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1.
Physiol Rep ; 12(13): e16132, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38993022

RESUMO

Different rat strains are used in various animal models of pulmonary hypertension and right ventricular (RV) failure. No systematic assessment has been made to test differences in RV response to pressure overload between rat strains. We compared RV adaptation to pulmonary trunk banding (PTB) in Wistar (W), Sprague Dawley (SD), and Fischer344 (F) rats by hemodynamic profiling focusing on diastolic function. Age-matched male rat weanlings were randomized to sham surgery (W-sham, n = 5; SD-sham, n = 4; F-sham, n = 4) or PTB (W-PTB, n = 8; SD-PTB, n = 8; F-PTB, n = 8). RV function was evaluated after 5 weeks by echocardiography, cardiac MRI, and invasive pressure-volume measurements. PTB caused RV failure and increased RV systolic pressures four-fold in all three PTB groups compared with sham. W- and SD-PTB had a 2.4-fold increase in RV end-systolic volume index compared with sham, while F-PTB rats were less affected. Diastolic and right atrial impairment were evident by increased RV end-diastolic elastance, filling pressure, and E/e' in PTB rats compared with sham, again F-PTB the least affected. In conclusions, PTB caused RV failure with signs of diastolic dysfunction. Despite a similar increase in RV systolic pressure, F-PTB rats showed less RV dilatation and a more preserved diastolic function compared with W- and SD-PTB.


Assuntos
Adaptação Fisiológica , Diástole , Ratos Sprague-Dawley , Ratos Wistar , Função Ventricular Direita , Animais , Masculino , Ratos , Diástole/fisiologia , Função Ventricular Direita/fisiologia , Adaptação Fisiológica/fisiologia , Disfunção Ventricular Direita/fisiopatologia , Disfunção Ventricular Direita/diagnóstico por imagem , Ratos Endogâmicos F344 , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/etiologia , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/diagnóstico por imagem , Especificidade da Espécie
2.
Function (Oxf) ; 5(4)2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38984994

RESUMO

While regular physical activity is a cornerstone of health, wellness, and vitality, the impact of endurance exercise training on molecular signaling within and across tissues remains to be delineated. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to characterize molecular networks underlying the adaptive response to exercise. Here, we describe the endurance exercise training studies undertaken by the Preclinical Animal Sites Studies component of MoTrPAC, in which we sought to develop and implement a standardized endurance exercise protocol in a large cohort of rats. To this end, Adult (6-mo) and Aged (18-mo) female (n = 151) and male (n = 143) Fischer 344 rats were subjected to progressive treadmill training (5 d/wk, ∼70%-75% VO2max) for 1, 2, 4, or 8 wk; sedentary rats were studied as the control group. A total of 18 solid tissues, as well as blood, plasma, and feces, were collected to establish a publicly accessible biorepository and for extensive omics-based analyses by MoTrPAC. Treadmill training was highly effective, with robust improvements in skeletal muscle citrate synthase activity in as little as 1-2 wk and improvements in maximum run speed and maximal oxygen uptake by 4-8 wk. For body mass and composition, notable age- and sex-dependent responses were observed. This work in mature, treadmill-trained rats represents the most comprehensive and publicly accessible tissue biorepository, to date, and provides an unprecedented resource for studying temporal-, sex-, and age-specific responses to endurance exercise training in a preclinical rat model.


Assuntos
Adaptação Fisiológica , Envelhecimento , Condicionamento Físico Animal , Ratos Endogâmicos F344 , Animais , Masculino , Feminino , Condicionamento Físico Animal/fisiologia , Adaptação Fisiológica/fisiologia , Ratos , Envelhecimento/fisiologia , Resistência Física/fisiologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Treino Aeróbico
3.
Neuroscience ; 551: 177-184, 2024 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-38823551

RESUMO

Dopamine D1 receptor agonists improve spatial working memory, but their effects on temporal order memory, particularly prone to the effects of aging, have not been studied. Two D1 agonists, PF6256142 (PF) and 2-methyldihydrexidine (2MDHX), were examined for their effects in a rodent temporal order recognition task. Our results are consistent with the hypothesis that there is an age-related decline in rodent temporal order memory. The data also show that either agonist rescues the poor memory performance with a large effective size. Interestingly, the optimal effective dose varied among individual rats of different age groups. PF showed greater potency for older rats, whereas 2MDHX showed better overall population effectiveness. Both PF and 2MDHX have high intrinsic activity at rodent D1-mediated cAMP synthesis. Conversely, at D1-mediated ß-arrestin recruitment, PF has essentially no intrinsic activity, whereas 2MDHX is a super-agonist. These findings suggest that D1 agonists have potential to treat age-related cognitive decline, and the pattern of functional selectivity may be useful for developing drugs with an improved therapeutic index.


