To compare the water absorption of 12 FDA-approved hyaluronic acid (HA) facial fillers in vitro in conditions relevant to in vivo injection.
The goal of this study was to provide long-term insight ...into an improved, tailored facial rejuvenation approach and to understand sequelae that could affect preoperative surgical planning.
In 2 experiments, 12 FDA-approved HA fillers were loaded into test tubes with nonpreserved normal saline and then placed in a 94.5°F-96°F environment for 1 month to allow water absorption by passive diffusion. The test tubes were centrifuged so that the hydrated filler could pass to the bottom of the tube. The tubes were centrifuged for 12 minutes at 1,200 revolutions per minute in the first experiment and for 7 minutes in the second experiment. A blue dye was then instilled to demarcate the filler/saline interface.
There was variation in the water absorption of different HAs. Low absorption occurred in non-animal-stabilized hyaluronic acid.
The pattern of water absorption was similar in the 2 experiments. The results inform us about in vivo conditions and provide guidance for filler selection.
The history of Earth's carbon cycle reflects trends in atmospheric composition convolved with the evolution of photosynthesis. Fortunately, key parts of the carbon cycle have been recorded in the ...carbon isotope ratios of sedimentary rocks. The dominant model used to interpret this record as a proxy for ancient atmospheric CO
is based on carbon isotope fractionations of modern photoautotrophs, and longstanding questions remain about how their evolution might have impacted the record. Therefore, we measured both biomass (ε
) and enzymatic (ε
) carbon isotope fractionations of a cyanobacterial strain (
PCC 7942) solely expressing a putative ancestral Form 1B rubisco dating to ≫1 Ga. This strain, nicknamed ANC, grows in ambient pCO
and displays larger ε
values than WT, despite having a much smaller ε
(17.23 ± 0.61‰ vs. 25.18 ± 0.31‰, respectively). Surprisingly, ANC ε
exceeded ANC ε
in all conditions tested, contradicting prevailing models of cyanobacterial carbon isotope fractionation. Such models can be rectified by introducing additional isotopic fractionation associated with powered inorganic carbon uptake mechanisms present in Cyanobacteria, but this amendment hinders the ability to accurately estimate historical pCO
from geological data. Understanding the evolution of rubisco and the CO
concentrating mechanism is therefore critical for interpreting the carbon isotope record, and fluctuations in the record may reflect the evolving efficiency of carbon fixing metabolisms in addition to changes in atmospheric CO
.
•Skin administration of bimatoprost led to a dose dependent reduction in weight gain.•Application led to reduction of fat under the skin and systemically.•Systemic effect mediated by a decrease in ...food intake and gastric emptying.•Extends previously published findings of bimatoprost and prostamides on adiposity.
Bimatoprost is a synthetic prostamide F2α analog that down-regulates adipogenesis in vitro. This effect has been attributed to participation in a negative feedback loop that regulates anandamide-induced adipogenesis. A follow-on investigation has now been conducted into the broader metabolic effects of bimatoprost using rats under both normal state and obesity-inducing conditions. Chronic bimatoprost administration attenuated weight gain in a dose dependent-manner in rats fed either standard max effect −7% or obesity-promoting diets max effect −23% over a 9–10 week period. Consistent with these findings, bimatoprost promoted satiety as measured by decreased food intake max effect, −7%, gastric emptying max effect, −33–50% and decreased circulating concentrations of the gut hormones, ghrelin and GLP-1 max effect, −33–50%. Additionally, subcutaneous, and visceral fat mass were distinctly affected by treatment −30% diet independent. Taken together, these results suggest that bimatoprost regulates energy homeostasis through promoting satiety and a decrease in food intake. These newly reported activities of bimatoprost reveal an additional method of metabolic disease intervention for potential therapeutic exploitation.
► PGE2 dose dependently inhibits IL-12 and IL-23 through different receptors. ► EP2 and EP4 have opposing action on IL-23 production. ► EP2 and EP4 inhibit IL-12p70, through inhibition of IL-12p40. ► ...EP2 inhibits through cAMP generation.
