BACKGROUND Epilepsy impacts millions of people,with many not responding to existing treatments.Some evidence links neuroinflammatory processes to epilepsy.Statins exhibit anti-inflammatory and neuroprotective properti...BACKGROUND Epilepsy impacts millions of people,with many not responding to existing treatments.Some evidence links neuroinflammatory processes to epilepsy.Statins exhibit anti-inflammatory and neuroprotective properties,potentially offering antiepileptic effects.AIM To evaluate the anticonvulsant effects of rosuvastatin in animal models of epilepsy.METHODS Ninety-six albino mice were divided into 16 groups.In the maximal electroshock seizure(MES)model,eight groups received intraperitoneal vehicle,carbama-zepine,rosuvastatin,or a combination.Outcomes measured included seizure protection[tonic hind limb extension(THLE)],duration of THLE,seizure duration,and mortality.In the pentylenetetrazol(PTZ)model,eight groups were pretreated with vehicle,valproate,rosuvastatin,or a combination,with outcomes measured as seizure latency,seizure duration,and mortality.RESULTS In the MES model,rosuvastatin exhibited protection against THLE in a small percentage of mice.Rosuvastatin shortens the duration of THLE in a dose-dependent manner.However,none of these were statistically significant com-pared to the control group.The combination of rosuvastatin 10 mg/kg with carbamazepine 4 mg/kg resulted in a significant reduction in seizure duration compared to the control group,better than carbamazepine alone at 4 mg/kg and 6 mg/kg.In the PTZ model,rosuvastatin alone showed no significant effects on latency,duration of seizure,or mortality.However,rosuvastatin 10 mg/kg combined with valproate 100 mg/kg significantly delayed the onset of seizures,seizure duration and mortality percentage,better than valproate alone at 100 mg/kg.CONCLUSION Rosuvastatin enhanced the anticonvulsant effects of carbamazepine and valproate.Further studies are required to explore the antiepileptic potential of rosuvastatin at various doses,durations,dosage forms,routes and models.展开更多
BACKGROUND Syngeneic orthotopic tumor models offer an optimal functional tumor–immune interface for hepatocellular carcinoma research.Yet,unpredictable growth kinetics and spontaneous regression pose major obstacles....BACKGROUND Syngeneic orthotopic tumor models offer an optimal functional tumor–immune interface for hepatocellular carcinoma research.Yet,unpredictable growth kinetics and spontaneous regression pose major obstacles.Efficient induction protocols and continuous monitoring are therefore essential.Routine exploratory surgeries are ethically untenable,making non-invasive imaging modalities attractive alternatives.High-resolution magnetic resonance imaging and microcomputed tomography deliver detailed insights but incur substantial equipment costs,radiation risks,time demands,and require specialized expertise—challenges that limit their routine use.In contrast,ultrasound(US)imaging emerges as a cost-effective,radiation-free,and rapid approach,facilitating practical and ethical longitudinal assessment of tumor progression in preclinical studies.AIM To optimize the orthotopic hepatocellular carcinoma model and evaluate the potential of US imaging for accurate and cost-effective tumor monitoring.METHODS Hepatocellular carcinoma was induced in 28 Sprague Dawley rats by implanting 5×10^(6) N1S1 cells into the left lateral hepatic lobe.Tumor progression was monitored weekly via US.Upon reaching 100-150 mm^(3),an experimental group(n=14)received Sorafenib(40 mg/kg)orally on alternate days for 28 days;efficacy was compared to untreated controls.US accuracy was validated against micro-computed tomography,gross caliper measurements and histopathological analysis.Reliability and operator proficiency in US assessment were also evaluated.RESULTS US images procured 7-day post-surgery revealed a well-defined hypoechoic nodule at the left liver lobe tip,confirming successful tumor induction(mean volume 130±39 mm^(3)).Only three animals exhibited spontaneous regression by week 2,underscoring the model’s stability.Sorafenib treatment elicited a marked tumor reduction(678±103 mm^(3))vs untreated control(6005±1760 mm^(3)).US assessment demonstrated robust intra and interobserver reproducibility with high sensitivity and specificity for tumor detection.Moreover,US derived volumes correlated strongly with gross caliper measurements,histopathological analysis,and microcomputed tomography imaging,validating its reliability as a non-invasive monitoring tool in preclinical hepatocellular carcinoma studies.CONCLUSION The results demonstrate that US imaging is a reliable,cost-effective,and animal sparing approach with an easy tomaster protocol,enabling monitoring of tumor progression and therapeutic response in orthotopic liver tumor models.展开更多
Celiac disease(CD)is a systemic autoimmune disorder triggered by gluten ingestion ingenetically predisposed individuals.It is characterized by intestinal histological damage and the production of specific autoantibodi...Celiac disease(CD)is a systemic autoimmune disorder triggered by gluten ingestion ingenetically predisposed individuals.It is characterized by intestinal histological damage and the production of specific autoantibodies.The latest European Society for Paediatric Gastroenterology,Hepatology,and Nutrition(ESPGHAN)2020 guidelines have excluded human leukocyte antigen(HLA)genotyping from the no-biopsy diagnostic approach due to its weak positive predictive value,limited availability,and high cost in some countries.However,HLA genetic testing remains valuable in certain clinical contexts.This study provided practical indications for when to request and how to interpret HLA genotyping,emphasizing its continued relevance for CD diagnosis in specific cases.We also proposed a strategy for monitoring the risk of developing type 1 diabetes(T1D)in patients with CD,based on the risk stratification carried by different HLA genotypes.A retrospective analysis of 746 patients with CD and 627 controls was conducted at our hospital starting in2012,when HLA genotyping became mandatory for the diagnosis of CD.We identified key clinical scenarios where HLA testing remains useful.Several high risk HLA-DQ genotypes strongly associated with CD were highlighted,including HLA-DQ2.5/HLA-DQ2.2and HLA-DQ2.5/HLA-DQ2.5.Notably,while the HLA-DQ2.5/HLA-DQ2.2 genotype is linked to CD,it appears to confer protection against T1D.To support clinical practice,we presented a table clarifying commonly used HLA terminology,and another summarized the main clinical situations in which HLAgenotyping should still be considered.These findings underscore the dual role of HLA testing:Not only can it help rule out CD in selected cases,but it also identifies patients with CD at risk for T1D,guiding personalized monitoring strategies.展开更多
Being widespread across the globe,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)keeps evolving and generating new variants and continuously poses threat to public health,especially to the population with ...Being widespread across the globe,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)keeps evolving and generating new variants and continuously poses threat to public health,especially to the population with chronic comorbidities.Diabetes mellitus is one of high-risk factors for severe outcome of coronavirus disease 2019(COVID-19).Establishment of animal models that parallel the clinical and pathological features of COVID-19 complicated with diabetes is thus highly essential.Here,in this study,we constructed leptin receptor gene knockout hamsters with the phenotype of diabetes mellitus(db/db),and revealed that the diabetic hamsters were more susceptible to SARS-CoV-2 and its variants than wild-type hamsters.SARS-CoV-2 and its variants induced a stronger immune cytokine response in the lungs of diabetic hamsters than in wild-type hamsters.Comparative histopathology analyses also showed that infection of SARS-CoV-2 and the variants caused more severe lung tissue injury in diabetic hamsters,and may induce serious complications such as diabetic kidney disease and cardiac lesions.Our findings demonstrated that despite the decreased respiratory pathogenicity,the SARS-CoV-2 variants were still capable of impairing other organs such as kidney and heart in diabetic hamsters,suggesting that the risk of evolving SARS-CoV-2 variants to diabetic patients should never be neglected.This hamster model may help better understand the pathogenesis mechanism of severe COVID-19 in patients with diabetes.It will also aid in development and testing of effective therapeutics and prophylactic treatments against SARS-CoV-2 variants among these high-risk populations.展开更多
