double transgenic mice
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Author(s):  
Joachim Neumann ◽  
Denise Schwarzer ◽  
Charlotte Fehse ◽  
Rebecca Schwarz ◽  
Margareta Marusakova ◽  
...  

AbstractIn the past, we generated transgenic mice that overexpress the human histamine 2 (H2)-receptor (H2-TG) or that overexpress the human serotonin 4 (5-HT4)-receptor (5-HT4-TG) in the heart. Here, we crossbred these lines of mice to generate double transgenic mice that overexpress both receptors (DT). This was done to study a conceivable interaction between these receptors in the mouse heart as a model for the human heart. When in left atria, initially, force of contraction was elevated maximally with 1 µM serotonin, and subsequently, histamine was cumulatively applied; a biphasic effect of histamine was noted: the force of contraction initially decreased, maximally at 10 nM histamine, and thereafter, the force of contraction increased again at 1 µM histamine. Notably, functional interaction between 5-HT and histamine was also identified in isolated electrically stimulated trabeculae carneae from human right atrium (obtained during cardiac surgery). These functional and biochemical data together are consistent with a joint overexpression of inotropically active H2-receptors and 5-HT4-receptors in the same mouse heart. We also describe an antagonistic interaction on the force of contraction of both receptors in the mouse atrium (DT) and in the human atrial muscle strips. We speculate that via this interaction, histamine might act as a “brake” on the cardiac actions of 5-HT via inhibitory GTP-binding proteins acting on the activity of adenylyl cyclase.


2021 ◽  
Vol 22 (17) ◽  
pp. 9448
Author(s):  
Mara-Francine Dörner ◽  
Peter Boknik ◽  
Friedrich Köpp ◽  
Igor B. Buchwalow ◽  
Joachim Neumann ◽  
...  

As part of our ongoing studies on the potential pathophysiological role of serine/threonine phosphatases (PP) in the mammalian heart, we have generated transgenic mice with cardiac muscle cell-specific overexpression of PP2Acα (PP2A) and PP5 (PP5). For further studies we crossbred PP2A and PP5 mice to obtain PP2AxPP5 double transgenic mice (PP2AxPP5, DT) and compared them with littermate wild-type mice (WT) serving as a control. The mortality of DT mice was greatly enhanced vs. other genotypes. Cardiac fibrosis was noted histologically and mRNA levels of collagen 1α, collagen 3α and fibronectin 1 were augmented in DT. DT and PP2A mice exhibited an increase in relative heart weight. The ejection fraction (EF) was reduced in PP2A and DT but while the EF of PP2A was nearly normalized after β-adrenergic stimulation by isoproterenol, it was almost unchanged in DT. Moreover, left atrial preparations from DT were less sensitive to isoproterenol treatment both under normoxic conditions and after hypoxia. In addition, levels of the hypertrophy markers atrial natriuretic peptide and B-type natriuretic peptide as well as the inflammation markers interleukin 6 and nuclear factor kappa B were increased in DT. PP2A enzyme activity was enhanced in PP2A vs. WT but similar to DT. This was accompanied by a reduced phosphorylation state of phospholamban at serine-16. Fittingly, the relaxation times in left atria from DT were prolonged. In summary, cardiac co-overexpression of PP2A and PP5 were detrimental to animal survival and cardiac function, and the mechanism may involve dephosphorylation of important regulatory proteins but also fibrosis and inflammation.


2021 ◽  
Vol 11 ◽  
Author(s):  
Risheng Ma ◽  
Syed A. Morshed ◽  
Rauf Latif ◽  
Terry F. Davies

BackgroundMany tissues, including the thyroid, contain resident (adult) stem cells that are responsible for regeneration and repair after injury. The mechanisms of thyroid regeneration and the role of thyroid stem cells and thyroid progenitor cells in this process are not well understood. We have now used a new mouse thyroid injury model to gain insight into this phenomenon.MethodsTamoxifen induced TPO-Cre mice (TPOCreER2) were crossed with inducible Diphtheria Toxin Receptor homozygous mice (ROSA26iDTR) to give rise to TPOCreER2/iDTR mice, allowing for the Cre-mediated expression of the DTR and rendering TPO expressing thyroid cells highly sensitive to diphtheria toxin (DT). This model of TPOCreER2/iDTR mice allowed us to study the repair/regeneration of thyroid follicles after diphtheria toxin induced thyroid damage by measuring serum thyroid hormones and cell fate.ResultsIn TPOCreER2/iDTR double transgenic mice we observed severe thyroid damage as early as 2 weeks after initiating intraperitoneal DT injections. There was marked thyroid tissue apoptosis and a ~50% drop in serum T4 levels (from 5.86 to 2.43 ug/dl) and a corresponding increase in serum TSH (from 0.18 to 8.39 ng/dl). In addition, there was a ~50% decrease in transcription of thyroid specific genes (thyroglobulin, TSH receptor, and sodium-iodide symporter). After suspending the DT administration, the thyroid rapidly recovered over a 4-week period during which we observed a transient surge in stem cell marker expression (including Oct4, Nanog, Sox2, and Rex1). In addition, cells immunostaining with stem cell markers Oct4 and Ssea-1 were found in clusters around new thyroid follicles in TPOCreER2/iDTR double transgenic mice. Furthermore, the presence of clusters of thyroid progenitor cells was also identified by Pax8 staining of thyroglobulin negative cells. This recovery of the injured gland was followed by a rapid and sequential restoration of thyroid function.ConclusionThese data demonstrate that a new model of thyroid cell damage induced by DT can be used to study the mobilization of resident adult stem cells. Furthermore, the model clearly demonstrates the involvement of both stem and progenitor cells in the in vivo regeneration of the thyroid after severe destruction.