Dendritic cells (DCs) are central players in coordinating immune responses, both innate and adaptive. While the role of lipid mediators in the immune response has been the subject of many investigations, the precise role of prostaglandins has often been plagued by contradictory studies. In this study, we examined the role of PGE2 on human DC function. Although studies have suggested that PGE2 specifically plays a role in DC motility and cytokine release profile, the precise receptor usage and signaling pathways involved remain unclear. In this report we found that irrespective of the human donor, monocyte-derived dendritic cells (MoDCs) express three of the four PGE2 receptor subtypes (EP2–4), although only EP2 and EP4 were active with respect to cytokine production. Using selective EP receptor antagonists and agonists, we demonstrate that PGE2 coordinates control of IL-23 release (a promoter of Th17, an autoimmune associated T cell subset) in a dose-dependent manner by differential use of EP2 and EP4 receptors in LPS-activated MoDCs. This is in contrast to IL-12, which is dose dependently inhibited by PGE2 through both receptor subtypes. Low concentrations (∼1–10nM) of PGE2 promoted IL-23 production via EP4 receptors, while at higher (>50nM), but still physiologically relevant concentrations, IL-23 is suppressed by an EP2 dependent mechanism. These results can be explained by differential regulation of the common subunit, IL-12p40, and IL-23p19, by EP2 and EP4. By these means, PGE2 can act as a regulatory switch of immune responses depending on its concentration in the microenvironment. In addition, we believe these results may also explain why seemingly conflicting biological functions assigned to PGE2 have been reported in the literature, as the concentration of ligand (PGE2) fundamentally alters the nature of the response. This finding also highlights the potential of designing therapeutics which differentially target these receptors.
Lipid mediators variedly affect adipocyte differentiation. Anandamide stimulates adipogenesis via CB1 receptors and peroxisome proliferator-activated receptor γ. Anandamide may be converted by PTGS2 ...(COX2) and prostaglandin F synthases, such as prostamide/prostaglandin F synthase, to prostaglandin F2α ethanolamide (PGF2αEA), of which bimatoprost is a potent synthetic analog. PGF2αEA/bimatoprost act via prostaglandin F2αFP receptor/FP alt4 splicing variant heterodimers. We investigated whether prostamide signaling occurs in preadipocytes and controls adipogenesis. Exposure of mouse 3T3-L1 or human preadipocytes to PGF2αEA/bimatoprost during early differentiation inhibits adipogenesis. PGF2αEA is produced from anandamide in preadipocytes and much less so in differentiating adipocytes, which express much less PTGS2, FP, and its alt4 splicing variant. Selective antagonism of PGF2αEA receptors counteracts prostamide effects on adipogenesis, as does inhibition of ERK1/2 phosphorylation. Selective inhibition of PGF2αEA versus prostaglandin F2α biosynthesis accelerates adipogenesis. PGF2αEA levels are reduced in the white adipose tissue of high fat diet-fed mice where there is a high requirement for new adipocytes. Prostamides also inhibit zebrafish larval adipogenesis in vivo. We propose that prostamide signaling in preadipocytes is a novel anandamide-derived antiadipogenic mechanism.
Background: Adipogenesis is the process by which adipocytes are formed to maintain or expand fat depots.
Results: Prostaglandin F2α ethanolamide (PGF2αEA) is produced from anandamide in preadipocytes and inhibits adipogenesis.
Conclusion: Conversion of proadipogenic anandamide to antiadipogenic PGF2αEA is a novel mechanism for the regulation of adipogenesis.
Significance: Discovering a PGF2αEA-mediated negative regulatory mechanism over adipogenesis may lead to the development of antiobesity therapies.