Assuntos
Envelhecimento , Agonistas de Dopamina , Receptores de Dopamina D1 , Animais , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Masculino , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Agonistas de Dopamina/farmacologia , Ratos , Fenantridinas/farmacologia , Relação Dose-Resposta a Droga , Reconhecimento Psicológico/efeitos dos fármacos , Ratos Sprague-Dawley , Ratos Endogâmicos F344 , AMP Cíclico/metabolismo
4.
Cells ; 13(12)2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38920644

RESUMO

Hepatocellular carcinoma (HCC) development is associated with altered modifications in DNA methylation, changing transcriptional regulation. Emerging evidence indicates that DNA methyltransferase 1 (DNMT1) plays a key role in the carcinogenesis process. This study aimed to investigate how pirfenidone (PFD) modifies this pathway and the effect generated by the association between c-Myc expression and DNMT1 activation. Rats F344 were used for HCC development using 50 mg/kg of diethylnitrosamine (DEN) and 25 mg/kg of 2-Acetylaminofluorene (2-AAF). The HCC/PFD group received simultaneous doses of 300 mg/kg of PFD. All treatments lasted 12 weeks. On the other hand, HepG2 cells were used to evaluate the effects of PFD in restoring DNA methylation in the presence of the inhibitor 5-Aza. Histopathological, biochemical, immunohistochemical, and western blot analysis were carried out and our findings showed that PFD treatment reduced the amount and size of tumors along with decreased Glipican-3, ß-catenin, and c-Myc expression in nuclear fractions. Also, this treatment improved lipid metabolism by modulating PPARγ and SREBP1 signaling. Interestingly, PFD augmented DNMT1 and DNMT3a protein expression, which restores global methylation, both in our in vivo and in vitro models. In conclusion, our results suggest that PFD could slow down HCC development by controlling DNA methylation.


Assuntos
Carcinoma Hepatocelular , DNA (Citosina-5-)-Metiltransferase 1 , Metilação de DNA , Antígeno Nuclear de Célula em Proliferação , Piridonas , Animais , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/genética , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Piridonas/farmacologia , Ratos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Humanos , Células Hep G2 , Antígeno Nuclear de Célula em Proliferação/metabolismo , Masculino , Ratos Endogâmicos F344 , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Dietilnitrosamina , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/patologia , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/genética
5.
Aging (Albany NY) ; 16(10): 8402-8416, 2024 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-38761177

RESUMO

Aging is associated with a decrease in N-methyl-D-aspartate (NMDA) receptor function, which is critical for maintaining synaptic plasticity, learning, and memory. Activation of the NMDA receptor requires binding of the neurotransmitter glutamate and also the presence of co-agonist D-serine at the glycine site. The enzymatic conversion of L-serine to D-serine is facilitated by the enzyme serine racemase (SR). Subsequently, SR plays a pivotal role in regulating NMDA receptor activity, thereby impacting synaptic plasticity and memory processes in the central nervous system. As such, age-related changes in the expression of SR could contribute to decreased NMDA receptor function. However, age-associated changes in SR expression levels in the medial and lateral prefrontal cortex (mPFC, lPFC), and in the dorsal hippocampal subfields, CA1, CA3, and dentate gyrus (DG), have not been thoroughly elucidated. Therefore, the current studies were designed to determine the SR expression profile, including protein levels and mRNA, for these regions in aged and young male and female Fischer-344 rats. Our results demonstrate a significant reduction in SR expression levels in the mPFC and all hippocampal subfields of aged rats compared to young rats. No sex differences were observed in the expression of SR. These findings suggest that the decrease in SR levels may play a role in the age-associated reduction of NMDA receptor function in brain regions crucial for cognitive function and synaptic plasticity.


Assuntos
Envelhecimento , Hipocampo , Córtex Pré-Frontal , Racemases e Epimerases , Animais , Córtex Pré-Frontal/metabolismo , Masculino , Envelhecimento/metabolismo , Feminino , Racemases e Epimerases/metabolismo , Racemases e Epimerases/genética , Hipocampo/metabolismo , Ratos , Ratos Endogâmicos F344 , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/genética , RNA Mensageiro/metabolismo , Plasticidade Neuronal
6.
J Agric Food Chem ; 72(23): 13111-13124, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38811015

RESUMO

Fruits are rich in bioactive compounds, such as (poly)phenols, and their intake is associated with health benefits, although recent animal studies have suggested that the photoperiod of consumption influences their properties. Fruit loss and waste are critical issues that can be reduced by obtaining functional fruit extracts. Therefore, the aim of this study was to obtain phenolic-enriched extracts from eight seasonal fruits that can modulate blood biochemical parameters and to investigate whether their effects depend on the photoperiod of consumption. Eight ethanol-based extracts were obtained and characterized, and their effects were studied in F344 rats exposed to short (6 h light, L6) and long (18 h light) photoperiods. Cherry and apricot extracts decreased blood triacylglyceride levels only when consumed under the L6 photoperiod. Pomegranate, grape, and orange extracts reduced cholesterol and fasting glucose levels during the L6 photoperiod; however, plum extract reduced fasting glucose levels only during the L18 photoperiod. The results showed the importance of photoperiod consumption in the effectiveness of phenolic-enriched fruit extracts and promising evidence regarding the use of some of the developed fruit extracts as potential functional ingredients for the management of several blood biomarkers.


