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Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 156
Author(s):  
Razia Sultana Mohammad ◽  
Mustafa F. Lokhandwala ◽  
Anees A. Banday

Age is one of the major risk factors for the development of chronic pathologies, including kidney diseases. Oxidative stress and mitochondrial dysfunction play a pathogenic role in aging kidney disease. Transcription factor NRF2, a master regulator of redox homeostasis, is altered during aging, but the exact implications of altered NRF2 signaling on age-related renal mitochondrial impairment are not yet clear. Herein, we investigated the role of sulforaphane, a well-known NRF2 activator, on age-related mitochondrial and kidney dysfunction. Young (2–4 month) and aged (20–24 month) male Fischer 344 rats were treated with sulforaphane (15 mg/kg body wt/day) in drinking water for four weeks. We observed significant impairment in renal cortical mitochondrial function along with perturbed redox homeostasis, decreased kidney function and marked impairment in NRF2 signaling in aged Fischer 344 rats. Sulforaphane significantly improved mitochondrial function and ameliorated kidney injury by increasing cortical NRF2 expression and activity and decreasing protein expression of KEAP1, an NRF2 repressor. Sulforaphane treatment did not affect the renal NRF2 expression or activity and mitochondrial function in young rats. Taken together, our results provide novel insights into the protective role of the NRF2 pathway in kidneys during aging and highlight the therapeutic potential of sulforaphane in mitigating kidney dysfunction in elders.


2021 ◽  
Vol 26 (4) ◽  
pp. 277-288
Author(s):  
Soo In Choi ◽  
Nayoung Kim ◽  
Ryoung Hee Nam ◽  
Ji Hyun Park ◽  
Heewon Nho ◽  
...  

2021 ◽  
pp. 2100552
Author(s):  
Iván Escobar‐Martínez ◽  
Verónica Arreaza‐Gil ◽  
Begoña Muguerza ◽  
Anna Arola‐Arnal ◽  
Francisca Isabel Bravo ◽  
...  

2021 ◽  
pp. 019262332110536
Author(s):  
Debra A. Tokarz ◽  
Margarita M. Gruebbel ◽  
Gabrielle A. Willson ◽  
Jerry F. Hardisty ◽  
Gail Pearse ◽  
...  

Spontaneous primary pleural mesotheliomas in Fischer 344 (F344) or other rat strains have rarely been reported. The objectives of this retrospective study were to develop historical incidence data and better characterize the light-microscopic morphology of these naturally occurring neoplasms in a large cohort of rats of several strains. A retrospective review was performed of National Toxicology Program (NTP) studies in rats conducted between 1980 and 2019 and comprising a total of 104,029 rats (51,326 males, 52,703 females), predominantly (90%) of the F344 strain. Of the 94,062 F344 rats surveyed, there were 30 cases of primary pleural mesotheliomas (22 males, 8 females). Of the 2998 Wistar Han rats surveyed, primary pleural mesotheliomas were present in 2 male rats. No primary pleural mesotheliomas were noted in male and female rats of other strains (6669 Sprague Dawley; 300 Osborne-Mendel). All primary pleural mesotheliomas in control and treated F344 and Wistar Han rats were considered spontaneous and unrelated to treatment. Based on light-microscopic evaluation of paraffin-embedded hematoxylin and eosin stained sections, only epithelioid and biphasic histologic subtypes were observed: 18 and 12 in F344 rats, respectively, and one each in Wistar Han rats. No sarcomatoid subtype cases were noted in any strain of rat.


Author(s):  
Giovanni E Finesso ◽  
Ross A McDevitt ◽  
Roshni Roy ◽  
Lauren R Brinster ◽  
Andrea Di Francesco ◽  
...  

Abstract Age-dependent differences in methylation at specific cytosine-guanosine sites (CpGs) have been used in “epigenetic clock” formulas to predict age. Deviations of epigenetic age from chronological age are informative of health status and are associated with adverse health outcomes, including mortality. In most cases, epigenetic clocks are performed on methylation from DNA extracted from circulating blood cells. However, the effect of neoplastic cells in the circulation on estimation and interpretation of epigenetic clocks is not well understood. Here, we explored this using Fischer 344 (F344) rats, a strain that often develops large granular lymphocyte leukemia (LGL). We found clear histological markers of LGL pathology in the spleens and livers of 27 out of 61 rats aged 17-27 months. We assessed DNA methylation by reduced representation bisulfite sequencing with coverage of 3 million cytosine residues. Although LGL broadly increased DNA methylation variability, it did not change epigenetic aging. Despite this, inclusion of rats with LGL in clock training sets significantly altered predictor selection probability at 83 of 121 commonly utilized CpGs. Furthermore, models trained on rat samples that included individuals with LGL had greater absolute age error than those trained exclusively on LGL-free rats (39% increase; p<0.0001). We conclude that the epigenetic signals for aging and LGL are distinct, such that LGL assessment is not necessary for valid measures of epigenetic age in F344 rats. The precision and architecture of constructed epigenetic clock formulas, however, can be influenced by the presence of neoplastic hematopoietic cells in training set populations.


