounds of mice on immune responses to food allergens upon epicutaneous sensitization is largely unknown.In this study,two strains of mice,i.e.,the BALB/c and C57BL/6 mice,were epicutaneously sensitized with ovalbumin on atopic dermatitis(AD)-like skin lesions,followed by intragastric challenge to induce IgE-mediated food allergy.Allergic outcomes were measured as clinical signs,specific antibodies and cytokines,and immune cell subpopulations,as well as changes in intestinal barrier function and gut microbiota.Results showed that both strains of mice exhibited typical food-allergic symptoms with a Th2-skewed response.The C57BL/6 mice,rather than the BALB/c mice,were fitter for establishing an epicutaneously sensitized model of food allergy since a stronger Th2-biased response and severer disruptions in the intestinal barrier and gut homeostasis were observed.This study provides knowledge for selecting an appropriate mouse model to study food-allergic responses associated with AD-like skin lesions and highlights the role of genetic variations in the immune mechanism underlying pathogenesis of food allergy.
文摘Anxiety disorder is a common mental disorder. It is necessary to establish a rapid, stable and specific anxiety model to provide a theoretical basis for further research on the pathogenesis of anxiety and drug development. A single intraperitoneal injection of m-chlorophenylpipera-zine (mCPP) (1, 2, 4 mg/kg) was given to male ICR mice to establish an anxiety model, and the effects of mCPP on anxiety behavior, pain, athletic ability, passive avoidance response ability and depressive behavior of male ICR mice were evaluated. A single intraperitoneal injection of mCPP shortened the time in open arms and decreased the percentage of time in open arms of mice in the elevated plus-maze test. mCPP also shortened center zone distance and reduced the number of entries to the central zone in the open field test. Moreover, mCPP reduced head-dip counts and increased the head-dip latency of mice in the hole-board test. After being administrated with a single intraperitoneal injection of mCPP for 24h, the mice showed no significant difference in the entry into the light side and the percentage of time in the light side of the light-dark box test. A single intraperitoneal injection of mCPP had no effects on tail flick latency, rotating time, number of errors and the step-down latency, the immobility time of mice in the tail-flick test, rotarod test, step-down test and TST respectively. In conclusion, we established a rapid and stable anxiety mouse model by single intraperitoneal injection of mCPP.
文摘Epilepsy is a common and serious neurological disease that causes recurrent seizures. The brain damage caused by seizures can lead to depression, anxiety, cognitive impairment, or disability. In almost all cases chronic seizures are difficult to cure. MicroRNAs are widely expressed in the central nervous system and play important roles in the pathogenesis of several neurological disorders, including epilepsy. A variety of animals(mostly mice and rats) have been used to induce experimental epilepsy using different protocols and miRNA profiling performed. Most of the recent studies reviewed had performed miRNA profiling in hippocampal tissues and a large number of microRNAs were dysregulated when compared to controls. Most notably, miR-132-3p,-146a-5p,-10a-5p,-21a-3p,-27a-3p,-142a-5p,-212-3p,-431-5p, and-155 were upregulated in both the mouse and rat studies. Overexpression of miR-137 and miR-219 decreased seizure severity in a mouse epileptic model, and suppression of miR-451,-10a-5p,-21a-5p,-27a-5p,-142a-5p,-431-5p,-155, and-134 had a positive influence on seizure behavior. In the rat studies, overexpression of miR-139-5p decreased neuronal damage in drug-resistant rats and inhibition of miR-129-2-3p,-27a-3p,-155,-134,-181a, and-146a had a positive effect on seizure behavior and/or reduced the loss of neuronal cells. Further studies are warranted using adult female and immature male and female animals. It would also be helpful to test the ability of specific agomirs and antagomirs to control seizure activity in a subhuman primate model of epilepsy such as adult marmosets injected intraperitoneally with pilocarpine or cynomolgus monkeys given intrahippocampal injections of kainic acid.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (CAS) (XDB29010102)National Natural Science Foundation of China (NSFC) (91957124,82161148010,32041010)+4 种基金Self-supporting Program of Guangzhou Laboratory (SRPG22-001)National Science and Technology Infrastructure of China (National Pathogen Resource Center-NPRC-32)Management Strategy of the Tertiary Prevention and Treatment of Diabetes Based on DIP system (supported by China Health Promotion Foundation)supported by the Youth Innovation Promotion Association of CAS (Y2021034)Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine (ZYYCXTD-D-202208)。
