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1.
Brain Nerve ; 74(1): 85-91, 2022 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-34992179

RESUMO

Repeat RNAs exhibit "RNA toxicity" by trapping RNA-binding proteins, thereby suppressing the proteins' native functions. The mismatch-binding molecules created in this study bound with high affinity and specificity to the slip-out structure formed by repeat DNA and RNA sequences, induced the shortening of repeat DNA length, and alleviated compound eye degeneration and splicing defects in animal models of Huntington's disease, spinocerebellar ataxia type 31, and myotonic dystrophy type 1.


Assuntos
Distrofia Miotônica , Ataxias Espinocerebelares , Animais , Modelos Animais , Distrofia Miotônica/tratamento farmacológico , Distrofia Miotônica/genética , RNA/genética , Proteínas de Ligação a RNA/genética
2.
Exp Neurol ; 347: 113879, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34597682

RESUMO

Reaching to grasp is an evolutionarily conserved behavior and a crucial part of the motor repertoire in mammals. As it is studied in the laboratory, reaching has become the prototypical example of dexterous forelimb movements, illuminating key principles of motor control throughout the spinal cord, brain, and peripheral nervous system. Here, we (1) review the motor elements or phases that comprise the reach, grasp, and retract movements of reaching behavior, (2) highlight the role of intersectional genetic tools in linking these movements to their neuronal substrates, (3) describe spinal cord cell types and their roles in skilled reaching, and (4) how descending pathways from the brain and the sensory systems contribute to skilled reaching. We emphasize that genetic perturbation experiments can pin-point the neuronal substrates of specific phases of reaching behavior.


Assuntos
Técnicas Genéticas , Modelos Animais , Destreza Motora/fisiologia , Animais , Encéfalo/fisiologia , Vias Eferentes/fisiologia , Camundongos , Medula Espinal/fisiologia
3.
Methods Mol Biol ; 2375: 177-189, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34591308

RESUMO

Preclinical testing in animal model is a required stage of vascular device development. Among small animal models, rabbits provide vasculature with relative larger caliber for anastomotic implantation of vascular grafts as preclinical testing before conducting large animal studies. Rabbits have similar hemostatic mechanism with human and can accommodate vascular grafts with various diameters at different locations, and thus provide a valid model to assess small-diameter vascular grafts. This chapter will describe the procedures and materials required to conduct survival surgery in rabbit carotid artery models for implantation of small-diameter tubular grafts with an end-to-side and end-to-end anastomotic technique.


Assuntos
Anastomose Cirúrgica , Animais , Aorta Abdominal , Artérias Carótidas/cirurgia , Modelos Animais , Coelhos , Túnica Íntima
4.
Zhonghua Nan Ke Xue ; 27(5): 394-402, 2021 May.
Artigo em Chinês | MEDLINE | ID: mdl-34914313