Assuntos
Biomarcadores , Frutas , Fenóis , Fotoperíodo , Extratos Vegetais , Ratos Endogâmicos F344 , Animais , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Extratos Vegetais/administração & dosagem , Frutas/química , Fenóis/química , Ratos , Masculino , Biomarcadores/sangue , Glicemia/metabolismo , Triglicerídeos/sangue , Colesterol/sangue , Humanos
7.
PLoS One ; 19(5): e0294998, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38713688

RESUMO

Tularemia is a zoonotic disease caused by the facultative intracellular gram-negative bacterium Francisella tularensis. F. tularensis has a very low infection dose by the aerosol route which can result in an acute, and potentially lethal, infection in humans. Consequently, it is classified as a Category A bioterrorism agent by the US Centers for Disease Control (CDC) and is a pathogen of concern for the International Biodefence community. There are currently no licenced tularemia vaccines. In this study we report on the continued assessment of a tularemia subunit vaccine utilising ß-glucan particles (GPs) as a vaccine delivery platform for immunogenic F. tularensis antigens. Using a Fischer 344 rat infection model, we demonstrate that a GP based vaccine comprising the F. tularensis lipopolysaccharide antigen together with the protein antigen FTT0814 provided partial protection of F344 rats against an aerosol challenge with a high virulence strain of F. tularensis, SCHU S4. Inclusion of imiquimod as an adjuvant failed to enhance protective efficacy. Moreover, the level of protection afforded was dependant on the challenge dose. Immunological characterisation of this vaccine demonstrated that it induced strong antibody immunoglobulin responses to both polysaccharide and protein antigens. Furthermore, we demonstrate that the FTT0814 component of the GP vaccine primed CD4+ and CD8+ T-cells from immunised F344 rats to express interferon-γ, and CD4+ cells to express interleukin-17, in an antigen specific manner. These data demonstrate the development potential of this tularemia subunit vaccine and builds on a body of work highlighting GPs as a promising vaccine platform for difficult to treat pathogens including those of concern to the bio-defence community.


Assuntos
Vacinas Bacterianas , Modelos Animais de Doenças , Francisella tularensis , Ratos Endogâmicos F344 , Tularemia , Vacinas de Subunidades Antigênicas , Animais , Tularemia/prevenção & controle , Tularemia/imunologia , Ratos , Vacinas Bacterianas/imunologia , Vacinas Bacterianas/administração & dosagem , Francisella tularensis/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Glucanos/imunologia , Glucanos/farmacologia , Linfócitos T/imunologia , Feminino , Antígenos de Bactérias/imunologia
8.
Sci Rep ; 14(1): 11973, 2024 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-38796617

RESUMO

The biology underlying proton minibeam radiation therapy (pMBRT) is not fully understood. Here we aim to elucidate the biological effects of pMBRT using Fourier Transform Infrared Microspectroscopy (FTIRM). In vitro (CTX-TNA2 astrocytes and F98 glioma rat cell lines) and in vivo (healthy and F98-bearing Fischer rats) irradiations were conducted, with conventional proton radiotherapy and pMBRT. FTIRM measurements were performed at ALBA Synchrotron, and multivariate data analysis methods were employed to assess spectral differences between irradiation configurations and doses. For astrocytes, the spectral regions related to proteins and nucleic acids were highly affected by conventional irradiations and the high-dose regions of pMBRT, suggesting important modifications on these biomolecules. For glioma, pMBRT had a great effect on the nucleic acids and carbohydrates. In animals, conventional radiotherapy had a remarkable impact on the proteins and nucleic acids of healthy rats; analysis of tumour regions in glioma-bearing rats suggested major nucleic acid modifications due to pMBRT.


Assuntos
Glioma , Terapia com Prótons , Ratos Endogâmicos F344 , Síncrotrons , Animais , Ratos , Glioma/radioterapia , Glioma/patologia , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Linhagem Celular Tumoral , Astrócitos/efeitos da radiação , Astrócitos/metabolismo , Ácidos Nucleicos/efeitos da radiação , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo
9.
Arch Toxicol ; 98(6): 1741-1756, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38573339