文摘Severe acute respiratory syndrome coronavirus 2(SARSCo V-2)infection can result in more severe syndromes and poorer outcomes in patients with diabetes and obesity.However,the precise mechanisms responsible for the combined impact of coronavirus disease 2019(COVID-19)and diabetes have not yet been elucidated,and effective treatment options for SARS-Co V-2-infected diabetic patients remain limited.To investigate the disease pathogenesis,K18-h ACE2 transgenic(h ACE2^(Tg))mice with a leptin receptor deficiency(h ACE2-Lepr^(-/-))and high-fat diet(h ACE2-HFD)background were generated.The two mouse models were intranasally infected with a 5×10^(5) median tissue culture infectious dose(TCID_(50))of SARSCo V-2,with serum and lung tissue samples collected at 3days post-infection.The h ACE2-Lepr^(-/-)mice were then administered a combination of low-molecular-weight heparin(LMWH)(1 mg/kg or 5 mg/kg)and insulin via subcutaneous injection prior to intranasal infection with1×10^(4) TCID_(50)of SARS-Co V-2.Daily drug administration continued until the euthanasia of the mice.Analyses of viral RNA loads,histopathological changes in lung tissue,and inflammation factors were conducted.Results demonstrated similar SARS-Co V-2 susceptibility in h ACE2^(Tg)mice under both lean(chow diet)and obese(HFD)conditions.However,compared to the h ACE2-Lepr^(+/+)mice,h ACE2-Lepr^(-/-)mice exhibited more severe lung injury,enhanced expression of inflammatory cytokines and hypoxia-inducible factor-1α(HIF-1α),and increased apoptosis.Moreover,combined LMWH and insulin treatment effectively reduced disease progression and severity,attenuated lung pathological changes,and mitigated inflammatory responses.In conclusion,preexisting diabetes can lead to more severe lung damage upon SARS-Co V-2 infection,and LMWH may be a valuable therapeutic approach for managing COVID-19patients with diabetes.
基金We thank D.D.Meigs(University of Nebraska Medical Center)and Tonya Cejka(freelance English editor)for editing assistance.C.B.G.is funded by NIH grants R35HG010719,R21GM129559,R21AI143394 and R21DA046831.M.O.is funded by 2016–2017 Tokai University School of Medicine Project Research,the Research Aid from the Institute of Medical Sciences in Tokai University,Grant-in-Aid for Scientific Research(25290035)from MEXTa Grant-in-Aid for Challenging Exploratory Research(15K14371)from JSPS.
文摘Genetically engineered mouse(GEM)models are commonly used in biomedical research.Generating GEMs involve complex set of experimental procedures requiring sophisticated equipment and highly skilled technical staff.Because of these reasons,most research institutes set up centralized core facilities where custom GEMs are created for research groups.Researchers,on the other hand,when they begin thinking about generating GEMs for their research,several questions arise in their minds.For example,what type of model(s)would be best useful for my research,how do I design them,what are the latest technologies and tools available for developing my model(s),and finally how to breed GEMs in my research.As there are several considerations and options in mouse designs,and as it is an expensive and time-consuming endeavor,careful planning upfront can ensure the highest chance of success.In this article,we provide brief answers to several frequently asked questions that arise when researchers begin thinking about generating mouse model(s)for their work.
文摘Parkinson's disease,the most common movement disorder,has a strong neuroinflammatory aspect.This is evident by increased pro-inflammatory cytokines in the serum,and the presence of activated microglial cells,and inflammatory cytokines in the substantia nigra of post-mortem brains as well as cerebrospinal fluid of Parkinson's disease patients.The central and peripheral neuroinflammatory aspects of Parkinson's disease can be investigated in vivo via administration of the inflammagen lipopolysaccharide,a component of the cell wall of gram-negative bacteria.In this mini-review,we will critically evaluate different routes of lipopolysaccharide administration(including intranasal systemic and ste reotasic),their relevance to clinical Parkinson's disease as well as the recent findings in lipopolysaccharide mouse models.We will also share our own expe riences with systemic and intrastriatal lipopolysaccharide models in C57BL/6 mice and will discuss the usefulness of lipopolysaccharide mouse models for future research in the field.
