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2021 ◽  
Vol 23 (1) ◽  
pp. 234
Author(s):  
Sandra Díaz del Moral ◽  
Maha Benaouicha ◽  
Ramón Muñoz-Chápuli ◽  
Rita Carmona

Insulin and Insulin-like growth factors (IGFs) perform key roles during embryonic development, regulating processes of cell proliferation and survival. The IGF signalling pathway comprises two IGFs (IGF1, IGF2), two IGF receptors (IGFR1, IGFR2), and six IGF binding proteins (IGFBPs) that regulate IGF transport and availability. The IGF signalling pathway is essential for cardiac development. IGF2 is the primary mitogen inducing ventricular cardiomyocyte proliferation and morphogenesis of the compact myocardial wall. Conditional deletion of the Igf1r and the insulin receptor (Insr) genes in the myocardium results in decreased cardiomyocyte proliferation and ventricular wall hypoplasia. The significance of the IGF signalling pathway during embryonic development has led to consider it as a candidate for adult cardiac repair and regeneration. In fact, paracrine IGF2 plays a key role in the transient regenerative ability of the newborn mouse heart. We aimed to review the current knowledge about the role played by the IGF signalling pathway during cardiac development and also the clinical potential of recapitulating this developmental axis in regeneration of the adult heart.


Author(s):  
Ying Zhong ◽  
Rose C Mahoney ◽  
Zehedina Khatun ◽  
Howard H Chen ◽  
Christopher T. Nguyen ◽  
...  

During newborn lung injury, excessive activity of lysyl oxidases (LOXs) disrupts extracellular matrix (ECM) formation. Previous studies indicate that TGFβ activation in the O2-injured mouse pup lung increases lysyl oxidase (LOX) expression. But how TGFβ regulates this, and whether the LOXs generate excess pulmonary aldehydes are unknown. First, we determined that O2-mediated lung injury increases LOX protein expression in TGFβ-stimulated pup lung interstitial fibroblasts. This regulation appeared to be direct; this is because TGFβ treatment also increased LOX protein expression in isolated pup lung fibroblasts. Then using a fibroblast cell line, we determined that TGFβ stimulates LOX expression at a transcriptional level via Smad2/3-dependent signaling. LOX is translated as a pro-protein that requires secretion and extracellular cleavage before assuming amine oxidase activity and, in some cells, reuptake with nuclear localization. We found that pro-LOX is processed in the newborn mouse pup lung. Also, O2-mediated injury was determined to increase pro-LOX secretion and nuclear LOX immunoreactivity particularly in areas populated with interstitial fibroblasts and exhibiting malformed ECM. Then, using molecular probes, we detected increased aldehyde levels in vivo in O2-injured pup lungs, which mapped to areas of increased pro-LOX secretion in lung sections. Increased activity of LOXs plays a critical role in the aldehyde generation; an inhibitor of LOXs prevented the elevation of aldehydes in the O2-injured pup lung. These results reveal new mechanisms of TGFβ and LOX in newborn lung disease and suggest that aldehyde-reactive probes might have utility in sensing the activation of LOXs in vivo during lung.


2021 ◽  
Author(s):  
Brenda Moore ◽  
Yona Levites ◽  
Guilian Xu ◽  
Hailey Hampton ◽  
Munir F Adamo ◽  
...  

Abstract Background Seeding of pathology related to Alzheimer’s disease (AD) and Lewy body disease (LBD) by the injection of tissue homogenates, purified proteins, or recombinant proteins into model systems has revealed prion-like seeding of the protein aggregates that define these disorders. Most commonly these homogenates are injected into adult mice stereotaxically. Injection of brain lysates into newborn mice represents an alternative approach of delivering seeds that could be used to direct the evolution of amyloid-β (Aβ) pathology co-mixed with either tau or α-synuclein (αSyn) pathology in vulnerable mouse models. Methods Homogenates of human pre-frontal cortex were prepared and injected into the lateral ventricles of newborn (P0) mice expressing a mutant humanized amyloid precursor protein (APP), human P301L tau, human wild type αSyn, or combinations thereof. The injected brain homogenates were prepared from AD and AD/LBD cases displaying variable degrees of Aβ pathology and co-existing tau and αSyn deposits. Behavioral assessments of APP transgenic mice injected with AD brain lysates were conducted. Results We observed that the lysates from the brains of individuals with AD (Aβ+, tau+), AD/LBD (Aβ+, tau+, αSyn+), or Pathological Aging (Aβ+, tau-, αSyn-) efficiently seeded diffuse Aβ deposits, composed primarily of Aβ42 peptides, in our transgenic host animals. Moderate seeding of cerebral amyloid angiopathy (CAA) was also observed. No animal of any genotype developed discernable tau or αSyn pathology. Fear conditioning, cognitive, outcome was not significantly altered in APP transgenic animals injected with AD brain lysates compared to nontransgenic controls. Conclusions These findings demonstrate that diffuse Aβ pathology, which is a common feature of AD, AD/LBD, and PA brains, can be easily induced by injecting newborn APP mice with crude brain homogenates. Seeding of tau or αSyn comorbidities was disappointingly inefficient in the models we used, indicating additional methodological refinement will be needed to efficiently seed AD or AD/LBD mixed pathologies by injecting newborn mice.


