Background:Wenqing Yin(WQY)is a classic prescription used to treat skin diseases like atopic dermatitis(AD)in China,and the aim of this study is to investigate the therapeutic effects and molecular mechanisms of WQY o...Background:Wenqing Yin(WQY)is a classic prescription used to treat skin diseases like atopic dermatitis(AD)in China,and the aim of this study is to investigate the therapeutic effects and molecular mechanisms of WQY on AD.Methods:The DNFB-induced mouse models of AD were established to investigate the therapeutic effects of WQY on AD.The symptoms of AD in the ears and backs of the mice were assessed,while inflammatory factors in the ear were quantified using quantitative real-time-polymerase chain reaction(qRT-PCR),and the percentages of CD4^(+)and CD8^(+)cells in the spleen were analyzed through flow cytometry.The compounds in WQY were identified using ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)analysis and the key targets and pathways of WQY to treat AD were predicted by network pharmacology.Subsequently,the key genes were tested and verified by qRT-PCR,and the potential active components and target proteins were verified by molecular docking.Results:WQY relieved the AD symptoms and histopathological injuries in the ear and back skin of mice with AD.Meanwhile,WQY significantly reduced the levels of inflammatory factors IL-6 and IL-1βin ear tissue,as well as the ratio of CD4^(+)/CD8^(+)cells in spleen.Additionally,a total of 142 compounds were identified from the water extract of WQY by UPLC-Orbitrap-MS/MS.39 key targets related to AD were screened out by network pharmacology methods.The KEGG analysis indicated that the effects of WQY were primarily mediated through pathways associated with Toll-like receptor signaling and T cell receptor signaling.Moreover,the results of qRT-PCR demonstrated that WQY significantly reduced the mRNA expressions of IL-4,IL-10,GATA3 and FOXP3,and molecular docking simulation verified that the active components of WQY had excellent binding abilities with IL-4,IL-10,GATA3 and FOXP3 proteins.Conclusion:The present study demonstrated that WQY effectively relieved AD symptoms in mice,decreased the inflammatory factors levels,regulated the balance of CD4^(+)and CD8^(+)cells,and the mechanism may be associated with the suppression of Th2 and Treg cell immune responses.展开更多
In the article titled“Inhibiting SHP2 reduces glycolysis,promotes microglial M1 polarization,and alleviates secondary inflammation following spinal cord injury in a mouse model,”published in Neural Regeneration Rese...In the article titled“Inhibiting SHP2 reduces glycolysis,promotes microglial M1 polarization,and alleviates secondary inflammation following spinal cord injury in a mouse model,”published in Neural Regeneration Research(Ding et al.,2025),the title was incorrectly presented due to an error during the language polishing process.展开更多
Spared regions of the damaged central nervous system undergo dynamic remodelling and exhibit a remarkable potential for therapeutic exploitation1.Lesion-remote astrocytes(LRAs),which interact with viable neurons and g...Spared regions of the damaged central nervous system undergo dynamic remodelling and exhibit a remarkable potential for therapeutic exploitation1.Lesion-remote astrocytes(LRAs),which interact with viable neurons and glia,undergo reactive transformations whose molecular and functional properties are poorly understood2.Here,using multiple transcriptional profiling methods,we investigated LRAs from spared regions of mouse spinal cord following traumatic spinal cord injury.展开更多
Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen r...Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.展开更多
This paper introduces part of the content in the association standard,T/CAAM0002–2020 Nomenclature and Location of Acupuncture Points for Laboratory Animals Part 3:Mouse.This standard was released by the China Associ...This paper introduces part of the content in the association standard,T/CAAM0002–2020 Nomenclature and Location of Acupuncture Points for Laboratory Animals Part 3:Mouse.This standard was released by the China Association of Acupuncture and Moxibustion on May 15,2020,implemented on October 31,2020,and published by Standards Press of China.The standard was drafted by the Institute of Acupuncture and Moxibustion,China Academy of Chinese Medical Sciences,and the Nanjing University of Chinese Medicine.Principal draftsmen:Xiang-hong JING and Xing-bang HUA.Participating draftsmen:Wan-zhu BAI,Bin XU,Dong-sheng XU,Yi GUO,Tie-ming MA,Xin-jun WANG,and Sheng-feng LU.展开更多
BACKGROUND Primary biliary cholangitis(PBC)is a chronic autoimmune-mediated cholestatic liver disease.Nanoparticles encapsulating rapamycin(ImmTOR)suppress adaptive immune responses and induce the hepatic tolerogenic ...BACKGROUND Primary biliary cholangitis(PBC)is a chronic autoimmune-mediated cholestatic liver disease.Nanoparticles encapsulating rapamycin(ImmTOR)suppress adaptive immune responses and induce the hepatic tolerogenic immune response.AIM To investigate the effects of ImmTOR in PBC mouse models.METHODS PBC models were induced in C57BL/6 mice by two immunizations of 2-octynoic acid-coupled bovine serum albumin at two-week intervals,and polycytidylic acid every three days.The PBC mouse models were separated into the treatment group and the control group.The levels of alkaline phosphatase(ALP)and alanine aminotransferase in the mice were detected using an automatic biochemical analyzer.Liver and spleen mononuclear cells were analyzed by flow cytometry,and serum anti-mitochondrial antibodies(AMA)and the related cytokines were analyzed by enzyme-linked immunosorbent assay.Liver histopathology was examined by hematoxylin and eosin staining and scored.RESULTS After treatment with ImmTOR,the ALP level was significantly decreased(189.60 U/L±27.25 U/L vs 156.00 U/L±17.21 U/L,P<0.05),the level of AMA was reduced(1.28 ng/mL±0.27 ng/mL vs 0.56 ng/mL±0.07 ng/mL,P<0.001)and the expression levels of interferon gamma and tumor necrosis factorαwere significantly decreased(48.29 pg/mL±10.84 pg/mL vs 25.01 pg/mL±1.49 pg/mL,P<0.0001)and(84.24 pg/mL±23.47 pg/mL vs 40.66 pg/mL±14.65 pg/mL,P<0.001).The CD4+T lymphocytes,CD8+T lymphocytes and B lymphocytes in the liver were significantly reduced,with statistically significant differences(24.21%±6.55%vs 15.98%±3.03%,P<0.05;9.09%±1.91%vs 5.49%±1.00%,P<0.001;80.51%±2.96%vs 75.31%±4.34%,P<0.05).The expression of CD8+T lymphocytes and B lymphocytes in the ImmTOR treatment group also decreased(9.09%±1.91%vs 5.49%±1.00%,P<0.001;80.51%±2.96%vs 75.31%±4.34%,P<0.05).The liver pathology of PBC mice in the treatment group showed reduced inflammation and a decreased total pathology score,and the difference in the scores was statistically significant(4.50±2.88 vs 1.75±1.28,P<0.05).CONCLUSION ImmTOR can improve biochemistry and pathology of liver obvious by inhibiting the expression of CD8+T cells and B cells,and reducing the titer of AMA.展开更多