Exercise training is critical for the early prevention and treatment of obesity and diabetes mellitus.However,the mechanism with gut microbiota and fecal metabolites underlying the effects of voluntary wheel running o...Exercise training is critical for the early prevention and treatment of obesity and diabetes mellitus.However,the mechanism with gut microbiota and fecal metabolites underlying the effects of voluntary wheel running on high-fat diet induced abnormal glucose metabolism has not been fully elaborated.C57BL/6 male mice were randomly assigned to 4 groups according to diets(fed with normal chow diet or high-fat diet)and running paradigm(housed in static cage or with voluntary running wheel).An integrative 16S rDNA sequencing and metabolites profiling was synchronously performed to characterize the effects of voluntary wheel running on gut microbiota and metabolites.It showed that voluntary wheel running prevented the detrimental effects of high-fat feeding on glucose metabolism 16S rDNA sequencing showed remarkable changes in Rikenella and Marvinbryantia genera.Metabolic profiling indicated multiple altered metabolites,which were enriched in secondary bile acid biosynthesis signaling.In conclusion,our study indicated that voluntary wheel running significantly improved glucose metabolism and counteracted the deleterious effects of high-fat feeding on body weight and glucose intolerance.We further found that voluntary wheel running could integratively program gut microbiota composition and fecal metabolites changes,and may regulate muricholic acid metabolism and secondary bile acid biosynthesis in high-fat fed mice.展开更多
Background:Ginkgo flavone aglycones(GA),a Ginkgo(Ginkgo biloba)extract,has been proven to have good biological activity in atherosclerosis(AS)treatment.Moreover,its active compounds and the corresponding mechanism for...Background:Ginkgo flavone aglycones(GA),a Ginkgo(Ginkgo biloba)extract,has been proven to have good biological activity in atherosclerosis(AS)treatment.Moreover,its active compounds and the corresponding mechanism for the treatment of AS remain unclear.Methods:To evaluate and identify the potential pharmacological mechanisms of GA in AS treatment,the program Cytoscape was used to generate network mappings of the GA-AS-potential target gene.GO and KEGG enrichment analyses were performed to further investigate the potential mechanism of AS and the pharmacological properties of GA.A molecular docking approach was utilized to determine the GA components that interact with Akt.In vitro experiments were carried out to identify the anti-atherosclerotic effects of GA by targeting Akt.Results:Network pharmacological research determined that the active components of GA(quercetin,kaempferol,and isorhamnetin)correlated with AS target genes such as AKT1,EGFR,SRC,ESR1,PTGS2,MMP9,KDR,GSK3B,APP,and MMP2,respectively.GO enrichment and KEGG analysis showed that PI3K-Akt signaling may play an important role in GA treatment.Molecular docking experiments indicated that quercetin,kaempferol,and isorhamnetin integrate into the binding pockets of the most potentially beneficial GA-AS target protein(Akt).Consequently,cell experiments were conducted to support the anti-atherosclerotic activity of GA on AS by inhibiting the phosphorylation of AKT1 and its downstream signaling molecules,which regulated the proliferation of HASMCs.Conclusion:Our results detailed GA's active ingredients,potential targets,and molecular basis against AS.GA may exert anti-atherosclerotic effects by suppressing Akt phosphorylation and inhibiting the proliferation of HASMCs.It also proposed a viable approach to determining the scientific foundation and therapeutic mechanism of Chinese herbal medicine extracts in disease therapy.展开更多
Background: We currently have international and national guidelines regarding the assessment and monitoring of clinical signs and humane endpoints in animals used in teaching and research, which make the performance o...Background: We currently have international and national guidelines regarding the assessment and monitoring of clinical signs and humane endpoints in animals used in teaching and research, which make the performance of these activities mandatory for any experiment and professional working in this area. Assigning the severity of a research experiment is the result of an analysis of records of observations of the animal’s behavior, and clinical signs. The aim of this study was to describe the importance of carrying out a severity assessment associated with clinical and behavioral monitoring of rodents and rabbits during experimentation to maintain the welfare of these animals undergoing scientific research. Methods: The literature search was carried out using the following terms: “Monitoring”;“Humane endpoints”;“Animal welfare”, “Rodents”;“Rabbits”, and as connectors “and”;“or”, in the following databases: PubMed;LILACS/BIREME and SciELO. Results: A total of 987 articles were identified in the databases, and 20 of these studies were included in this review. Conclusions: Humane endpoint protocols and procedure severity tables are of the utmost importance, both from an ethical point and to refine the results of research conducted on laboratory animals. They should be drawn up jointly by the teams responsible for the project and the maintenance of the animals during the research period, and the data obtained should be published so that the scientific community can have access to it, helping to disseminate these practices, as well as helping to draw up new procedures. Monitoring and evaluating the welfare and clinical condition of animals undergoing scientific research procedures is the responsibility of the professors, researchers, veterinarians, and animal facility coordinators. The Ethics Committee on the Use of Animals must monitor all the activities conducted with the animals, by inspecting the experimental procedures and the physical environment of the laboratory animal facility where the animals are housed.展开更多
BACKGROUND Superimposed high-frequency jet ventilation(SHFJV)is suitable for respiratory motion reduction and essential for effective lung tumor ablation.Fluid filling of the target lung wing one-lung flooding(OLF)is ...BACKGROUND Superimposed high-frequency jet ventilation(SHFJV)is suitable for respiratory motion reduction and essential for effective lung tumor ablation.Fluid filling of the target lung wing one-lung flooding(OLF)is necessary for therapeutic ultrasound applications.However,whether unilateral SHFJV allows adequate hemodynamics and gas exchange is unclear.AIM To compared SHFJV with pressure-controlled ventilation(PCV)during OLF by assessing hemodynamics and gas exchange in different animal positions.METHODS SHFJV or PCV was used alternatingly to ventilate the non-flooded lungs of the 12 anesthetized pigs during OLF.The animal positions were changed from left lateral position to supine position(SP)to right lateral position(RLP)every 30 min.In each position,ventilation was maintained for 15 min in both modalities.Hemodynamic variables and arterial blood gas levels were repeatedly measured.RESULTS Unilateral SHFJV led to lower carbon dioxide removal than PCV without abnormally elevated carbon dioxide levels.SHFJV slightly decreased oxygenation in SP and RLP compared with PCV;the lowest values of PaO_(2) and PaO_(2)/FiO_(2) ratio were found in SP[13.0;interquartile range(IQR):12.6-5.6 and 32.5(IQR:31.5-38.9)kPa].Conversely,during SHFJV,the shunt fraction was higher in all animal positions(highest in the RLP:0.30).CONCLUSION In porcine model,unilateral SHFJV may provide adequate ventilation in different animal positions during OLF.Lower oxygenation and CO_(2) removal rates compared to PCV did not lead to hypoxia or hypercapnia.SHFJV can be safely used for lung tumor ablation to minimize ventilation-induced lung motion.展开更多
Chronic pancreatitis (CP) is a progressive inflammatory disorder of the pancreas. It is predominantly idiopathic (with an unknown cause) in India and mostly due to alcohol in the West. Diabetes that occur secondary to...Chronic pancreatitis (CP) is a progressive inflammatory disorder of the pancreas. It is predominantly idiopathic (with an unknown cause) in India and mostly due to alcohol in the West. Diabetes that occur secondary to chronic pancreatitis (T3c Diabetes) is often brittle, and is difficult to attain normoglycemia with conventional treatment requiring multiple doses of insulin. Mild and severe model of CP was induced in mice by repeated intraperitoneal injections of cerulein and L-arginine respectively with an intent to study islet dysfunction and develop therapeutic strategy in animal models of CP. Dietary intervention of epigallocatechin-3-gallate (EGCG) was tested in both the models of CP for its beneficial effects on insulin secretory functions. Pancreata collected upon euthanasia were used to study alterations in the morphology of pancreatic parenchyma and inflammation by staining with H&E and fibrotic changes by Masson’s trichrome and picrosirius staining. Insulin secretory functions of islets were evaluated to test the efficacy of the dietary intervention on β-cell functions. Intraperitoneal glucose tolerance test was performed to monitor the glucose homeostasis before and after the dietary intervention. Both the models resulted in CP with dispersed acini, inflammation and fibrosis. The loss of acini and extent of fibrosis was more in L-arginine model. 2-fold improvement in glucose-stimulated insulin secretory functions of islets was observed with 0.5% EGCG dietary intervention in cerulein model of CP and 1.6-fold in L-arginine model of CP. A further improvement in insulin secretion by 3.2-fold was observed with additional dietary supplements like N-acetyl cysteine, curcumin in combination with EGCG. Our results thus demonstrate and highlight the therapeutic potential of dietary green tea (EGCG) supplementation in reversing islet dysfunction and improving glucose homeostasis in experimental chronic pancreatitis in mice.展开更多
