Expression and function of microRNA-188-5p in activated rheumatoid arthritis synovial fibroblasts

Activated synovial fibroblasts in rheumatoid arthritis (RASF) play a critical role in the pathology of rheumatoid arthritis (RA). Recent studies suggested that deregulation of microRNAs (miRs) affects the development and progression of RA. Therefore, we aimed to identify de-regulated miRs in RASF and to identify target genes that may contribute to the aggressive phenotype of RASF. Quantitative real-time PCR revealed a marked downregulation of miR-188-5p in synovial tissue samples of RA patients as well as in RASF. Exposure to the cytokine interleukine-1β lead to a further downregulation of miR-188-5p expression levels compared to control cells. Re-expression of miR-188-5p in RASF by transient transfection significantly inhibited cell migration. However, miR-188-5p re-expression had no effects on glycosaminoglycan degradation or expression of repellent factors, which have been previously shown to affect the invasive behavior of RASF. In search for target genes of miR-188-5p in RASF we performed gene expression profiling in RASF and found a strong regulatory effect of miR-188-5p on the hyaluronan binding protein KIAA1199 as well as collagens COL1A1 and COL12A1, which was confirmed by qRT-PCR. In silico analysis revealed that KIAA1199 carries a 3’UTR binding site for miR-188-5p. COL1A1 and COL12A1 showed no binding site in the mRNA region, suggesting an indirect regulation of these two genes by miR-188-5p. In summary, our study showed that miR-188-5p is down-regulated in RA in vitro and in vivo, most likely triggered by an inflammatory environment. MiR-188-5p expression is correlated to the activation state of RASF and inhibits migration of these cells. Furthermore, miR-188-5p is directly and indirectly regulating the expression of genes, which may play a role in extracellular matrix formation and destruction in RA. Herewith, this study identified potential novel therapeutic targets to inhibit the development and progression of RA.     

The development of autoimmune features in aging mice is closely associated with alterations of the peripheral CD4+ T‐cell compartment

Some signs of potential autoimmunity, such as the appearance of antinuclear antibodies (ANAs) become prevalent with age. In most cases, elderly people with ANAs remain healthy. Here, we investigated whether the same holds true for inbred strains of mice. Indeed, we show that most mice of the C57BL/6 (B6) strain spontaneously produced IgG ANA at 8–12 months of age, showed IgM deposition in kidneys and lymphocyte infiltrates in submandibular salivary glands. Despite all of this, the mice remained healthy. ANA production is likely CD4⁺ T‐cell dependent, since old (40–50 weeks of age) B6 mice deficient for MHC class II do not produce IgG ANAs. BM chimeras showed that ANA production was not determined by age‐related changes in radiosensitive, hematopoietic progenitor cells, and that the CD4⁺ T cells that promote ANA production were radioresistant. Thymectomy of B6 mice at 5 weeks of age led to premature alterations in T‐cell homeostasis and ANA production, by 15 weeks of age, similar to that in old mice. Our findings suggest that a disturbed T‐cell homeostasis may drive the onset of some autoimmune features.     

St. John's Wort Reduces Beta‐Amyloid Accumulation in a Double Transgenic Alzheimer's Disease Mouse Model—Role of P‐Glycoprotein

The adenosine triphosphate‐binding cassette transport protein P‐glycoprotein (ABCB1) is involved in the export of beta‐amyloid from the brain into the blood, and there is evidence that age‐associated deficits in cerebral P‐glycoprotein content may be involved in Alzheimer''s disease pathogenesis. P‐glycoprotein function and expression can be pharmacologically induced by a variety of compounds including extracts of Hypericum perforatum (St. John''s Wort). To clarify the effect of St. John''s Wort on the accumulation of beta‐amyloid and P‐glycoprotein expression in the brain, St. John''s Wort extract (final hyperforin concentration 5%) was fed to 30‐day‐old male C57BL/6J‐APP/PS1 ^+/− mice over a period of 60 or 120 days, respectively. Age‐matched male C57BL/6J‐APP/PS1 ^+/− mice receiving a St. John''s Wort‐free diet served as controls. Mice receiving St. John''s Wort extract showed (i) significant reductions of parenchymal beta‐amyloid 1–40 and 1–42 accumulation; and (ii) moderate, but statistically significant increases in cerebrovascular P‐glycoprotein expression. Thus, the induction of cerebrovascular P‐glycoprotein may be a novel therapeutic strategy to protect the brain from beta‐amyloid accumulation, and thereby impede the progression of Alzheimer''s disease.     

Left ventricular mass and function with reduced-fat or reduced-carbohydrate hypocaloric diets in overweight and obese subjects

In animals, carbohydrate and fat composition during dietary interventions influenced cardiac metabolism, structure, and function. Because reduced-carbohydrate and reduced-fat hypocaloric diets are commonly used in the treatment of obesity, we investigated whether these interventions differentially affect left ventricular mass, cardiac function, and blood pressure. We randomized 170 overweight and obese subjects (body mass index, 32.9±4.4; range, 26.5-45.4 kg/m(2)) to 6-month hypocaloric diets with either reduced carbohydrate intake or reduced fat intake. We obtained cardiac MRI and ambulatory blood pressure recordings over 24 hours before and after 6 months. Ninety subjects completing the intervention period had a full cardiac MRI data set. Subjects lost 7.3±4.0 kg (7.9±3.8%) with reduced-carbohydrate diet and 6.2±4.2 kg (6.7±4.4%) with reduced-fat diet (P<0.001 within each group; P=not significant between interventions). Caloric restriction led to similar significant decreases in left ventricular mass with low-carbohydrate diets (5.4±5.4 g) or low-fat diets (5.2±4.8 g; P<0.001 within each group; P=not significant between interventions). Systolic and diastolic left ventricular function did not change with either diet. The 24-hour systolic blood pressure decreased similarly with both interventions. Body weight change (β=0.33; P=0.02) and percentage of ingested n-3 polyunsaturated fatty acids (β=-0.27; P=0.03) predicted changes in left ventricular mass. In conclusion, weight loss induced by reduced-fat diets or reduced-carbohydrate diets similarly improved left ventricular mass in overweight and obese subjects over a 6-month period. However, n-3 polyunsaturated fatty acid ingestion may have an independent beneficial effect on left ventricular mass.