Ischemia‐reperfusion injury. A phenomenon,that also occurs in the bone

Ischemia‐reperfusion injury of the bone occurs due to traumatic and non‐traumatic alterations affecting blood supply to the bone. It is likely to occur also upon insertion of an implant. Ischemia‐reperfusion injury of the bone has been studied by interruption of blood supply in situ, in limb replantation/transplantation models, in revascularized bone grafts and non‐vascularized bone fragments, as well as in isolated cultured cells. All cells of the bone are affected, including osteoblasts, osteocytes, osteoclasts, chondrocytes, and bone marrow cells. Critical ischemia times for induction of bone cell death, either in the ischemic period or following reperfusion, are in the range of 3 to 7 h. These critical ischemia times are significantly increased by decreasing the temperature from 37 °C to 0–4 °C. Anoxia is the most likely trigger of cell injury in the ischemic phase. In the reperfusion phase, reactive oxygen species are decisively involved in the injurious process. In general, however, the available information on the mechanism of ischemia‐reperfusion injury of the bone is relatively sparse. On the other hand, there are clear similarities to the mechanisms of ischemia‐reperfusion injury known from other organs, and there is a clear potential for protection against ischemia‐reperfusion injury of the bone.     

Lipid-Lowering Effect of Eriocitrin, the Main Flavonoid in Lemon Fruit, in Rats on a High-Fat and High-Cholesterol Diet

ABSTRACT:  Eriocitrin (eriodictyol 7- O -β-rutinoside) is the main flavonoid in lemon fruit. In this study, eriocitrin was investigated for its lowering effect on serum and hepatic lipids in high-fat and high-cholesterol fed rats. Rats in the control group ( N = 6) were fed a 20% lard and 1% cholesterol diet for 21 d, and rats in the 0.35% eriocitrin group ( N = 6) and 0.70% eriocitrin group ( N = 6) were fed a diet supplemented with eriocitrin 0.35% and 0.70%, respectively. The content of hepatic total cholesterol and triglyceride in the eriocitrin group was no different from that of the control group. The total cholesterol, VLDL+LDL, triglyceride, and phospholipid in the serum of the 0.35% eriocitrin group showed significantly lower concentrations than the control group ( P < 0.05), although there was no difference in the HDL concentrations among the groups. The lowering effect of eriocitrin for serum total cholesterol was thought to be caused by a decrease in VLDL+LDL. The 0.35% eriocitrin group was shown to have a significant increase in excretion of fecal bile acid ( P < 0.05) and a tendency for enhanced hepatic m-RNA levels of LDL receptor in comparison with the control group.     

Thick bone section preparation using a silicon-rubber-based sealant

A method has been developed, using a silicon-rubber-based sealant, which allows 2–3-mm-thick specimens to be maintained in a protected fluid environment for a number of months, without risk of dehydration. Following this, the specimen can be retrieved, stained, embedded and sectioned further. For example, 2-mm-thick sections of fixed unstained bone are easily examined by means of epi-illuminated polarized light and fluorescence microscopies using either conventional or confocal optics. The method could easily be extended to other tissues, for example brain tissue.     

基于全信息新陈代谢的GM（1，1）电力预测

传统的灰色预测模型所需的样本容量较少,仅4个数据就可以建立灰色预测模型。虽然传统的灰预测建模较为简单,但是忽略了对预测较为确利的新信息,容易产生预测模型老化的现象,预测精度不高。全信息新陈代谢的GM（1,1）灰色预测模型更为合理、科学,全信息建模避免了局部信息建模的局限性,每预测一个结果去除原始数列的最老数据的新陈代谢处理保证了预测数列的实效性,并用Matlab实现改进GM（1,1）模型的编程计算,应用于双流县电力需求量的预测,预测精度好。     

Polycyclic Aromatic Hydrocarbons Activate the Aryl Hydrocarbon Receptor and the Constitutive Androstane Receptor to Regulate Xenobiotic Metabolism in Human Liver Cells