Nonalcoholic fatty liver disease(NAFLD) is associated with obesity,insulin resistance,and type 2 diabetes.NAFLD represents a large spectrum of diseases ranging from(1) fatty liver(hepatic steatosis);(2) steatosis with...Nonalcoholic fatty liver disease(NAFLD) is associated with obesity,insulin resistance,and type 2 diabetes.NAFLD represents a large spectrum of diseases ranging from(1) fatty liver(hepatic steatosis);(2) steatosis with inflammation and necrosis;to(3) cirrhosis.The animal models to study NAFLD/nonalcoholic steatohepatitis(NASH) are extremely useful,as there are still many events to be elucidated in the pathology of NASH.The study of the established animal models has provided many clues in the pathogenesis of steatosis and steatohepatitis,but these remain incompletely understood.The different mouse models can be classified in two large groups.The first one includes genetically modified(transgenic or knockout) mice that spontaneously develop liver disease,and the second one includes mice that acquire the disease after dietary or pharmacological manipulation.Although the molecular mechanism leading to the development of hepatic steatosis in the pathogenesis of NAFLD is complex,genetically modified animal models may be a key for the treatment of NAFLD.Ideal animal models for NASH should closely resemble the pathological characteristics observed in humans.To date,no single animal model has encompassed the full spectrum of human disease progression,but they can imitate particular characteristics of human disease.Therefore,it is important that the researchers choose the appropriate animal model.This review discusses various genetically modified animal models developed and used in research on NAFLD.展开更多
Recurrent oral ulcer is a painful oral mucosal disorder that affects 20%of the world’s population.The lack of a radical cure due to its unknown underlying cause calls for innovative symptomatic treatments.This work r...Recurrent oral ulcer is a painful oral mucosal disorder that affects 20%of the world’s population.The lack of a radical cure due to its unknown underlying cause calls for innovative symptomatic treatments.This work reports a hyaluronic acid-based dissolvablemicroneedle patch(ROUMNpatch,short for recurrent oral ulcer microneedle)loaded with dexamethasone acetate,vitamin C and tetracaine hydrochloride for the treatment of recurrent oral ulcers.The ROUMN patch shows enhancement in both the anti-inflammatory effect elicited by dexamethasone and the pro-proliferation effect of vitamin C.In vitro experiments show that ROUMN has a higher efficiency in suppressing lipopolysaccharide(LPS)-induced interleukin-6(IL-6)expression than dexamethasone alone.Cell proliferation and migrationwere also significantly promoted byROUMNcompared to vitamin C alone.The healing-promoting effect of ROUMN was also verified in vivo using an acetic acid-cauterized oral ulcer model in rats.ROUMN as a treatment accelerated the healing process of oral ulcers,shortening the total healing time to 5 days compared with the 7 days required by treatment using watermelon frost,a commonly used over-the-counter(OTC)drug for oral ulcers.The rapid dissolution of the hyaluronic acid-based microneedles and the superior healing-promoting effect of the drug combination could lead to a broad application prospect of the ROUMN patch in the treatment of recurrent oral ulcers.展开更多
99mTc-Methylene diphosphonate （99mTc-MDP） is widely used in clinical settings to detect bone abnormalities. However, the mechanism of 99mTc-MDP uptake in bone is not well elucidated. In this study, we utilized a mou...99mTc-Methylene diphosphonate （99mTc-MDP） is widely used in clinical settings to detect bone abnormalities. However, the mechanism of 99mTc-MDP uptake in bone is not well elucidated. In this study, we utilized a mouse tibia injury model, single-photon emission computed tomography （gamma scintigraphy or SPECT）, ex vivo micro-computed tomography, and histology to monitor 99mTc-MDP uptake in injury sites during skeletal healing. In an ex vivo culture system, calvarial cells were differentiated into osteoblasts with osteogenic medium, pulsed with 99mTc-MDP at different time points, and quantitated for 99mTc-MDP uptake with a gamma counter. We demonstrated that 99mTc-MDP uptake in the injury sites corresponded to osteoblast generation in those sites throughout the healing process. The 99mTc-MDP uptake within the injury sites peaked on day 7 post-injury, while the injury sites were occupied by mature osteoblasts also starting from day 7. ~mTc-MDP uptake started to decrease 14 days post-surgery, when we observed the highest level of bony tissue in the injury sites. We also found that 99mTc-MDP uptake was associated with osteoblast maturation and mineralization in vitro. This study provides direct and biological evidence for 99mTc-MDP uptake in osteoblasts during bone healing in vivo and in vitro.展开更多
AIM： To investigate ASCA production over time in CD and murine colitis in order to further our understanding of their etiology. MATERIALS AND METHODS： Sixty-six CD patients were compared to ulcerative colitis （UC）...AIM： To investigate ASCA production over time in CD and murine colitis in order to further our understanding of their etiology. MATERIALS AND METHODS： Sixty-six CD patients were compared to ulcerative colitis （UC） and irritable bowel syndrome patients with respect to ASCA production as measured by ELISA. ASCA IgG or IgA positivity as well as change in titers over a period of up to 3 years （△tgG/A） was correlated with clinical parameters such as CD activity index （CDM） and C-reactive protein levels （CRP）. Moreover, two murine models of colitis （DSS and IL-10 knock out） were compared to control animals with respect to ASCA titers after oral yeast exposure. RESULTS： ASCA IgG and IgA titers are stable over time in CD and non-CD patients. Fistular disease was associated with a higher rate of ASCA IgA positivity （P = 0.014）. Ileal disease was found to have a significant influence on the △tgG of ASCA （P = 0.032）. There was no correlation found between ASCA positivity or △tgG/A and clinical parameters of CD： CDAI and CRP. In mice, neither healthy animals nor animals with DSS-induced or spontaneous colitis exhibited a marked increase in ASCA titers after high-dose yeast exposure. On the other hand, mice immunized intraperitoneally with mannan plus adjuvant showed a marked and significant increase in ASCA titers compared to adjuvant-only immunized controls （P = 0.014）. CONCLUSION： The propensity to produce ASCA in a subgroup of CD patients is largely genetically predetermined as evidenced by their stability and lack of correlation with clinical disease activity parameters. Furthermore, in animal models of colitis, mere oral exposure of mice to yeast does not lead to the induction of marked ASCA titers irrespective of concomitant colonic inflammation. Hence, environment may play only a minor role in inducing ASCA.展开更多
Adriamycin(doxorubicin),a common cancer chemotherapeutic drug,can be used to induce a model of chronic progressive glomerular disease in rodents.In our studies,we evahuated renal changes in a rat model after Adriamydi...Adriamycin(doxorubicin),a common cancer chemotherapeutic drug,can be used to induce a model of chronic progressive glomerular disease in rodents.In our studies,we evahuated renal changes in a rat model after Adriamydin injection using two photon microscopy(TPM),optical coherence tomography(OCT)and Doppler OCT(DOCT).Taking advantage of deep penetra-tion and fast scanning speed for three dimensional(3D)label-free imaging,OCT/DOCT system was able to reveal glomerular and tubular pathology noninvasively and in real time.By imaging renal pathology following the infusion of fAuorophore-labeled dextrans of different molecular weights,TPM can provide direct views of glomerular and tubular flow dynamics with the onset and progression of renal disease.Specifically,glomerular permeability and filtration,proximal and distal tubular flow dynamics can be revealed.6-8 weeks after injection of Adriamycin,TPM and OCT/DOCT imaging revealed glomerular sclerosis,compromised flow across the glomerular wall,tubular atrophy,tubular dilation,and variable intra-tubular flow dynamics.Our results indicate that TPM and OCT/DOCT provide real-time imaging of renal pathology in vivo that has not been previously available using conventional microscopic procedures.展开更多