RESUMO

Humans are chronically exposed to furan, a potent liver toxicant and carcinogen that occurs in a variety of heat-processed foods. Assessment of human exposure based on the furan content in foods is, however, subject to some uncertainty due to the high volatility of furan. Biomarker monitoring is thus considered an alternative or complementary approach to furan exposure assessment. Previous work suggested that urinary furan metabolites derived from the reaction of cis-2-butene-1,4-dial (BDA), the reactive intermediate of furan, with glutathione (GSH) or amino acids may serve as potential biomarkers of furan exposure. However, some metabolites were also reported to occur in urine of untreated animals, indicating either background contamination via animal feed or endogenous sources, which may limit their suitability as biomarkers of exposure. The overall aim of the present study was to accurately establish the correlation between external dose and concentration of furan metabolites in urine over time and to discriminate against endogenous formation and furan intake via feed. To this end, the furan metabolites GSH-BDA (N-[4-carboxy-4-(3-mercapto-1H-pyrrol-1-yl)-1-oxobutyl]-L-cysteinylglycine), NAcLys-BDA (R-2-(acetylamino)-6-(2,5-dihydro-2-oxo-1H-pyrrol-1-yl)-1-hexanoic acid), NAcCys-BDA-NAcLys (N-acetyl-S-[1-[5-(acetylamino)-5-carboxypentyl]-1H-pyrrol-3-yl]-L-cysteine) and NAcCys-BDA-NAcLys sulfoxide (N-acetyl-S-[1-[5-(acetylamino)-5-carboxypentyl]-1H-pyrrol-3-yl]-L-cysteine sulfoxide) were simultaneously analyzed by stable isotope dilution ESI-LC-MS/MS as unlabeled and [13C4]-furan dependent metabolites following oral administration of a single oral dose of isotopically labelled [13C4]-furan (0.1, 1, 10, 100 and 1000 µg/kg bw) to male and female F344/DuCrl rats. Although a linear correlation between urinary excretion of [13C4]-furan-dependent metabolites was observed, analysis of unlabeled NAcLys-BDA, NAcCys-BDA-NAcLys and NAcCys-BDA-NAcLys sulfoxide revealed substantial, fairly constant urinary background levels throughout the course of the study. Analysis of furan in animal feed excluded feed as a source for these background levels. GSH-BDA was identified as the only furan metabolite without background occurrence, suggesting that it may present a specific biomarker to monitor external furan exposure. Studies in humans are now needed to establish if analysis of urinary GSH-BDA may provide reliable exposure estimates.


Assuntos
Biomarcadores , Furanos , Glutationa , Ratos Endogâmicos F344 , Furanos/urina , Animais , Biomarcadores/urina , Masculino , Glutationa/metabolismo , Glutationa/urina , Marcação por Isótopo , Ratos , Espectrometria de Massas em Tandem/métodos , Acetilcisteína/urina , Acetilcisteína/análogos & derivados
10.
Am J Vet Res ; 85(6)2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38626794

RESUMO

OBJECTIVE: The aim of this study was to assess the efficacy and safety of a third-generation lentivirus-based vector encoding the feline erythropoietin (EPO) (feEPO) gene in vitro and in rodent models in vivo. This vector incorporates a genetic mechanism to facilitate the termination of the therapeutic effect in the event of supraphysiologic polycythemia, the herpes simplex virus thymidine kinase (HSV-TK) "suicide gene." ANIMALS: CFRK cells and replication-defective lentiviral vectors encoding feEPO were used for in vitro experiments. Eight Fischer rats were enrolled in the pilot in vivo study, 24 EPO-deficient mice were used in the initial mouse study, and 15 EPO-deficient mice were enrolled in the final mouse study. METHODS: Efficacy of a third-generation lentivirus encoding feEPO was determined in vitro using western blot assays. Subsequently, in a series of rodent experiments, animals were administered the viral vector in progressively increasing inoculation doses with serial measurements of blood packed cell volume (PCV) over time. RESULTS: We documented production of feEPO protein in transduced CRFK cells with subsequent cessation of production when treated with the HSV-TK substrate ganciclovir. In vivo, we demonstrated variably persistent elevated PCV values in treated rats and mice with eventual return to baseline values over time. CLINICAL RELEVANCE: These results provide justification for a lentiviral gene therapy approach to the treatment of nonregenerative anemia associated with chronic renal disease in cats.


Assuntos
Anemia , Eritropoetina , Terapia Genética , Vetores Genéticos , Lentivirus , Ratos Endogâmicos F344 , Animais , Eritropoetina/genética , Terapia Genética/veterinária , Lentivirus/genética , Camundongos , Anemia/veterinária , Anemia/terapia , Gatos , Ratos , Insuficiência Renal Crônica/terapia , Insuficiência Renal Crônica/veterinária , Masculino , Feminino , Linhagem Celular
11.
Aging (Albany NY) ; 16(7): 5811-5828, 2024 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-38613791

RESUMO

Studies suggest that ketogenic diets (KD) may improve memory in mouse models of aging and Alzheimer's disease (AD). This study determined whether a continuous or intermittent KD (IKD) enhanced cognitive behavior in the TgF344-AD rat model of AD. At 6 months-old, TgF344-AD and wild-type (WT) littermates were placed on a control (CD), KD, or IKD (morning CD and afternoon KD) provided as two meals per day for 2 or 6 months. Cognitive and motor behavior and circulating ß-hydroxybutyrate (BHB), AD biomarkers and blood lipids were assessed. Animals on a KD diet had elevated circulating BHB, with IKD levels intermediate to CD and KD. TgF344-AD rats displayed impaired spatial learning memory in the Barnes maze at 8 and 12 months of age and impaired motor coordination at 12 months of age. Neither KD nor IKD improved performance compared to CD. At 12 months of age, TgF344-AD animals had elevated blood lipids. IKD reduced lipids to WT levels with KD further reducing cholesterol below WT levels. This study shows that at 8 or 12 months of age, KD or IKD intervention did not improve measures of cognitive or motor behavior in TgF344-AD rats; however, both IKD and KD positively impacted circulating lipids.