Current strategies to manage preterm labor center around inhibition of uterine myometrial contractions, yet do not improve neonatal outcomes as they do not address activation of inflammation. Here, ...we identify that during human labor, activated oxytocin receptor (OTR) reprograms the prostaglandin E2 receptor, EP2, in the pregnant myometrium to suppress relaxatory/Gαs-cAMP signaling and promote pro-labor/inflammatory responses via altered coupling of EP2 from Gαq/11 to Gαi/o. The ability of EP2 to signal via Gαi/o is recapitulated with
in vitro
OT and only following OTR activation, suggesting direct EP2-OTR crosstalk. Super-resolution imaging with computational modeling reveals OT-dependent reorganization of EP2-OTR complexes to favor conformations for Gαi over Gαs activation. A selective EP2 ligand, PGN9856i, activates the relaxatory/Gαs-cAMP pathway but not the pro-labor/inflammatory responses in term-pregnant myometrium, even following OT. Our study reveals a mechanism, and provides a potential therapeutic solution, whereby EP2-OTR functional associations could be exploited to delay preterm labor.
•
EP2 activity is reprogrammed toward pro-inflammatory pathways during human labor
•
Oxytocin downregulates EP2-Gαs signaling and switches EP2-Gαq/11 signaling to Gαi/o
•
EP2/OTR heterotetramers are reorganized by oxytocin to conformations favoring Gαi
•
EP2 agonist PGN9856i does not activate pro-labor signals even after oxytocin treatment
The prostanoid receptor EP2 maintains myometrial quiescence during pregnancy. Walker et al. show that during human labor, EP2 signaling switches toward an inflammatory profile driven by functional crosstalk with the activated oxytocin receptor. An EP2 ligand, PGN9856i, is “resistant” to this crosstalk and could be exploited to delay preterm labor.
Recent years have seen a decline in herbage production and tiller populations in New Zealand's perennial ryegrass (Lolium perenne) dairy pastures. One hypothesis is that modern genotypes are less ...suited to the warmer, drier weather experienced under changing climate patterns. In this study, a combination of long‐term trial data (2011–2017) and a process‐based pasture model (BASGRA) was used to explore the causes and possible mitigation of the observed production and population loss at three sites (dryland sites in Northland and Waikato and an irrigated site in Canterbury). Bayesian calibration was used to identify the model parameter sets that were consistent with the trial data and to identify differences in plant morphology and responses between sites. The model successfully simulated the observed differences in tiller numbers between the dryland sites, where populations and production declined rapidly after the second year and the irrigated site where populations and production were maintained. Analysis of the model calibrations along with preliminary scenario simulations suggests that increased tiller mortality associated with drought was the main cause of persistence failure at the dryland sites and that decreasing grazing pressure or breeding for tolerance to higher temperatures may not be successful in preventing this.
Mouse models are useful for glaucoma research, but it is unclear whether intraocular pressure (IOP) regulation in mice operates through mechanisms similar to those in humans. Our goal was to ...determine whether pharmacologic compounds that affect conventional outflow facility in human eyes exert similar effects in C57BL/6 mice.
A computerized perfusion system was used to measure conventional outflow facility in enucleated mouse eyes ex vivo. Paired eyes were perfused sequentially, either immediately after enucleation or after 3 hours storage at 4°C. Three groups of experiments examined sphingosine 1-phosphate (S1P), S1P with antagonists to S1P(1) and S1P(2) receptors, and the prostanoid EP(4) receptor agonist 3,7-dithia PGE(1). We also examined whether a 24-hour postmortem delay affected the response to 3,7-dithia prostaglandin E(1) (PGE(1)).
S1P decreased facility by 39%, and was blocked almost completely by an S1P(2), but not S1P(1), receptor antagonist. The S1P(2) receptor antagonist alone increased facility nearly 2-fold. 3,7-dithia PGE(1) increased facility by 106% within 3 hours postmortem. By 24 hours postmortem, the facility increase caused by 3,7-dithia PGE(1) was reduced 3-fold, yet remained statistically detectable.