2021 ◽  
Vol 22 (21) ◽  
pp. 11360
Author(s):  
Jorge Antonio Silva-Gomez ◽  
Marina Galicia-Moreno ◽  
Ana Sandoval-Rodriguez ◽  
Hipolito Otoniel Miranda-Roblero ◽  
Silvia Lucano-Landeros ◽  
...  

Targeted therapies for regulating processes such as inflammation, apoptosis, and fibrogenesis might modulate human HCC development. Pirfenidone (PFD) has shown anti-fibrotic and anti-inflammatory functions in both clinical and experimental studies. The aim of this study was to evaluate PPARγ expression and localization in samples of primary human tumors and assess PFD-effect in early phases of hepatocarcinogenic process. Human HCC tissue samples were obtained by surgical resection. Experimental hepatocarcinogenesis was induced in male Fischer-344 rats. TGF-β1 and α-SMA expression was evaluated as fibrosis markers. NF-kB cascade, TNFα, IL-6, and COX-2 expression and localization were evaluated as inflammation indicators. Caspase-3, p53, and PARP-1 were used as apoptosis markers, PCNA for proliferation. Finally, PPARα and PPARγ expression were evaluated to understand the effect of PFD on the activation of such pathways. PPARγ expression was predominantly localized in cytoplasm in human HCC tissue. PFD was effective to prevent histopathological damage and TGF-β1 and α-SMA overexpression in the experimental model. Anti-inflammatory effects of PFD correlate with diminished IKK and decrease in both IkB-phosphorylation/NF-kB p65 expression and p65-translocation into the nucleus. Pro-apoptotic PFD-induced effects are related with p53 expression, Caspase-3 p17 activation, and PARP-1-cleavage. In conclusion, PFD acts as a tumor suppressor by preventing fibrosis, reducing inflammation, and promoting apoptosis in MRHM.


Nutrients ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 3643
Author(s):  
Ma. Josefina Ruiz de Azua ◽  
Álvaro Cruz-Carrión ◽  
Begoña Muguerza ◽  
Anna Arola-Arnal ◽  
Manuel Suarez

The phytochemical composition of fruits, especially polyphenols, depends on the environmental conditions under which these fruits are cultivated and the agronomic practices followed. Therefore, the consumption of fruits from different origins, with different polyphenol signatures, could have differential effects on health. In addition, recent studies have shown that variation in the biological rhythms due to changes in the photoperiod in the different seasons differentially affect the metabolism in animal models, thus conditioning their response to food consumption. Considering all, this article evaluates the effects of consumption of sweet cherry from different sources, local (LC) and non-local (nLC), on plasma metabolic parameters and the gene expression of key enzymes of lipid metabolism in Fischer 344 rats under photoperiods simulating different seasons. Animals were classified into three photoperiods (L6, L12 and L18) and three treatments (LC, nLC and VH). Both the photoperiod and the treatments significantly affected the evaluated parameters. An effect of the photoperiod on triacylglycerides, non-esterified fatty acids and the mRNA concentration of crucial enzymes from the hepatic lipid metabolism was observed. Furthermore, the consumption of fruit in L12 lowered blood glucose, while the different treatments affected the hepatic expression of genes related with lipidic enzymes.


Author(s):  
Caitlin Fowler ◽  
Dana Goerzen ◽  
Dan Madularu ◽  
Gabriel A. Devenyi ◽  
M. Mallar Chakravarty ◽  
...  

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 638
Author(s):  
Julie A. Lovchik ◽  
Douglas S. Reed ◽  
Julie A. Hutt ◽  
Fangfang Xia ◽  
Rick L. Stevens ◽  
...  

Pneumonic tularemia is a highly debilitating and potentially fatal disease caused by inhalation of Francisella tularensis. Most of our current understanding of its pathogenesis is based on the highly virulent F. tularensis subsp. tularensis strain SCHU S4. However, multiple sources of SCHU S4 have been maintained and propagated independently over the years, potentially generating genetic variants with altered virulence. In this study, the virulence of four SCHU S4 stocks (NR-10492, NR-28534, NR-643 from BEI Resources and FTS-635 from Battelle Memorial Institute) along with another virulent subsp. tularensis strain, MA00-2987, were assessed in parallel. In the Fischer 344 rat model of pneumonic tularemia, NR-643 and FTS-635 were found to be highly attenuated compared to NR-10492, NR-28534, and MA00-2987. In the NZW rabbit model of pneumonic tularemia, NR-643 caused morbidity but not mortality even at a dose equivalent to 500x the LD50 for NR-10492. Genetic analyses revealed that NR-10492 and NR-28534 were identical to each other, and nearly identical to the reference SCHU S4 sequence. NR-643 and FTS-635 were identical to each other but were found to have nine regions of difference in the genomic sequence when compared to the published reference SCHU S4 sequence. Given the genetic differences and decreased virulence, NR-643/FTS-635 should be clearly designated as a separate SCHU S4 substrain and no longer utilized in efficacy studies to evaluate potential vaccines and therapeutics against tularemia.


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