An Orbital Venous Varix Presenting as a Strain-Induced Lower Eyelid Mass.

ABSTRACT: Orbital varix is uncommon disease entity, accounting for less than 1% of orbital tumor. Authors report a case of tumor mimicking lower eyelid varix of inferior palpebral vein induced by forced closure of the patient's eyelids. A 21-year-old female visited our institution with a complaint of eyelid mass that only appeared on frowning. A 0.5 × 1.0 cm2 sized soft, nontender and nonpulsating mass was observed at her left lower eyelid when she frowned. Preoperative ultrasound imaging revealed a hypoechoic cystic lesion above orbicularis oculi muscle. A surgical resection through transconjunctival approach was performed. Congestion of perforating inferior palpebral vein caused by contraction of orbicularis oculi muscle was observed intraoperatively. Histopathology has confirmed dilated venous structures. The symptom was immediately resolved after surgery. No sign of recurrence was detected after two years of follow-up.

Protective Functions of Group 3 Late Embryogenesis Abundant (G3LEA) Proteins in Enterococcus faecium During Vancomycin Treatment.

Late embryogenesis abundant (LEA) proteins protect organisms from various environmental stresses; however, the underlying mechanism of LEA mediated therapeutic evasion is still unclear in both eukaryotes and prokaryotes. In this study, group 3 LEA protein (G3LEA) of vancomycin-resistant Enterococcus faecium under sublethal concentration of vancomycin stress was evaluated and shown to have two functions: the first is the reduction of reactive oxygen species (ROS) content, preventing apoptosis by suppressing apoptotic proteins Cas3 and MAOB, and the second is activating specific drug efflux pumps. Sublethal vancomycin model was established with using Propidium Iodide (PI) stain. Real-time PCR was conducted to evaluate the expression of G3lea. Flow cytometry and confocal microscope using Anti- G3LEA, anti- MAOB, and anti- Cas3 were performed to assess the expression of G3LEA. Under sublethal vancomycin stress, G3LEA is upregulated, suppressing the expression of apoptotic markers and increasing specific efflux markers. These results suggest that G3LEA protein suppresses antibiotic mediated apoptosis in prokaryotic cells and plays a key role in understanding and preventing antibiotic resistance.

Thin PEGylated Carbon Nitrides: Water-Dispersible Organic Nanodots as Bioimaging Probes.

Fluorescent materials are being used for the optical/fluorescence imaging of living cells and animal models. As such, the development of heavy-metal-free, water-dispersible, and biocompatible imaging probes is still important. Carbon nitride (C3 N4 ) is used as a bioimaging probe due to its suitable optical properties, thus enhancing its biocompatibility and dispersibility in aqueous media is required. In this study, we incorporated short-chain polyethylene glycol (PEG) groups onto a carbon nitride network by the simple N-alkylation of hexaethylene glycolic mesylate with nucleophilic nitrogen atoms on oxidized carbon nitride (OCN). The PEGylated OCN (PEG-OCN) was well dispersed in water as nanodots with a lateral dimension of approximately 30 nm and a thickness of 0.5-1.2 nm and showed strong photoluminescence in the visible region. Cell-viability testing confirmed that these "heavy-metal-free" organic nanodots were highly biocompatible and noncytotoxic. In particular, the developed nanodots could provide clear confocal images of RAW 264.7 cells without weakening cell activity and displaying any aggregation in a range of concentrations (25-100 µg mL-1 ) with bright-green emission in the cytoplasm.

Localization patterns of dopamine active transporter synthesizing cells during development of brine shrimp.

