Activation of the IKK2/NF-κB pathway in VSMCs inhibits calcified vascular stiffness in CKD

IKK2/NF-κB pathway–mediated inflammation in vascular smooth muscle cells (VSMCs) has been proposed to be an etiologic factor in medial calcification and stiffness. However, the role of the IKK2/NF-κB pathway in medial calcification remains to be elucidated. In this study, we found that chronic kidney disease (CKD) induces inflammatory pathways through the local activation of the IKK2/NF-κB pathway in VMSCs associated with calcified vascular stiffness. Despite reducing the expression of inflammatory mediators, complete inhibition of the IKK2/NF-κB pathway in vitro and in vivo unexpectedly exacerbated vascular mineralization and stiffness. In contrast, activation of NF-κB by SMC-specific IκBα deficiency attenuated calcified vascular stiffness in CKD. Inhibition of the IKK2/NF-κB pathway induced cell death of VSMCs by reducing anti–cell death gene expression, whereas activation of NF-κB reduced CKD-dependent vascular cell death. In addition, increased calcification of extracellular vesicles through the inhibition of the IKK2/NF-κB pathway induced mineralization of VSMCs, which was significantly reduced by blocking cell death in vitro and in vivo. This study reveals that activation of the IKK2/NF-κB pathway in VSMCs plays a protective role in CKD-dependent calcified vascular stiffness by reducing the release of apoptotic calcifying extracellular vesicles

Activating transcription factor-4 promotes mineralization in vascular smooth muscle cells

Emerging evidence indicates that upregulation of the ER stress–induced pro-osteogenic transcription factor ATF4 plays an important role in vascular calcification, a common complication in patients with aging, diabetes, and chronic kidney disease (CKD). In this study, we demonstrated the pathophysiological role of ATF4 in vascular calcification using global Atf4 KO, smooth muscle cell–specific (SMC-specific) Atf4 KO, and transgenic (TG) mouse models. Reduced expression of ATF4 in global ATF4-haplodeficient and SMC-specific Atf4 KO mice reduced medial and atherosclerotic calcification under normal kidney and CKD conditions. In contrast, increased expression of ATF4 in SMC-specific Atf4 TG mice caused severe medial and atherosclerotic calcification. We further demonstrated that ATF4 transcriptionally upregulates the expression of type III sodium-dependent phosphate cotransporters (PiT1 and PiT2) by interacting with C/EBPβ. These results demonstrate that the ER stress effector ATF4 plays a critical role in the pathogenesis of vascular calcification through increased phosphate uptake in vascular SMCs

Action of dexmedetomidine on the substantia gelatinosa neurons of the rat spinal cord

Dexmedetomidine is a highly specific, potent and selective α2-adrenoceptor agonist. Although intrathecal and epidural administration of dexmedetomidine has been found to produce analgesia, whether this analgesia results from an effect on spinal cord substantia gelatinosa (SG) neurons remains unclear. Here, we investigated the effects of dexmedetomidine on postsynaptic transmission in SG neurons of rat spinal cord slices using the whole-cell patch-clamp technique. In 92% of the SG neurons examined (n= 84), bath-applied dexmedetomidine induced outward currents at −70 mV in a concentration-dependent manner, with the value of effective concentration producing a half-maximal response (0.62 μm). The outward currents induced by dexmedetomidine were suppressed by the α2-adrenoceptor antagonist yohimbine, but not by prazosin, an α1-, α2B- and α2C-adrenoceptor antagonist. Moreover, the dexmedetomidine-induced currents were partially suppressed by the α2C-adrenoceptor antagonist JP-1302, while simultaneous application of JP-1302 and the α2A-adrenoceptor antagonist BRL44408 abolished the current completely. The action of dexmedetomidine was mimicked by the α2A-adrenoceptor agonist oxymetazoline. Plots of the current–voltage relationship revealed a reversal potential at around −86 mV. Dexmedetomidine-induced currents were blocked by the addition of GDP-β-S [guanosine-5′-O-(2-thiodiphosphate)] or Cs+ to the pipette solution. These findings suggest that dexmedetomidine hyperpolarizes the membrane potentials of SG neurons by G-protein-mediated activation of K+ channels through α2A- and α2C-adrenoceptors. This action of dexmedetomidine might contribute, at least in part, to its antinociceptive action in the spinal cord

