The pathogenic potential of the combined action of chronic Opisthorchis felineus infection and repeated social defeat stress in C57BL/6 mice

Parasitic food-borne diseases and chronic social stress are frequent attributes of day-to-day human life. Therefore, our aim was to model the combined action of chronic Opisthorchis felineus infection and repeated social defeat stress in C57BL/6 mice. Histological examination of the liver revealed inflammation sites, pronounced periductal fibrosis, and cholangiofibrosis together with proliferation of bile ducts and hepatocyte dystrophy in the infected mice, especially in the stress-exposed ones. Simultaneously with liver pathology, we detected significant structural changes in the cerebral cortex. Immunohistochemical analysis of the hippocampus indicated the highest increase in numerical density of Iba 1-, IL-6-, iNOS-, and Arg1-positive cells in mice simultaneously subjected to the two adverse factors. The number of GFAP-positive cells rose during repeated social defeat stress, most strongly in the mice subjected to both infection and stress. Real-time PCR analysis showed that the expression of genes Aif1 and Il6 differed among the analysed brain regions (hippocampus, hypothalamus, and frontal cortex) and depended on the adverse factors applied. In addition, among the brain regions, there was no consistent increase or decrease in these parameters when the two adverse treatments were combined: (i) in the hippocampus, there was upregulation of Aif1 and no change in Il6 expression; (ii) in the hypothalamus, expression levels of Aif1 and Il6 were not different from controls; and (iii) in the frontal cortex, Aif1 expression did not change while Il6 expression increased. It can be concluded that a combination of two long-lasting adverse factors, O. felineus infection and repeated social defeat stress, worsens not only the hepatic but also brain state, as evidenced behaviorally by disturbances of the startle response in mice.     

Strategic Habitat Conservation for Beach Mice: Estimating Management Scenario Efficiencies

The Perdido Key beach mouse (Peromyscus polionotus trissyllepsis), Choctawhatchee beach mouse (P. p. allophrys), and St. Andrew beach mouse (P. p. peninsularis) are 3 federally endangered subspecies that inhabit coastal dunes of Alabama and Florida, USA. Conservation opportunities for these subspecies are limited and costly. Consequently, well-targeted efforts are required to achieve their downlisting criteria. To aid the development of targeted management scenarios that are designed to achieve downlisting criteria, we developed a Bayesian network model that uses habitat characteristics to predict the probability of beach mouse presence at a 30-m resolution across a portion of the Florida Panhandle. We then designed alternative management scenarios for a variety of habitat conditions for coastal dunes. Finally, we estimated how much area is needed to achieve the established downlisting criterion (i.e., habitat objective) and the amount of effort needed to achieve the habitat objective (i.e., management efficiency). The results suggest that after 7 years of post-storm recolonization, habitat objectives were met for Perdido Key (within its Florida critical habitat) and Choctawhatchee beach mice. The St. Andrew beach mouse required 5.14 km² of additional critical habitat to be protected and occupied. The St. Andrew beach mouse habitat objective might be achieved by first restoring protected critical habitat to good dune conditions and then protecting or restoring the unprotected critical habitat with the highest predicted probability of beach mouse presence. This scenario provided a 28% increase in management efficiency compared to a scenario that randomly protected or restored undeveloped unprotected critical habitat. In total, when coupled with established downlisting criteria, these quantitative and spatial decision support tools could provide insight into how much habitat is available, how much more is needed, and targeted conservation or restoration efforts that might efficiently achieve habitat objectives. © 2020 The Wildlife Society.     

α1-肾上腺素受体对胶原诱导性关节炎小鼠Treg细胞功能的影响*

目的: 利用胶原诱导性关节炎 (CIA) 模型小鼠,探讨去甲肾上腺素 (NE) 及其α1-肾上腺素受体 (AR ) 对CIA小鼠Treg细胞的作用。方法: 雄性DBA/1小鼠 32 只,随机分为对照组 (n=8) 和CIA模型组 (n=24)。II型胶原 (CII) 乳剂100 μl 尾根部注射DBA/1小鼠制备CIA小鼠模型,在初次免疫后第 41 日,用免疫荧光法检测小鼠脾脏中CD4⁺T与α1-AR的共定位情况;用Western blot法检测小鼠踝关节和脾脏中α1-AR的蛋白表达。分离纯化CIA小鼠脾脏中CD4⁺ T细胞,用抗CD3和抗CD28的单克隆抗体刺激CD4⁺T细胞,进行细胞培养,分为未加药组和加药组,加药组用NE或α1-AR激动剂苯肾上腺素 (phenylephrine) 处理细胞,用流式细胞术检测CIA小鼠CD4⁺T细胞中Treg的细胞数;用Western blot法检测CIA小鼠CD4⁺T中转化生长因子-β (TGF-β) 和IL-10的蛋白表达。结果: CD4⁺ T细胞能够表达α1-AR;与对照组相比,CIA小鼠踝关节和脾脏中α1-AR的蛋白表达显著降低(P＜0.01);与未加药的CIA小鼠的CD4⁺ T细胞相比,NE加入后的CIA小鼠CD4⁺ T细胞中Treg细胞的功能显著增强(P＜0.01);α1-AR激动剂phenylephrine加入后的CIA小鼠CD4⁺ T细胞中Treg细胞的功能显著增强(P＜ 0.01)。结论: 激活CIA小鼠CD4⁺ T细胞上的α1-AR可增强Treg细胞的功能,促进CD4⁺ T细胞向Treg细胞方向分化,发挥抗炎作用。     

Bone phenotype of P2X4 receptor knockout mice: implication of a P2X7 receptor mutation?