There have been many studies on dopamine active transporter (DAT) in humans and laboratory animals; however, there is a lack of information on DAT in brine shrimp. In this study, we demonstrated the neuronal and nonneuronal characteristics of DAT-synthesizing (DAT+ cells) during development of brine shrimp. In neuronal cells, the DAT+ neurons in the central body and lobes of a protocerebrum (PC) controlled the deutocerebrum. The sensory cells of nauplius eyes projected their decussated axons to the PC, and the DAT+ cells at the posterior region were associated with migration and control of the 10 posterior neurons during the early nauplius stage. In nonneuronal cells, the five types of glands, that is, the salt, antennal, mandible, and accessory glands and posterior gland1 and gland2 synthesized DAT protein. In addition, the gut and rectum dilator muscles and renal cells expressed DAT protein. Thus, DAT protein acts in the development of several types of cells during development of brine shrimp.

Non-alcoholic fatty liver disease among sasang constitutional types: a population-based study in Korea.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is highly prevalent in populations with metabolic conditions such as obesity and type II diabetes. Specific types of Sasang constitution can act as a risk factor for metabolic diseases, but there are no studies addressing the association between the Sasang constitutional types (SCTs) and NAFLD. METHODS: A total of 1184 individuals (508 males, 676 females) that enrolled in the Korean Genome and Epidemiology Study were included in the present study. Classification of SCTs was done with an integrated diagnostic model. NAFLD was diagnosed when the liver attenuation index (LAI) value was <5 Hounsfield units using computed tomography. Relationships between the SCTs and NAFLD were analyzed using multiple logistic regressions. RESULTS: The average LAI was 13.3±6.0 in the So-eum (SE) type, 12.3±7.0 in the So-yang (SY) type, and 6.5±9.9 in the Tae-eum (TE) type. Prevalence of NAFLD was 4.7% in the SE type, 14.0% in the SY type, and 34% in the TE type. Even after adjusting for possible confounders, the SY and TE types continued to show a 3.90-fold (95% CI, 1.60-9.51; P=0.0028) and 3.36-fold (95% CI, 1.42-7.92; P=0.0057) increase in chance of having NAFLD, respectively, compared with the SE type. In the additional analysis including only non-obese subjects, the odds ratio of NAFLD was 3.27 (95% CI, 1.29-8.29; P=0.0126) in the SY type and 3.53 (95% CI, 1.30-9.58; P=0.0134) in the TE type compared with SE type. In the multivariate analysis to determine which parameter had an independent association with NAFLD, higher body mass index, alanine aminotransferase (ALT), triglyceride (TG), and low high-density lipoprotein cholesterol were independently associated with developing NAFLD in the SY type. In contrast, male sex, alcohol consumption, higher ALT, TG, and fasting glucose were risk factors for NAFLD in the TE type. CONCLUSIONS: These results indicated that the SY and TE types are independent risk factors for NAFLD.

Tissue Expansion after Non-Skin-Sparing Mastectomy: A Comparative Study of Expansion Courses of Prepectoral and Subpectoral Tissue Expander Placement with Acellular Dermal Matrix.

Although skin- or nipple-sparing mastectomy has been popular in the treatment of breast cancer, the radical excision of breast tissue is unavoidable in certain circumstances. However, the ability of an acellular dermal matrix (ADM) to expand remains questionable, and this situation may further hinder tissue expansion. From October 2017 to January 2020, patients who underwent immediate breast reconstruction with tissue expander placement using ADM whose initial fill volume was less than 50 mL were retrospectively reviewed. The primary outcomes were the number of visits and number of days required to complete the expansion, and the secondary outcomes were the amount of postoperative expansions, expander fill ratio and expander volume. Between the prepectoral group (n = 26) and subpectoral group (n = 39), the mean number of days (81.46 days versus 88.64 days, p = 0.365) and mean number of visits (5.08 versus 5.69, p = 0.91) required to complete expansion exhibited no significant differences. Additionally, there were no significant differences in the mean amount of postoperative expansion (314.23 mL versus 315.38 mL, p = 0.950), the mean final volume (353.08 mL versus 339.62 mL, p = 0.481) or the mean final volume ratio (0.89 versus 0.86, p = 0.35) between the two groups. Therefore, we suggest that prepectoral tissue expander placement after conventional mastectomy can be a valid option.

A comparative study of pre- or subpectoral expander position with the fenestrated Acellular dermal matrix anterior coverage, on drainage volume and Seroma Formation after Non-Nipple-Sparing Mastectomy.

BACKGROUND: It has been reported that the use of the acellular dermal matrix (ADM) in expander-based breast reconstruction is related to an increase in seroma-related complications. The aim of this study is to compare the actual drainage volume, time to drain removal, and seroma formation rate in patients with prepectoral expander placement with anterior coverage of a fenestrated ADM to those patients with partial subpectoral expander placement with inferior coverage of a fenestrated ADM. METHODS: This is a single-surgeon retrospective review of patients who underwent prepectoral expander-based breast reconstruction following non-nipple-sparing mastectomy. Patient demographics, operative data, and complications were analyzed and multivariate linear regression analyses were conducted to evaluate the significance of factors that influences total volume of fluid formation. RESULTS: A total of 89 breasts from 87 patients were included in the study. Twenty-seven breasts had prepectoral expander reconstruction and 62 breasts had partial subpectoral expander reconstruction. Mean total volumes of fluid formation (total drainage volume + additional aspirated volume) were not significantly different (p = 0.190) in the two groups. In the subpectoral group only, high body mass index (BMI) was correlated with the total volume of fluid formation among the independent factors. (p = 0.017) CONCLUSIONS: Although total drainage volume was not significantly different between prepectoral and subpectoral groups, prepectoral positioning of the expander can be a protective factor against seroma formation in high BMI patients. Further definitive studies with larger patient numbers are warranted to corroborate these data and draw definitive conclusions.

PAR-1622 is a selective peroxisome proliferator-activated receptor gamma partial activator with preserved antidiabetic efficacy and broader safety profile for fluid retention.

Peroxisome proliferator-activated receptor (PPAR) gamma is known to be a key regulator of insulin resistance. PAR-1622 is a novel small molecule compound synthesized in Dong-A research center. In this study, we characterized the pharmacological profiles of PAR-1622, a selective partial activator of PPARgamma. In transient transactivation assays, PAR-1622 [(S)-2-ethoxy-3(4-(5-(4-(5-(methoxymethyl)isoxazol-3-yl)phenyl)-3-methylthiophen-2-yl)methoxy)phenyl)propanoic acid] showed a partial activator against human PPARgamma with an EC(50) of 41 nM and a maximal response of 37% relative to the full agonist rosiglitazone without activating human PPARdelta. PAR-1622 was 56 folds more selective for human PPARgamma than for human PPARalpha (EC(50), 2304 nM), which means that it is a selective partial activator of PPARgamma. PAR-1622 also showed a partial activator against mouse PPARgamma with an EC(50) of 427 nM and a maximal response was 57% of that of rosiglitazone. INT-131, a selective PPARgamma partial agonist in clinical stage, also was a partial activator against human PPARgamma with an EC(50) of 83 nM and a maximal response achieved by INT-131 was 49% of that observed with full agonist rosiglitazone. In functional assays using human mesenchymal stem cells, PAR-1622 induced adipocyte differentiation, which was 3-fold more potent with a comparable maximum response compared to INT-131. Furthermore, PAR-1622 significantly improved hyperglycemia in db/db when orally administered at a dose of 1 mg/kg/day for 5 days. In hemodilution assays with Evans Blue, rosiglitazone significantly increased the plasma volume in ICR mice that were orally administered 30 mg/kg/day for 9 days; however, PAR-1622 showed no significant effects on plasma volume, similar to INT-131. These results suggest that PAR-1622 is a selective partial activator of PPARgamma and has excellent antihyperglycemic activities and a broad safety profile for fluid retention.

Untargeted metabolomics analysis of rat hippocampus subjected to sleep fragmentation.

