Macrophage secretion of miR-106b-5p causes renin-dependent hypertension.

Myeloid cells are known mediators of hypertension, but their role in initiating renin-induced hypertension has not been studied. Vitamin D deficiency causes pro-inflammatory macrophage infiltration in metabolic tissues and is linked to renin-mediated hypertension. We tested the hypothesis that impaired vitamin D signaling in macrophages causes hypertension using conditional knockout of the myeloid vitamin D receptor in mice (KODMAC). These mice develop renin-dependent hypertension due to macrophage infiltration of the vasculature and direct activation of renal juxtaglomerular (JG) cell renin production. Induction of endoplasmic reticulum stress in knockout macrophages increases miR-106b-5p secretion, which stimulates JG cell renin production via repression of transcription factors E2f1 and Pde3b. Moreover, in wild-type recipient mice of KODMAC/miR106b-/- bone marrow, knockout of miR-106b-5p prevents the hypertension and JG cell renin production induced by KODMAC macrophages, suggesting myeloid-specific, miR-106b-5p-dependent effects. These findings confirm macrophage miR-106b-5p secretion from impaired vitamin D receptor signaling causes inflammation-induced hypertension.

Effect of Al(3+) co-doping on the luminescence properties of Cu doped Na2SiF6.

Studies were carried out to assess the correlation between thermoluminescence (TL) and optically stimulated luminescence (OSL) of this phosphor. It was observed that the OSL and TL glow curve consists of a wide distribution of traps having different photo-ionization cross-sections, trap depths and frequency factors. In case of Al doped sample, some of the traps up to 200°C are assumed to act as a source traps for the observance of OSL due to thermal transfer of charge carriers into the deep traps beyond 480°C. This suggests that Al impurities play an important role in the thermal transfer OSL process. As most of the work on this phenomenon is done on natural materials (mainly quartz) in which aluminum is a natural impurity, this study will explain the role of Al in this phenomenon.

Optically stimulated luminescence studies in combustion synthesized Al2O3:C,Cu,P.

A new Al2O3:C,Cu,P phosphor is developed by the combustion synthesis technique which exhibits entirely different OSL properties as compared to that of the commercial alumina. No thermoluminescence (TL) is observed in this phosphor which also differentiates the present phosphor from the commercially available Al2O3:C (Landauer). The phosphor shows good optically stimulated luminescence (OSL) sensitivity for ionizing radiation with a fast OSL decay as compared to the commercial Al2O3:C. The phosphor heated in air followed by heating under the reactive atmosphere exhibits maximum sensitivity amongst several other phosphors. On the basis of area integration method; integrated over initial 3s, the sensitivity of this phosphor is about 67% of that of commercial Al2O3:C.

Na2SiF6:Cu,P: a new OSL phosphor for the radiation dosimetric applications.

A new Cu,P-doped, sodium fluorosilicate-based optically stimulated luminescence (OSL) phosphor is developed. This phosphor shows good OSL properties, and the sensitivity is comparable with that of the commercial Al(2)O(3):C (Landauer, Inc.) phosphor. For the luminescence averaged over initial 1 s, blue-stimulated luminescence and green-stimulated luminescence sensitivities were found to be 0.76 and 3.8 times, respectively, of Al(2)O(3):C (Landauer, Inc.) with 28 % of post-irradiation fading in 3 days and nil thereafter. The simple preparation procedure, fast decay, very good sensitivity and moderate fading will make this phosphor suitable for radiation dosimetry, using OSL.

Dosimetric investigations of Tb3+-doped strontium silicate phosphor.

Tb(3+)-doped SrSiO(3) phosphor synthesised by co-precipitation technique exhibits intense green emission due to cross-relaxation phenomena between Tb(3+) ions. Dosimetric properties of this phosphor have been investigated using thermoluminescence (TL) technique. A dosimetrically useful glow peak observed was at 581 K along with a linear dose response over the wide dose range (100 mGy-4 Gy). TL parameters such as trap depth (E), frequency factor (s) and the order of kinetics (b) are determined by different methods such as Chen's peak shape, initial rise, isothermal decay and variable heating rate methods. Results of these methods are compared and reported in this study.

Reduced incidence and severity of experimental autoimmune arthritis in mice expressing catalytically inactive A disintegrin and metalloproteinase 8 (ADAM8).

A disintegrin and metalloproteinase 8 (ADAM8), a catalytically active member of the ADAMs family of enzymes, is expressed primarily on immune cells and thus probably involved in inflammatory responses. ADAM8 is also produced by chondrocytes, and recombinant ADAM8 can induce cartilage catabolism. We therefore decided to test the role of ADAM8 in autoimmune inflammatory arthritis using transgenic mice expressing catalytically inactive ADAM8. Transgenic DBA/1J mice expressing an inactivating point mutation in the ADAM8 gene to change Glu330 to Gln330 (ADAM8(EQ)) were generated to evaluate the proteolytic function of ADAM8 in an lipopolysaccharide-synchronized collagen-induced arthritis (LPS-CIA) model of autoimmune arthritis. The systemic inflammatory reaction to LPS was also evaluated in these mice. Expression profiling of paw joints from wild-type mice revealed that ADAM8 mRNA levels increased at the onset of clinical arthritis and correlated well with cellular macrophage markers. When subjected to LPS-CIA, ADAM8(EQ) mice demonstrated decreased incidence and severity of clinical arthritis compared to wild-type mice. Histological examination of paw joints from ADAM8(EQ) mice confirmed marked attenuation of synovial inflammation, cartilage degradation and bone resorption when compared to wild-type mice. However, transgenic mice and wild-type mice responded similarly to LPS-induced systemic inflammation with regard to mortality, organ weights, neutrophil sequestration and serum cytokine/chemokine production. We conclude that ADAM8 proteolytic activity plays a key role in the development of experimental arthritis and may thus be an attractive target for the treatment of arthritic disorders while minimizing risk of immunocompromise.

Transcriptional profiling and pathway analysis of monosodium iodoacetate-induced experimental osteoarthritis in rats: relevance to human disease.

OBJECTIVE: The objective of this study was to characterize the rat monosodium iodoacetate (MIA)-induced model for osteoarthritis (OA) and determine the translatability of this model to human disease. This was accomplished through pathway, network and system level comparisons of transcriptional profiles generated from animal and human disease cartilage. METHODS: An OA phenotype was induced in rat femorotibial joints following a single injection of 200mug MIA per knee joint for a period of 2 or 4 weeks. Lesion formation in the rat joints was confirmed by histology. Gene expression changes were measured using the Agilent rat whole genome microarrays. Cartilage was harvested from human knees and gene expression changes were measured using the Agilent human arrays. RESULTS: One thousand nine hundred and forty-three oligos were differentially expressed in the MIA model, of these, approximately two-thirds were up-regulated. In contrast, of the 2130 differentially expressed oligos in human disease tissue, approximately two-thirds were down-regulated. This dramatic difference was observed throughout each level of the comparison. The total overlap of genes modulated in the same direction between rat and human was less than 4%. Matrix degradation and inflammatory genes were differentially regulated to a much greater extent in MIA than human disease tissue. CONCLUSION: This study demonstrated, through multiple levels of analysis, that little transcriptional similarity exists between rat MIA and human OA derived cartilage. As disease modulatory activities for potential therapeutic agents often do not translate from animal models to human disease, this and like studies may provide a basis for understanding the discrepancies.