Measurement and comparison of individual external doses of high-school students living in Japan, France, Poland and Belarus -- the "D-shuttle" project --

Twelve high schools in Japan (of which six are in Fukushima Prefecture), four in France, eight in Poland and two in Belarus cooperated in the measurement and comparison of individual external doses in 2014. In total 216 high-school students and teachers participated in the study. Each participant wore an electronic personal dosimeter "D-shuttle" for two weeks, and kept a journal of his/her whereabouts and activities. The distributions of annual external doses estimated for each region overlap with each other, demonstrating that the personal external individual doses in locations where residence is currently allowed in Fukushima Prefecture and in Belarus are well within the range of estimated annual doses due to the background radiation level of other regions/countries

The gut microbiota and cardiovascular health benefits: a focus on wholegrain oats

Existing scientific data suggest that a high intake of wholegrain foods contributes to improved gut health and a reduced risk of cardiovascular disease. Wholegrain oats are rich in dietary fibre and an important source of many bioactive components, including minerals, vitamins and phenolic compounds. The oat β‐glucans have been reported to lower low‐density lipoprotein cholesterol through their ability to increase the viscosity of intestinal chime, change the gut microbiota composition and increase the production of short‐chain fatty acids, which may contribute to the inhibition of hepatic cholesterol synthesis. Oats are also a rich source of phenolic acids, which are predominantly bound to cell wall polysaccharides through ester bonds. This bound state within oats means that phenolic acid bioavailability will largely be determined by interactions with the colonic microbiota in the large intestine. However, results from in vitro, animal and human studies have been inconsistent in relation to the impact of oats on the gut microbiota, possibly due to differences in experimental techniques and because compounds in oats, other than β‐glucans, have not been considered. This review focuses on the interaction of oat β‐glucans and phenolic acids with gut microbiota, and the subsequent link to cardiovascular health

Pharmacological Applications of Bile Acids and Their Derivatives in the Treatment of Metabolic Syndrome

Apart from well-known functions of bile acids in digestion and solubilization of lipophilic nutrients and drugs in the small intestine, the emerging evidence from the past two decades identified the role of bile acids as signaling, endocrine molecules that regulate the glucose, lipid, and energy metabolism through complex and intertwined pathways that are largely mediated by activation of nuclear receptor farnesoid X receptor (FXR) and cell surface G protein-coupled receptor 1, TGR5 (also known as GPBAR1). Interactions of bile acids with the gut microbiota that result in the altered composition of circulating and intestinal bile acids pool, gut microbiota composition and modified signaling pathways, are further extending the complexity of biological functions of these steroid derivatives. Thus, bile acids signaling pathways have become attractive targets for the treatment of various metabolic diseases and metabolic syndrome opening the new potential avenue in their treatment. In addition, there is a significant effort to unveil some specific properties of bile acids relevant to their intrinsic potency and selectivity for particular receptors and to design novel modulators of these receptors with improved pharmacokinetic and pharmacodynamic profiles. This resulted in synthesis of few semi-synthetic bile acids derivatives such as 6a-ethyl-chenodeoxycholic acid (obeticholic acid, OCA), norursodeoxycholic acid (norUDCA), and 12-monoketocholic acid (12-MKC) that are proven to have positive effect in metabolic and hepato-biliary disorders. This review presents an overview of the current knowledge related to bile acids implications in glucose, lipid and energy metabolism, as well as a potential application of bile acids in metabolic syndrome treatment with future perspectives

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection