Background-In ambulatory patients with heart failure with reduced ejection fraction (HFrEF), high systolic blood pressure (SBP) is associated with better outcomes. However, it is not known whether there is a ceiling beyond which high SBP has a detrimental effect. Thus, our aim was to assess the linearity of association between SBP and mortality.

Prostacyclin (PGI(2)) is a key vascular protector, metabolized from endogenous arachidonic acid (AA). Its actions are mediated through the PGI(2) receptor (IP) and nuclear receptor, peroxisome proliferator-activated receptor γ (PPARγ). Here, we found that PGI(2) is involved in regulating cellular microRNA (miRNA) expression through its receptors in a mouse adipose tissue-derived primary culture cell line expressing a novel hybrid enzyme gene (COX-1-10aa-PGIS), cyclooxygenase-1 (COX-1) and PGI(2) synthase (PGIS) linked with a 10-amino acid linker. The triple catalytic functions of the hybrid enzyme in these cells successfully redirected the endogenous AA metabolism toward a stable and dominant production of PGI(2). The miRNA microarray analysis of the cell line with upregulated PGI(2) revealed a significant upregulation (711, 148b, and 744) and downregulation of miRNAs of interest, which were reversed by antagonists of the IP and PPARγ receptors. Furthermore, we also found that the insulin-mediated lipid deposition was inhibited in the PGI(2)-upregulated adipocytes. The study also initiated a discussion that suggested that the endogenous PGI(2) inhibition of lipid deposition in adipocytes could involve miRNA-mediated inhibition of expression of the targeted genes. This indicated that PGI(2)-miRNA regulation could exist in broad pathophysiological processes involving PGI(2) (i.e., apoptosis, vascular inflammation, cancer, embryo implantation, and obesity).

BACKGROUND The study proposes a novel protocol for targeting the jowls using deoxycholic acid (DCA) injections, with emphasis on safety and feasibility of the procedure. METHODS This prospective study was conducted at a cosmetic practice between June 2016 and May 2017. Twelve consecutive patients seeking reduction/improvement in mild/moderate jowl fat were injected with DCA subcutaneously in a predefined circular area 1.0 cm above the mandibular border. Treatment response was assessed using physician-evaluated Global Aesthetic Improvement Scale (GAIS) and Subject GAIS. RESULTS Twelve patients (11 women and 1 man) with mild (n = 8) or moderate (n = 4) jowls were treated. After the first treatment, GAIS responses for 24 jowls showed 5 jowls with vast improvement, 15 with moderate improvement, and 4 with no change. After the second session for 5 jowls in 3 patients, GAIS responses showed vast improvement in 4 jowls and moderate improvement in 1. Adverse events included induration (n = 4), bruising (n = 6), numbness (n = 2), pain (n = 5), redness (n = 3), edema (n = 9), and dysphagia (n = 1). CONCLUSION Results of this early experience showed that DCA injections were safe and effective for nonsurgical jowl reduction.

BackgroundConventionally the active ingredients in herbal extracts are separated into individual components, by fractionation, desalting, and followed by high-performance liquid chromatography (HPLC). In this study we have tried to directly screen water-soluble fractions of herbs with potential active ingredients before purification or extraction. We propose that the herbal extracts mimicking prostaglandin E1 (PGE1) and E2 (PGE2) can be identified in the water-soluble non-purified fraction. PGE1 is a potent anti-inflammatory molecule used for treating peripheral vascular diseases while PGE2 is an inflammatory molecule.MethodsWe used cell-based assays (CytoFluor multi-well plate reader and fluorescence microscopy) in which a calcium signal was generated by the recombinant EP1 receptor stably expressed in HEK293 cells (human embryonic kidney). PGE1 and PGE2 were tested for their ability to generate a calcium signal. Ninety-six water soluble fractions of Treasures of the east (single Chinese herb dietary supplements) were screened.ResultsAfter screening, the top ten stimulators were identified. The identified herbs were then desalted and the calcium fluorescent signal reconfirmed using fluorescence microscopy. Among these top ten agonists identified, seven stimulated the calcium signaling (1-40 μM concentration) using fluorescence microscopy.ConclusionsFluorescence microscopy and multi-well plate readers can be used as a target specific method for screening water soluble fractions with active ingredients at a very early stage, before purification. Our future work consists of purifying and separating the active ingredients and repeating fluorescence microscopy. Under ordinary circumstances we would have to purify the compounds first and then test all the extracts from 96 herbs. Conventionally, for screening natural product libraries, the procedure followed is the automated separation of all constituents into individual components using fractionation and high performance liquid chromatography. We, however, demonstrated that the active ingredients of the herbal extracts can be tested before purification using an agonist sensitive, quick and simple cell-based signaling assay for ligands mimicking the agonists, PGE1 and PGE2.

A newly created hybrid enzyme (COX-2-10aa-mPGES-l), which mimics the specific biosynthesis ofthe inflammatory PGE 2 through COX-2's coupling to mPGES-l, was stably expressed in HEK293 cells. The stable cell line, which consistently expresses the superior triple catalytic (Trip-Cat) activities from COX-2 and mPGES-l, was able to directly convert arachidonic acid into the pathogenic PGE 2 and distinguish it from other PGE 2 synthesizing pathways, as confirmed by enzyme immunoassay, LC/MS analysis and a specific [I4C]-AA (arachidonic acid) metabolite analysis approach. A competitive assay confirmed that the endogenous cPGES and mPGES-2 in the HEK293 cells had little involvement in the presence of the expressed COX-2-10aa-mPGES-l for the synthesis of pathogenic PGE 2• Furthermore, subcutaneous injection of the stable cell lines into nulnu mice revealed 100% (10 out 10) occurrence of tumor mass formation beginning on Day 7 and a continuous progression of the masses to the maximal size which required sacrificing the mice. In contrast, only 10% occurrence oftumor masses, though smaller and with slower growth rates, were observed for the group ofvector-transfected HEK293 control cells expressing only endogenous cPGES andlor mPGES-2. The PGE 2 produced from multiple pathways by the HEK293 cells co-expressing the individual wild type COX-2 and mPGES-l, and in the presence of endogenous cPGES and mPGES-2, showed also a significantly increased tumor occurrence rate to 30%, which confirmed that the sole coupling of COX-2 to mPGES-l is a powerful tumor-advancing factor. This result implies that the engineered COX-2-10aa-mPGES-l could be a promising molecule as a drug developing target against the pathway ofCOX-2 coupled to mPGES-l to treat inflammatory diseases and cancers.Prostaglandin E z (PGE z ) is produced from arachidonic acid (AA) and requires three catalytic activities from two enzymes, cyclooxygenase (COX) isoform-I or -2 and PGE z synthase (PGES) (l, 2). During the reactions, endogenous AA is converted into PGG z and then PGH z by the cyclooxygenase and peroxidase activities of COX-lor -2. The unstable PGH z is further isomerized to PGE z by prostaglandin E z synthases. There are three PGES enzymes which share the same PGH z as a substrate, including the non-inducible cytosolic PGES (cPGES) (3), and the inducible microsomal PGES (mPGES) -1