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants produced by incomplete combustion of organic matter. They induce their own metabolism by upregulating xenobiotic-metabolizing enzymes such as cytochrome P450 monooxygenase 1A1 (CYP1A1) by activating the aryl hydrocarbon receptor (AHR). However, previous studies showed that individual PAHs may also interact with the constitutive androstane receptor (CAR). Here, we studied ten PAHs, different in carcinogenicity classification, for their potential to activate AHR- and CAR-dependent luciferase reporter genes in human liver cells. The majority of investigated PAHs activated AHR, while non-carcinogenic PAHs tended to activate CAR. We further characterized gene expression, protein abundancies and activities of the AHR targets CYP1A1 and 1A2, and the CAR target CYP2B6 in human HepaRG hepatoma cells. Enzyme induction patterns strongly resembled the profiles obtained at the receptor level, with AHR-activating PAHs inducing CYP1A1/1A2 and CAR-activating PAHs inducing CYP2B6. In summary, this study provides evidence that beside well-known activation of AHR, some PAHs also activate CAR, followed by subsequent expression of respective target genes. Furthermore, we found that an increased PAH ring number is associated with AHR activation as well as the induction of DNA double-strand breaks, whereas smaller PAHs activated CAR but showed no DNA-damaging potential.     

Increased Bone Resorption during Lactation in Pycnodysostosis

Pycnodysostosis, a rare autosomal recessive skeletal dysplasia, is caused by a deficiency of cathepsin K. Patients have impaired bone resorption in the presence of normal or increased numbers of multinucleated, but dysfunctional, osteoclasts. Cathepsin K degrades collagen type I and generates N-telopeptide (NTX) and the C-telopeptide (CTX) that can be quantified. Levels of these telopeptides are increased in lactating women and are associated with increased bone resorption. Nothing is known about the consequences of cathepsin K deficiency in lactating women. Here we present for the first time normalized blood and CTX measurements in a patient with pycnodysostosis, exclusively related to the lactation period. In vitro studies using osteoclasts derived from blood monocytes during lactation and after weaning further show consistent bone resorption before and after lactation. Increased expression of cathepsins L and S in osteoclasts derived from the lactating patient suggests that other proteinases could compensate for the lack of cathepsin K during the lactation period of pycnodysostosis patients.     

Energy Metabolites as Biomarkers in Ischemic and Dilated Cardiomyopathy

With more than 25 million people affected, heart failure (HF) is a global threat. As energy production pathways are known to play a pivotal role in HF, we sought here to identify key metabolic changes in ischemic- and non-ischemic HF by using a multi-OMICS approach. Serum metabolites and mRNAseq and epigenetic DNA methylation profiles were analyzed from blood and left ventricular heart biopsy specimens of the same individuals. In total we collected serum from n = 82 patients with Dilated Cardiomyopathy (DCM) and n = 51 controls in the screening stage. We identified several metabolites involved in glycolysis and citric acid cycle to be elevated up to 5.7-fold in DCM (p = 1.7 × 10⁻⁶). Interestingly, cardiac mRNA and epigenetic changes of genes encoding rate-limiting enzymes of these pathways could also be found and validated in our second stage of metabolite assessment in n = 52 DCM, n = 39 ischemic HF and n = 57 controls. In conclusion, we identified a new set of metabolomic biomarkers for HF. We were able to identify underlying biological cascades that potentially represent suitable intervention targets.     

A Holistic Evolutionary and 3D Pharmacophore Modelling Study Provides Insights into the Metabolism,Function, and Substrate Selectivity of the Human Monocarboxylate Transporter 4 (hMCT4)

Monocarboxylate transporters (MCTs) are of great research interest for their role in cancer cell metabolism and their potential ability to transport pharmacologically relevant compounds across the membrane. Each member of the MCT family could potentially provide novel therapeutic approaches to various diseases. The major differences among MCTs are related to each of their specific metabolic roles, their relative substrate and inhibitor affinities, the regulation of their expression, their intracellular localization, and their tissue distribution. MCT4 is the main mediator for the efflux of L-lactate produced in the cell. Thus, MCT4 maintains the glycolytic phenotype of the cancer cell by supplying the molecular resources for tumor cell proliferation and promotes the acidification of the extracellular microenvironment from the co-transport of protons. A promising therapeutic strategy in anti-cancer drug design is the selective inhibition of MCT4 for the glycolytic suppression of solid tumors. A small number of studies indicate molecules for dual inhibition of MCT1 and MCT4; however, no selective inhibitor with high-affinity for MCT4 has been identified. In this study, we attempt to approach the structural characteristics of MCT4 through an in silico pipeline for molecular modelling and pharmacophore elucidation towards the identification of specific inhibitors as a novel anti-cancer strategy.