BACKGROUND The prognosis of gastric cancer continues to remain poor,and epigenetic drugs like histone deacetylase inhibitors(HDACi)have been envisaged as potential therapeutic agents.Nevertheless,clinical trials are f...BACKGROUND The prognosis of gastric cancer continues to remain poor,and epigenetic drugs like histone deacetylase inhibitors(HDACi)have been envisaged as potential therapeutic agents.Nevertheless,clinical trials are facing issues with toxicity and efficacy against solid tumors,which may be partly due to the lack of patient stratification for effective treatments.To study the need of patient stratification before HDACi treatment,and the efficacy of pre-treatment of HDACi as a chemotherapeutic drug sensitizer.METHODS The expression activity of class 1 HDACs and histone acetylation was examined in human gastric cancer cells and tissues.The potential combinatorial regime of HDACi and chemotherapy drugs was defined on the basis of observed drug binding assays,chromatin remodeling and cell death.RESULTS In the present study,the data suggest that the differential increase in HDAC activity and the expression of class 1 HDACs are associated with hypoacetylation of histone proteins in tumors compared to normal adjacent mucosa tissue samples of gastric cancer.The data highlights for the first time that pretreatment of HDACi results in an increased amount of DNA-bound drugs associated with enhanced histone acetylation,chromatin relaxation and cell cycle arrest.Fraction-affected plots and combination index-based analysis show that pre-HDACi chemo drug combinatorial regimes,including valproic acid with cisplatin or oxaliplatin and trichostatin A with epirubicin,exhibit synergism with maximum cytotoxic potential due to higher cell death at low combined doses in gastric cancer cell lines.CONCLUSION Expression or activity of class 1 HDACs among gastric cancer patients present an effective approach for patient stratification.Furthermore,HDACi therapy in pretreatment regimes is more effective with chemotherapy drugs,and may aid in predicting individual patient prognosis.展开更多
AIM:To study,in intact male transgenic mice,the effects of three diets based on olive oil and olive oil diet supplemented with lovastatin and orlistat on hepatic lipogenic enzymes expression,considered markers of cell...AIM:To study,in intact male transgenic mice,the effects of three diets based on olive oil and olive oil diet supplemented with lovastatin and orlistat on hepatic lipogenic enzymes expression,considered markers of cell proliferation.METHODS:Forty ApcMin/+mice were randomly divided into 4 groups and fed for 10 wk:olive oil(OO)group,n=10 animals received a diet with olive oil 12%;olive oil plus lovastatin(LOVA)group,n=10 animals received the same diet with olive oil supplemented with lovastatin 5 mg/kg;olive oil plus orlistat(OR)group,n=10 animals fed the diet with olive oil supplemented with orlistat 50 mg/kg and SD group,n=10 animals fed a standard diet.The activity of lipogenic enzymes and their gene expression were evaluated by radiomet-ric and real-time reverse transcription-polymerase chain reaction assay,respectively.RESULTS:After 10 wk of dietary treatment,the body weight was no different among animal groups(21.3±3.1 g for standard group,22.1±3.6 g for OO group,22.0±3.2 g for LOVA group and 20.7±3.4 g for OR group,data expressed as mean±SD),observing a generalized well-being in all animals.All the dietary managed treated groups presented significantly reduced hepatic levels of fatty acid synthase,farnesyl pyrophosphate synthase and 3-hydroxyl-3-methyl-glutaryl CoA reductase activity and gene expression when compared with the mice fed the standard diet.To evaluate cell proliferation in the liver of treated mice,the levels of cyclin E mRNA have been measured,demonstrating a significant reduction of cyclin E gene expression in all treated groups.Evidence of reduced hepatic cell proliferation was present overall in OO group mice.CONCLUSION:We confirm the role of lipogenic enzymes as markers of cell proliferation,suggesting that appropriate dietary management alone or with drugs can be a feasible approach to counteract hepatic cell proliferation in mice.展开更多
Animal models are being developed for testing different vaccine candidates as well as testing of new antitubercular since a long time.Mice,guinea pigs and rabbits are animals which are frequently used.Though each mode...Animal models are being developed for testing different vaccine candidates as well as testing of new antitubercular since a long time.Mice,guinea pigs and rabbits are animals which are frequently used.Though each model has got its merits as well as demerits and each of them differ from human tuberculosis in one aspect or the other but none of the model completely mimics the human disease.Out of the different animal species, guinea pig model is one of the better models as it is very sensitive to M.tuberculosis infection but it has certain limitations like paucity of immunological reagents.However,it is the best model for tuberculosis research.展开更多
Microtubule-severing proteins(MTSPs),are a family of proteins which use adenosine triphosphate to sever microtubules.MTSPs have been shown to play an important role in multiple microtubule-involved cellular processes....Microtubule-severing proteins(MTSPs),are a family of proteins which use adenosine triphosphate to sever microtubules.MTSPs have been shown to play an important role in multiple microtubule-involved cellular processes.One member of this family,fidgetin(FIGN),is also involved in male fertility;however,no studies have explored its roles in female fertility.In this study,we found mouse fidgetin is rich within oocyte zona pellucida(ZP)and is the only MTSP member to do so.Fidgetin also appears to interact with all three ZP proteins.These findings prompted us to propose that fidgetin might prevent polyspermy.Results from in vitro maturation oocytes analysis showed that fidgetin knockdown did cause polyspermy.We then deleted all three fidgetin isoforms with CRISPR/Cas9 technologies;however,female mice remained healthy and with normal fertility.Of all mouse MTSPs,only the mRNA level of fidgetin-like 1(FIGNL1)significantly increased.Therefore,we assert that fidgetin-like 1 compensates fidgetin's roles in fidgetin knockout female mice.展开更多
Goats or sheep are the preferred animal model for the preclinical evaluation of cartilage repair techniques due to the similarity of the goat stifle joint to the human knee.The medial femoral condyle of the stifle joi...Goats or sheep are the preferred animal model for the preclinical evaluation of cartilage repair techniques due to the similarity of the goat stifle joint to the human knee.The medial femoral condyle of the stifle joint is the preferred site for the assessment of articular cartilage repair,as this is the primary location for this type of lesion in the human knee.Proper surgical exposure of the medial femoral condyle is paramount to obtain reproducible results without surgical error.When applying the standard human medial arthrotomy technique on the goat stifle joint,there are some key aspects to consider in order to prevent destabilization of the extensor apparatus and subsequent postoperative patellar dislocations with associated animal discomfort.This paper describes a modified surgical technique to approach the medial femoral condyle of the caprine stifle joint.The modified technique led to satisfactory exposure without postoperative incidence of patellar luxations and no long-term adverse effects on the joint.展开更多
文摘BACKGROUND Epilepsy impacts millions of people,with many not responding to existing treatments.Some evidence links neuroinflammatory processes to epilepsy.Statins exhibit anti-inflammatory and neuroprotective properties,potentially offering antiepileptic effects.AIM To evaluate the anticonvulsant effects of rosuvastatin in animal models of epilepsy.METHODS Ninety-six albino mice were divided into 16 groups.In the maximal electroshock seizure(MES)model,eight groups received intraperitoneal vehicle,carbama-zepine,rosuvastatin,or a combination.Outcomes measured included seizure protection[tonic hind limb extension(THLE)],duration of THLE,seizure duration,and mortality.In the pentylenetetrazol(PTZ)model,eight groups were pretreated with vehicle,valproate,rosuvastatin,or a combination,with outcomes measured as seizure latency,seizure duration,and mortality.RESULTS In the MES model,rosuvastatin exhibited protection against THLE in a small percentage of mice.Rosuvastatin shortens the duration of THLE in a dose-dependent manner.However,none of these were statistically significant com-pared to the control group.The combination of rosuvastatin 10 mg/kg with carbamazepine 4 mg/kg resulted in a significant reduction in seizure duration compared to the control group,better than carbamazepine alone at 4 mg/kg and 6 mg/kg.In the PTZ model,rosuvastatin alone showed no significant effects on latency,duration of seizure,or mortality.However,rosuvastatin 10 mg/kg combined with valproate 100 mg/kg significantly delayed the onset of seizures,seizure duration and mortality percentage,better than valproate alone at 100 mg/kg.CONCLUSION Rosuvastatin enhanced the anticonvulsant effects of carbamazepine and valproate.Further studies are required to explore the antiepileptic potential of rosuvastatin at various doses,durations,dosage forms,routes and models.