基金supported by National Key R&D Program of China (2018YFD0901101)the Natural Science Foundation of Guangdong Province Research (2019A1515012230)+1 种基金Development Program in Key Areas of Guangdong Province (2019B020210002)the Fundamental Research Funds for the Central Universities (2019KZ01)。
文摘Mitochondrial dysfunction is proposed to be substantially associated with ageing and ageing-related diseases like Alzheimer's disease(AD). However, it is unclear whether different mouse models with mitochondrialrelated diseases have similar changes in mitochondrial morphology of the same tissues. Moreover, whether similarities in mitochondrial morphology can be a suitable marker for screening and/or discovering mitochondrial-protective substances remains unknown. Mitochondria morphology in different tissues of a novel mitochondrial outer membrane protein Slc25a46 knockout mouse and a traditional APP_(SWE)/PS1ΔE9 transgenic mouse were examined using transmission electron microscope(TEM). Both young Slc25a46 knockout mice and aged APP_(SWE)/PS1ΔE9 mice models showed similar mitochondrial damage in cerebellum tissues. The results indicated that different mitochondrial-related diseases shared similar alteration and defects in mitochondrial morphology. Furthermore, Lycium ruthenicum Murr. extract, a bioactive food substance with cognition-improving property, could effectively improve muscle strength and increase body weight in the Slc25a46 knockout mice. These findings suggest that mitochondrial morphology defects in mice models, particularly in the mitochondrial compartment, represent a unified and effective marker for screening and validating natural product-derived functional substances with mitochondrial protective properties. It also holds potential application in mitochondrial-impaired senile neurodegenerative diseases, especially in AD.
基金Key R&D Program of China,Grant/Award Number:2022YFC2503700 and 2022YFC2503703National Natural Science Foundation of China,Grant/Award Number:81773226,82103483 and U1967220Shanghai Sailing Program,Grant/Award Number:20YF1459700。
文摘Background:Hepatocellular carcinoma(HCC)is the most common type of liver cancer.Recently,developments in radiotherapy technology have led to radiotherapy becoming one of the main therapeutics of HCC.Therefore,a suitable animal model for radiotherapy of the orthotopic HCC mouse model is urgently needed.Methods:In the present study,Hepa1-6 cells were injected into the liver of C57BL/6 mice in situ to mimic the pathological characteristics of the original HCC.Tumor formation was monitored by applying magnetic resonance imaging techniques and verified by H&E histopathological staining,AFP staining,and Ki67 staining.A single dose of 10 Gy X-ray was applied to simulate clinical radiotherapy plans using image-guided radiotherapy(IGRT)equipment.The efficiency of radiotherapy was then assessed by examining tumor size and weight one week after radiation.Cleaved-caspase3 staining and TUNEL were used to assess apoptosis in tumor tissues.Results:Intrahepatic tumor development was detected in the liver according using MRI.A high-density shadow could be seen 10 days after cell injection,which indicated the formation of HCC in vivo.The tumors grew steadily bigger,and underwent precision radiotherapy 20 days after injection.The typical pathological characteristics of HCC,such as large,deeply stained nuclei and irregular cell size,were visible with H&E staining.After radiotherapy,significantly higher expression of the immunohistochemical markers Ki67 and AFP were detected in tumor tissue than in the nearby normal tissue.Compared with the control group,the tumor volume(p=0.05)and weight(p<0.05)of the irradiated group were significantly reduced.In addition,a higher frequency of apoptosis was identified in irradiated HCC tumor tissue using the TUNEL and cleaved-caspase3 staining assay.Conclusions:In a well-established orthotopic HCC model,MRI was utilized to monitor the formation of tumors,and IGRT was used to simulate clinical radiotherapy.The present study could provide a suitable preclinical system for HCC radiotherapyrelated studies.