Transgenic and knockout animal models are widely used to investigate the role of receptors, signaling pathways, and other peptides and proteins. Varying results are often published on the same model from different groups, and much effort has been put into understanding the underlying causes of these sometimes conflicting results. Recently, it has been shown that a P2X4R knockout model carries a so-called passenger mutation in the P2X7R gene, potentially affecting the interpretation of results from studies using this animal model. We therefore report this case to raise awareness about the potential pitfalls using genetically modified animal models, especially within P2 receptor research. Although purinergic signaling has been recognized as an important contributor to the regulation of bone remodeling, the process that maintains the bone quality during life, little is known about the role of the P2X4 receptor (P2X4R) in regulation of bone remodeling in health and disease. To address this, we analyzed the bone phenotype of P2rx4tm1Rass (C57BL/6J) knockout mice and corresponding wildtype using microCT and biomechanical testing. Overall, we found that the P2X4R knockout mice displayed improved bone microstructure and stronger bones in an age- and gender-dependent manner. While cortical BMD, trabecular BMD, and bone volume were higher in the 6-month-old females and 3-month-old males, this was not the case for the 3-month-old females and the 6-month-old males. Bone strength was only affected in the females. Moreover, we found that P2X4R KO mice carried the P2X7 receptor 451P wildtype allele, whereas the wildtype mice carried the 451L mutant allele. In conclusion, this study suggests that P2X4R could play a role in bone remodeling, but more importantly, it underlines the potential pitfalls when using knockout models and highlights the importance of interpreting results with great caution. Further studies are needed to verify any specific effects of P2X4R on bone metabolism.

     

Chronic antioxidant therapy reduces oxidative stress in a mouse model of Alzheimer's disease

Oxidative modifications are a hallmark of oxidative imbalance in the brains of individuals with Alzheimer's, Parkinson's and prion diseases and their respective animal models. While the causes of oxidative stress are relatively well-documented, the effects of chronically reducing oxidative stress on cognition, pathology and biochemistry require further clarification. To address this, young and aged control and amyloid-β protein precursor-over-expressing mice were fed a diet with added R-alpha lipoic acid for 10 months to determine the effect of chronic antioxidant administration on the cognition and neuropathology and biochemistry of the brain. Both wild type and transgenic mice treated with R-alpha lipoic acid displayed significant reductions in markers of oxidative modifications. On the other hand, R-alpha lipoic acid had little effect on Y-maze performance throughout the study and did not decrease end-point amyloid-β load. These results suggest that, despite the clear role of oxidative stress in mediating amyloid pathology and cognitive decline in ageing and AβPP-transgenic mice, long-term antioxidant therapy, at levels within tolerable nutritional guidelines and which reduce oxidative modifications, have limited benefit.     

Regulation of DNA glycosylases and their role in limiting disease

Abstract

This review will present a current understanding of mechanisms for the initiation of base excision repair (BER) of oxidatively-induced DNA damage and the biological consequences of deficiencies in these enzymes in mouse model systems and human populations.     

The α1-adrenergic receptors: diversity of signaling networks and regulation

The α₁-adrenergic receptor (AR) subtypes (α_1a, α_1b, and α_1d) mediate several physiological effects of epinephrine and norepinephrine. Despite several studies in recombinant systems and insight from genetically modified mice, our understanding of the physiological relevance and specificity of the α₁-AR subtypes is still limited. Constitutive activity and receptor oligomerization have emerged as potential features regulating receptor function. Another recent paradigm is that βarrestins and G protein-coupled receptors themselves can act as scaffolds binding a variety of proteins and this can result in growing complexity of the receptor-mediated cellular effects. The aim of this review is to summarize our current knowledge on some recently identified functional paradigms and signaling networks that might help to elucidate the functional diversity of the α₁-AR subtypes in various organs.     

The effect of substituted thiophene and benzothiophene derivates on PPARγ expression and glucose metabolism

Eighteen substituted thiophene and benzothiophene derivatives were studied for their effects on peroxisome proliferator-activated receptor γ (PPARγ) in HepG2 cells. Three derivatives (compounds 5, 120.97%; 15, 102.14%; and 17, 113.82%) were found to transactivate PPARγ in vitro. By comparison, the positive control rosiglitazone (Ros) transactivated PPARγ by 311.53%. The three compounds were studied for their effects on glucose metabolism in vivo in KK/Ay diabetic mice. In vivo, the 2-(β-carbonyl/sulfonyl) butyryl-thiophene compounds 5 and 15 significantly decreased blood glucose levels (compounds 5, to?<?15.6?mmol/L; 15, to?<?10?mmol/L), improved glucose tolerance, improved impaired pancreatic islet β-cells, and lowered serum insulin levels.