基金Supported by Amrita Vishwa Vidyapeetham Seed Grant,No.K-PHAR-24-722DST INSPIRE Fellowship,No.IF190226.
文摘BACKGROUND Syngeneic orthotopic tumor models offer an optimal functional tumor–immune interface for hepatocellular carcinoma research.Yet,unpredictable growth kinetics and spontaneous regression pose major obstacles.Efficient induction protocols and continuous monitoring are therefore essential.Routine exploratory surgeries are ethically untenable,making non-invasive imaging modalities attractive alternatives.High-resolution magnetic resonance imaging and microcomputed tomography deliver detailed insights but incur substantial equipment costs,radiation risks,time demands,and require specialized expertise—challenges that limit their routine use.In contrast,ultrasound(US)imaging emerges as a cost-effective,radiation-free,and rapid approach,facilitating practical and ethical longitudinal assessment of tumor progression in preclinical studies.AIM To optimize the orthotopic hepatocellular carcinoma model and evaluate the potential of US imaging for accurate and cost-effective tumor monitoring.METHODS Hepatocellular carcinoma was induced in 28 Sprague Dawley rats by implanting 5×10^(6) N1S1 cells into the left lateral hepatic lobe.Tumor progression was monitored weekly via US.Upon reaching 100-150 mm^(3),an experimental group(n=14)received Sorafenib(40 mg/kg)orally on alternate days for 28 days;efficacy was compared to untreated controls.US accuracy was validated against micro-computed tomography,gross caliper measurements and histopathological analysis.Reliability and operator proficiency in US assessment were also evaluated.RESULTS US images procured 7-day post-surgery revealed a well-defined hypoechoic nodule at the left liver lobe tip,confirming successful tumor induction(mean volume 130±39 mm^(3)).Only three animals exhibited spontaneous regression by week 2,underscoring the model’s stability.Sorafenib treatment elicited a marked tumor reduction(678±103 mm^(3))vs untreated control(6005±1760 mm^(3)).US assessment demonstrated robust intra and interobserver reproducibility with high sensitivity and specificity for tumor detection.Moreover,US derived volumes correlated strongly with gross caliper measurements,histopathological analysis,and microcomputed tomography imaging,validating its reliability as a non-invasive monitoring tool in preclinical hepatocellular carcinoma studies.CONCLUSION The results demonstrate that US imaging is a reliable,cost-effective,and animal sparing approach with an easy tomaster protocol,enabling monitoring of tumor progression and therapeutic response in orthotopic liver tumor models.
基金Supported by Fondazione di Sardegna,No.2020.2284.
文摘Celiac disease(CD)is a systemic autoimmune disorder triggered by gluten ingestion ingenetically predisposed individuals.It is characterized by intestinal histological damage and the production of specific autoantibodies.The latest European Society for Paediatric Gastroenterology,Hepatology,and Nutrition(ESPGHAN)2020 guidelines have excluded human leukocyte antigen(HLA)genotyping from the no-biopsy diagnostic approach due to its weak positive predictive value,limited availability,and high cost in some countries.However,HLA genetic testing remains valuable in certain clinical contexts.This study provided practical indications for when to request and how to interpret HLA genotyping,emphasizing its continued relevance for CD diagnosis in specific cases.We also proposed a strategy for monitoring the risk of developing type 1 diabetes(T1D)in patients with CD,based on the risk stratification carried by different HLA genotypes.A retrospective analysis of 746 patients with CD and 627 controls was conducted at our hospital starting in2012,when HLA genotyping became mandatory for the diagnosis of CD.We identified key clinical scenarios where HLA testing remains useful.Several high risk HLA-DQ genotypes strongly associated with CD were highlighted,including HLA-DQ2.5/HLA-DQ2.2and HLA-DQ2.5/HLA-DQ2.5.Notably,while the HLA-DQ2.5/HLA-DQ2.2 genotype is linked to CD,it appears to confer protection against T1D.To support clinical practice,we presented a table clarifying commonly used HLA terminology,and another summarized the main clinical situations in which HLAgenotyping should still be considered.These findings underscore the dual role of HLA testing:Not only can it help rule out CD in selected cases,but it also identifies patients with CD at risk for T1D,guiding personalized monitoring strategies.
基金supported by the National Natural Science Foundation of Jiangsu Province(BE20197310 to J-M.L.)the National Key R&D Program of China(2021YFF0702500 to J-M.L.and A-M.S.,and the Start-up Funding of Scientific Researches for Postdoc in Guangzhou,Guangdong Province to H-F.L.).
文摘Being widespread across the globe,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)keeps evolving and generating new variants and continuously poses threat to public health,especially to the population with chronic comorbidities.Diabetes mellitus is one of high-risk factors for severe outcome of coronavirus disease 2019(COVID-19).Establishment of animal models that parallel the clinical and pathological features of COVID-19 complicated with diabetes is thus highly essential.Here,in this study,we constructed leptin receptor gene knockout hamsters with the phenotype of diabetes mellitus(db/db),and revealed that the diabetic hamsters were more susceptible to SARS-CoV-2 and its variants than wild-type hamsters.SARS-CoV-2 and its variants induced a stronger immune cytokine response in the lungs of diabetic hamsters than in wild-type hamsters.Comparative histopathology analyses also showed that infection of SARS-CoV-2 and the variants caused more severe lung tissue injury in diabetic hamsters,and may induce serious complications such as diabetic kidney disease and cardiac lesions.Our findings demonstrated that despite the decreased respiratory pathogenicity,the SARS-CoV-2 variants were still capable of impairing other organs such as kidney and heart in diabetic hamsters,suggesting that the risk of evolving SARS-CoV-2 variants to diabetic patients should never be neglected.This hamster model may help better understand the pathogenesis mechanism of severe COVID-19 in patients with diabetes.It will also aid in development and testing of effective therapeutics and prophylactic treatments against SARS-CoV-2 variants among these high-risk populations.