Background:Over the past few decades,a threefold increase in obesity and type 2 diabetes(T2D)has placed a heavy burden on the health-care system and society.Previous studies have shown correlations between obesity,T2D...Background:Over the past few decades,a threefold increase in obesity and type 2 diabetes(T2D)has placed a heavy burden on the health-care system and society.Previous studies have shown correlations between obesity,T2D,and neurodegenera-tive diseases,including dementia.It is imperative to further understand the relation-ship between obesity,T2D,and cognitive deficits.Methods:This investigation tested and evaluated the cognitive impact of obesity and T2D induced by high-fat diet(HFD)and the effect of the host genetic background on the severity of cognitive decline caused by obesity and T2D in collaborative cross(CC)mice.The CC mice are a genetically diverse panel derived from eight inbred strains.Results:Our findings demonstrated significant variations in the recorded phenotypes across different CC lines compared to the reference mouse line,C57BL/6J.CC037 line exhibited a substantial increase in body weight on HFD,whereas line CC005 ex-hibited differing responses based on sex.Glucose tolerance tests revealed significant variations,with some lines like CC005 showing a marked increase in area under the curve(AUC)values on HFD.Organ weights,including brain,spleen,liver,and kidney,varied significantly among the lines and sexes in response to HFD.Behavioral tests using the Morris water maze indicated that cognitive performance was differentially affected by diet and genetic background.Conclusions:Our study establishes a foundation for future quantitative trait loci map-ping using CC lines and identifying genes underlying the comorbidity of Alzheimer's disease(AD),caused by obesity and T2D.The genetic components may offer new tools for early prediction and prevention.展开更多
Substantial evidence points to the early onset of peripheral inflammation in the development of Parkinson's disease(PD),supporting the“body-first”hypothesis.However,there remains a notable absence of PD-specific...Substantial evidence points to the early onset of peripheral inflammation in the development of Parkinson's disease(PD),supporting the“body-first”hypothesis.However,there remains a notable absence of PD-specific animal models induced by inflammatory cytokines.This study introduces a novel mouse model of PD driven by the proinflammatory cytokine CXCL1,identified in our previous research.The involvement of CXCL1 in PD pathogenesis was validated using subacute and chronic MPTP-induced mouse models.Based on these findings,2-month-old C57BL/6J mice were intravenously administered CXCL1(20 ng/kg/day)for 2 weeks(5 days per week),successfully replicating motor deficits and pathological alterations in the substantia nigra observed in the chronic MPTP model.These results demonstrate the potential of CXCL1-induced inflammation as a mechanism for PD modeling.The model revealed activation of the PPAR signaling pathway in CXCL1-mediated neuronal damage by CXCL1.Linoleic acid,a PPAR-γactivator,significantly mitigated MPTPand CXCL1-induced toxicity and reduced serum CXCL1levels.In addition,the CXCL1-injected mouse model shortened the timeline for developing chronic PD mouse model to 2 weeks,offering an efficient platform for studying inflammation-driven processes in PD.The findings provide critical insights into the inflammatory mechanisms underlying PD and identify promising therapeutic targets for intervention.展开更多
Alzheimer'sdisease(AD)isaprogressive neurodegenerative disorder characterized by cognitive impairment and distinct neuropathological features,including amyloid-βplaques,neurofibrillary tangles,and reactive astrog...Alzheimer'sdisease(AD)isaprogressive neurodegenerative disorder characterized by cognitive impairment and distinct neuropathological features,including amyloid-βplaques,neurofibrillary tangles,and reactive astrogliosis.Developing effective diagnostic,preventative,and therapeutic strategies for AD necessitates the establishment of animal models that accurately recapitulate the pathophysiological processes of the disease.Existing transgenic mouse models have significantly contributed to understanding AD pathology but often fail to replicate the complexity of human AD.Additionally,these models are limited in their ability to elucidate the interplay among amyloid-βplaques,neurofibrillary tangles,and reactive astrogliosis due to the absence of spatially and temporally specific genetic manipulation.In this study,we introduce a novel AD mouse model(APP/PS1-TauP301L-Adeno mice)designed to rapidly induce pathological symptoms and enhance understanding of AD mechanisms.Neurofibrillary tangles and severe reactive astrogliosis were induced by injecting AAVDJ-EF1a-hTauP301L-EGFP and Adeno-GFAP-GFP viruses into the hippocampi of 5-month-old APP/PS1 mice.Three months post-injection,these mice exhibited pronounced astrogliosis,substantial amyloid-βplaque accumulation,extensiveneurofibrillarytangles,accelerated neuronal loss,elevated astrocytic GABA levels,and significant spatial memory deficits.Notably,these pathological features were less severe in AAVTauP301L-expressing APP/PS1 mice without augmented reactive astrogliosis.These findings indicate an exacerbating role of severe reactive astrogliosis in amyloid-βplaque and neurofibrillary tangle-associated pathology.The APP/PS1-TauP301L-Adeno mouse model provides a valuable tool for advancing therapeutic research aimed at mitigating the progression of AD.展开更多
To investigate the mechanisms underlying the onset and progression of ischemic stroke,some methods have been proposed that can simultaneously monitor and create embolisms in the animal cerebral cortex.However,these me...To investigate the mechanisms underlying the onset and progression of ischemic stroke,some methods have been proposed that can simultaneously monitor and create embolisms in the animal cerebral cortex.However,these methods often require complex systems and the effect of age on cerebral embolism has not been adequately studied,although ischemic stroke is strongly age-related.In this study,we propose an optical-resolution photoacoustic microscopy-based visualized photothrombosis methodology to create and monitor ischemic stroke in mice simultaneously using a 532 nm pulsed laser.We observed the molding process in mice of different ages and presented age-dependent vascular embolism differentiation.Moreover,we integrated optical coherence tomography angiography to investigate age-associated trends in cerebrovascular variability following a stroke.Our imaging data and quantitative analyses underscore the differential cerebrovascular responses to stroke in mice of different ages,thereby highlighting the technique's potential for evaluating cerebrovascular health and unraveling age-related mechanisms involved in ischemic strokes.展开更多
Age-related osteoporosis poses a significant challenge in musculoskeletal health;a condition characterized by reduced bone density and increased fracture susceptibility in older individuals necessitates a better under...Age-related osteoporosis poses a significant challenge in musculoskeletal health;a condition characterized by reduced bone density and increased fracture susceptibility in older individuals necessitates a better understanding of underlying molecular and cellular mechanisms.Emerging evidence suggests that osteocytes are the pivotal orchestrators of bone remodeling and represent novel therapeutic targets for age-related bone loss.Our study uses the prematurely aged PolgD257A/D257A(PolgA)mouse model to scrutinize age-and sex-related alterations in musculoskeletal health parameters(frailty,grip strength,gait data),bone and particularly the osteocyte lacuno-canalicular network(LCN).Moreover,a new quantitative in silico image analysis pipeline is used to evaluate the alterations in the osteocyte network with aging.Our findings underscore the pronounced degenerative changes in the musculoskeletal health parameters,bone,and osteocyte LCN in PolgA mice as early as 40 weeks,with more prominent alterations evident in aged males.Our findings suggest that the PolgA mouse model serves as a valuable model for studying the cellular mechanisms underlying age-related bone loss,given the comparable aging signs and age-related degeneration of the bone and the osteocyte network observed in naturally aging mice and elderly humans.展开更多