Author(s):  
Jungsil Kim ◽  
Austin J. Cocciolone ◽  
Marius C. Staiculescu ◽  
Robert P. Mecham ◽  
Jessica E. Wagenseil

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2368
Author(s):  
Anh Cuong Hoang ◽  
Haidong Yu ◽  
Tamás Röszer

The present study sought to identify gene networks that are hallmarks of the developing inguinal subcutaneous adipose tissue (iWAT) and the interscapular brown adipose tissue (BAT) in the mouse. RNA profiling revealed that the iWAT of postnatal (P) day 6 mice expressed thermogenic and lipid catabolism transcripts, along with the abundance of transcripts associated with the beige adipogenesis program. This was an unexpected finding, as thermogenic BAT was believed to be the only site of nonshivering thermogenesis in the young mouse. However, the transcriptional landscape of BAT in P6 mice suggests that it is still undergoing differentiation and maturation, and that the iWAT temporally adopts thermogenic and lipolytic potential. Moreover, P6 iWAT and adult (P56) BAT were similar in their expression of immune gene networks, but P6 iWAT was unique in the abundant expression of antimicrobial proteins and virus entry factors, including a possible receptor for SARS-CoV-2. In summary, postnatal iWAT development is associated with a metabolic shift from thermogenesis and lipolysis towards fat storage. However, transcripts of beige-inducing signal pathways including β-adrenergic receptors and interleukin-4 signaling were underrepresented in young iWAT, suggesting that the signals for thermogenic fat differentiation may be different in early postnatal life and in adulthood.


2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Yanqing Guo ◽  
Linlin Bao ◽  
Yanfeng Xu ◽  
Fengdi Li ◽  
Qi Lv ◽  
...  

Zika virus (ZIKV) has attracted the wide global attention due to its causal link to microcephaly. In this study, two amino acid (aa) mutation (E143K and R3394K) were identified at the fourth generation (named ZKC2P4) during the serial passage of ZIKV-Asian lineage ZKC2/2016 strain in the newborn mouse brain, while another seven aa deletions in envelope (E) protein were detected in ZKC2P6. ZKC2P6 is a novel nonglycosylated E protein Asian ZIKV we first identified and provides the first direct supporting evidence that glycosylation motif could be lost during the passage in neonatal mice. To study the impact of E protein glycosylation ablation, we compared the pathogenicity of ZKC2P6 with that of ZKC2P4. The results showed that the loss of E protein glycosylation accelerated the disease progression, as evidenced by an earlier weight loss and death, a thinner cerebral cortex, and more serious tissue lesions and inflammation/necrosis. Furthermore, ZKC2P6 exhibited a greater ability to replicate and caused severer cell apoptosis than that of ZKC2P4. Therefore, the ablation of E glycosylation generally enhances the neurovirulence of ZIKV and cell apoptosis in newborn mice.


2021 ◽  
Vol 23 (2) ◽  
pp. 131-138
Author(s):  
Georgy N. Kokaya ◽  
Anna A. Kokaya ◽  
Vladimir P. Kozyakov ◽  
Aleksander Vladimirovich Zavirsky ◽  
Viktor V. Zatsepin ◽  
...  