基金sponsored by National Natural Science Foundation of China (81800703 and 81970701)Beijing Nova Program (Z201100006820117 and 20220484181)+7 种基金Beijing Municipal Natural Science Foundation (7184252 and 7214258)the Fundamental Research Funds for the Central Universitiesthe Fundamental Research Funds for the Central Universities (BMU2021MX013)Peking University Clinical Scientist Training Program (BMU2023PYJH022)China Endocrine and Metabolism Young Scientific Talent Research Project (2022-N-02-01)Peking University Medicine Seed Fund for Interdisciplinary ResearchChina Diabetes Young Scientific Talent Research ProjectBethune-Merck Diabetes Research Fund of Bethune Charitable Foundation (G2018030)。
文摘Exercise training is critical for the early prevention and treatment of obesity and diabetes mellitus.However,the mechanism with gut microbiota and fecal metabolites underlying the effects of voluntary wheel running on high-fat diet induced abnormal glucose metabolism has not been fully elaborated.C57BL/6 male mice were randomly assigned to 4 groups according to diets(fed with normal chow diet or high-fat diet)and running paradigm(housed in static cage or with voluntary running wheel).An integrative 16S rDNA sequencing and metabolites profiling was synchronously performed to characterize the effects of voluntary wheel running on gut microbiota and metabolites.It showed that voluntary wheel running prevented the detrimental effects of high-fat feeding on glucose metabolism 16S rDNA sequencing showed remarkable changes in Rikenella and Marvinbryantia genera.Metabolic profiling indicated multiple altered metabolites,which were enriched in secondary bile acid biosynthesis signaling.In conclusion,our study indicated that voluntary wheel running significantly improved glucose metabolism and counteracted the deleterious effects of high-fat feeding on body weight and glucose intolerance.We further found that voluntary wheel running could integratively program gut microbiota composition and fecal metabolites changes,and may regulate muricholic acid metabolism and secondary bile acid biosynthesis in high-fat fed mice.
基金supported by the Science and Technology Foundation of Basic Research Program of Guizhou Province([2023]General 371,[2020]1Y381)the Administration of Traditional Chinese Medicine of Guizhou Province(QZYY-2018-130)+3 种基金the project of Key Laboratory of Basic Pharmacology of Ministry of Education,Zunyi Medicial University(No.qianjiaoheKYzi[2022]395)the Cultivation Plan of the NSFC(National Natural Science Foundation of China)of the affiliated hospital of Guizhou Medical University(GYFYNSFC-2021-55,GYFYNSFC-2021-56)the Cultivation Plan of the NSFC(National Natural Science Foundation of China)of Guizhou Medical University(21NSFCP13)the Science and Technology Foundation of Health Commission of Guizhou Province(gzwkj 2022-221).
文摘Background:Ginkgo flavone aglycones(GA),a Ginkgo(Ginkgo biloba)extract,has been proven to have good biological activity in atherosclerosis(AS)treatment.Moreover,its active compounds and the corresponding mechanism for the treatment of AS remain unclear.Methods:To evaluate and identify the potential pharmacological mechanisms of GA in AS treatment,the program Cytoscape was used to generate network mappings of the GA-AS-potential target gene.GO and KEGG enrichment analyses were performed to further investigate the potential mechanism of AS and the pharmacological properties of GA.A molecular docking approach was utilized to determine the GA components that interact with Akt.In vitro experiments were carried out to identify the anti-atherosclerotic effects of GA by targeting Akt.Results:Network pharmacological research determined that the active components of GA(quercetin,kaempferol,and isorhamnetin)correlated with AS target genes such as AKT1,EGFR,SRC,ESR1,PTGS2,MMP9,KDR,GSK3B,APP,and MMP2,respectively.GO enrichment and KEGG analysis showed that PI3K-Akt signaling may play an important role in GA treatment.Molecular docking experiments indicated that quercetin,kaempferol,and isorhamnetin integrate into the binding pockets of the most potentially beneficial GA-AS target protein(Akt).Consequently,cell experiments were conducted to support the anti-atherosclerotic activity of GA on AS by inhibiting the phosphorylation of AKT1 and its downstream signaling molecules,which regulated the proliferation of HASMCs.Conclusion:Our results detailed GA's active ingredients,potential targets,and molecular basis against AS.GA may exert anti-atherosclerotic effects by suppressing Akt phosphorylation and inhibiting the proliferation of HASMCs.It also proposed a viable approach to determining the scientific foundation and therapeutic mechanism of Chinese herbal medicine extracts in disease therapy.
文摘Background: We currently have international and national guidelines regarding the assessment and monitoring of clinical signs and humane endpoints in animals used in teaching and research, which make the performance of these activities mandatory for any experiment and professional working in this area. Assigning the severity of a research experiment is the result of an analysis of records of observations of the animal’s behavior, and clinical signs. The aim of this study was to describe the importance of carrying out a severity assessment associated with clinical and behavioral monitoring of rodents and rabbits during experimentation to maintain the welfare of these animals undergoing scientific research. Methods: The literature search was carried out using the following terms: “Monitoring”;“Humane endpoints”;“Animal welfare”, “Rodents”;“Rabbits”, and as connectors “and”;“or”, in the following databases: PubMed;LILACS/BIREME and SciELO. Results: A total of 987 articles were identified in the databases, and 20 of these studies were included in this review. Conclusions: Humane endpoint protocols and procedure severity tables are of the utmost importance, both from an ethical point and to refine the results of research conducted on laboratory animals. They should be drawn up jointly by the teams responsible for the project and the maintenance of the animals during the research period, and the data obtained should be published so that the scientific community can have access to it, helping to disseminate these practices, as well as helping to draw up new procedures. Monitoring and evaluating the welfare and clinical condition of animals undergoing scientific research procedures is the responsibility of the professors, researchers, veterinarians, and animal facility coordinators. The Ethics Committee on the Use of Animals must monitor all the activities conducted with the animals, by inspecting the experimental procedures and the physical environment of the laboratory animal facility where the animals are housed.
文摘BACKGROUND Superimposed high-frequency jet ventilation(SHFJV)is suitable for respiratory motion reduction and essential for effective lung tumor ablation.Fluid filling of the target lung wing one-lung flooding(OLF)is necessary for therapeutic ultrasound applications.However,whether unilateral SHFJV allows adequate hemodynamics and gas exchange is unclear.AIM To compared SHFJV with pressure-controlled ventilation(PCV)during OLF by assessing hemodynamics and gas exchange in different animal positions.METHODS SHFJV or PCV was used alternatingly to ventilate the non-flooded lungs of the 12 anesthetized pigs during OLF.The animal positions were changed from left lateral position to supine position(SP)to right lateral position(RLP)every 30 min.In each position,ventilation was maintained for 15 min in both modalities.Hemodynamic variables and arterial blood gas levels were repeatedly measured.RESULTS Unilateral SHFJV led to lower carbon dioxide removal than PCV without abnormally elevated carbon dioxide levels.SHFJV slightly decreased oxygenation in SP and RLP compared with PCV;the lowest values of PaO_(2) and PaO_(2)/FiO_(2) ratio were found in SP[13.0;interquartile range(IQR):12.6-5.6 and 32.5(IQR:31.5-38.9)kPa].Conversely,during SHFJV,the shunt fraction was higher in all animal positions(highest in the RLP:0.30).CONCLUSION In porcine model,unilateral SHFJV may provide adequate ventilation in different animal positions during OLF.Lower oxygenation and CO_(2) removal rates compared to PCV did not lead to hypoxia or hypercapnia.SHFJV can be safely used for lung tumor ablation to minimize ventilation-induced lung motion.