Background:Terpinen-4-ol(T4O),a key constituent of tea tree essential oil and various aromatic plants,has shown promising antiproliferative and pro-apoptotic effects in melanoma and other cancer types.However,its effi...Background:Terpinen-4-ol(T4O),a key constituent of tea tree essential oil and various aromatic plants,has shown promising antiproliferative and pro-apoptotic effects in melanoma and other cancer types.However,its efficacy against cutaneous squamous cell carcinoma(cSCC)remains unclear.Thus,in this study,we investigated the in vivo and in vitro effects of T4O on cSCC cell lines and preliminarily explored its impacting pathways.Methods:Using CCK8 and assay colony formation,we assessed the viability of cSCC A431,SCL-1,and COLO-16 cells treated with T40 at varying concentrations(0,1,2,and 4μM).Flow cytometry was employed to evaluate T4O’s effect on cSCC cell’s cycle progression and apoptosis induction.Additionally,western blotting was utilized to examine the expression intensities of N-cadherin and E-cadherin,two indicative markers of the epithelial-mesenchymal transition(EMT)pathway.T4O’s in vivo effect on inhibiting tumor progression was evaluated on an established xenograft tumor model.Then,the molecular mechanisms of T4O’s antitumor effect were explored by an integrated genome-wide transcriptomics and proteomics study on cSCC A431c cells.Finally,calpain-2’s potential mediator role in T4O’s anti-tumor mechanism was investigated in calpain-2 knockdown cell lines prepared via siRNA transfection.Result:It’s demonstrated that T4O treatment inhibited cSCC proliferation,clonogenicity,migration,and invasion while inducing apoptosis and suppressing the EMT pathway.T4O administration also inhibited cSCC tumorigenesis in the xenograft tumor model.RNA-sequencing and iTRAQ analysis detected significant upregulation of calpain-2 expression in T4O-treated cSCC cells.Western blotting confirmed that T4O significantly increased calpain-2 expression and promoted proteolytic cleavage ofβ-catenin and caspase-12,two calpain-2 target proteins.Importantly,siRNA-mediated calpain-2 knockdown relieved T4O’s suppressive effect on cSCC cell proliferation and motility.Mechanistically,T4O upregulates calpain-2 expression and promotes the cleavage ofβ-catenin and caspase-12,with siRNA-mediated calpain-2 knockdown mitigating T4O’s suppressive effects.Conclusion:These findings suggest that T4O’s antitumor activity in cSCC is mediated through the upregulation of calpain-2 expression and subsequent modulation ofβ-catenin and caspase-12.展开更多
Antipsychotic(AP)medications are used to treat schizophrenia and a number off-label conditions.Although effective in reducing psychoses these drugs increase the risk of developing cardiometabolic disease,and are one o...Antipsychotic(AP)medications are used to treat schizophrenia and a number off-label conditions.Although effective in reducing psychoses these drugs increase the risk of developing cardiometabolic disease,and are one of the reasons why individuals with schizophrenia live∼15–20 years less than the general population.While weight gain has traditionally been thought to be the primary culprit linked to increases in rates of cardiometabolic disease,there are weight-gain independent effects of antipsychotics.The purpose of the current review was to highlight the acute metabolic complications of antipsychotics and to address the question:are exercise and targeting“exercise-activated”signaling pathways,a viable approach to offset the metabolic complications of APs?The possibility of fibroblast growth factor 21 being a common factor mediating the protective effects of exercise and certain nutritional approaches against the acute metabolic complications of antipsychotics was also discussed.The research highlighted in this narrative review provides evidence,in preclinical models,that exercise and certain exercise-activated pathways,can protect against acute perturbations in glucose metabolism.While promising,further work is needed to confirm these findings in clinical populations prescribed antipsychotics.展开更多
Background:Inhalation exposure is the gold standard when assessing pulmonary tox-icity.However,it typically requires substantial amounts of test material.Intratracheal instillation is an alternative administration tec...Background:Inhalation exposure is the gold standard when assessing pulmonary tox-icity.However,it typically requires substantial amounts of test material.Intratracheal instillation is an alternative administration technique,where the test substance is suspended in a liquid vehicle and deposited into the lung via the trachea.Instillation requires minimal test material,delivers an exact dose deep into the lung,and is less labor-intensive than inhalation exposures.However,one shortcoming is that the pro-cedure may induce short-term inflammation.To minimize this,we tested different modifications of the technique to identify the potential for refinement.Methods:First,we tested whether previous findings of increased inflammation could be confirmed.Next,we tested whether instillation with a disposable 1 mL syringe with ball-tipped steel-needle(Disposable-syringe/steel-needle)induced less inflammation than the use of our standard set-up,a 250μL reusable glass syringe with a disposable plastic catheter(Glass-syringe/plastic-catheter).Finally,we tested if access to pelleted and liquid feed prior to instillation affected inflammation.We evaluated inflammation by neutrophil numbers in bronchoalveolar fluid 24 h post-exposure.Results:Vehicle-instilled mice showed a small increase in neutrophil numbers com-pared to untreated mice.Neutrophil numbers were slightly elevated in the groups in-stilled with Disposable-syringe/steel-needle;an interaction with feed type indicated that the increase in neutrophils was more pronounced in combination with feed pel-lets compared to liquid feed.We found no difference between the feed types when using the Glass-syringe/plastic-catheter combination.Conclusion:The Glass-syringe/plastic-catheter combination induced the least exposure-related inflammation,confirming this as a preferred instillation procedure.展开更多
Colorectal cancer is the third most diagnosed malignancy and the second-leading cause of cancer-related deaths worldwide.Management includes a combination of surgery,radiotherapy,and systemic therapy that is tailored ...Colorectal cancer is the third most diagnosed malignancy and the second-leading cause of cancer-related deaths worldwide.Management includes a combination of surgery,radiotherapy,and systemic therapy that is tailored to the stage of the disease.However,each tumor has a unique genetic profile that influences the treatment response and the overall prognosis.Biomarkers guide treatment decisions,but many chemotherapeutics lack reliable predictors.To bridge this gap patient-derived xenograft models were developed and are valuable preclinical tools.These systems utilize patient-derived tumor tissue grafted into an animal host that provides a platform for personalized drug profiling.This article surveyed recent advances in mouse and zebrafish colorectal cancer patient-derived xenografts,emphasizing their clinical utility for functional precision oncology.We explored the impact of these models on translational research,discussed current limitations,and outlined key priorities for future development.展开更多