RESUMO

Objective: To investigate the effect of epigenetic regulation on spermatogenic dysfunction-related infertility (SDI) in C57BL/6J male mice. METHODS: Sixty C57BL/6J male mice were randomly divided into a normal control and an SDI model group and the SDI model was established using the epididymis-targeting polypeptide CSA combined with indocyanine green-loaded free nanoparticles (ICG-NPS), busufan and dimethyl sulfoxide (DSMO). After intervention with 5-AZA-DC, the epididymides were collected from the mice for measurement of the rates of sperm DNA fragmentation (SDF), sperm acrosome integrity (SAI) and spontaneous acrosome reaction (SAR), amplification of the ERp29 gene by FISH, determination of the mRNA and protein expressions of DNMT1, ERp29, PTEN and TSC2 by quantitative real-time PCR and Western blot, and analysis of the ERp29, PTEN and TSC2 genes by methylated DNA immunoprecipitation sequencing (MeDIP-seq). RESULTS: After 5-AZA-DC intervention, statistically significant differences were observed between the normal control and the SDI model groups in the rates of SDF (ï¼»15.67 ± 1.33ï¼½% vs ï¼»30.15 ± 2.87ï¼½%, P < 0.05) and SAI (ï¼»65.33 ± 7.14ï¼½% vs ï¼»47.16 ± 3.45ï¼½%, P < 0.05), but not SAR (ï¼»11.52 ± 2.31ï¼½% vs ï¼»11.48 ± 2.27ï¼½%, P > 0.05). FISH confirmed evident amplification of the ERp29 gene in the SDI model but not in the normal control group. Compared with the baseline, the SDI model mice showed significant decreases after intervention in the mRNA and protein expressions of DNMT1 (ï¼»9.33 ± 1.15ï¼½ vs ï¼»7.01 ± 1.14ï¼½, P < 0.05; ï¼»15.66 ± 1.45ï¼½ vs ï¼»12.33 ± 1.27ï¼½, P < 0.05), but increases in those of ERp29 (ï¼»3.04 ± 1.13ï¼½ vs ï¼»6.54 ± 1.18ï¼½, P < 0.05; ï¼»4.37 ± 1.02ï¼½ vs ï¼»6.95 ± 1.03ï¼½, P < 0.05), PTEN (ï¼»3.25 ± 1.01ï¼½ vs ï¼»5.85 ± 1.04ï¼½, P < 0.05; ï¼»3.54 ± 1.01ï¼½ vs ï¼»5.17 ± 1.02ï¼½, P < 0.05) and TSC2 (ï¼»4.27 ± 1.16ï¼½ vs ï¼»6.98 ± 1.13ï¼½, P < 0.05; ï¼»3.83 ± 1.12ï¼½ vs ï¼»6.98 ± 1.13ï¼½, P < 0.05). No statistically significant differences, however, were found in the above parameters in the normal control group before and after intervention (P > 0.05). MeDIP-seq manifested 18 significantly differential genes were highly expressed and another 25 lowly expressed in the epididymal tissue of the model mice, all the former 18 down-regulated and all the latter 25 up-regulated after intervention, particularly ERp29, PTEN and TSC2. But there were no statistically significant differences in the expressions of the above genes in the control group (P > 0.05). MeDIP-seq also showed significant differences in the regional methylation levels of the Erp29, PTEN and TSC2 promoters in the epididymal tissue of the model mice (P < 0.05), but not in that of the normal controls after intervention (P > 0.05). CONCLUSIONS: A stable and efficient animal model provided valuable experimental evidence for the diagnosis and treatment of spermatogenic dysfunction-related infertility. ERp29 is an important gene involved in infertility and can be used as a potential target for epigenetic regulation in the treatment of infertility.


Assuntos
Epigênese Genética , Infertilidade , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais
5.
PLoS One ; 16(12): e0261447, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34919595

RESUMO

BACKGROUND: Defining reference intervals in experimental animal models plays a crucial role in pre-clinical studies. The hepatic parameters in healthy animals provide useful information about type and extension of hepatic damage. However, in the majority of the cases, to obtain them require an invasive techniques. Our study combines these determinations with dynamic functional test and imaging techniques to implement a non-invasive protocol for liver evaluation. The aim of the study was to determine reference intervals for hepatic function, perfusion and parenchyma attenuation with analytical and biochemical blood parameters, indocyanine green, ultrasound and computed tomography in six healthy SD rats. METHODS: Six males healthy SD rats were followed for 4 weeks. To determine hepatic function, perfusion and parenchyma attenuation analytical and biochemical blood parameters, indocyanine green, ultrasound and computed tomography were studied. Results were expressed as Means ± standard error of mean (SEM). The significance of differences was calculated by using student t-test, p < 0.05 was considered statistically significant. RESULTS: Indocyanine green clearance 5 and 10 minutes after its injection was 80.12% and 96.59%, respectively. Approximate rate of decay during the first 5 minutes after injection was 38% per minute. Hepatic perfusion evaluation with the high-frequency ultrasound was related to cardiovascular hemodynamic and renal perfusion. Portal area, hepatic artery resistance index, hepatic artery and portal peak systolic velocity and average between hepatic artery and porta was 3.41 ± 0.62 mm2, 0.57 ± 0.04 mm2/s, 693.24±102.53 mm2/s, 150.72 ± 17.80 mm2/s and 4.82 ± 0.96 mm2/s, respectively. Heart rate, cardiac output, left renal artery diammetre and renal blood flow were 331.01 ± 22.22 bpm, 75.58 ± 8.72 mL/min, 0.88 ± 0.04 mm2 and 13.65 ± 1.95 mm2/s. CT-scan hepatic average volume for each rat were 21.08±3.32, 17.57±2.76, 14.87±2.83 and 13.67±2.45 cm3 with an average attenuation coefficient of 113.51±18.08, 129,19±7.18, 141,47±1.95 y 151,67±1.2 HU. CONCLUSION: Indocyanine green and high-frequency ultrasound could be used in rats as a suitable marker of liver function. Computed tomography, through the study of raw data, help to characterize liver parenchyma, and could be a potential tool for early detection of liver parenchymal alterations and linear follow-up of patients. Further studies in rats with liver disease are necessary to verify the usefulness of these parameters.