Assuntos
Doença de Alzheimer , Cognição , Dieta Cetogênica , Lipídeos , Animais , Ratos , Cognição/fisiologia , Masculino , Doença de Alzheimer/dietoterapia , Doença de Alzheimer/sangue , Lipídeos/sangue , Ratos Endogâmicos F344 , Modelos Animais de Doenças , Ácido 3-Hidroxibutírico/sangue , Aprendizagem em Labirinto , Atividade Motora , Ratos Transgênicos , Comportamento Animal
12.
Toxicol Sci ; 200(1): 70-78, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38565259

RESUMO

Peritubular macrophages (PTMφ) are predominantly localized near spermatogonial stem cells in the testis. We previously revealed that exposure of peripubertal male Fischer rats to mono-(2-ethylhexyl) phthalate (MEHP) leads to increased PTMφs in the testis. The mechanisms that trigger increases in PTMφs in the testis are poorly understood. However, MEHP exposure is known to both induce spermatocyte apoptosis and to perturb the blood-testis barrier (BTB). This study aims to elucidate the association between the disruption of BTB and the increases of PTMφs in the testis by comparing the effects observed with MEHP to 2 other testicular toxicants with variable effects on the BTB and subtype of germ cell undergoing apoptosis. Methoxyacetic acid (MAA) acts directly on spermatocytes and does not affect BTB function, whereas cadmium chloride (CdCl2) induces profound injury to BTB. The results indicated that MAA exposure significantly increased spermatocyte apoptosis, whereas no significant changes in the numbers of PTMφs in the testis occurred. In contrast, CdCl2 exposure disrupted BTB function and increased the abundance of PTMφs in the testis. To further investigate whether MEHP-induced changes in BTB integrity accounted for the increase in PTMφs, a plasmid for LG3/4/5, the functional component of laminin-alpha 2, was overexpressed in the testis to stabilize BTB integrity before MEHP exposure. The results showed that LG3/4/5 overexpression substantially reduced the ability of MEHP to compromise BTB integrity and prevented the increase in PTMφ numbers after MEHP exposure. These results indicate that BTB disruption is necessary to increase PTMφs in the testis induced by toxicants.


Assuntos
Apoptose , Barreira Hematotesticular , Dietilexilftalato , Macrófagos , Ratos Endogâmicos F344 , Testículo , Animais , Masculino , Barreira Hematotesticular/efeitos dos fármacos , Barreira Hematotesticular/patologia , Barreira Hematotesticular/metabolismo , Dietilexilftalato/toxicidade , Dietilexilftalato/análogos & derivados , Testículo/efeitos dos fármacos , Testículo/patologia , Testículo/metabolismo , Macrófagos/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Cloreto de Cádmio/toxicidade , Acetatos/toxicidade , Ratos , Espermatócitos/efeitos dos fármacos , Espermatócitos/patologia
13.
Alzheimers Dement ; 20(5): 3543-3550, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38624069

RESUMO

INTRODUCTION: Alzheimer's disease (AD) is characterized by cognitive impairments; however, heightened anxiety often accompanies and, in some cases, exacerbates cognitive its. The present study aims to understand the influence of multiple variables on anxiety-like behavior in TgF344-AD rats and determine whether anxiety impacts memory performance. METHODS: An elevated plus maze was used to assess anxiety-like behavior in the established colony (n = 107). Influences of age, sex, genotype, and exercise on anxiety were evaluated via multiple linear regression. Correlation analysis evaluated the relationship between anxiety and memory performance. RESULTS: Age (P < 0.05) and AD genotype (P < 0.001) were associated with increasing anxiety, while exercise (P < 0.05) was associated with decreasing anxiety. Female AD animals displayed more anxiety-like behavior versus wild-type female (P < 0.001) and AD male (P < 0.05) littermates. DISCUSSION: Concluding that while factors such as age, sex, AD genotype, and training status can impact anxiety levels in the TgF344-AD model, anxiety level did not impact memory performance. HIGHLIGHTS: Increased anxiety-like behavior in TgF344-AD rats does not correlate with declines in memory performance. Predictors of higher anxiety-like behaviors in the TgF344-AD rat include age, Alzheimer's disease (AD) genotype, and sex with female AD animals experiencing greater anxiety compared to female wild-type or male AD. Exercise training leads to decreased anxiety-like behaviors in the TgF344-AD rat.