Tauopathies represent a class of neurodegenerative diseases(NDs),including Alzheimer’s disease(AD),progressive supranuclear palsy(PSP),Pick’s disease(PiD),and corticobasal degeneration(CBD),defined by intracellular ...Tauopathies represent a class of neurodegenerative diseases(NDs),including Alzheimer’s disease(AD),progressive supranuclear palsy(PSP),Pick’s disease(PiD),and corticobasal degeneration(CBD),defined by intracellular accumulation of misfolded and hyperphosphorylated tau protein.The pathogenic cascade involves hyperphosphorylation,conformational changes,and aggregation into neurofibrillary tangles(NFTs),which are spatially and functionally linked to neuronal dysfunction,synaptic loss,and progressive cognitive and motor decline.To elucidate tau-mediated mechanisms,diverse transgenic rodent models expressing wild-type or mutant forms of human TAU have been generated.Although these models have advanced understanding of tau aggregation and propagation,tau-targeting therapies have failed to produce clinical benefits,raising concerns about the precise mechanism underlying tauopathies and the fidelity of animal models in evaluating therapeutic targets.This review systematically examines the neuropathological and behavioral phenotypes across established rodent and non-human primate(NHP)tauopathy models,highlighting mechanistic insights into tau-driven pathology.The advantages,limitations,and translational barriers of each model are critically evaluated to inform the development of more predictive preclinical platforms for therapeutic discovery.展开更多
Monkeypox virus(MPXV),a member of the Orthopoxvirus genus,caused a large-scale global outbreak in 2022.Developing mouse models for MPXV infection is crucial for advancing research on vaccines and therapeutic intervent...Monkeypox virus(MPXV),a member of the Orthopoxvirus genus,caused a large-scale global outbreak in 2022.Developing mouse models for MPXV infection is crucial for advancing research on vaccines and therapeutic interventions.To address this,we conducted a comparative study on the susceptibility of six mouse strains—severe combined immune-deficiency(SCID),nude,genetically diabetic(db/db)and obese(ob/ob),C57BL/6J,and BALB/c—to MPXV infection.Mouse strains were infected with MPXV via intranasal inoculation,and body weight changes and mortality were monitored post-infection.Additionally,the tissue distribution of MPXV and the pathological changes in the lung tissues of the infected mice were evaluated.The results demonstrated that SCID and nude mice exhibited significant weight loss following MPXV infection,with 100%mortality observed in SCID mice,while no mortality occurred in nude mice.In contrast,the other mouse strains showed no significant weight loss or mortality.Notably,the viral load in the lung tissues of SCID and nude mice was the highest among the tested strains.Furthermore,we investigated the impact of different inoculation routes—intranasal(I.N.),intraperitoneal(I.P.),and intravenous(I.V.)—on the pathogenicity of MPXV in mice.The results revealed that the intravenous route induced more pronounced pathogenic effects compared to the intranasal and intraperitoneal routes.In summary,this study provides valuable insights into the development of MPXV-infected mouse models,offering a foundation for further research on MPXV pathogenesis and therapeutic drug development.展开更多
Background:This study investigated the impacts and mechanisms of yunweiling in the management of Functional Constipation(FC)using network pharmacology and experimental research.Methods:Using the Traditional Chinese Me...Background:This study investigated the impacts and mechanisms of yunweiling in the management of Functional Constipation(FC)using network pharmacology and experimental research.Methods:Using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),Genecard,and Online Mendelian Inheritance in Man(OMIM)databases,a potential gene target for yunweiling in treating FC was found.A pharmacological network was built and viewed in Cytoscape.A protein interac-tion map was created with STRING and Cytoscape.‘clusterProfiler’helped uncover its mechanism.Molecular docking was done with AutoDock Vina.In a constipation mouse model,Western blot was used to assess yunweiling's effectiveness.Results:To investigate yunweiling's therapeutic effects on FC,we employed a loperamide-induced constipation model.Successful model establishment was con-firmed by first black stool time,reduced stool output,and impaired gastrointestinal motility.Yunweiling treatment,especially at high and medium doses,significantly al-leviated constipation symptoms by reducing first black stool time,increasing stool output,and enhancing gastrointestinal motility.HE staining revealed yunweiling's ability to restore colon tissue structure.Yunweiling modulated the expression of key proteins TP53,P-AKT,P-PI3K,RET,and Rai,implicating its involvement in the PI3K-Akt signaling pathway.Comparative analysis showed yunweiling to be more effective than its individual components(shionone,β-sitosterol,and daucosterol)in improving constipation.The combination of yunweiling with TP53 and PI3K-Akt inhibitors fur-ther enhanced its therapeutic effects,suggesting a synergistic mechanism.Conclusions:The integration of network pharmacology and experimental investiga-tions indicated the effectiveness of yunweiling in managing FC,offering essential theoretical support for clinical application.展开更多
Background:Spinocerebellar ataxia type 2(SCA2)is a neurodegenerative disease marked by significant clinical and genetic heterogeneity,primarily caused by expanded CAG mutations in the ATXN2 gene.The unstable expansion...Background:Spinocerebellar ataxia type 2(SCA2)is a neurodegenerative disease marked by significant clinical and genetic heterogeneity,primarily caused by expanded CAG mutations in the ATXN2 gene.The unstable expansion of CAG repeats disrupts the genetic stability of animal models,which is detrimental to disease research.Methods:In this study,we established a mouse model in which CAG repeats do not undergo microsatellite instability(MSI)across generations.A humanized ATXN2 cDNA with four CAA interruptions within 73 CAG expansions was inserted into the Rosa26 locus of C57BL/6J mice.A 23 CAG control mouse model was also generated to verify ATXN2 integration and expression.Results:In our model,the number of CAG repeats remained stable during transmission,with no CAG repeat expansion observed in 64 parent-to-offspring transmissions.Compared with SCA2-Q23 mice,SCA2-Q73 mice exhibited progressive motor impairment,reduced Purkinje cell count and volume(indicative of cell atrophy),and muscle atrophy.These observations in the mice suggest that the behavioral and neuropathological phenotypes may reflect the features of SCA2 patients.RNA-seq analysis of the gastrocnemius muscle in SCA2-Q73 mice showed significant changes in muscle differentiation and development gene expression at 56 weeks,with no significant differences at 16 weeks compared to SCA2-Q23 mice.The expression level of the Myf6 gene significantly changed in the muscles of aged mice.Conclusion:In summary,the establishment of this model not only provides a stable animal model for studying CAG transmission in SCA2 but also indicates that the lack of long-term neural stimulation leads to muscle atrophy.展开更多
基金supported by grants from the National Natural Science Foundation of China(82004252)the Project of Administration of Traditional Chinese Medicine of Guangdong Province(202405112017596500)the Basic and Applied Basic Research Foundation of Guangzhou Municipal Science and Technology Bureau(202102020533).