Assuntos
Verde de Indocianina/metabolismo , Testes de Função Hepática/métodos , Fígado/metabolismo , Tecido Parenquimatoso/metabolismo , Animais , Masculino , Modelos Animais , Ratos , Ratos Sprague-Dawley , Valores de Referência , Tomografia Computadorizada por Raios X , Ultrassonografia
6.
Int J Mol Sci ; 22(24)2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34948215

RESUMO

Prerequisite to any biological laboratory assay employing living animals is consideration about its necessity, feasibility, ethics and the potential harm caused during an experiment. The imperative of these thoughts has led to the formulation of the 3R-principle, which today is a pivotal scientific standard of animal experimentation worldwide. The rising amount of laboratory investigations utilizing living animals throughout the last decades, either for regulatory concerns or for basic science, demands the development of alternative methods in accordance with 3R to help reduce experiments in mammals. This demand has resulted in investigation of additional vertebrate species displaying favourable biological properties. One prominent species among these is the zebrafish (Danio rerio), as these small laboratory ray-finned fish are well established in science today and feature outstanding biological characteristics. In this review, we highlight the advantages and general prerequisites of zebrafish embryos and larvae before free-feeding stages for toxicological testing, with a particular focus on cardio-, neuro, hepato- and nephrotoxicity. Furthermore, we discuss toxicokinetics, current advances in utilizing zebrafish for organ toxicity testing and highlight how advanced laboratory methods (such as automation, advanced imaging and genetic techniques) can refine future toxicological studies in this species.


Assuntos
Alternativas aos Testes com Animais/métodos , Embrião não Mamífero/metabolismo , Larva/metabolismo , Testes de Toxicidade/métodos , Peixe-Zebra/metabolismo , Animais , Humanos , Modelos Animais
7.
Mol Cells ; 44(12): 861-878, 2021 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-34963103

RESUMO

The human genome contains many retroviral elements called human endogenous retroviruses (HERVs), resulting from the integration of retroviruses throughout evolution. HERVs once were considered inactive junk because they are not replication-competent, primarily localized in the heterochromatin, and silenced by methylation. But HERVs are now clearly shown to actively regulate gene expression in various physiological and pathological conditions such as developmental processes, immune regulation, cancers, autoimmune diseases, and neurological disorders. Recent studies report that HERVs are activated in patients suffering from coronavirus disease 2019 (COVID-19), the current pandemic caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. In this review, we describe internal and external factors that influence HERV activities. We also present evidence showing the gene regulatory activity of HERV LTRs (long terminal repeats) in model organisms such as mice, rats, zebrafish, and invertebrate models of worms and flies. Finally, we discuss several molecular and cellular pathways involving various transcription factors and receptors, through which HERVs affect downstream cellular and physiological events such as epigenetic modifications, calcium influx, protein phosphorylation, and cytokine release. Understanding how HERVs participate in various physiological and pathological processes will help develop a strategy to generate effective therapeutic approaches targeting HERVs.