C57BL/6 mice showed opposing effects of S1P(2) and EP(4) receptor activation on conventional outflow facility, as observed in human eyes. Pharmacologic effects on facility were detectable up to 24 hours postmortem in enucleated mouse eyes. Mice are suitable models to examine the pharmacology of S1P and EP(4) receptor stimulation on IOP regulation as occurs within the conventional outflow pathway of human eyes, and are promising for studying other aspects of aqueous outflow dynamics.
Prostaglandin E2 (PGE2)-2-glyceryl ester is a cyclo-oxygenase 2 product of the endocannabinoid 2-arachidonyl glycerol. It is claimed as pharmacologically novel, but this is complicated by rapid and ...irreversible isomerization to the 1(3) ester. For ocular studies, enzymatic hydrolysis of the ester moiety creates an additional complication. PG-glyceryl esters were stabilized to isomerization and hydrolysis by replacing the noncarbonyl O with NH, to form the serinolamide and propanediolamide as stable analogs of PG-2-glyceryl and PG-2-1(3) glyceryl esters, respectively. Intraocular pressure was measured in conscious dogs and conscious laser-induced ocular hypertensive monkeys. Pharmacological studies involved stable transfectants for each of the human recombinant prostanoid receptors and the isolated feline iris for prostamide activity. PGE2-serinolamide and PGE2- propanediolamide were essentially inactive at all receptors except the EP3 receptor (EC50, ∼500 nM). This obliged elucidation of EP3 receptor involvement in the intraocular pressure response to these PGE2-glycyerl ester analogs. Since the EP3 receptor agonists sulprostone and GR 63799 did not lower monkey intraocular pressure, a role for EP3 receptors in mediating the effects of PGE2-serinolamide and PGE2-propanediolamide is not indicated. PGE2-glyceryl ester (0.01% and 0.1%) substantially lowered intraocular pressure in monkeys. PGE2-propanediolamide was more efficacious than PGE2-serinolamide in lowering intraocular pressure in monkey eyes, but both appeared equieffective in dog eyes. PGE2-serinolamide dose-dependently (0.01- 0.1%) lowered intraocular pressure in both species, but PGF2 α-serinolamide was inactive. In conclusion, stable PGE2-glyceryl ester analogs lowered intraocular pressure. These findings are consistent with the presence of a PGE2-glyceryl ester-specific recognition site in the eye.
The goal of the study was to examine secreted protein response and withdrawal profiles from cultured human trabecular meshwork (HTM) cells following short- and long-term glucocorticoid treatment. ...Primary cultures of five human HTM cell strains isolated from 5 different individual donor eyes were tested. Confluent HTM cells were differentiated in culture media containing 1% FBS for at least one week, and then treated with Dexamethasone (Dex, 100 nM) 3 times/week for 1 or 4 weeks. Cell culture supernatants were collected 3 times per week for 8 weeks. Secretion profiles of myocilin (MYOC), matrix metalloproteinase-2 (MMP2) and fibronectin (FN) were determined by Western blot analysis and MMP2 activity by zymography. Dex treatment reduced MMP2 expression and activity, returning to normal levels shortly after Dex withdrawal in 5 HTM cell strains. All five cell strains significantly upregulated MYOC in response to Dex treatment by an average of 17-fold, but recovery to basal levels after Dex withdrawal took vastly different periods of time depending on cell strain and treatment duration. Dex treatment significantly increased FN secretion in all strains but one, which decreased FN secretion in the presence of Dex. Interestingly, secretion of FN and MYOC negatively correlated during a 4 week recovery period following 4 weeks of Dex treatment. Taken together, the time course and magnitude of response and recovery for three different secreted, extracellular matrix-associated proteins varied greatly between HTM cell strains, which may underlie susceptibility to glucocorticoid-induced ocular hypertension.
•Secretory responses to dexamethasone and recovery was highly variable, depending upon the human TM cell strain tested.•In 14 out of 15 cases, human TM cell strains responded to dexamethasone treatment in the same direction.•MYOC and FN secretion levels were inversely related from different human TM cell strains.