Medication-related osteonecrosis of the jaw (MRONJ) represents a complication of bisphosphonate treatment that responds poorly to standard treatment. In a retrospective cohort study we investigated a possible role of Actinomyces spp. in the pathogenesis of MRONJ. Deep biopsies of necrotic bone were collected during surgical treatment of MRONJ and evaluated by histology and microbiology for the presence of Actinomyces spp. Microbiological, demographic and clinicpathological data were analyzed for risk of Actinomyces-associated MRONJ. Between 2005 and 2014, 111 patients suffering from histologically-confirmed MRONJ were identified. Actinomyces spp. were detected in 99 cases (89%) by histology and in six further patients by microbiological culture. A diverse microbial flora was found in all specimens without association with Actinomyces spp. Demographic and clinicopathological characteristics did not separate significantly Actinomyces-positive from Actinomyces-negative cases. Our observations confirm previous reports of a high prevalence of Actinomyces spp. in MRONJ in the single largest cohort available up to now. The high prevalence of Actinomyces spp. and the lack of clinicopathological risk factors underline the prominent role of Actinomyces spp. in MRONJ and may change the current understanding of MRONJ. Established prolonged antimicrobial treatment regimens against Actinomyces spp. infection could therefore be a mainstay of future MRONJ management.

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Adiponectin is an adipocyte-derived adipokine with potent antidiabetic, anti-inflammatory, and antiatherogenic activity. Long-term, high-fat diet results in gain of body weight, adiposity, further inflammatory-based cardiovascular diseases, and reduced adiponectin secretion. Vitamin A derivatives/retinoids are involved in several of these processes, which mainly take place in white adipose tissue (WAT). In this study, we examined adiponectin expression as a function of dietary high-fat and high–vitamin A conditions in mice. A decrease of adiponectin expression in addition to an up-regulation of aldehyde dehydrogenase A1 (ALDH1A1), retinoid signaling, and retinoic acid response element signaling was selectively observed in WAT of mice fed a normal–vitamin A, high-fat diet. Reduced adiponectin expression in WAT was also observed in mice fed a high–vitamin A diet. Adipocyte cell culture revealed that endogenous and synthetic retinoic acid receptor (RAR)α- and RARγ-selective agonists, as well as a synthetic retinoid X receptor agonist, efficiently reduced adiponectin expression, whereas ALDH1A1 expression only increased with RAR agonists. We conclude that reduced adiponectin expression under high-fat dietary conditions is dependent on 1) increased ALDH1A1 expression in adipocytes, which does not increase all-trans-retinoic acid levels; 2) further RAR ligand–induced, WAT-selective, increased retinoic acid response element–mediated signaling; and 3) RAR ligand–dependent reduction of adiponectin expression.—Landrier, J.-F., Kasiri, E., Karkeni, E., Mihály, J., Béke, G., Weiss, K., Lucas, R., Aydemir, G., Salles, J., Walrand, S., de Lera, A. R., Rühl, R. Reduced adiponectin expression after high-fat diet is associated with selective up-regulation of ALDH1A1 and further retinoic acid receptor signaling in adipose tissue.

9 Abstract Nuclear hormone receptors are transcription 10 factors that can be activated by nutrition-derived ligands 11 and alter the expression of various specific target genes. 12 Stearoyl-Coenzyme A desaturase (SCD1) converts palmitic 13 acid (16:0) to palmitoleic acid (16:1n-7) as well as stearic 14 acid (18:0) to oleic acid (18:1n-9). At the same time, 15 elongase 6 (ELOVL6) elongates 16:1n-7 and 18:1n-9 to 16 vaccenic acid (18:1n-7) and eicosenoic acid (20:1n-9). We 17 examined how synthetic selective ligands of nuclear hor-18 mone receptors alter the gene expression of hepatic 19 enzymes in mice. In addition, we examined how the regu-20 lation of these two enzymes influences fatty acid compo-21 sition of phospholipids in liver and plasma. Mice were 22 gavaged daily for 1 week with synthetic ligands of perox-23 isome proliferator-activated receptor (PPAR) a, b/d, c, liver 24 X receptor (LXR), retinoic acid receptor (RAR) and reti-25 noid-X receptor (RXR) for 1 week. Phospholipids from 26 liver and plasma were analysed using ESI-MS/MS and GC 27 after saponification. Hepatic gene expression of SCD1 and 28 ELOVL6 was measured using QRT-PCR. SCD1 and 29 ELOVL6 expression increased after the gavage of LXR and 30 RXR ligands. The analysis of fatty acid composition of total 31 phospholipids in plasma and liver showed increased per-32 centage contributions of the SCD1 and ELOVL6 products 33 18:1n-9, 18:1n-7 and 20:1n-9 after LXR and RXR ligand 34 application. Analysis of total phospholipids from plasma 35 and liver revealed a significant increase in monounsaturated 36 fatty acids bound in phosphatidylcholine (PtdCho)

Dietary fat and vitamin A provide important precursors for potent bioactive ligands of nuclear hormone receptors, which regulate various enzymes involved in lipid homeostasis, metabolism and inflammation. We determined the effects of dietary fat and dietary vitamin A on hepatic expression of two fatty acid metabolizing enzymes, elongase 6 (ELOVL6) and stearoyl-coenzyme A desaturase 1 (SCD1) and the concentration of saturated fatty acids (SAFA) and monounsaturated fatty acid (MUFA) of phospholipids in serum and liver. Mice (n = 6) were fed 4 weeks with diets containing 2, 5 and 25 % of fat or vitamin A (0, 2,500 and 326,500 RE/kg as retinyl palmitate). MUFAs and SAFAs were measured using GC and ESI-MS/MS. Hepatic expression of metabolizing enzymes was determined using QRT-PCR. ELOVL6 was significantly down-regulated in response to a high-fat diet (p < 0.001) and significantly up-regulated in response to low-fat diet (p < 0.05). SCD1 expression was significantly lower in high- versus low-fat diet (p < 0.05). The vitamin A content in the diet did not influence the hepatic expression of both enzymes. In plasma, the amounts of MUFAs bound to phospholipids significantly decreased in response to a high-fat diet and increased after a low-fat diet. This tendency was also observed in the liver for various phospholipids sub-classes. In summary, this study shows that fat content in the diet has a stronger impact than the content of vitamin A on hepatic gene expression of SCD1 and ELOVL6 and thereby on MUFA and SAFA concentrations in liver and plasma.