Assuntos
Doenças Autoimunes/genética , Retrovirus Endógenos/genética , Regulação da Expressão Gênica , Modelos Animais , Neoplasias/genética , Sequências Repetidas Terminais/genética , Animais , Doenças Autoimunes/virologia , COVID-19/genética , COVID-19/virologia , Humanos , Neoplasias/virologia , SARS-CoV-2/fisiologia
8.
PLoS One ; 16(12): e0261289, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34941926

RESUMO

White Feces Syndrome (WFS) is an emergent disease of penaeid shrimp (Penaeus monodon and P. vannamei) that is identified by the presence of floating white fecal strings on pond water in grow-out ponds. Although the clinical manifestations of WFS are well defined, the underling etiology remains obscure. WFS has been associated with several enteric pathogens, including Enterocytozoon hepatopenaei (EHP). The association is based on studies that found areas where WFS has been reported, the prevalence and severity of EHP infection are high. In this study, we describe an experimental reproduction of WFS in P. vannamei pre-infected with EHP and challenged with a unique isolate of Vibrio parahaemolyticus isolated from the gastrointestinal tract of a shrimp displaying WFS. Upon laboratory challenge, shrimp displaying white fecal strings and white discoloration of the gastrointestinal tract were analyzed by histopathology, in-situ hybridization and quantitative PCR. Histological analysis confirmed the lesions of EHP and septic hepatopancreatic necrosis in the hepatopancreas of shrimp exposed to both pathogens. Quantitative PCR showed shrimp infected with both EHP and V. parahaemolyticus had a significantly higher load of EHP compared to shrimp infected with EHP alone. This is the first demonstration of experimental reproduction of WFS under laboratory conditions when animals are infected with EHP and V. parahaemolyticus concurrently. The data revealed a synergistic relation between EHP and V. parahaemolyticus isolate that led to the manifestation of WFS. We propose the gross signs of WFS can be used as an indicator of the presence of EHP infection in association with a particular strain of an enteric Vibrio spp. in countries where EHP is endemic.


Assuntos
Penaeidae/microbiologia , Penaeidae/parasitologia , Animais , Aquicultura/métodos , Enterocytozoon/patogenicidade , Fezes/microbiologia , Trato Gastrointestinal , Hibridização In Situ , Modelos Animais , Reação em Cadeia da Polimerase , Prevalência , Alimentos Marinhos/microbiologia , Vibrio parahaemolyticus/patogenicidade
9.
Zhonghua Nan Ke Xue ; 27(3): 256-261, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-34914309

RESUMO

Erectile dysfunction (ED) is a common andrological disorder, and traditional oral drugs often fail to achieve satisfactory therapeutic effects. As a new field of biomedicine, stem cell therapy (SCT) has seen a significantly increasing number of researches on its treatment of ED in recent years. Preclinical animal models for the study of ED mainly include the models of diabetes mellitus-, aging-, cavernous nerve injury-, and Peyronie's disease-related ED. Previous studies indicated that SCT improved erectile function through paracrine and was more effective when combined with other therapies than used alone in restoring ED-induced pathological changes. Although clinical trials on SCT have partially proved its safety and effectiveness for the treatment of ED, they were still in the early stages and with relatively small sample sizes. This article summarizes the latest advances in the treatment of ED by SCT.


