Tetracyclines convert the osteoclastic-differentiation pathway of progenitor cells to produce dendritic cell-like cells

Tetracyclines, such as doxycycline and minocycline, are used to suppress the growth of bacteria in patients with inflammatory diseases. Tetracyclines have been shown to prevent bone loss, but the mechanism involved is unknown. Osteoclasts and dendritic cells (DCs) are derived from common progenitors, such as bone marrow-derived macrophages (BMMs). In this article, we show that tetracyclines convert the differentiation pathway, resulting in DC-like cells not osteoclasts. Doxycycline and minocycline inhibited the receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis of BMMs, but they had no effects on cell growth and phagocytic activity. They influenced neither the proliferation nor the differentiation of bone-forming osteoblasts. Surprisingly, doxycycline and minocycline induced the expression of DC markers, CD11c and CD86, in BMMs in the presence of RANKL. STAT5 is involved in DC differentiation induced by GM-CSF. Midostaurin, a STAT5-signaling inhibitor, and an anti-GM-CSF-neutralizing Ab suppressed the differentiation induced by GM-CSF but not by tetracyclines. In vivo, the injection of tetracyclines into RANKL-injected mice and RANKL-transgenic mice suppressed RANKL-induced osteoclastogenesis and promoted the concomitant appearance of CD11c(+) cells. These results suggested that tetracyclines prevent bone loss induced by local inflammation, including rheumatoid arthritis and periodontitis, through osteoclast-DC-like cell conversion.     

Fibroblast growth factor-2 is an important factor that maintains cellular immaturity and contributes to aggressiveness of osteosarcoma

Osteosarcoma is the most frequent, nonhematopoietic, primary malignant tumor of bone. Histopathologically, osteosarcoma is characterized by complex mixtures of different cell types with bone formation. The role of environmental factors in the formation of such a complicated tissue structure as osteosarcoma remains to be elucidated. Here, a newly established murine osteosarcoma model was used to clarify the roles of environmental factors such as fibroblast growth factor-2 (Fgf2) or leukemia-inhibitory factor (Lif) in the maintenance of osteosarcoma cells in an immature state. These factors were highly expressed in tumor environmental stromal cells, rather than in osteosarcoma cells, and they potently suppressed osteogenic differentiation of osteosarcoma cells in vitro and in vivo. Further investigation revealed that the hyperactivation of extracellular signal-regulated kinase (Erk)1/2 induced by these factors affected in the process of osteosarcoma differentiation. In addition, Fgf2 enhanced both proliferation and migratory activity of osteosarcoma cells and modulated the sensitivity of cells to an anticancer drug. The results of the present study suggest that the histology of osteosarcoma tumors which consist of immature tumor cells and pathologic bone formations could be generated dependent on the distribution of such environmental factors. The combined blockade of the signaling pathways of several growth factors, including Fgf2, might be useful in controlling the aggressiveness of osteosarcoma.     

Effects of Intensive Blood Pressure Lowering on Cardiovascular and Renal Outcomes: A Systematic Review and Meta-Analysis

Background

Guidelines recommend intensive blood pressure (BP) lowering in patients at high risk. While placebo-controlled trials have demonstrated 22% reductions in coronary heart disease (CHD) and stroke associated with a 10-mmHg difference in systolic BP, it is unclear if more intensive BP lowering strategies are associated with greater reductions in risk of CHD and stroke. We did a systematic review to assess the effects of intensive BP lowering on vascular, eye, and renal outcomes.

Methods and Findings

We systematically searched Medline, Embase, and the Cochrane Library for trials published between 1950 and July 2011. We included trials that randomly assigned individuals to different target BP levels.We identified 15 trials including a total of 37,348 participants. On average there was a 7.5/4.5-mmHg BP difference. Intensive BP lowering achieved relative risk (RR) reductions of 11% for major cardiovascular events (95% CI 1%–21%), 13% for myocardial infarction (0%–25%), 24% for stroke (8%–37%), and 11% for end stage kidney disease (3%–18%). Intensive BP lowering regimens also produced a 10% reduction in the risk of albuminuria (4%–16%), and a trend towards benefit for retinopathy (19%, 0%–34%, p = 0.051) in patients with diabetes. There was no clear effect on cardiovascular or noncardiovascular death. Intensive BP lowering was well tolerated; with serious adverse events uncommon and not significantly increased, except for hypotension (RR 4.16, 95% CI 2.25 to 7.70), which occurred infrequently (0.4% per 100 person-years).

Conclusions

Intensive BP lowering regimens provided greater vascular protection than standard regimens that was proportional to the achieved difference in systolic BP, but did not have any clear impact on the risk of death or serious adverse events. Further trials are required to more clearly define the risks and benefits of BP targets below those currently recommended, given the benefits suggested by the currently available data. Please see later in the article for the Editors'' Summary.     

Possible Negative Effect of General Flowering on Tree Growth and Aboveground Biomass Increment in a Bornean Tropical Rain Forest

We tested the effect of general flowering (GF), community‐wide masting, and drought stress on current‐year tree diameter growth and aboveground biomass increment (ABI). General flowering but not drought had a marginally significant negative effect on tree growth and ABI at the community level. Analyses of dominant species clarified this pattern.     