Sleep fragmentation (SF) commonly occurs in several pathologic conditions and is especially associated with impairments of hippocampus-dependent neurocognitive functions. Although the effects of SF on hippocampus in terms of protein or gene levels were examined in several studies, the impact of SF at the metabolite level has not been investigated. Thus, in this study, the differentially expressed large-scale metabolite profiles of hippocampus in a rat model of SF were investigated using untargeted metabolomics approaches. Forty-eight rats were divided into the following 4 groups: 4-day SF group, 4-day exercise control (EC) group, 15-day SF group, and 15-day EC group (n = 12, each). SF was accomplished by forced exercise using a walking wheel system with 30-s on/90-s off cycles, and EC condition was set at 10-min on/30-min off. The metabolite profiles of rat hippocampi in the SF and EC groups were analyzed using liquid chromatography/mass spectrometry. Multivariate analysis revealed distinctive metabolic profiles and marker signals between the SF and corresponding EC groups. Metabolic changes were significant only in the 15-day SF group. In the 15-day SF group, L-tryptophan, myristoylcarnitine, and palmitoylcarnitine were significantly increased, while adenosine monophosphate, hypoxanthine, L-glutamate, L-aspartate, L-methionine, and glycerophosphocholine were decreased compared to the EC group. The alanine, aspartate, and glutamate metabolism pathway was observed as the common key pathway in the 15-day SF groups. The results from this untargeted metabolomics study provide a perspective on metabolic impact of SF on the hippocampus.

Bioactivity of Fermented Green Coffee Bean Extract Containing High Chlorogenic Acid and Surfactin.

Chlorogenic acid (CGA) is a major component of green coffee beans. Surfactin, a cyclic lipopeptide, is produced and secreted by Bacillus subtilis strains. In this study, bioactivities of fermented green coffee bean extract (FGCBE) and the individual compounds, CGA and surfactin. were compared in HepG2 cells. The concentration of surfactin and CGA in the FGCBE and non-fermented green coffee bean extract (NFGCBE) were determined to be 9.2 and 7.33 and 0.72 and 0.53 mg·mL-1, respectively. The FGCBE contained about 20% and 26% more CGA and surfactin than the NFGCBE. Although CGA and surfactin exhibited cytotoxicity at concentrations more than 100 and 20 µg respectively, the FGCBE 50 containing CGA (460 µg·mL-1) and surfactin (720 µg·mL-1) effectively prevented cell death by oxidative stress and also strongly activated the proliferation of cells incubated with under 50 µM H2O2. The CGA and surfactin in FGCBE were 9.2 and 72 times higher than the CGA and surfactin compounds (50 and 10 µg·mL-1). The relative proliferation of the FGCBE-treated cells also was 3.3 and 8.8 times higher than the CGA and surfactin compounds treated the oxidative stressed cells with 50 µM H2O2. These results suggest that the single compounds such as CGA and surfactin generally have cytotoxicity at low concentration of them but FGCBE contained them acted as strong antioxidants, activators of cell proliferation, inhibitors of cell apoptosis. Various bioactive compounds in fermented coffee bean also seem to help cell proliferation and decreasing of cytotoxicity by CGA and surfactin in coffee bean.

Macrophage cell tracking PET imaging using mesoporous silica nanoparticles via in vivo bioorthogonal F-18 labeling.

We introduce an efficient cell tracking imaging protocol using positron emission tomography (PET). Since macrophages are known to home and accumulate in tumor tissues and atherosclerotic plaque, we design a PET imaging protocol for macrophage cell tracking using aza-dibenzocyclooctyne-tethered PEGylated mesoporous silica nanoparticles (DBCO-MSNs) with the short half-life F-18-labeled azide-radiotracer via an in vivo strain-promoted alkyne azide cycloaddition (SPAAC) covalent labeling reaction inside macrophage cells in vivo. This PET imaging protocol for in vivo cell tracking successfully visualizes the migration of macrophage cells into the tumor site by the bioorthogonal SPAAC reaction of DBCO-MSNs with [18F]fluoropentaethylene glycolic azide ([18F]2) to form 18F-labeled aza-dibenzocycloocta-triazolic MSNs (18F-DBCOT-MSNs) inside RAW 264.7 cells. The tissue radioactivity distribution results were consistent with PET imaging findings. In addition, PET images of atherosclerosis in ApoE-/- mice fed a western diet for 30 weeks were obtained using the devised macrophage cell-tracking protocol.