Assuntos
Doença de Alzheimer , Ansiedade , Modelos Animais de Doenças , Genótipo , Condicionamento Físico Animal , Ratos Transgênicos , Animais , Doença de Alzheimer/genética , Feminino , Masculino , Ratos , Ansiedade/genética , Fatores Sexuais , Memória/fisiologia , Fatores Etários , Ratos Endogâmicos F344 , Aprendizagem em Labirinto/fisiologia
14.
Exp Gerontol ; 190: 112423, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38608790

RESUMO

Aging is associated with impaired strength and power during isometric and shortening contractions, however, during lengthening (i.e., eccentric) contractions, strength is maintained. During daily movements, muscles undergo stretch-shortening cycles (SSCs). It is unclear whether the age-related maintenance of eccentric strength offsets age-related impairments in power generation during SSCs owing to the utilization of elastic energy or other cross-bridge based mechanisms. Here we investigated how aging influences SSC performance at the single muscle fibre level and whether performing active lengthening prior to shortening protects against age-related impairments in power generation. Single muscle fibres from the psoas major of young (∼8 months; n = 31 fibres) and old (∼32 months; n = 41 fibres) male F344BN rats were dissected and chemically permeabilized. Fibres were mounted between a force transducer and length controller and maximally activated (pCa 4.5). For SSCs, fibres were lengthened from average sarcomere lengths of 2.5 to 3.0 µm and immediately shortened back to 2.5 µm at both fast and slow (0.15 and 0.60 Lo/s) lengthening and shortening speeds. The magnitude of the SSC effect was calculated by comparing work and power during shortening to an active shortening contraction not preceded by active lengthening. Absolute isometric force was ∼37 % lower in old compared to young rat single muscle fibres, however, when normalized to cross-sectional area (CSA), there was no longer a significant difference in isometric force between age groups, meanwhile there was an ∼50 % reduction in absolute power in old as compared with young. We demonstrated that SSCs significantly increased power production (75-110 %) in both young and old fibres when shortening occurred at a fast speed and provided protection against power-loss with aging. Therefore, in older adults during everyday movements, power is likely 'protected' in part due to the stretch-shortening cycle as compared with isolated shortening contractions.


Assuntos
Envelhecimento , Contração Muscular , Fibras Musculares Esqueléticas , Força Muscular , Animais , Masculino , Ratos , Envelhecimento/patologia , Envelhecimento/fisiologia , Contração Isométrica/fisiologia , Cinética , Contração Muscular/fisiologia , Fibras Musculares de Contração Rápida/patologia , Fibras Musculares de Contração Rápida/fisiologia , Fibras Musculares Esqueléticas/patologia , Fibras Musculares Esqueléticas/fisiologia , Força Muscular/fisiologia , Ratos Endogâmicos BN , Ratos Endogâmicos F344
15.
Int J Mol Sci ; 25(7)2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38612383

RESUMO

Polyacrylic acid (PAA), an organic chemical, has been used as an intermediate in the manufacture of pharmaceuticals and cosmetics. It has been suggested recently that PAA has a high pulmonary inflammatory and fibrotic potential. Although endoplasmic reticulum stress is induced by various external and intracellular stimuli, there have been no reports examining the relationship between PAA-induced lung injury and endoplasmic reticulum stress. F344 rats were intratracheally instilled with dispersed PAA (molecular weight: 269,000) at low (0.5 mg/mL) and high (2.5 mg/mL) doses, and they were sacrificed at 3 days, 1 week, 1 month, 3 months and 6 months after exposure. PAA caused extensive inflammation and fibrotic changes in the lungs' histopathology over a month following instillation. Compared to the control group, the mRNA levels of endoplasmic reticulum stress markers Bip and Chop in BALF were significantly increased in the exposure group. In fluorescent immunostaining, both Bip and Chop exhibited co-localization with macrophages. Intratracheal instillation of PAA induced neutrophil inflammation and fibrosis in the rat lung, suggesting that PAA with molecular weight 269,000 may lead to pulmonary disorder. Furthermore, the presence of endoplasmic reticulum stress in macrophages was suggested to be involved in PAA-induced lung injury.


Assuntos
Acrilatos , Lesão Pulmonar , Polímeros , Ratos , Animais , Ratos Endogâmicos F344 , Estresse do Retículo Endoplasmático , Inflamação , Pulmão
16.
Cells ; 13(7)2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38607090