文摘Chronic pancreatitis (CP) is a progressive inflammatory disorder of the pancreas. It is predominantly idiopathic (with an unknown cause) in India and mostly due to alcohol in the West. Diabetes that occur secondary to chronic pancreatitis (T3c Diabetes) is often brittle, and is difficult to attain normoglycemia with conventional treatment requiring multiple doses of insulin. Mild and severe model of CP was induced in mice by repeated intraperitoneal injections of cerulein and L-arginine respectively with an intent to study islet dysfunction and develop therapeutic strategy in animal models of CP. Dietary intervention of epigallocatechin-3-gallate (EGCG) was tested in both the models of CP for its beneficial effects on insulin secretory functions. Pancreata collected upon euthanasia were used to study alterations in the morphology of pancreatic parenchyma and inflammation by staining with H&E and fibrotic changes by Masson’s trichrome and picrosirius staining. Insulin secretory functions of islets were evaluated to test the efficacy of the dietary intervention on β-cell functions. Intraperitoneal glucose tolerance test was performed to monitor the glucose homeostasis before and after the dietary intervention. Both the models resulted in CP with dispersed acini, inflammation and fibrosis. The loss of acini and extent of fibrosis was more in L-arginine model. 2-fold improvement in glucose-stimulated insulin secretory functions of islets was observed with 0.5% EGCG dietary intervention in cerulein model of CP and 1.6-fold in L-arginine model of CP. A further improvement in insulin secretion by 3.2-fold was observed with additional dietary supplements like N-acetyl cysteine, curcumin in combination with EGCG. Our results thus demonstrate and highlight the therapeutic potential of dietary green tea (EGCG) supplementation in reversing islet dysfunction and improving glucose homeostasis in experimental chronic pancreatitis in mice.
文摘Nonalcoholic fatty liver disease(NAFLD) is associated with obesity,insulin resistance,and type 2 diabetes.NAFLD represents a large spectrum of diseases ranging from(1) fatty liver(hepatic steatosis);(2) steatosis with inflammation and necrosis;to(3) cirrhosis.The animal models to study NAFLD/nonalcoholic steatohepatitis(NASH) are extremely useful,as there are still many events to be elucidated in the pathology of NASH.The study of the established animal models has provided many clues in the pathogenesis of steatosis and steatohepatitis,but these remain incompletely understood.The different mouse models can be classified in two large groups.The first one includes genetically modified(transgenic or knockout) mice that spontaneously develop liver disease,and the second one includes mice that acquire the disease after dietary or pharmacological manipulation.Although the molecular mechanism leading to the development of hepatic steatosis in the pathogenesis of NAFLD is complex,genetically modified animal models may be a key for the treatment of NAFLD.Ideal animal models for NASH should closely resemble the pathological characteristics observed in humans.To date,no single animal model has encompassed the full spectrum of human disease progression,but they can imitate particular characteristics of human disease.Therefore,it is important that the researchers choose the appropriate animal model.This review discusses various genetically modified animal models developed and used in research on NAFLD.
基金the National Natural Science Foundation of China(Nos.62003023,32071407,52073138,52003018 and 52003019)Beijing Natural Science Foundation(No.7212204)Beijing Advanced Innovation Center for Biomedical Engineering and Beihang University.
文摘Recurrent oral ulcer is a painful oral mucosal disorder that affects 20%of the world’s population.The lack of a radical cure due to its unknown underlying cause calls for innovative symptomatic treatments.This work reports a hyaluronic acid-based dissolvablemicroneedle patch(ROUMNpatch,short for recurrent oral ulcer microneedle)loaded with dexamethasone acetate,vitamin C and tetracaine hydrochloride for the treatment of recurrent oral ulcers.The ROUMN patch shows enhancement in both the anti-inflammatory effect elicited by dexamethasone and the pro-proliferation effect of vitamin C.In vitro experiments show that ROUMN has a higher efficiency in suppressing lipopolysaccharide(LPS)-induced interleukin-6(IL-6)expression than dexamethasone alone.Cell proliferation and migrationwere also significantly promoted byROUMNcompared to vitamin C alone.The healing-promoting effect of ROUMN was also verified in vivo using an acetic acid-cauterized oral ulcer model in rats.ROUMN as a treatment accelerated the healing process of oral ulcers,shortening the total healing time to 5 days compared with the 7 days required by treatment using watermelon frost,a commonly used over-the-counter(OTC)drug for oral ulcers.The rapid dissolution of the hyaluronic acid-based microneedles and the superior healing-promoting effect of the drug combination could lead to a broad application prospect of the ROUMN patch in the treatment of recurrent oral ulcers.
基金supported by the Van Andel Research Instituteby a grant to BOW from the NIH/NIAMS (AR053293)
文摘99mTc-Methylene diphosphonate （99mTc-MDP） is widely used in clinical settings to detect bone abnormalities. However, the mechanism of 99mTc-MDP uptake in bone is not well elucidated. In this study, we utilized a mouse tibia injury model, single-photon emission computed tomography （gamma scintigraphy or SPECT）, ex vivo micro-computed tomography, and histology to monitor 99mTc-MDP uptake in injury sites during skeletal healing. In an ex vivo culture system, calvarial cells were differentiated into osteoblasts with osteogenic medium, pulsed with 99mTc-MDP at different time points, and quantitated for 99mTc-MDP uptake with a gamma counter. We demonstrated that 99mTc-MDP uptake in the injury sites corresponded to osteoblast generation in those sites throughout the healing process. The 99mTc-MDP uptake within the injury sites peaked on day 7 post-injury, while the injury sites were occupied by mature osteoblasts also starting from day 7. ~mTc-MDP uptake started to decrease 14 days post-surgery, when we observed the highest level of bony tissue in the injury sites. We also found that 99mTc-MDP uptake was associated with osteoblast maturation and mineralization in vitro. This study provides direct and biological evidence for 99mTc-MDP uptake in osteoblasts during bone healing in vivo and in vitro.
基金Supported by the Swiss National Science Foundation grant nu SNSF 31-59031.99 to F. Seibold
文摘AIM： To investigate ASCA production over time in CD and murine colitis in order to further our understanding of their etiology. MATERIALS AND METHODS： Sixty-six CD patients were compared to ulcerative colitis （UC） and irritable bowel syndrome patients with respect to ASCA production as measured by ELISA. ASCA IgG or IgA positivity as well as change in titers over a period of up to 3 years （△tgG/A） was correlated with clinical parameters such as CD activity index （CDM） and C-reactive protein levels （CRP）. Moreover, two murine models of colitis （DSS and IL-10 knock out） were compared to control animals with respect to ASCA titers after oral yeast exposure. RESULTS： ASCA IgG and IgA titers are stable over time in CD and non-CD patients. Fistular disease was associated with a higher rate of ASCA IgA positivity （P = 0.014）. Ileal disease was found to have a significant influence on the △tgG of ASCA （P = 0.032）. There was no correlation found between ASCA positivity or △tgG/A and clinical parameters of CD： CDAI and CRP. In mice, neither healthy animals nor animals with DSS-induced or spontaneous colitis exhibited a marked increase in ASCA titers after high-dose yeast exposure. On the other hand, mice immunized intraperitoneally with mannan plus adjuvant showed a marked and significant increase in ASCA titers compared to adjuvant-only immunized controls （P = 0.014）. CONCLUSION： The propensity to produce ASCA in a subgroup of CD patients is largely genetically predetermined as evidenced by their stability and lack of correlation with clinical disease activity parameters. Furthermore, in animal models of colitis, mere oral exposure of mice to yeast does not lead to the induction of marked ASCA titers irrespective of concomitant colonic inflammation. Hence, environment may play only a minor role in inducing ASCA.