基金supported by a core fund from Tel Aviv University and the Department of Oral and Maxillofacial Surgery,Baruch Padeh Medical Center,Poriya,Israel。
文摘Head and neck squamous cell cancer(HNSCC)is a leading global malignancy.Every year,More than 830000 people are diagnosed with HNSCC globally,with more than 430000 fatalities.HNSCC is a deadly diverse malignancy with many tumor locations and biological characteristics.It originates from the squamous epithelium of the oral cavity,oropharynx,nasopharynx,larynx,and hypopharynx.The most frequently impacted regions are the tongue and larynx.Previous investigations have demonstrated the critical role of host genetic susceptibility in the progression of HNSCC.Despite the advances in our knowledge,the improved survival rate of HNSCC patients over the last 40 years has been limited.Failure to identify the molecular origins of development of HNSCC and the genetic basis of the disease and its biological heterogeneity impedes the development of new therapeutic methods.These results indicate a need to identify more genetic factors underlying this complex disease,which can be better used in early detection and prevention strategies.The lack of reliable animal models to investigate the underlying molecular processes is one of the most significant barriers to understanding HNSCC tumors.In this report,we explore and discuss potential research prospects utilizing the Collaborative Cross mouse model and crossing it to mice carrying single or double knockout genes(e.g.Smad 4 and P53 genes)to identify genetic factors affecting the development of this complex disease using genome-wide association studies,epigenetics,micro RNA,long noncoding RNA,lnc RNA,histone modifications,methylation,phosphorylation,and proteomics.
基金supported by the Natural Science Foundation of Guangdong Province of China,No.2018A030313427the Science and Technology Program of Guangzhou of China,No.202002030393(both to LMW)。
文摘The current animal models of stroke primarily model a single intracerebral hemorrhage(ICH)attack,and there is a lack of a reliable model of recurrent ICH.In this study,we established 16-month-old C57 B L/6 male mouse models of ICH by injecting collagenaseⅦ-S into the left striatum.Twenty-one days later,we injected collagenaseⅦ-S into the right striatum to simulate recurrent ICH.Our results showed that mice subjected to bilateral striatal hemorrhage had poorer neurological function at the early stage of hemorrhage,delayed recovery in locomotor function,motor coordination,and movement speed,and more obvious emotional and cognitive dysfunction than mice subjected to unilate ral striatal hemorrhage.These findings indicate that mouse models of bilateral striatal hemorrhage can well simulate clinically common recurrent ICH.These models should be used as a novel tool for investigating the pathogenesis and treatment targets of recurrent ICH.
基金the National Key Research and Development Project of Stem Cell and Transformation Research,No.2019YFA0112100the National Natural Science Foundation of China(Key Program),No.81930070(both to SF)。
文摘Patients with potential spinal stenosis are susceptible to central cord syndrome induced by blunt trauma.Suitable animal models are helpful for studying the pathogenesis and treatment of such injuries.In this study,we established a mouse model of acute blunt traumatic spinal cord injury by compressing the C6 spinal cord with 5 and 10 g/mm~2 compression weights to simulate cervical central cord syndrome.Behavioral testing confirmed that this model exhibited the characteristics of central cord syndrome because motor function in the front paws was impaired,whereas basic motor and sensory functions of the lower extremities were retained.Hematoxylin-eosin staining showed that the diseased region of the spinal cord in this mouse model was restricted to the gray matter of the central cord,whereas the white matter was rarely affected.Magnetic resonance imaging showed a hypointense signal in the lesion after mild and severe injury.In addition,immunofluorescence staining showed that the degree of nerve tract injury in the spinal cord white matter was mild,and that there was a chronic inflammation reaction.These findings suggest that this mouse model of central cord syndrome can be used as a model for preclinical research,and that gray matter is most vulnerable to injury in central cord syndrome,leading to impaired motor function.