RESUMO

BACKGROUND/AIM: Activin A is involved in the pathogenesis of human liver diseases, but its therapeutic targeting is not fully explored. Here, we tested the effect of novel, highly specific small-molecule-based activin A antagonists (NUCC-474/555) in improving liver regeneration following partial hepatectomy and halting fibrosis progression in models of chronic liver diseases (CLDs). METHODS: Cell toxicity of antagonists was determined in rat hepatocytes and Huh-7 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. Hepatocytes and hepatic stellate cells (HSCs) were treated with activin A and NUCC-555 and analyzed by reverse transcription-polymerase chain reaction and immunohistochemistry. Partial hepatectomized Fisher (F)344 rats were treated with NUCC-555, and bromodeoxyuridine (BrdU) incorporation was determined at 18/24/36/120/240 h. NUCC-555 was administered into thioacetamide- or carbon tetrachloride-treated F344 rats or C57BL/6 mice, and the fibrosis progression was studied. RESULTS: NUCC-474 showed higher cytotoxicity in cultured hepatic cells; therefore, NUCC-555 was used in subsequent studies. Activin A-stimulated overexpression of cell cycle-/senescence-related genes (e.g., p15INK4b, DEC1, Glb1) was near-completely reversed by NUCC-555 in hepatocytes. Activin A-mediated HSC activation was blocked by NUCC-555. In partial hepatectomized rats, antagonizing activin A signaling resulted in a 1.9-fold and 2.3-fold increase in BrdU+ cells at 18 and 24 h, respectively. Administration of NUCC-555 in rats and mice with progressing fibrosis significantly reduced collagen accumulation (7.9-fold), HSC activation indicated by reduced alpha smooth muscle actin+ and vimentin+ cells, and serum aminotransferase activity. CONCLUSIONS: Our studies demonstrate that activin A antagonist NUCC-555 promotes liver regeneration and halts fibrosis progression in CLD models, suggesting that blocking activin A signaling may represent a new approach to treating people with CLD.


Assuntos
Ativinas , Hepatopatias , Transdução de Sinais , Animais , Humanos , Camundongos , Ratos , Bromodesoxiuridina , Fibrose , Hepatopatias/tratamento farmacológico , Camundongos Endogâmicos C57BL , Ratos Endogâmicos F344 , Transdução de Sinais/efeitos dos fármacos
17.
J Neuroinflammation ; 21(1): 108, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38664840

RESUMO

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by the presence of proteinaceous alpha-synuclein (α-syn) inclusions (Lewy bodies), markers of neuroinflammation and the progressive loss of nigrostriatal dopamine (DA) neurons. These pathological features can be recapitulated in vivo using the α-syn preformed fibril (PFF) model of synucleinopathy. We have previously determined that microglia proximal to PFF-induced nigral α-syn inclusions increase in soma size, upregulate major-histocompatibility complex-II (MHC-II) expression, and increase expression of a suite of inflammation-associated transcripts. This microglial response is observed months prior to degeneration, suggesting that microglia reacting to α-syn inclusion may contribute to neurodegeneration and could represent a potential target for novel therapeutics. The goal of this study was to determine whether colony stimulating factor-1 receptor (CSF1R)-mediated microglial depletion impacts the magnitude of α-syn aggregation, nigrostriatal degeneration, or the response of microglial in the context of the α-syn PFF model. METHODS: Male Fischer 344 rats were injected intrastriatally with either α-syn PFFs or saline. Rats were continuously administered Pexidartinib (PLX3397B, 600 mg/kg), a CSF1R inhibitor, to deplete microglia for a period of either 2 or 6 months. RESULTS: CSF1R inhibition resulted in significant depletion (~ 43%) of ionized calcium-binding adapter molecule 1 immunoreactive (Iba-1ir) microglia within the SNpc. However, CSF1R inhibition did not impact the increase in microglial number, soma size, number of MHC-II immunoreactive microglia or microglial expression of Cd74, Cxcl10, Rt-1a2, Grn, Csf1r, Tyrobp, and Fcer1g associated with phosphorylated α-syn (pSyn) nigral inclusions. Further, accumulation of pSyn and degeneration of nigral neurons was not impacted by CSF1R inhibition. Paradoxically, long term CSF1R inhibition resulted in increased soma size of remaining Iba-1ir microglia in both control and PFF rats, as well as expression of MHC-II in extranigral regions. CONCLUSIONS: Collectively, our results suggest that CSF1R inhibition does not impact the microglial response to nigral pSyn inclusions and that CSF1R inhibition is not a viable disease-modifying strategy for PD.


Assuntos
Microglia , Ratos Endogâmicos F344 , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos , alfa-Sinucleína , Animais , Microglia/metabolismo , Microglia/efeitos dos fármacos , alfa-Sinucleína/metabolismo , Ratos , Masculino , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Pirróis/farmacologia , Aminopiridinas/farmacologia , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Substância Negra/metabolismo , Substância Negra/patologia , Substância Negra/efeitos dos fármacos , Modelos Animais de Doenças
18.
Sci Rep ; 14(1): 8294, 2024 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-38670985

RESUMO

Rats are multiparous rodents that have been used extensively in research; however, the low reproductive performance of some rat strains hampers the broader use of rats as a biomedical model. In this study, the possibility of increasing the litter size after natural mating in rats through superovulation using an anti-inhibin monoclonal antibody (AIMA) was examined. In outbred Wistar rats, AIMA increased the number of ovulated oocytes by 1.3-fold. AIMA did not affect fertilization and subsequent embryonic development, resulting in a 1.4-fold increase in litter size and a high pregnancy rate (86%). In contrast, conventional superovulation by eCG/hCG administration decreased the pregnancy rate to 6-40% and did not increase the litter size. In inbred Brown Norway rats, AIMA increased the litter size by 1.2-fold, and the pregnancy rate increased more than twice (86% versus 38% in controls). AIMA also increased the litter size by 1.5-fold in inbred Tokai High Avoiders and Fischer 344 rats. AIMA increased the efficiency of offspring production by 1.5-, 2.7-, 1.4-, and 1.4-fold, respectively, in the four rat strains. Thus, AIMA may consistently improve the reproductive performance through natural mating in rats, which could promote the use of AIMA in biomedical research.