Resilience of native ant community against invasion of exotic ants after anthropogenic disturbances of forest habitats

The positive association between disturbances and biological invasions is a widely observed ecological pattern in the Anthropocene. Such patterns have been hypothesized to be driven by the superior competitive ability of invaders or by modified environments, as well as by the interaction of these factors. An experimental study that tests these hypotheses is usually less feasible, especially in protected nature areas. An alternative approach is to focus on community resilience over time after the anthropogenic disturbance of habitats. Here, we focused on ant communities within a forest to examine their responses after disturbance over time. We selected the Yanbaru region of northern Okinawa Island, which is a biodiversity hotspot in East Asia. We compared ant communities among roadside environments in forests where the road age differed from 5 to 25 years. We also monitored the ant communities before and after disturbance from forest thinning. We found that the species richness and abundance of exotic ants were higher in recently disturbed environments (roadsides of 5–15 years old roads), where the physical environment was warmer and drier. In contrast, the roadsides of 25‐year‐old roads indicated the potential recovery of the physical environment with cooler and moister conditions, likely owing to regrowth of roadside vegetation. At these sites, there were few exotic ants, except for those immediately adjacent to the road. The population density of the invasive species Technoymex brunneus substantially increased 1–2 years after forest thinning. There was no evidence of the exclusion of native ants by exotic ants that were recorded after disturbance. Our results suggest that local ant communities in the Yanbaru forests have some resilience to disturbance. We suggest that restoration of environmental components is a better strategy for maintaining native ant communities, rather than removing exotic ants after anthropogenic disturbance.     

Catechin safely improved higher levels of fatness, blood pressure, and cholesterol in children

Objective: The purpose of this study was to evaluate the effects of a catechin‐rich beverage on body fat and cardiovascular disease risk factors in obese children and to verify the safety of its use. Methods and Procedures: Obese or near‐obese Japanese children were recruited for this study. A double‐blind, randomized, controlled study was performed with a 4‐week lead‐in, a 24‐week beverage ingestion period and a 12‐week follow‐up. Subjects ingested green tea containing 576 mg catechins (catechin group) or 75 mg catechins (control group) once per day for 24 weeks. Randomization was stratified by gender, age, and BMI. Subjects were instructed to maintain their usual lifestyles during the study period. Results: Data were analyzed using samples from 40 subjects (catechin group; n = 21, control group; n = 19). There were no significant differences in major outcome variables, such as body fat mass, between the catechin and the control groups. When, however, the analysis was stratified using the median of the week‐0 values, the decrease at week 24 in waist circumference, systolic blood pressure, and low‐density lipoprotein cholesterol in the catechin group was significantly greater than that in the control group for the above‐median category. Ingestion of the catechin‐rich beverage was not associated with any adverse effects. Discussion: These findings suggest that ingestion of a catechin‐rich beverage ameliorates serious obesity and cardiovascular disease risk factors without raising any safety concerns in Japanese children.     

Preparation of Controlled-Release Fine Particles Using a Dry Coating Method

Wet coating methods use organic solvents to prepare layered particles that provide controlled-release medications. However, this approach has disadvantages in that it can cause particle agglomeration, reduce pharmaceutical stability, and leave residual organic solvents. We used a dry coating method to overcome these issues. Fine particles (less than 50 μm in diameter) of controlled-release theophylline were created using theophylline (TP; model drug), polyethylene glycol 20,000 (PEG; drug fixative), hydrogenated castor oil (HCO; controlled-release material), hydrogenated rapeseed oil (HRSO; controlled-release material), and cornstarch (CS; core particle). An ultrahigh-speed mixer was employed to mix TP and CS for 5 min at 28,000 rpm. Subsequent addition of PEG produced single-core particles with a drug reservoir coating. Addition of HCO and HRSO to these particles produced a controlled-release layer on their surface, resulting in less than 10% TP dissolution after 8 h. We successfully demonstrated that this dry coating method could be used to coat 16-μm CS particles with a drug reservoir layer and a controlled-release layer, producing multi-layer coated single-core particles that were less than 50 μm in diameter. These can be used to prepare controlled-release tablets, capsules, and orally disintegrating tablets.     

Immunobiotic Bifidobacteria Strains Modulate Rotavirus Immune Response in Porcine Intestinal Epitheliocytes via Pattern Recognition Receptor Signaling

In this work, we aimed to characterize the antiviral response of an originally established porcine intestinal epithelial cell line (PIE cells) by evaluating the molecular innate immune response to rotavirus (RVs). In addition, we aimed to select immunomodulatory bacteria with antiviral capabilities. PIE cells were inoculated with RVs isolated from different host species and the infective titers and the molecular innate immune response were evaluated. In addition, the protection against RVs infection and the modulation of immune response by different lactic acid bacteria (LAB) strains was studied. The RVs strains OSU (porcine) and UK (bovine) effectively infected PIE cells. Our results also showed that RVs infection in PIE cells triggered TLR3-, RIG-I- and MDA-5-mediated immune responses with activation of IRF3 and NF-κB, induction of IFN-β and up-regulation of the interferon stimulated genes MxA and RNase L. Among the LAB strains tested, Bifidobacterium infantis MCC12 and B. breve MCC1274 significantly reduced RVs titers in infected PIE cells. The beneficial effects of both bifidobacteria were associated with reduction of A20 expression, and improvements of IRF-3 activation, IFN-β production, and MxA and RNase L expressions. These results indicate the value of PIE cells for studying RVs molecular innate immune response in pigs and for the selection of beneficial bacteria with antiviral capabilities.