Non-steroidal anti-inflammatory drugs (NSAIDs) display anti-inflammatory, antipyretic and analgesic properties by inhibiting cyclooxygenases and blocking prostaglandin production. Previous studies, however, suggested that some NSAIDs also modulate peroxisome proliferator activated receptors (PPARs), raising the possibility that such off target effects contribute to the spectrum of clinically relevant NSAID actions. In this study, we set out to understand how peroxisome proliferator activated receptor-γ (PPARγ/PPARG) interacts with NSAIDs using X-ray crystallography and to relate ligand binding modes to effects on receptor activity. We find that several NSAIDs (sulindac sulfide, diclofenac, indomethacin and ibuprofen) bind PPARγ and modulate PPARγ activity at pharmacologically relevant concentrations. Diclofenac acts as a partial agonist and binds to the PPARγ ligand binding pocket (LBP) in typical partial agonist mode, near the β-sheets and helix 3. By contrast, two copies of indomethacin and sulindac sulfide bind the LBP and, in aggregate, these ligands engage in LBP contacts that resemble agonists. Accordingly, both compounds, and ibuprofen, act as strong partial agonists. Assessment of NSAID activities in PPARγ-dependent 3T3-L1 cells reveals that NSAIDs display adipogenic activities and exclusively regulate PPARγ-dependent target genes in a manner that is consistent with their observed binding modes. Further, PPARγ knockdown eliminates indomethacin activities at selected endogenous genes, confirming receptor-dependence of observed effects. We propose that it is important to consider how individual NSAIDs interact with PPARγ to understand their activities, and that it will be interesting to determine whether high dose NSAID therapies result in PPAR activation.

No abstract

Thyroid hormone (TH) modulates serum cholesterol by acting on TH receptor β1 (TRβ1) in liver to regulate metabolic gene sets. In rodents, one important TH regulated step involves induction of Cyp7a1, an enzyme in the cytochrome P450 family, which enhances cholesterol to bile acid conversion and plays a crucial role in regulation of serum cholesterol levels. Current models suggest, however, that Cyp7a1 has lost the capacity to respond to THs in humans. We were prompted to re-examine TH effects on cholesterol metabolic genes in human liver cells by a recent study of a synthetic TH mimetic which showed that serum cholesterol reductions were accompanied by increases in a marker for bile acid synthesis in humans. Here, we show that TH effects upon cholesterol metabolic genes are almost identical in mouse liver, mouse and human liver primary cells and human hepatocyte cell lines. Moreover, Cyp7a1 is a direct TR target gene that responds to physiologic TR levels through a set of distinct response elements in its promoter. These findings suggest that THs regulate cholesterol to bile acid conversion in similar ways in humans and rodent experimental models and that manipulation of hormone signaling pathways could provide a strategy to enhance Cyp7a1 activity in human patients.

Sobetirome binds selectively to the main hepatic form of thyroid hormone (TH) receptor, TRβ1, compared to TRα1, which is principally responsible for thyrotoxic effects on heart, muscle and bone. Sobetirome also preferentially accumulates in liver. It was originally envisaged that sobetirome could be used to stimulate hepatic pathways that lower cholesterol without harmful side effects and might be used in conjunction with statins. Indeed, sobetirome progressed through preclinical animal studies and Phase I human clinical trials with excellent results and without obvious harmful side effects. Despite the fact that cardiovascular disease remains a major cause of mortality and that new therapies are desperately needed, it is unlikely that sobetirome will progress in further human clinical trials in the near future. The emergence of alternative cholesterol-lowering therapeutics may render selective thyromimetics redundant. Further, fears of thyrotoxic effects in the heart and emergence of cartilage defects in dogs after long-term use of eprotirome, a similar though not identical compound, has reduced enthusiasm for this strategy. We argue that it is nevertheless important to explore uses of sobetirome in humans; more treatment strategies would help patients with hard-to-treat dyslipidemias. Sobetirome may also have additional applications in orphan indications and short-term controlled weight loss.

Cortical spreading depolarization (SD) waves negatively affect neuronal survival and outcome after ischemic stroke. We here aimed to investigate the effects of vagus nerve stimulation (VNS) on SDs in a rat model of focal ischemia. To this end, we delivered non-invasive VNS (nVNS) or invasive VNS (iVNS) during permanent middle cerebral artery occlusion (MCAO), and found that both interventions significantly reduced the frequency of SDs in the cortical peri-infarct area compared to sham VNS, without affecting relative blood flow changes, blood pressure, heart rate or breathing rate. In separate groups of rats subjected to transient MCAO, we found that cortical stroke volume was reduced 72 h after transient MCAO, whereas stroke volume in the basal ganglia remained unchanged. In rats treated with nVNS, motor outcome was improved 2 days after transient MCAO, but was similar to sham VNS animals 3 days after ischemia. We postulate that VNS may be a safe and efficient intervention to reduce the clinical burden of SD waves in stroke and other conditions.

Poly(propylene fumarate) (PPF) has shown potential for the treatment of bone defects as it can be 3D printed into scaffolds to suit patient-specific needs with strength comparable to that of bone. However, the lack of specific cell attachment and osteogenic signaling moieties have limited their utility as it is necessary to provide these signals to aid in bone tissue formation. To address this issue and provide a platform for functionalization, Bioglass (∼1−2 μm) microparticles have been incorporated into PPF to create a 3D printable resin with concentrations ranging from 0 to 10 wt %. The zero-shear viscosity of PPF-Bioglass resins increased proportionally from 0 to 2.5 wt % Bioglass, with values of 0.22 and 0.34 Pa•s, respectively. At higher Bioglass concentrations, 5 and 10 wt %, the resin viscosity increased to 0.44 and 1.31 Pa•s, exhibiting a 2-and 6-fold increase from the 0 wt % Bioglass resin. Despite this increase in viscosity, all resins remained printable with no print failures. In addition, the surface available Bioglass can tether catechol containing molecules for postprinting functionalization. Analysis of PPF-Bioglass functionalization using a catechol dye analyte shows functionalization increases with Bioglass concentration, up to 157 nmol/ cm 2 , and demonstrates it is possible to modulate functionalization. This presents a versatile and highly translationally relevant strategy to functionalize 3D printed scaffolds post printing with a diverse array of functional species.

No abstract

The use of robotic surgery in the hepatobilio-pancreatic (HBP) field is still limited. Our aim is to present our early experience of robotic liver resection. A retrospective review of robotic pancreatic and liver resection was performed at Sanchinarro University hospital from October 2010 to April 2016. Since the beginning of the robotic program in our center, 22 hepatic procedures and 45 pancreatic robotic procedures have been performed. Of the 21 patients subjected to liver resection, 13 (65%) were for malignancy. There were two left hepatectomies, one right hepatectomy, one associated liver partition and portal vein ligation staged procedure (both steps by robotic approach), three bisegmentectomies and three segmentectomies, eight wedge resections, and three pericystectomies. The mean operating time was 282 min. The overall conversion rate and postoperative complication rate were 4.7 and 19%, respectively. The mean length of hospital stay was 13.4 days (range 4-64 days). Of the 45 patients subjected to pancreatic resection, 22 were male and 23 female. The average age of all patients was 62 years (range 31-82 years). The mean operating room (OR) time was 370 min (120-780 min). Among the procedures performed were 15 pancreatico-duodenectomies, 19 distal pancreatectomies, and 11 enucleations. All procedures in the HBP area were R0. Our early experience shows that robotic surgery is a safe and feasible procedure in the HBP area. The complication and mortality rates are comparable to those of open surgery, but with the advantages of minimally invasive surgery.