Toll-like receptor 9 negatively regulates pancreatic islet beta cell growth and function in a mouse model of type 1 diabetes

Aims/hypothesis Innate immune effectors interact with the environment to contribute to the pathogenesis of the autoimmune disease, type 1 diabetes. Although recent studies have suggested that innate immune Toll-like receptors (TLRs) are involved in tissue development, little is known about the role of TLRs in tissue development, compared with autoimmunity. We aimed to fill the knowledge gap by investigating the role of TLR9 in the development and function of islet beta cells in type 1 diabetes, using NOD mice. Methods We generated Tlr9−/− NOD mice and examined them for type 1 diabetes development and beta cell function, including insulin secretion and glucose tolerance. We assessed islet and beta cell number and characterised CD140a expression on beta cells by flow cytometry. We also tested beta cell function in Tlr9−/− C57BL/6 mice. Finally, we used TLR9 antagonists to block TLR9 signalling in wild-type NOD mice to verify the role of TLR9 in beta cell development and function. Results TLR9 deficiency promoted pancreatic islet development and beta cell differentiation, leading to enhanced glucose tolerance, improved insulin sensitivity and enhanced first-phase insulin secretory response. This was, in part, mediated by upregulation of CD140a (also known as platelet-derived growth factor receptor-α [PDGFRα]). In the absence of TLR9, induced by either genetic targeting or treatment with TLR9 antagonists, which had similar effects on ontogenesis and function of beta cells, NOD mice were protected from diabetes. Conclusions/interpretation Our study links TLR9 and the CD140a pathway in regulating islet beta cell development and function and indicates a potential therapeutic target for diabetes prevention and/or treatment

Deacetylation of HSD17B10 by SIRT3 regulates cell growth and cell resistance under oxidative and starvation stresses.

17-beta-hydroxysteroid dehydrogenase 10 (HSD17B10) plays an important role in mitochondrial fatty acid metabolism and is also involved in mitochondrial tRNA maturation. HSD17B10 missense mutations cause HSD10 mitochondrial disease (HSD10MD). HSD17B10 with mutations identified from cases of HSD10MD show loss of function in dehydrogenase activity and mitochondrial tRNA maturation, resulting in mitochondrial dysfunction. It has also been implicated to play roles in the development of Alzheimer disease (AD) and tumorigenesis. Here, we found that HSD17B10 is a new substrate of NAD-dependent deacetylase Sirtuin 3 (SIRT3). HSD17B10 is acetylated at lysine residues K79, K99 and K105 by the acetyltransferase CBP, and the acetylation is reversed by SIRT3. HSD17B10 acetylation regulates its enzymatic activity and the formation of mitochondrial RNase P. Furthermore, HSD17B10 acetylation regulates the intracellular functions, affecting cell growth and cell resistance in response to stresses. Our results demonstrated that acetylation is an important regulation mechanism for HSD17B10 and may provide insight into interrupting the development of AD

Qishen Yiqi dripping pills for chronic ischaemic heart failure:results of the CACT-IHF randomized clinical trial

10.1002/ehf2.12980ESC Heart Failure763881-389

The gut microbiome in atherosclerotic cardiovascular disease

The gut microbiota may play a role in cardiovascular diseases. Here, the authors perform a metagenome-wide association study on stools from individuals with atherosclerotic cardiovascular disease and healthy controls, identifying microbial strains and functions associated with the disease

Research on the deformation and failure depth of the floor in fully mechanized top coal caving of extra-thick seam

In order to explore the deformation and failure depth of the floor under the condition of fully mechanized top coal caving of extra-thick coal seam, this paper takes 1305 working face of Dongtan Coal Mine of Yankuang Energy Group Co., Ltd. as the background. The deformation and failure depth of the floor in the mining coal seam of the working face is comprehensively analyzed by using field measurement, numerical simulation and theoretical calculation. The field measurement results using the strain induction method and borehole imaging technology show the following results. The floor is affected by mining ground pressure, and there are obvious characteristics in horizontal and vertical directions. In the horizontal direction, the position near the advanced support measuring point of 50 m and at the depth of 10 m in the shallow part of the floor starts to be affected by the mining ground pressure. After the working face is pushed over a certain distance, the deformation and failure of the floor are severe. The variation range of crossover distance and lag distance in the horizontal direction of different depths of the floor is 96-115 m and 48-52 m respectively. The deformation and failure depth of the floor in fully mechanized top coal caving of the working face is 16-20 m. The floor rock below the vertical depth of 20 m is mainly elastic deformation. The distribution characteristics of the plastic zone in different depths of the floor by numerical simulation show that the farther the distance from the working face floor is, the smaller the influence of mining pressure is, and the smaller the range of the plastic zone is. The 20 m under the floor is basically not damaged. The result of the theoretical calculation confirms that the deformation and failure depth of the floor is 19.2 m. Based on the results of field measurement, numerical simulation and theoretical calculation, the deformation and failure depth of the floor in 1305 working face is less than 20 m. The research results can provide the quantitative basis for the prevention and control of floor water disasters in fully mechanized top coal caving of extra-thick coal seams