Assuntos
Disfunção Erétil , Induração Peniana , Animais , Disfunção Erétil/terapia , Humanos , Masculino , Modelos Animais , Ereção Peniana , Induração Peniana/terapia , Transplante de Células-Tronco
10.
An Acad Bras Cienc ; 93(suppl 4): e20210481, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34730624

RESUMO

Epidemiological studies have shown an inverse association between coffee consumption and the development of Parkinson's disease (PD). The effects of the oral treatment with green (non-roasted) coffee extracts (CE, 100 or 400 mg/kg) and caffeine (31.2 mg/kg) were evaluated on catalepsy induced by haloperidol in mice, and unilateral 6-OHDA lesion of medial forebrain bundle (MFB) or striatum in rats. Also, the in vitro antioxidant activity and the monoamine levels in the striatum were investigated. CE presented a mild antioxidant activity in vitro and its administration decreased the catalepsy index. CE at the dose of 400 mg/kg induced ipsilateral rotations 14 days after lesion; however, chronic 30-day CE and caffeine treatments did not interfere with the animals' rotation after apomorphine or methamphetamine challenges in animals with MFB lesion, nor on monoamines levels. Furthermore, CE and caffeine were effective in inhibiting the asymmetry between ipsilateral and contralateral rotations induced by methamphetamine and apomorphine in animals with lesion in the striatum but did not avoid the monoamines depletion. These results indicate that CE components indirectly modulate dopaminergic transmission, suggesting a pro-dopaminergic action of CE, and further investigation must be conducted to elucidate the mechanisms of action and the possible neuroprotective role in PD.


Assuntos
Café , Doença de Parkinson , Animais , Comportamento Animal , Modelos Animais de Doenças , Camundongos , Modelos Animais , Oxidopamina/toxicidade , Doença de Parkinson/tratamento farmacológico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos
11.
Medicine (Baltimore) ; 100(41): e27496, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34731131

RESUMO

ABSTRACT: Using animal models and molecular biology researches, hyperuricemia has been shown to instruct renal arteriolopathy, arterial hypertension, and microvascular injury involving the renin-angiotensin system and resulting in renal function impairment. Nevertheless, the association between uric acid levels and the development of albuminuria has been under-investigated in patients with type 2 diabetes mellitus. Patients with type 2 diabetes and regular outpatient visits were recruited from the Puli Branch of the Taichung Veterans General Hospital in Taiwan since January 2014. Demographics, lifestyle features, and medical history were gathered by well-trained interviewers. All participants underwent comprehensive physical examinations, including a biochemical assay of venous blood specimens and urine samples after an 8-hour overnight fast. Participants were followed until June 2018. The primary outcome was the albuminuria incidence. Univariable and multivariable Cox regression analysis were employed to explore the relation between uric acid and incident albuminuria. Uric acid cutoffs for incident albuminuria were determined with the receiver operator characteristic curve. We included 247 qualified subjects (mean age: 64.78 years old [standard deviation = 11.29 years]; 138 [55.87%] men). During a 4.5-year follow-up duration, 20 subjects with incident albuminuria were recognized. Serum uric acid was significantly associated with an increased risk of incident albuminuria (adjusted hazard ratio = 2.39; 95% confidence interval: 1.53-3.75; P < .001) with potential confounders adjustment. The uric acid cutoff point was 6.9 mg/dL (area under the curve 0.708, sensitivity 60.0%, specificity 84.58%) for incident albuminuria. Serum uric acid was associated with incident albuminuria among patients with type 2 diabetes.


Assuntos
Albuminúria/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/urina , Ácido Úrico/sangue , Idoso , Albuminúria/etiologia , Animais , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/complicações , Feminino , Humanos , Hipertensão/complicações , Hiperuricemia/complicações , Incidência , Masculino , Camundongos , Microvasos/lesões , Pessoa de Meia-Idade , Modelos Animais , Insuficiência Renal/etiologia , Sistema Renina-Angiotensina/fisiologia , Fatores de Risco , Taiwan/epidemiologia
12.
Medicine (Baltimore) ; 100(41): e27508, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34731136