基金the National Institutes of Health(NIH)Grant Nos.R21AG042700 and R21DK088066。
文摘Adriamycin(doxorubicin),a common cancer chemotherapeutic drug,can be used to induce a model of chronic progressive glomerular disease in rodents.In our studies,we evahuated renal changes in a rat model after Adriamydin injection using two photon microscopy(TPM),optical coherence tomography(OCT)and Doppler OCT(DOCT).Taking advantage of deep penetra-tion and fast scanning speed for three dimensional(3D)label-free imaging,OCT/DOCT system was able to reveal glomerular and tubular pathology noninvasively and in real time.By imaging renal pathology following the infusion of fAuorophore-labeled dextrans of different molecular weights,TPM can provide direct views of glomerular and tubular flow dynamics with the onset and progression of renal disease.Specifically,glomerular permeability and filtration,proximal and distal tubular flow dynamics can be revealed.6-8 weeks after injection of Adriamycin,TPM and OCT/DOCT imaging revealed glomerular sclerosis,compromised flow across the glomerular wall,tubular atrophy,tubular dilation,and variable intra-tubular flow dynamics.Our results indicate that TPM and OCT/DOCT provide real-time imaging of renal pathology in vivo that has not been previously available using conventional microscopic procedures.
基金Supported by TMH-IRG(account number-466/2012 and 164/2016)LTMT grant for project funding+1 种基金ACTREC-TMC for funding to Gupta labsupported by ACTREC fellowships
文摘BACKGROUND The prognosis of gastric cancer continues to remain poor,and epigenetic drugs like histone deacetylase inhibitors(HDACi)have been envisaged as potential therapeutic agents.Nevertheless,clinical trials are facing issues with toxicity and efficacy against solid tumors,which may be partly due to the lack of patient stratification for effective treatments.To study the need of patient stratification before HDACi treatment,and the efficacy of pre-treatment of HDACi as a chemotherapeutic drug sensitizer.METHODS The expression activity of class 1 HDACs and histone acetylation was examined in human gastric cancer cells and tissues.The potential combinatorial regime of HDACi and chemotherapy drugs was defined on the basis of observed drug binding assays,chromatin remodeling and cell death.RESULTS In the present study,the data suggest that the differential increase in HDAC activity and the expression of class 1 HDACs are associated with hypoacetylation of histone proteins in tumors compared to normal adjacent mucosa tissue samples of gastric cancer.The data highlights for the first time that pretreatment of HDACi results in an increased amount of DNA-bound drugs associated with enhanced histone acetylation,chromatin relaxation and cell cycle arrest.Fraction-affected plots and combination index-based analysis show that pre-HDACi chemo drug combinatorial regimes,including valproic acid with cisplatin or oxaliplatin and trichostatin A with epirubicin,exhibit synergism with maximum cytotoxic potential due to higher cell death at low combined doses in gastric cancer cell lines.CONCLUSION Expression or activity of class 1 HDACs among gastric cancer patients present an effective approach for patient stratification.Furthermore,HDACi therapy in pretreatment regimes is more effective with chemotherapy drugs,and may aid in predicting individual patient prognosis.
文摘AIM:To study,in intact male transgenic mice,the effects of three diets based on olive oil and olive oil diet supplemented with lovastatin and orlistat on hepatic lipogenic enzymes expression,considered markers of cell proliferation.METHODS:Forty ApcMin/+mice were randomly divided into 4 groups and fed for 10 wk:olive oil(OO)group,n=10 animals received a diet with olive oil 12%;olive oil plus lovastatin(LOVA)group,n=10 animals received the same diet with olive oil supplemented with lovastatin 5 mg/kg;olive oil plus orlistat(OR)group,n=10 animals fed the diet with olive oil supplemented with orlistat 50 mg/kg and SD group,n=10 animals fed a standard diet.The activity of lipogenic enzymes and their gene expression were evaluated by radiomet-ric and real-time reverse transcription-polymerase chain reaction assay,respectively.RESULTS:After 10 wk of dietary treatment,the body weight was no different among animal groups(21.3±3.1 g for standard group,22.1±3.6 g for OO group,22.0±3.2 g for LOVA group and 20.7±3.4 g for OR group,data expressed as mean±SD),observing a generalized well-being in all animals.All the dietary managed treated groups presented significantly reduced hepatic levels of fatty acid synthase,farnesyl pyrophosphate synthase and 3-hydroxyl-3-methyl-glutaryl CoA reductase activity and gene expression when compared with the mice fed the standard diet.To evaluate cell proliferation in the liver of treated mice,the levels of cyclin E mRNA have been measured,demonstrating a significant reduction of cyclin E gene expression in all treated groups.Evidence of reduced hepatic cell proliferation was present overall in OO group mice.CONCLUSION:We confirm the role of lipogenic enzymes as markers of cell proliferation,suggesting that appropriate dietary management alone or with drugs can be a feasible approach to counteract hepatic cell proliferation in mice.
文摘Animal models are being developed for testing different vaccine candidates as well as testing of new antitubercular since a long time.Mice,guinea pigs and rabbits are animals which are frequently used.Though each model has got its merits as well as demerits and each of them differ from human tuberculosis in one aspect or the other but none of the model completely mimics the human disease.Out of the different animal species, guinea pig model is one of the better models as it is very sensitive to M.tuberculosis infection but it has certain limitations like paucity of immunological reagents.However,it is the best model for tuberculosis research.
基金supported by the National Natural Science Foundation of China(Grant No.31671561)to Dong Zhang.
文摘Microtubule-severing proteins(MTSPs),are a family of proteins which use adenosine triphosphate to sever microtubules.MTSPs have been shown to play an important role in multiple microtubule-involved cellular processes.One member of this family,fidgetin(FIGN),is also involved in male fertility;however,no studies have explored its roles in female fertility.In this study,we found mouse fidgetin is rich within oocyte zona pellucida(ZP)and is the only MTSP member to do so.Fidgetin also appears to interact with all three ZP proteins.These findings prompted us to propose that fidgetin might prevent polyspermy.Results from in vitro maturation oocytes analysis showed that fidgetin knockdown did cause polyspermy.We then deleted all three fidgetin isoforms with CRISPR/Cas9 technologies;however,female mice remained healthy and with normal fertility.Of all mouse MTSPs,only the mRNA level of fidgetin-like 1(FIGNL1)significantly increased.Therefore,we assert that fidgetin-like 1 compensates fidgetin's roles in fidgetin knockout female mice.
文摘Goats or sheep are the preferred animal model for the preclinical evaluation of cartilage repair techniques due to the similarity of the goat stifle joint to the human knee.The medial femoral condyle of the stifle joint is the preferred site for the assessment of articular cartilage repair,as this is the primary location for this type of lesion in the human knee.Proper surgical exposure of the medial femoral condyle is paramount to obtain reproducible results without surgical error.When applying the standard human medial arthrotomy technique on the goat stifle joint,there are some key aspects to consider in order to prevent destabilization of the extensor apparatus and subsequent postoperative patellar dislocations with associated animal discomfort.This paper describes a modified surgical technique to approach the medial femoral condyle of the caprine stifle joint.The modified technique led to satisfactory exposure without postoperative incidence of patellar luxations and no long-term adverse effects on the joint.