It was found that acute exposure to ionizing radiation at doses of 7.5 and 8 Gy leads to the development of bone marrow syndrome of acute radiation sickness in mice. On the 7th day after exposure at doses of 7.5 Gy and 8 Gy, the mortality rate of animals was 66.7%, on the 10th day 83.3 and 86.7%, and by the 14th day it reached 91.7 and 100%, respectively. Prophylactic exposure to electromagnetic radiation from a helium-neon laser modulated with preparations with the tissue of the hypothalamic structures of the brain, spleen and bone marrow of a newborn mouse (P1-4) before X-ray irradiation at doses of 7.5 and 8 Gy contributed to a decrease in the mortality of animals from acute radiation sickness during the first 14 days, which was 28.6 and 50%, respectively. However, with this method of protective action, by the 22nd day after the radiation damage of 7.5 Gy, the mortality rate reached 64.3%, and 8 Gy-90%. On the contrary, with a therapeutic and preventive method of exposure to electromagnetic radiation by a helium-neon laser modulated by drugs with tissue from hypothalamic structures of the brain, spleen and bone marrow of a newborn mouse (R1-4) after a radiation lesion at a dose of 7.5 Gy, the mortality on the 25th day was 23.3%, and 8 Gy 30% and remained at this level for more than 30 days. We believe that the increase in the resistance of mice to ionizing radiation and the different nature of the course of acute radiation sickness with preventive and therapeutic methods of exposure is due to several factors. On the one hand, it is the realization of antihypoxic, antioxidant effects when exposed to electromagnetic radiation modulated by drugs with tissue from hypothalamic structures of the brain, spleen and bone marrow of a newborn mouse. On the other hand, the effect of electromagnetic radiation modulated by the preparation of the bone marrow and spleen of a newborn mouse has a cytoprotective effect on the bone marrow cells of mice with acute radiation sickness. It is also possible that this effect contributes to adequate neuroimmune regulation in the development of acute radiation sickness in mice.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tomoko Nakanishi ◽  
Aya Maekawa ◽  
Mariko Suzuki ◽  
Hirotaka Tabata ◽  
Kumiko Sato ◽  
...  

AbstractSimultaneous expression of multiplex guide RNAs (gRNAs) is valuable for knockout of multiple genes and also for effective disruption of a gene by introducing multiple deletions. We developed a method of Tetraplex-guide Tandem for construction of cosmids containing four and eight multiplex gRNA-expressing units in one step utilizing lambda in vitro packaging. Using this method, we produced an adenovirus vector (AdV) containing four multiplex-gRNA units for two double-nicking sets. Unexpectedly, the AdV could stably be amplified to the scale sufficient for animal experiments with no detectable lack of the multiplex units. When the AdV containing gRNAs targeting the H2-Aa gene and an AdV expressing Cas9 nickase were mixed and doubly infected to mouse embryonic fibroblast cells, deletions were observed in more than 80% of the target gene even using double-nicking strategy. Indels were also detected in about 20% of the target gene at two sites in newborn mouse liver cells by intravenous injection. Interestingly, when one double-nicking site was disrupted, the other was simultaneously disrupted, implying that two genes in the same cell may simultaneously be disrupted in the AdV system. The AdVs expressing four multiplex gRNAs could offer simultaneous knockout of four genes or two genes by double-nicking cleavages with low off-target effect.


Author(s):  
Lina Zhang ◽  
Ping Wang ◽  
Yanhong Shen ◽  
Tao Huang ◽  
Xiaoyun Hu ◽  
...  

Objective Bronchopulmonary dysplasia (BPD) is a pulmonary injury related to inflammation and is a major cause of premature infant death. Long noncoding RNAs (lncRNAs) are important regulators in pulmonary injury and inflammation. We investigated the molecular mechanism of lncRNA H19 in pulmonary injury and inflammation in hyperoxia (Hyp)-induced BPD mice. Study Design The BPD newborn mouse model was established and intervened with H19 to evaluate the pathologic conditions and radial alveolar count (RAC) in lung tissues of mice in the room air (RA) and Hyp group on the 4th, 7th, and 14th days after birth. The levels of BPD-related biomarkers vascular endothelial growth factor (VEGF), transforming growth factor β1 (TGF-β1), and surfactant protein C (SPC) in lung tissues were detected on the 14th day after birth. The expression of and relationships among H19 and miR-17, miR-17, and STAT3 were detected and verified. Levels of interleukin (IL)-6, IL-1β, p-STAT3, and STAT3 levels in mouse lung tissues were detected on the 14th day after birth. Results Hyp-induced mice showed increased alveolar diameter, septum, and hyperemia and inflammatory cell infiltration, upregulated H19, decreased overall number and significantly reduced RAC on the 7th and 14th days after birth, which were reversed in the si-H19-treated mice. VEGF was upregulated and TGF-β1 and SPC was decreased in si-H19-treated mice. Moreover, H19 competitively bound to miR-17 to upregulate STAT3. IL-6 and IL-1β expressions and p-STAT3 and STAT3 levels were downregulated after inhibition of H19. Conclusion Downregulated lncRNA H19 relieved pulmonary injury via targeting miR-17 to downregulate STAT3 and reduced inflammatory response caused by p-STAT3 in BPD newborn mice. Key Points


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