文摘Background:Wenqing Yin(WQY)is a classic prescription used to treat skin diseases like atopic dermatitis(AD)in China,and the aim of this study is to investigate the therapeutic effects and molecular mechanisms of WQY on AD.Methods:The DNFB-induced mouse models of AD were established to investigate the therapeutic effects of WQY on AD.The symptoms of AD in the ears and backs of the mice were assessed,while inflammatory factors in the ear were quantified using quantitative real-time-polymerase chain reaction(qRT-PCR),and the percentages of CD4^(+)and CD8^(+)cells in the spleen were analyzed through flow cytometry.The compounds in WQY were identified using ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)analysis and the key targets and pathways of WQY to treat AD were predicted by network pharmacology.Subsequently,the key genes were tested and verified by qRT-PCR,and the potential active components and target proteins were verified by molecular docking.Results:WQY relieved the AD symptoms and histopathological injuries in the ear and back skin of mice with AD.Meanwhile,WQY significantly reduced the levels of inflammatory factors IL-6 and IL-1βin ear tissue,as well as the ratio of CD4^(+)/CD8^(+)cells in spleen.Additionally,a total of 142 compounds were identified from the water extract of WQY by UPLC-Orbitrap-MS/MS.39 key targets related to AD were screened out by network pharmacology methods.The KEGG analysis indicated that the effects of WQY were primarily mediated through pathways associated with Toll-like receptor signaling and T cell receptor signaling.Moreover,the results of qRT-PCR demonstrated that WQY significantly reduced the mRNA expressions of IL-4,IL-10,GATA3 and FOXP3,and molecular docking simulation verified that the active components of WQY had excellent binding abilities with IL-4,IL-10,GATA3 and FOXP3 proteins.Conclusion:The present study demonstrated that WQY effectively relieved AD symptoms in mice,decreased the inflammatory factors levels,regulated the balance of CD4^(+)and CD8^(+)cells,and the mechanism may be associated with the suppression of Th2 and Treg cell immune responses.
文摘In the article titled“Inhibiting SHP2 reduces glycolysis,promotes microglial M1 polarization,and alleviates secondary inflammation following spinal cord injury in a mouse model,”published in Neural Regeneration Research(Ding et al.,2025),the title was incorrectly presented due to an error during the language polishing process.
文摘Spared regions of the damaged central nervous system undergo dynamic remodelling and exhibit a remarkable potential for therapeutic exploitation1.Lesion-remote astrocytes(LRAs),which interact with viable neurons and glia,undergo reactive transformations whose molecular and functional properties are poorly understood2.Here,using multiple transcriptional profiling methods,we investigated LRAs from spared regions of mouse spinal cord following traumatic spinal cord injury.
基金supported by the National Key R&D Program of China,No.2021YFA0805200(to SY)the National Natural Science Foundation of China,No.31970954(to SY)two grants from the Department of Science and Technology of Guangdong Province,Nos.2021ZT09Y007,2020B121201006(both to XJL)。
文摘Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.
文摘This paper introduces part of the content in the association standard,T/CAAM0002–2020 Nomenclature and Location of Acupuncture Points for Laboratory Animals Part 3:Mouse.This standard was released by the China Association of Acupuncture and Moxibustion on May 15,2020,implemented on October 31,2020,and published by Standards Press of China.The standard was drafted by the Institute of Acupuncture and Moxibustion,China Academy of Chinese Medical Sciences,and the Nanjing University of Chinese Medicine.Principal draftsmen:Xiang-hong JING and Xing-bang HUA.Participating draftsmen:Wan-zhu BAI,Bin XU,Dong-sheng XU,Yi GUO,Tie-ming MA,Xin-jun WANG,and Sheng-feng LU.
基金Supported by Cultivation Project of Hebei Natural Science Foundation-Precision Medicine Joint Fund,No.H2021206239.
文摘BACKGROUND Primary biliary cholangitis(PBC)is a chronic autoimmune-mediated cholestatic liver disease.Nanoparticles encapsulating rapamycin(ImmTOR)suppress adaptive immune responses and induce the hepatic tolerogenic immune response.AIM To investigate the effects of ImmTOR in PBC mouse models.METHODS PBC models were induced in C57BL/6 mice by two immunizations of 2-octynoic acid-coupled bovine serum albumin at two-week intervals,and polycytidylic acid every three days.The PBC mouse models were separated into the treatment group and the control group.The levels of alkaline phosphatase(ALP)and alanine aminotransferase in the mice were detected using an automatic biochemical analyzer.Liver and spleen mononuclear cells were analyzed by flow cytometry,and serum anti-mitochondrial antibodies(AMA)and the related cytokines were analyzed by enzyme-linked immunosorbent assay.Liver histopathology was examined by hematoxylin and eosin staining and scored.RESULTS After treatment with ImmTOR,the ALP level was significantly decreased(189.60 U/L±27.25 U/L vs 156.00 U/L±17.21 U/L,P<0.05),the level of AMA was reduced(1.28 ng/mL±0.27 ng/mL vs 0.56 ng/mL±0.07 ng/mL,P<0.001)and the expression levels of interferon gamma and tumor necrosis factorαwere significantly decreased(48.29 pg/mL±10.84 pg/mL vs 25.01 pg/mL±1.49 pg/mL,P<0.0001)and(84.24 pg/mL±23.47 pg/mL vs 40.66 pg/mL±14.65 pg/mL,P<0.001).The CD4+T lymphocytes,CD8+T lymphocytes and B lymphocytes in the liver were significantly reduced,with statistically significant differences(24.21%±6.55%vs 15.98%±3.03%,P<0.05;9.09%±1.91%vs 5.49%±1.00%,P<0.001;80.51%±2.96%vs 75.31%±4.34%,P<0.05).The expression of CD8+T lymphocytes and B lymphocytes in the ImmTOR treatment group also decreased(9.09%±1.91%vs 5.49%±1.00%,P<0.001;80.51%±2.96%vs 75.31%±4.34%,P<0.05).The liver pathology of PBC mice in the treatment group showed reduced inflammation and a decreased total pathology score,and the difference in the scores was statistically significant(4.50±2.88 vs 1.75±1.28,P<0.05).CONCLUSION ImmTOR can improve biochemistry and pathology of liver obvious by inhibiting the expression of CD8+T cells and B cells,and reducing the titer of AMA.