RESUMO

BACKGROUND: Erectile dysfunction is a disease commonly caused by diabetes mellitus (DMED) and cavernous nerve injury (CNIED). Bioinformatics analyses including differentially expressed genes (DEGs), enriched functions and pathways (EFPs), and protein-protein interaction (PPI) networks were carried out in DMED and CNIED rats in this study. The critical biomarkers that may intervene in nitric oxide synthase (NOS, predominantly nNOS, ancillary eNOS, and iNOS)-cyclic guanosine monophosphate (cGMP)-phosphodiesterase 5 enzyme (PDE5) pathway, an important mechanism in erectile dysfunction treatment, were then explored for potential clinical applications. METHODS: GSE2457 and GSE31247 were downloaded. Their DEGs with a |logFC (fold change)| > 0 were screened out. Database for Annotation, Visualization and Integrated Discovery (DAVID) online database was used to analyze the EFPs in Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes networks based on down-regulated and up-regulated DEGs respectively. PPI analysis of 2 datasets was performed in Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and Cytoscape. Interactions with an average score greater than 0.9 were chosen as the cutoff for statistical significance. RESULTS: From a total of 1710 DEGs in GSE2457, 772 were down-regulated and 938 were up-regulated, in contrast to the 836 DEGs in GSE31247, from which 508 were down-regulated and 328 were up-regulated. The 25 common EFPs such as aging and response to hormone were identified in both models. PPI results showed that the first 10 hub genes in DMED were all different from those in CNIED. CONCLUSIONS: The intervention of iNOS with the hub gene complement component 3 in DMED and the aging process in both DMED and CNIED deserves attention.


Assuntos
Biomarcadores/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Disfunção Erétil/metabolismo , Óxido Nítrico Sintase/metabolismo , Nucleotídeos Cíclicos/metabolismo , Animais , Biologia Computacional/métodos , Bases de Dados Genéticas , Complicações do Diabetes/epidemiologia , Disfunção Erétil/epidemiologia , Disfunção Erétil/fisiopatologia , Regulação da Expressão Gênica/genética , Ontologia Genética/estatística & dados numéricos , Redes Reguladoras de Genes/genética , Humanos , Masculino , Modelos Animais , Mapas de Interação de Proteínas/genética , Ratos
13.
J Immunol ; 207(10): 2473-2488, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34625520

RESUMO

Because of its size, anatomical similarities, and now also accessibility to genetic manipulations, pigs are used as animal models for human diseases and immune system development. However, expression and function of CD28, the most important costimulatory receptor expressed by T cells, so far is poorly understood in this species. Using a newly generated mAb (mAb 3D11) with specificity for pig CD28, we detected CD28 on CD8+ and CD4+ αß T cells. Among γδ T cells, CD28 expression was restricted to a small CD2+ subpopulation of phenotypically naive cells. Functionally, CD28 ligation with mAb 3D11-costimulated porcine T cells, enhanced proliferation and cytokine secretion in vitro. We used a second, likewise newly generated but superagonistic, anti-CD28 mAb (CD28-SA; mAb 4D12) to test the function of CD28 on porcine T cells in a pilot study in vivo. Injection of the CD28-SA into pigs in vivo showed a very similar dose-response relationship as in humans (i.e., 100 µg/kg body weight [BW]) of CD28-SA induced a cytokine release syndrome that was avoided at a dose of 10 µg/kg BW and below. The data further suggest that low-dose (10 µg/kg BW) CD28-SA infusion was sufficient to increase the proportion of Foxp3+ regulatory T cells among CD4+ T cells in vivo. The pig is thus a suitable animal model for testing novel immunotherapeutics. Moreover, data from our pilot study in pigs further suggest that low-dose CD28-SA infusion might allow for selective expansion of CD4+ regulatory T cells in humans.