基金supported by the US National Institutes of Health (R01CA160331, R01CA163377, R01CA202919,R01CA239128, P01AG031862, P50CA228991 to R.G.Z. and K99CA241395 to S.K.)US Department of Defense (OC180109 and OC190181 to R.G.Z.)+2 种基金The Honorable Tina Brozman Foundation for Ovarian Cancer Research (to R.G.Z.)Ovarian Cancer Research Alliance Collaborative Research Development Grant (to R.G.Z.)Core facilities support was provided by a Cancer Centre Support Grant(CA010815) to the Wistar Institute。
文摘Epithelial ovarian cancer(EOC) is the leading cause of gynecological cancer-related mortality in the developed world. EOC is a heterogeneous disease represented by several histological and molecular subtypes. Therefore, exploration of relevant preclinical animal models that consider the heterogenic nature of EOC is of great importance for the development of novel therapeutic strategies that can be translated clinically to combat this devastating disease. In this review, we discuss recent progress in the development of preclinical mouse models for EOC study as well as their advantages and limitations.
基金supported by grants from the National Natural Science Foundation of China (81030036, 81270012, 81170809)Special Funds for Major State Basic Research Program of China (973 Program) (2014CB942904) +1 种基金the Committee of Science and Technology of Chongqing (CSTC 2011jjA1468)the foundation from national key laboratory (SKLZZ201017)
文摘Fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling plays essential roles in bone development and diseases. Missense mutations in FGFs and FGFRs in humans can cause various congenital bone diseases, including chondrodysplasia syndromes, craniosynostosis syndromes and syndromes with dysregulated phosphate metabolism. FGF/FGFR signaling is also an important pathway involved in the maintenance of adult bone homeostasis. Multiple kinds of mouse models, mimicking human skeleton diseases caused by missense mutations in FGFs and FGFRs, have been established by knock-m/out and transgenic technologies. These genetically modified mice provide good models for studying the role of FGF/FGFR signaling in skeleton development and homeostasis. In this review, we summarize the mouse models of FGF signaling-related skeleton diseases and recent progresses regarding the molecular mechanisms, underlying the role of FGFs/FGFRs in the regulation of bone development and homeostasis. This review also provides a perspective view on future works to explore the roles of FGF signaling in skeletal development and homeostasis.
基金Supported by Shanghai Science and Technology Development Foundation Project,No.12140900300Shanghai Municipal Commission of Health and Family Planning Project,No.20144Y0073+1 种基金Shanghai Public Health Clinical Center Project,No.2014M08National Science and Technology Major Project,No.2017ZX10304402-001-012
文摘AIM To establish an inducible liver injury mouse model and transplant human hepatocytes to obtain liverhumanized mice.METHODS We crossed three mouse strains,including albumin(Alb)-cre transgenic mice,inducible diphtheria toxin receptor(DTR) transgenic mice and severe combined immune deficient(SCID)-beige mice,to create Alb-cre/DTR/SCID-beige(ADSB) mice,which coincidentally harbor Alb-cre and DTR transgenes and are immunodeficient. As the Cre expression is driven by the liver-specific promoter Alb(encoding ALB),the DTR stop signal flanked by two lox P sites can be deleted in the ADSB mice,resulting in DTR expression in the liver. ADSB mice aged 8-10 wk were injected intraperitoneally(i.p.) with diphtheria toxin(DT) and liver damage was assessed by serum alanine aminotransferase(ALT) level. Two days later,mouse livers were sampled for histological analysis,and human hepatocytes were transplanted into the livers on the same day. A human ALB enzyme-linked immunosorbent assay was performed 7,14,21 and 28 d after transplantation. Human CD68 immunohistochemistry was performed 30 and 90 d after transplantation.RESULTS We crossed Alb-cre with DTR and SCID-beige mice to obtain ADSB mice. These mice were found to have liver damage 4 d after i.p. injection of 2.5 ng/g bodyweight DT. Bodyweight began to decrease on day 2,increased on day 7,and was lowest on day 4(range,10.5%-13.4%). Serum ALT activity began to increase on day 2 and reached a peak value of 289.7 ± 16.2 IU/m L on day 4,then returned to background values on day 7. After transplantation of human liver cells,peripheral blood human ALB level was 1580 ± 454.8 ng/m L(range,750.2-3064.9 ng/m L) after 28 d and Kupffer cells were present in the liver at 30 d in ADSB mice.CONCLUSION Human hepatocytes were successfully repopulated in the livers of ADSB mice. The inducible mouse model of humanized liver in ADSB mice may have functional applications,such as hepatocyte transplantation,hepatic regeneration and drug metabolism.