文摘Background:Over the past few decades,a threefold increase in obesity and type 2 diabetes(T2D)has placed a heavy burden on the health-care system and society.Previous studies have shown correlations between obesity,T2D,and neurodegenera-tive diseases,including dementia.It is imperative to further understand the relation-ship between obesity,T2D,and cognitive deficits.Methods:This investigation tested and evaluated the cognitive impact of obesity and T2D induced by high-fat diet(HFD)and the effect of the host genetic background on the severity of cognitive decline caused by obesity and T2D in collaborative cross(CC)mice.The CC mice are a genetically diverse panel derived from eight inbred strains.Results:Our findings demonstrated significant variations in the recorded phenotypes across different CC lines compared to the reference mouse line,C57BL/6J.CC037 line exhibited a substantial increase in body weight on HFD,whereas line CC005 ex-hibited differing responses based on sex.Glucose tolerance tests revealed significant variations,with some lines like CC005 showing a marked increase in area under the curve(AUC)values on HFD.Organ weights,including brain,spleen,liver,and kidney,varied significantly among the lines and sexes in response to HFD.Behavioral tests using the Morris water maze indicated that cognitive performance was differentially affected by diet and genetic background.Conclusions:Our study establishes a foundation for future quantitative trait loci map-ping using CC lines and identifying genes underlying the comorbidity of Alzheimer's disease(AD),caused by obesity and T2D.The genetic components may offer new tools for early prediction and prevention.
基金supported by the National Natural Science Foundation of China (32471049,32170984,32471188,32200802)Natural Science Foundation of Shandong Province (ZR2023QH110)。
文摘Substantial evidence points to the early onset of peripheral inflammation in the development of Parkinson's disease(PD),supporting the“body-first”hypothesis.However,there remains a notable absence of PD-specific animal models induced by inflammatory cytokines.This study introduces a novel mouse model of PD driven by the proinflammatory cytokine CXCL1,identified in our previous research.The involvement of CXCL1 in PD pathogenesis was validated using subacute and chronic MPTP-induced mouse models.Based on these findings,2-month-old C57BL/6J mice were intravenously administered CXCL1(20 ng/kg/day)for 2 weeks(5 days per week),successfully replicating motor deficits and pathological alterations in the substantia nigra observed in the chronic MPTP model.These results demonstrate the potential of CXCL1-induced inflammation as a mechanism for PD modeling.The model revealed activation of the PPAR signaling pathway in CXCL1-mediated neuronal damage by CXCL1.Linoleic acid,a PPAR-γactivator,significantly mitigated MPTPand CXCL1-induced toxicity and reduced serum CXCL1levels.In addition,the CXCL1-injected mouse model shortened the timeline for developing chronic PD mouse model to 2 weeks,offering an efficient platform for studying inflammation-driven processes in PD.The findings provide critical insights into the inflammatory mechanisms underlying PD and identify promising therapeutic targets for intervention.
基金supported by the National Research Foundation of Korea (NRF)funded by the Ministry of Science,ICT&Future Planning (2022R1A2C2006229,2022R1A6A3A01086868)Korea Dementia Research Project through the Korea Dementia Research Center (KDRC)funded by the Ministry of Health&Welfare and Ministry of Science and ICT,Republic of Korea (RS-2024-00345328)KIST Institutional Grant (2E32851)。
文摘Alzheimer'sdisease(AD)isaprogressive neurodegenerative disorder characterized by cognitive impairment and distinct neuropathological features,including amyloid-βplaques,neurofibrillary tangles,and reactive astrogliosis.Developing effective diagnostic,preventative,and therapeutic strategies for AD necessitates the establishment of animal models that accurately recapitulate the pathophysiological processes of the disease.Existing transgenic mouse models have significantly contributed to understanding AD pathology but often fail to replicate the complexity of human AD.Additionally,these models are limited in their ability to elucidate the interplay among amyloid-βplaques,neurofibrillary tangles,and reactive astrogliosis due to the absence of spatially and temporally specific genetic manipulation.In this study,we introduce a novel AD mouse model(APP/PS1-TauP301L-Adeno mice)designed to rapidly induce pathological symptoms and enhance understanding of AD mechanisms.Neurofibrillary tangles and severe reactive astrogliosis were induced by injecting AAVDJ-EF1a-hTauP301L-EGFP and Adeno-GFAP-GFP viruses into the hippocampi of 5-month-old APP/PS1 mice.Three months post-injection,these mice exhibited pronounced astrogliosis,substantial amyloid-βplaque accumulation,extensiveneurofibrillarytangles,accelerated neuronal loss,elevated astrocytic GABA levels,and significant spatial memory deficits.Notably,these pathological features were less severe in AAVTauP301L-expressing APP/PS1 mice without augmented reactive astrogliosis.These findings indicate an exacerbating role of severe reactive astrogliosis in amyloid-βplaque and neurofibrillary tangle-associated pathology.The APP/PS1-TauP301L-Adeno mouse model provides a valuable tool for advancing therapeutic research aimed at mitigating the progression of AD.
基金supported by University of Macao,China,Nos.MYRG2022-00054-FHS and MYRG-GRG2023-00038-FHS-UMDF(to ZY)the Macao Science and Technology Development Fund,China,Nos.FDCT0048/2021/AGJ and FDCT0020/2019/AMJ and FDCT 0011/2018/A1(to ZY)Natural Science Foundation of Guangdong Province of China,No.EF017/FHS-YZ/2021/GDSTC(to ZY)。
文摘To investigate the mechanisms underlying the onset and progression of ischemic stroke,some methods have been proposed that can simultaneously monitor and create embolisms in the animal cerebral cortex.However,these methods often require complex systems and the effect of age on cerebral embolism has not been adequately studied,although ischemic stroke is strongly age-related.In this study,we propose an optical-resolution photoacoustic microscopy-based visualized photothrombosis methodology to create and monitor ischemic stroke in mice simultaneously using a 532 nm pulsed laser.We observed the molding process in mice of different ages and presented age-dependent vascular embolism differentiation.Moreover,we integrated optical coherence tomography angiography to investigate age-associated trends in cerebrovascular variability following a stroke.Our imaging data and quantitative analyses underscore the differential cerebrovascular responses to stroke in mice of different ages,thereby highlighting the technique's potential for evaluating cerebrovascular health and unraveling age-related mechanisms involved in ischemic strokes.
基金the European Research Council(ERC Advanced MechAGE-ERC-2016-ADG-741883)the Swiss National Science Foundation(no.188522).