Assuntos
Anticorpos Monoclonais/imunologia , Antígenos CD28/imunologia , Modelos Animais , Suínos/imunologia , Linfócitos T/imunologia , Animais , Anticorpos Monoclonais/farmacologia , Humanos , Ativação Linfocitária/imunologia
14.
Elife ; 102021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34617510

RESUMO

Senescent cells have detrimental effects across tissues with aging but may have beneficial effects on tissue repair, specifically on skin wound healing. However, the potential role of senescent cells in fracture healing has not been defined. Here, we performed an in silico analysis of public mRNAseq data and found that senescence and senescence-associated secretory phenotype (SASP) markers increased during fracture healing. We next directly established that the expression of senescence biomarkers increased markedly during murine fracture healing. We also identified cells in the fracture callus that displayed hallmarks of senescence, including distension of satellite heterochromatin and telomeric DNA damage; the specific identity of these cells, however, requires further characterization. Then, using a genetic mouse model (Cdkn2aLUC) containing a Cdkn2aInk4a-driven luciferase reporter, we demonstrated transient in vivo senescent cell accumulation during callus formation. Finally, we intermittently treated young adult mice following fracture with drugs that selectively eliminate senescent cells ('senolytics', Dasatinib plus Quercetin), and showed that this regimen both decreased senescence and SASP markers in the fracture callus and significantly accelerated the time course of fracture healing. Our findings thus demonstrate that senescent cells accumulate transiently in the murine fracture callus and, in contrast to the skin, their clearance does not impair but rather improves fracture healing.


Assuntos
Senescência Celular , Consolidação da Fratura , Animais , Biomarcadores , Dano ao DNA , Feminino , Humanos , Masculino , Camundongos , Modelos Animais
15.
J Exp Psychol Anim Learn Cogn ; 47(3): 337-356, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34618532

RESUMO

A fundamental question in comparative cognition concerns the ability to remember back in time to an earlier event or episode. This ability is referred to as episodic memory. Whether nonhumans can be used to model human episodic memory has engendered much interest and debate for over 2 decades. The central hypothesis of an animal model of episodic memory is that, at the moment of the memory assessment, the animal remembers back in time to a specific earlier event or episode. I describe (a) an approach for evaluating evidence of episodic memory in animal models (b) what aspects of episodic memory are being modeled in animals (c) what standards ought to be applied to a candidate model of episodic memory in nonhumans (d) the first evidence of episodic memory in nonhumans, and (e) a brief overview of the diversity of approaches that are now available. The remainder of the article focuses on the development of a robust model of episodic memory in rats. Converging lines of evidence suggest that rats provide a good model for exploring episodic memory. This evidence includes studies that focus on (a) what-where-when memory (b) source memory (c) binding of episodic memories (d) memory of multiple Items in context using episodic memory (e) replay of episodic memories (f), recollection, and (g) answering an unexpected question after incidental encoding. In each of these domains, I describe evidence for episodic memory in the absence of nonepisodic judgments of familiarity. I end with some consideration of future directions. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Memória Episódica , Animais , Cognição , Rememoração Mental , Modelos Animais , Ratos , Reconhecimento Psicológico
16.
PLoS One ; 16(10): e0258046, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34610023

RESUMO

In the last 25 years, numerous tissue engineered heart valve (TEHV) strategies have been studied in large animal models. To evaluate, qualify and summarize all available publications, we conducted a systematic review and meta-analysis. We identified 80 reports that studied TEHVs of synthetic or natural scaffolds in pulmonary position (n = 693 animals). We identified substantial heterogeneity in study designs, methods and outcomes. Most importantly, the quality assessment showed poor reporting in randomization and blinding strategies. Meta-analysis showed no differences in mortality and rate of valve regurgitation between different scaffolds or strategies. However, it revealed a higher transvalvular pressure gradient in synthetic scaffolds (11.6 mmHg; 95% CI, [7.31-15.89]) compared to natural scaffolds (4,67 mmHg; 95% CI, [3,94-5.39]; p = 0.003). These results should be interpreted with caution due to lack of a standardized control group, substantial study heterogeneity, and relatively low number of comparable studies in subgroup analyses. Based on this review, the most adequate scaffold model is still undefined. This review endorses that, to move the TEHV field forward and enable reliable comparisons, it is essential to define standardized methods and ways of reporting. This would greatly enhance the value of individual large animal studies.