基金Supported by the Ahvaz Jundishapur University of Medical Sciences(No.IORC-9203)
文摘AIM: To investigate the effects of periocular injection of propranolol and celecoxib on ocular levels of vascular endothelial growth factor (VEGF) in a diabetic mouse model. METHODS: Forty 4-6wk BALB-C male mice weighing 20-25 g were used. The study groups included: nondiabetic control (group 1), diabetic control (group 2), diabetic propranolol (group 3), and diabetic celecoxib (group 4). After induction of type 1 diabetes by streptozotocin, propranolol (10 μg) and celecoxib (200 μg dissolved in carboxymethylcellulose 0.5%) were injected periocularly. The ocular level of VEGF was measured in all the study groups using enzyme-linked immuno sorbent assay (ELISA) method. RESULTS: Ocular VEGF level was significantly increased (1.25 fold) in the diabetic control group when compared to the non-diabetic group one week after induction with streptozotocin (P=0.002). Both periocular propranolol and celecoxib significantly reduced ocular VEGF levels (P=0.047 and P〈0.001, respectively). The effect was more pronounced with celecoxib, CONCLUSION: The periocular administration of propranolol and celecoxib can significantly reduce ocular VEGF levels in a diabetic mouse model.
基金CAMS Innovation Fund for Medical Sciences,Grant/Award Number:2016-12M-2-006 and 2019-I2M-1-003Young Elite Scientists Sponsorship Program by CAST(YESS),Grant/Award Number:2019QNRC001+1 种基金National Natural Science Foundation of China,Grant/Award Number:81901114Fundamental Research Funds for the Central Universities,Grant/Award Number:3332019091。
文摘Background:Alzheimer's disease(AD)is an incurable and irreversible neurodegen-erative disease,without a clear pathogenesis.Therefore,identification of candidates before amyloid-βplaque(Aβ)deposition proceeds is of major significance for earlier intervention in AD.Methods:To explore the potential noninvasive earlier biomarkers of AD in a 5XFAD mouse model,microRNAs(miRNAs)from urinary exosomes in 1-month-old pre-Aβaccumulation 5XFAD mice models and their littermate controls were profiled by mi-croarray analysis.The differentially expressed miRNAs were further analyzed via droplet digital PCR(ddPCR).Results:Microarray analysis demonstrated that 48 differentially expressed miRNAs(18 upregulated and 30 downregulated),of which six miRNAs-miR-196b-5p,miR-339-3p,miR-34a-5p,miR-376b-3p,miR-677-5p,and miR-721-were predicted to display gene targets and important signaling pathways closely associated with AD pathogenesis and verified by ddPCR.Conclusions:Urinary exosomal miRNAs showing differences in expression prior to Aβ-plaque deposition were identified.These exosomal miRNAs represent potential noninvasive biomarkers that may be used to prevent AD in clinical applications.
基金supported in part by the NIH grant R01CA241134supported in part by the NSF grant CMMI-1552764+3 种基金supported in part by the NSF grants DMS-1349724 and DMS-2052465supported in part by the NSF grant CCF-1740761supported in part by the U.S.-Norway Fulbright Foundation and the Research Council of Norway R&D Grant 309273supported in part by the Norwegian Centennial Chair grant and the Doctoral Dissertation Fellowship from the University of Minnesota.