文摘Age-related osteoporosis poses a significant challenge in musculoskeletal health;a condition characterized by reduced bone density and increased fracture susceptibility in older individuals necessitates a better understanding of underlying molecular and cellular mechanisms.Emerging evidence suggests that osteocytes are the pivotal orchestrators of bone remodeling and represent novel therapeutic targets for age-related bone loss.Our study uses the prematurely aged PolgD257A/D257A(PolgA)mouse model to scrutinize age-and sex-related alterations in musculoskeletal health parameters(frailty,grip strength,gait data),bone and particularly the osteocyte lacuno-canalicular network(LCN).Moreover,a new quantitative in silico image analysis pipeline is used to evaluate the alterations in the osteocyte network with aging.Our findings underscore the pronounced degenerative changes in the musculoskeletal health parameters,bone,and osteocyte LCN in PolgA mice as early as 40 weeks,with more prominent alterations evident in aged males.Our findings suggest that the PolgA mouse model serves as a valuable model for studying the cellular mechanisms underlying age-related bone loss,given the comparable aging signs and age-related degeneration of the bone and the osteocyte network observed in naturally aging mice and elderly humans.
基金supported by the Basic Research Program of the Guizhou Science Cooperation Foundation Project(Grant Number:ZK[2021]466)Guizhou Provincial Health Commission(Grant Number:gzwkj2022-062).
文摘Background:Terpinen-4-ol(T4O),a key constituent of tea tree essential oil and various aromatic plants,has shown promising antiproliferative and pro-apoptotic effects in melanoma and other cancer types.However,its efficacy against cutaneous squamous cell carcinoma(cSCC)remains unclear.Thus,in this study,we investigated the in vivo and in vitro effects of T4O on cSCC cell lines and preliminarily explored its impacting pathways.Methods:Using CCK8 and assay colony formation,we assessed the viability of cSCC A431,SCL-1,and COLO-16 cells treated with T40 at varying concentrations(0,1,2,and 4μM).Flow cytometry was employed to evaluate T4O’s effect on cSCC cell’s cycle progression and apoptosis induction.Additionally,western blotting was utilized to examine the expression intensities of N-cadherin and E-cadherin,two indicative markers of the epithelial-mesenchymal transition(EMT)pathway.T4O’s in vivo effect on inhibiting tumor progression was evaluated on an established xenograft tumor model.Then,the molecular mechanisms of T4O’s antitumor effect were explored by an integrated genome-wide transcriptomics and proteomics study on cSCC A431c cells.Finally,calpain-2’s potential mediator role in T4O’s anti-tumor mechanism was investigated in calpain-2 knockdown cell lines prepared via siRNA transfection.Result:It’s demonstrated that T4O treatment inhibited cSCC proliferation,clonogenicity,migration,and invasion while inducing apoptosis and suppressing the EMT pathway.T4O administration also inhibited cSCC tumorigenesis in the xenograft tumor model.RNA-sequencing and iTRAQ analysis detected significant upregulation of calpain-2 expression in T4O-treated cSCC cells.Western blotting confirmed that T4O significantly increased calpain-2 expression and promoted proteolytic cleavage ofβ-catenin and caspase-12,two calpain-2 target proteins.Importantly,siRNA-mediated calpain-2 knockdown relieved T4O’s suppressive effect on cSCC cell proliferation and motility.Mechanistically,T4O upregulates calpain-2 expression and promotes the cleavage ofβ-catenin and caspase-12,with siRNA-mediated calpain-2 knockdown mitigating T4O’s suppressive effects.Conclusion:These findings suggest that T4O’s antitumor activity in cSCC is mediated through the upregulation of calpain-2 expression and subsequent modulation ofβ-catenin and caspase-12.
文摘Antipsychotic(AP)medications are used to treat schizophrenia and a number off-label conditions.Although effective in reducing psychoses these drugs increase the risk of developing cardiometabolic disease,and are one of the reasons why individuals with schizophrenia live∼15–20 years less than the general population.While weight gain has traditionally been thought to be the primary culprit linked to increases in rates of cardiometabolic disease,there are weight-gain independent effects of antipsychotics.The purpose of the current review was to highlight the acute metabolic complications of antipsychotics and to address the question:are exercise and targeting“exercise-activated”signaling pathways,a viable approach to offset the metabolic complications of APs?The possibility of fibroblast growth factor 21 being a common factor mediating the protective effects of exercise and certain nutritional approaches against the acute metabolic complications of antipsychotics was also discussed.The research highlighted in this narrative review provides evidence,in preclinical models,that exercise and certain exercise-activated pathways,can protect against acute perturbations in glucose metabolism.While promising,further work is needed to confirm these findings in clinical populations prescribed antipsychotics.
基金This work was supported by the Focused Research Effort on Chemicals in the Working Environment(FFIKA)from the Danish Government.
文摘Background:Inhalation exposure is the gold standard when assessing pulmonary tox-icity.However,it typically requires substantial amounts of test material.Intratracheal instillation is an alternative administration technique,where the test substance is suspended in a liquid vehicle and deposited into the lung via the trachea.Instillation requires minimal test material,delivers an exact dose deep into the lung,and is less labor-intensive than inhalation exposures.However,one shortcoming is that the pro-cedure may induce short-term inflammation.To minimize this,we tested different modifications of the technique to identify the potential for refinement.Methods:First,we tested whether previous findings of increased inflammation could be confirmed.Next,we tested whether instillation with a disposable 1 mL syringe with ball-tipped steel-needle(Disposable-syringe/steel-needle)induced less inflammation than the use of our standard set-up,a 250μL reusable glass syringe with a disposable plastic catheter(Glass-syringe/plastic-catheter).Finally,we tested if access to pelleted and liquid feed prior to instillation affected inflammation.We evaluated inflammation by neutrophil numbers in bronchoalveolar fluid 24 h post-exposure.Results:Vehicle-instilled mice showed a small increase in neutrophil numbers com-pared to untreated mice.Neutrophil numbers were slightly elevated in the groups in-stilled with Disposable-syringe/steel-needle;an interaction with feed type indicated that the increase in neutrophils was more pronounced in combination with feed pel-lets compared to liquid feed.We found no difference between the feed types when using the Glass-syringe/plastic-catheter combination.Conclusion:The Glass-syringe/plastic-catheter combination induced the least exposure-related inflammation,confirming this as a preferred instillation procedure.
基金Supported by the European Union,the Romanian Government and the Health Program(Medical Applications of High-Power Lasers-Dr.LASER),cod MySMIS2021/SMIS2021+326475.
文摘Colorectal cancer is the third most diagnosed malignancy and the second-leading cause of cancer-related deaths worldwide.Management includes a combination of surgery,radiotherapy,and systemic therapy that is tailored to the stage of the disease.However,each tumor has a unique genetic profile that influences the treatment response and the overall prognosis.Biomarkers guide treatment decisions,but many chemotherapeutics lack reliable predictors.To bridge this gap patient-derived xenograft models were developed and are valuable preclinical tools.These systems utilize patient-derived tumor tissue grafted into an animal host that provides a platform for personalized drug profiling.This article surveyed recent advances in mouse and zebrafish colorectal cancer patient-derived xenografts,emphasizing their clinical utility for functional precision oncology.We explored the impact of these models on translational research,discussed current limitations,and outlined key priorities for future development.