Assuntos
Anticorpos Monoclonais , Inibinas , Tamanho da Ninhada de Vivíparos , Superovulação , Animais , Feminino , Tamanho da Ninhada de Vivíparos/efeitos dos fármacos , Gravidez , Ratos , Superovulação/efeitos dos fármacos , Anticorpos Monoclonais/farmacologia , Taxa de Gravidez , Ratos Wistar , Reprodução/efeitos dos fármacos , Masculino , Ratos Endogâmicos F344
19.
Sci Rep ; 14(1): 9573, 2024 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-38670993

RESUMO

P2X7 receptors mediate immune and endothelial cell responses to extracellular ATP. Acute pharmacological blockade increases renal blood flow and filtration rate, suggesting that receptor activation promotes tonic vasoconstriction. P2X7 expression is increased in kidney disease and blockade/knockout is renoprotective. We generated a P2X7 knockout rat on F344 background, hypothesising enhanced renal blood flow and protection from angiotensin-II-induced renal injury. CRISPR/Cas9 introduced an early stop codon into exon 2 of P2rx7, abolishing P2X7 protein in kidney and reducing P2rx7 mRNA abundance by ~ 60% in bone-marrow derived macrophages. The M1 polarisation response to lipopolysaccharide was unaffected but P2X7 receptor knockout suppressed ATP-induced IL-1ß release. In male knockout rats, acetylcholine-induced dilation of the renal artery ex vivo was diminished but not the response to nitroprusside. Renal function in male and female knockout rats was not different from wild-type. Finally, in male rats infused with angiotensin-II for 6 weeks, P2X7 knockout did not reduce albuminuria, tubular injury, renal macrophage accrual, and renal perivascular fibrosis. Contrary to our hypothesis, global P2X7 knockout had no impact on in vivo renal hemodynamics. Our study does not indicate a major role for P2X7 receptor activation in renal vascular injury.


Assuntos
Angiotensina II , Rim , Ratos Endogâmicos F344 , Receptores Purinérgicos P2X7 , Animais , Receptores Purinérgicos P2X7/metabolismo , Receptores Purinérgicos P2X7/genética , Masculino , Ratos , Rim/metabolismo , Rim/patologia , Feminino , Técnicas de Inativação de Genes , Macrófagos/metabolismo , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/genética , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia
20.
Transpl Int ; 37: 12556, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38650846

RESUMO

Macrophages contribute to post-transplant lung rejection. Disulfiram (DSF), an anti-alcoholic drug, has an anti-inflammatory effect and regulates macrophage chemotactic activity. Here, we investigated DSF efficacy in suppressing acute rejection post-lung transplantation. Male Lewis rats (280-300 g) received orthotopic left lung transplants from Fisher 344 rats (minor histocompatibility antigen-mismatched transplantation). DSF (0.75 mg/h) monotherapy or co-solvent only (50% hydroxypropyl-ß-cyclodextrin) as control was subcutaneously administered for 7 days (n = 10/group). No post-transplant immunosuppressant was administered. Grades of acute rejection, infiltration of immune cells positive for CD68, CD3, or CD79a, and gene expression of monocyte chemoattractant protein and pro-inflammatory cytokines in the grafts were assessed 7 days post-transplantation. The DSF-treated group had significantly milder lymphocytic bronchiolitis than the control group. The infiltration levels of CD68+ or CD3+ cells to the peribronchial area were significantly lower in the DSF than in the control groups. The normalized expression of chemokine ligand 2 and interleukin-6 mRNA in allografts was lower in the DSF than in the control groups. Validation assay revealed interleukin-6 expression to be significantly lower in the DSF than in the control groups. DSF can alleviate acute rejection post-lung transplantation by reducing macrophage accumulation around peripheral bronchi and suppressing pro-inflammatory cytokine expression.


Assuntos
Dissulfiram , Rejeição de Enxerto , Transplante de Pulmão , Macrófagos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Animais , Transplante de Pulmão/efeitos adversos , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/imunologia , Masculino , Dissulfiram/farmacologia , Dissulfiram/uso terapêutico , Ratos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Aloenxertos , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Quimiocina CCL2/metabolismo , Pulmão/patologia , Pulmão/efeitos dos fármacos
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