2021 ◽  
Vol 36 ◽  
pp. 153331752110276
Author(s):  
Yuchen He ◽  
Yi Qiang

This paper studied the influence of exercise on the cognitive ability of AD patients and elucidated potential mechanisms. The expression of SNHG14 was validated by qRT-PCR. The cognitive impairment of mice was examined by MWM Test. ELISA tests were applied to discover the influence of SNHG14 on inflammation. Overexpression of SNHG14 was found in AD patients and underexpression of SNHG14 was identified in these AD patients after exercise. In APP/PS1 double transgenic mice, SNHG14 reversed the protective impacts of exercise on escape latency and distance moved. The upregulation of SNHG14 also inhibited the effects of exercise on the percentage of time spent in the target quadrant and times of platform crossing. Besides, overexpression of SNHG14 reversed the repressed expression of IL-6, IL-1β, and TNF-α. In total, exercise could ameliorate cognitive disorder and inflammation activity by reducing the levels of SNHG14.


2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Zhourui Wu ◽  
Xia Liu ◽  
Liming Cheng ◽  
Keqiang Ye

AbstractAlzheimer’s disease (AD) is the most common neurodegenerative disease with multifactorial pathologies including Aβ containing senile plaques and neurofibrillary tangles (NFT) consisted of aggregated Tau. Most of the AD patients are sporadic and the familial mutation hereditary patients are composed only 1% of all cases. However, the current AD mouse models employ mutated APP, PS1, or even Tau mutant, in order to display a portion of AD pathologies. Delta-secretase (legumain, or asparaginyl endopeptidase, AEP) simultaneously cleaves both APP and Tau and augments Aβ production and Tau hyperphosphorylation and aggregation, contributing to AD pathogenesis. Here we show that δ-secretase is sufficient to promote prominent AD pathologies in wild-type hAPP/hMAPT double transgenic mice. We crossed hAPP l5 mice and hMAPT mice to generate double transgenic mouse model carrying both human wild-type APP and Tau. Compared to the single transgenic parents, these double transgenic mice demonstrated AD-related pathologies in one-year-old hAPP/hMAPT mice. Notably, overexpression of δ-secretase in hAPP/hMAPT double-transgenic mice evidently accelerated enormous senile plaques and NFT, associated with prominent synaptic defects and cognitive deficits. Hence, δ-secretase facilitates AD pathogenesis independent of any patient-derived mutation.


2020 ◽  
Vol 12 ◽  
Author(s):  
Zequn Yin ◽  
Xuerui Wang ◽  
Shihong Zheng ◽  
Peichang Cao ◽  
Yuanli Chen ◽  
...  

Alzheimer’s disease (AD) is the most common form of dementia in the elderly. It may be caused by oxidative stress, inflammation, and cerebrovascular dysfunctions in the brain. LongShengZhi Capsule (LSZ), a traditional Chinese medicine, has been approved by the China Food and Drug Administration for treatment of patients with cardiovascular/cerebrovascular disease. LSZ contains several neuroprotective ingredients, including Hirudo, Astmgali Radix, Carthami Flos (Honghua), Persicae Semen (Taoren), Acori Tatarinowii Rhizoma (Shichangpu), and Acanthopanax Senticosus (Ciwujia). In this study, we aimed to determine the effect of LSZ on the AD process. Double transgenic mice expressing the amyloid-β precursor protein and mutant human presenilin 1 (APP/PS1) to model AD were treated with LSZ for 7 months starting at 2 months of age. LSZ significantly improved the cognition of the mice without adverse effects, indicating its high degree of safety and efficacy after a long-term treatment. LSZ reduced AD biomarker Aβ plaque accumulation by inhibiting β-secretase and γ-secretase gene expression. LSZ also reduced p-Tau expression, cell death, and inflammation in the brain. Consistently, in vitro, LSZ ethanol extract enhanced neuronal viability by reducing L-glutamic acid-induced oxidative stress and inflammation in HT-22 cells. LSZ exerted antioxidative effects by enhancing superoxide dismutase and glutathione peroxidase expression, reduced Aβ accumulation by inhibiting β-secretase and γ-secretase mRNA expression, and decreased p-Tau level by inhibiting NF-κB-mediated inflammation. It also demonstrated neuroprotective effects by regulating the Fas cell surface death receptor/B-cell lymphoma 2/p53 pathway. Taken together, our study demonstrates the antioxidative stress, anti-inflammatory, and neuroprotective effects of LSZ in the AD-like pathological process and suggests it could be a potential medicine for AD treatment.


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