基金supported by the National Key Research and Development Program of China(2021YFF0702201,2021YFF0702204)Natural Science Foundation of Guangdong Province(2022A1515012651)。
文摘Tauopathies represent a class of neurodegenerative diseases(NDs),including Alzheimer’s disease(AD),progressive supranuclear palsy(PSP),Pick’s disease(PiD),and corticobasal degeneration(CBD),defined by intracellular accumulation of misfolded and hyperphosphorylated tau protein.The pathogenic cascade involves hyperphosphorylation,conformational changes,and aggregation into neurofibrillary tangles(NFTs),which are spatially and functionally linked to neuronal dysfunction,synaptic loss,and progressive cognitive and motor decline.To elucidate tau-mediated mechanisms,diverse transgenic rodent models expressing wild-type or mutant forms of human TAU have been generated.Although these models have advanced understanding of tau aggregation and propagation,tau-targeting therapies have failed to produce clinical benefits,raising concerns about the precise mechanism underlying tauopathies and the fidelity of animal models in evaluating therapeutic targets.This review systematically examines the neuropathological and behavioral phenotypes across established rodent and non-human primate(NHP)tauopathy models,highlighting mechanistic insights into tau-driven pathology.The advantages,limitations,and translational barriers of each model are critically evaluated to inform the development of more predictive preclinical platforms for therapeutic discovery.
基金financially supported by the National Key Research and Development Program of China(No.2023YFD1800403 and 2023YFD1800404)。
文摘Monkeypox virus(MPXV),a member of the Orthopoxvirus genus,caused a large-scale global outbreak in 2022.Developing mouse models for MPXV infection is crucial for advancing research on vaccines and therapeutic interventions.To address this,we conducted a comparative study on the susceptibility of six mouse strains—severe combined immune-deficiency(SCID),nude,genetically diabetic(db/db)and obese(ob/ob),C57BL/6J,and BALB/c—to MPXV infection.Mouse strains were infected with MPXV via intranasal inoculation,and body weight changes and mortality were monitored post-infection.Additionally,the tissue distribution of MPXV and the pathological changes in the lung tissues of the infected mice were evaluated.The results demonstrated that SCID and nude mice exhibited significant weight loss following MPXV infection,with 100%mortality observed in SCID mice,while no mortality occurred in nude mice.In contrast,the other mouse strains showed no significant weight loss or mortality.Notably,the viral load in the lung tissues of SCID and nude mice was the highest among the tested strains.Furthermore,we investigated the impact of different inoculation routes—intranasal(I.N.),intraperitoneal(I.P.),and intravenous(I.V.)—on the pathogenicity of MPXV in mice.The results revealed that the intravenous route induced more pronounced pathogenic effects compared to the intranasal and intraperitoneal routes.In summary,this study provides valuable insights into the development of MPXV-infected mouse models,offering a foundation for further research on MPXV pathogenesis and therapeutic drug development.
基金funded by the TCM Spleen and Stomach Discipline Leader Project of High-level Talents in Yunnan Province (no grant number)TCM Joint Project of Yunnan Provincial Science and Technology Department (grant number 202101AZ070001-209).
文摘Background:This study investigated the impacts and mechanisms of yunweiling in the management of Functional Constipation(FC)using network pharmacology and experimental research.Methods:Using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),Genecard,and Online Mendelian Inheritance in Man(OMIM)databases,a potential gene target for yunweiling in treating FC was found.A pharmacological network was built and viewed in Cytoscape.A protein interac-tion map was created with STRING and Cytoscape.‘clusterProfiler’helped uncover its mechanism.Molecular docking was done with AutoDock Vina.In a constipation mouse model,Western blot was used to assess yunweiling's effectiveness.Results:To investigate yunweiling's therapeutic effects on FC,we employed a loperamide-induced constipation model.Successful model establishment was con-firmed by first black stool time,reduced stool output,and impaired gastrointestinal motility.Yunweiling treatment,especially at high and medium doses,significantly al-leviated constipation symptoms by reducing first black stool time,increasing stool output,and enhancing gastrointestinal motility.HE staining revealed yunweiling's ability to restore colon tissue structure.Yunweiling modulated the expression of key proteins TP53,P-AKT,P-PI3K,RET,and Rai,implicating its involvement in the PI3K-Akt signaling pathway.Comparative analysis showed yunweiling to be more effective than its individual components(shionone,β-sitosterol,and daucosterol)in improving constipation.The combination of yunweiling with TP53 and PI3K-Akt inhibitors fur-ther enhanced its therapeutic effects,suggesting a synergistic mechanism.Conclusions:The integration of network pharmacology and experimental investiga-tions indicated the effectiveness of yunweiling in managing FC,offering essential theoretical support for clinical application.
基金CAMS Innovation Fund for Medical Sciences,Grant/Award Number:CIFMS,2021-I2M-1-024The Joint Fund for the Department of Science and Technology of Yunnan Province-Kunming Medical University,Grant/Award Number:202201AY070001-007+1 种基金Open Research Fund Project of Yunnan Provincial Key Laboratory of Pharmacology of Natural Medicines,Grant/Award Number:YKLPNP-G2403The Science and Technology Leading Talent Program of Yunnan Province,Grant/Award Number:202405AB350002。
文摘Background:Spinocerebellar ataxia type 2(SCA2)is a neurodegenerative disease marked by significant clinical and genetic heterogeneity,primarily caused by expanded CAG mutations in the ATXN2 gene.The unstable expansion of CAG repeats disrupts the genetic stability of animal models,which is detrimental to disease research.Methods:In this study,we established a mouse model in which CAG repeats do not undergo microsatellite instability(MSI)across generations.A humanized ATXN2 cDNA with four CAA interruptions within 73 CAG expansions was inserted into the Rosa26 locus of C57BL/6J mice.A 23 CAG control mouse model was also generated to verify ATXN2 integration and expression.Results:In our model,the number of CAG repeats remained stable during transmission,with no CAG repeat expansion observed in 64 parent-to-offspring transmissions.Compared with SCA2-Q23 mice,SCA2-Q73 mice exhibited progressive motor impairment,reduced Purkinje cell count and volume(indicative of cell atrophy),and muscle atrophy.These observations in the mice suggest that the behavioral and neuropathological phenotypes may reflect the features of SCA2 patients.RNA-seq analysis of the gastrocnemius muscle in SCA2-Q73 mice showed significant changes in muscle differentiation and development gene expression at 56 weeks,with no significant differences at 16 weeks compared to SCA2-Q23 mice.The expression level of the Myf6 gene significantly changed in the muscles of aged mice.Conclusion:In summary,the establishment of this model not only provides a stable animal model for studying CAG transmission in SCA2 but also indicates that the lack of long-term neural stimulation leads to muscle atrophy.