Assuntos
Próteses Valvulares Cardíacas/efeitos adversos , Valva Pulmonar/transplante , Engenharia Tecidual/métodos , Animais , Modelos Animais
17.
J Neural Transm (Vienna) ; 128(10): 1507-1527, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34613484

RESUMO

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), and dysautonomia with cerebellar ataxia or parkinsonian motor features. Isolated autonomic dysfunction with predominant genitourinary dysfunction and orthostatic hypotension and REM sleep behavior disorder are common characteristics of a prodromal phase, which may occur years prior to motor-symptom onset. MSA is a unique synucleinopathy, in which alpha-synuclein (aSyn) accumulates and forms insoluble inclusions in the cytoplasm of oligodendrocytes, termed glial cytoplasmic inclusions (GCIs). The origin of, and precise mechanism by which aSyn accumulates in MSA are unknown, and, therefore, disease-modifying therapies to halt or slow the progression of MSA are currently unavailable. For these reasons, much focus in the field is concerned with deciphering the complex neuropathological mechanisms by which MSA begins and progresses through the course of the disease. This review focuses on the history, etiopathogenesis, neuropathology, as well as cell and animal models of MSA.


Assuntos
Atrofia de Múltiplos Sistemas , Animais , Corpos de Inclusão , Modelos Animais , Atrofia de Múltiplos Sistemas/patologia , Degeneração Neural/patologia , alfa-Sinucleína
19.
Nat Commun ; 12(1): 5758, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34599173

RESUMO

Various behavioral and cognitive states exhibit circadian variations in animals across phyla including Drosophila melanogaster, in which only ~0.1% of the brain's neurons contain circadian clocks. Clock neurons transmit the timing information to a plethora of non-clock neurons via poorly understood mechanisms. Here, we address the molecular underpinning of this phenomenon by profiling circadian gene expression in non-clock neurons that constitute the mushroom body, the center of associative learning and sleep regulation. We show that circadian clocks drive rhythmic expression of hundreds of genes in mushroom body neurons, including the Neurofibromin 1 (Nf1) tumor suppressor gene and Pka-C1. Circadian clocks also drive calcium rhythms in mushroom body neurons via NF1-cAMP/PKA-C1 signaling, eliciting higher mushroom body activity during the day than at night, thereby promoting daytime wakefulness. These findings reveal the pervasive, non-cell-autonomous circadian regulation of gene expression in the brain and its role in sleep.


Assuntos
Relógios Circadianos/fisiologia , Proteínas de Drosophila/metabolismo , Corpos Pedunculados/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo , Animais , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Drosophila melanogaster , Regulação da Expressão Gênica/fisiologia , Modelos Animais , Corpos Pedunculados/citologia , RNA-Seq , Transdução de Sinais/fisiologia , Sono/fisiologia , Vigília/fisiologia
20.
Chem Pharm Bull (Tokyo) ; 69(10): 962-969, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34602577

RESUMO

Experimental animals are indispensable in life science-related research, including cancer studies. After rats and mice, small fishes, such as zebrafish and medaka, are the second most frequently used model species. Fish models have some advantageous physical characteristics that make them suitable for research, including their small size, some transparency, genetic manipulability, ease of handling, and highly ortholog correspondence with humans. This review introduces technological advances in carcinogenesis model production using small fish. Carcinogenesis model production begins with chemical carcinogenesis, followed by mutagenesis. Gene transfer technology has made it possible to incorporate various mechanisms that act on cancer-related genes in individuals. For example, scientists may now spatiotemporally control gene expression in a single fish through methods including the localization of an expression site via a tissue-specific promoter and expression control using light, heat, or a chemical substance. In addition, genome editing technology is realizing more specific and more efficient gene disruption than conventional mutagenesis, in which the disruption of the gene of interest depends on chance. These technological advances have improved animal models and will soon create carcinogenesis models that better mimic human pathology. We conclude by discussing future expectations for cancer research using small fish.


Assuntos
Carcinogênese/genética , Modelos Animais , Animais , Peixes
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