文摘The spread of an advantageous mutation through a population is of fundamental interest in population genetics. While the classical Moran model is formulated for a well-mixed population, it has long been recognized that in real-world applications, the population usually has an explicit spatial structure which can significantly influence the dynamics. In the context of cancer initiation in epithelial tissue, several recent works have analyzed the dynamics of advantageous mutant spread on integer lattices, using the biased voter model from particle systems theory. In this spatial version of the Moran model, individuals first reproduce according to their fitness and then replace a neighboring individual. From a biological standpoint, the opposite dynamics, where individuals first die and are then replaced by a neighboring individual according to its fitness, are equally relevant. Here, we investigate this death-birth analogue of the biased voter model. We construct the process mathematically, derive the associated dual process, establish bounds on the survival probability of a single mutant, and prove that the process has an asymptotic shape. We also briefly discuss alternative birth-death and death-birth dynamics, depending on how the mutant fitness advantage affects the dynamics. We show that birth-death and death-birth formulations of the biased voter model are equivalent when fitness affects the former event of each update of the model, whereas the birth-death model is fundamentally different from the death-birth model when fitness affects the latter event.
基金supported by ASBMR Research Career Enhancement Award (to LQ)NIH grants AR060991 (to LQ)AR062908 (to ME-I)
文摘Osteoarthritis (OA) is a degenerative joint disease and a major cause of pain and disability in older adults. We have previously identified epidermal growth factor receptor (EGFR) signaling as an important regulator of cartilage matrix degradation during epiphyseal cartilage development. To study its function in OA progression, we performed surgical destabilization of the medial meniscus (DMM) to induce OA in two mouse models with reduced EGFR activity, one with genetic modification (, was/+ mice) and the other one with pharmacological inhibition (gefitinib treatment). Histological analyses and scoring at 3 months post-surgery revealed increased cartilage destruction and accelerated OA progression in both mouse models. TUNEL staining demonstrated that EGFR signaling protects chondrocytes from OA-induced apoptosis, which was further confirmed in primary chondrocyte culture. Immunohistochemistry showed increased aggrecan degradation in these mouse models, which coincides with elevated amounts of ADAMTS5 and matrix metalloproteinase 13 (MMP13), the principle proteinases responsible for aggrecan degradation, in the articular cartilage after DMM surgery. Furthermore, hypoxia-inducible factor 2α (HIF2α), a critical catabolic transcription factor stimulating MMP13 expression during OA, was also upregulated in mice with reduced EGFR signaling. Taken together, our findings demonstrate a primarily protective role of EGFR during OA progression by regulating chondrocyte survival and cartilage degradation.
基金Supported by National Science and Technology Major Project of China(No.2011ZXJ09104-10C)
文摘AIM: To choose appropriate concentration of sodium hydroxide(Na OH) solution to establish a stable and consistent corneal alkali burn mouse model in grade II.·METHODS: The mice(n =60) were randomly divided into four groups and 15 mice each group. Corneal alkali burns were induced by placing circle filter paper soaked with Na OH solutions on the right central cornea for 30 s.The concentrations of Na OH solutions of groups A, B, C,and D were 0.1 mol/L, 0.15 mol/L, 0.2 mol/L, and 1.0 mol/L respectively. Then these corneas were irrigated with 20 m L physiological saline(0.9% Na Cl). On day 7 postburn, slit lamp microscope was used to observe corneal opacity,corneal epithelial sodium fluorescein staining positive rate, incidence of corneal ulcer and corneal neovascularization, meanwhile pictures of the anterior eyes were taken. Cirrus spectral domain optical coherence tomography was used to scan cornea to observe corneal epithelial defect and corneal ulcer.·RESULTS: Corneal opacity scores( x ±s) were not significantly different between the group A and group B(P =0.097). Incidence of corneal ulcer in group B was significantly higher than that in group A(P =0.035).Incidence of corneal ulcer and perforation rate in group B was lower than that in group C. Groups C and D had corneal neovascularization, and incidence of corneal neovascularization in group D was significantly higher than that in group C(P =0.000).·CONCLUSION: Using 0.15 mol/L Na OH can establish grade II mouse model of corneal alkali burns.
文摘Colorectal cancer is a worldwide health burden,with high incidence and mortality,especially in the advanced stages of the disease.Preclinical models are very important and valuable to discover and validate early and specific biomarkers as well as new therapeutic targets.In order to accomplish that,the animal models must replicate the clinical evolution of the disease in all of its phases.In this article,we review the existent mouse models,with their strengths and weaknesses in the replication of human cancer disease progression,with major focus on orthotopic models.