PAR-5359, a well-balanced PPARalpha/gamma dual agonist, exhibits equivalent antidiabetic and hypolipidemic activities in vitro and in vivo.

Peroxisome proliferator-activated receptor (PPAR) alpha and gamma are key regulators of lipid homeostasis and insulin resistance. In this study, we characterize the pharmacological profiles of PAR-5359, a dual agonist of PPARalpha and gamma with well-balanced activities. In transient transactivation assay, PAR-5359 (3-(4-(2[4-(4chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethoxy)-phenyl)-(2S)-ethoxy-propionic acid) significantly activated human and mouse PPARalpha and gamma without activating PPARdelta. In functional assays using human mesenchymal stem cells and human hepatoma HepG2 cells, PAR-5359 significantly induced adipocyte differentiation and human ApoA1 secretion, which coincided with its transactivation potencies against the corresponding human receptor subtypes. Interestingly, PAR-5359 showed equivalent potencies against the mouse receptor subtypes (alpha and gamma; 2.84 microM and 3.02 microM, respectively), which suggests the possibility that PAR-5359 could simultaneously activates each subtype of receptors subtype in under physiological conditions. In an insulin-resistant ob/ob mouse model, PAR-5359 significantly reduced plasma insulin levels, improved insulin sensitivity (HOMA-IR), and completely normalized plasma glucose levels. In a severe diabetic db/db mouse model, PAR-5359 dose-dependently reduced the plasma levels of glucose (ED(30) = 0.07 mg/kg). Furthermore, it lowered plasma levels of non HDL- (ED(30) = 0.13 mg/kg) and total cholesterol (ED(30) = 0.03 mg/kg) in high cholesterol diet-fed rats for 4 days treatment. These results suggest that PAR-5359 has the balanced activities for PPARalpha and PPARgamma in vivo as well as in vitro. And its balanced activities may render PAR-5359 as a pharmacological tool in elucidating the complex roles of PPARalpha/gamma dual agonists.

Design, synthesis, and evaluation of novel aryl-tetrahydropyridine PPARalpha/gamma dual agonists.

Aryl-tetrahydropyridine derivatives were prepared and their PPARalpha/gamma dual agonistic activities were evaluated. Among them, compound (S)-5b was identified as a potent PPARalpha/gamma dual agonist with an EC(50) of 1.73 and 0.64 microM in hPPARalpha and gamma, respectively. In diabetic (db/db) mice, compound (S)-5b showed good glucose lowering efficacy and favorable pharmacokinetic properties.

Association of Sasang Constitutional Types with Incident Hypertension: A 12-Year Follow-Up Study.

OBJECTIVES: Sasang constitutional types (SCTs) are four distinct classifications of people based on physiologic and physical characteristics. The different types have been reported to have different disease susceptibility, but there are no studies reporting the association of SCT and hypertension (HTN) over a long-term follow-up period. This study prospectively investigated the association between SCT and incidence of HTN. DESIGN: This was a prospective study in a population-based cohort study in Korea. SUBJECTS: Data from two independent population-based cohorts that are embedded within the Korean Genome and Epidemiology Study were used. A total of 2083 subjects who were free of HTN at baseline were selected for the analysis. OUTCOME MEASURES: HTN was diagnosed as systolic blood pressure (BP) ≥140 mmHg and diastolic BP ≥90 mmHg, use of antihypertensive medication, or diagnosis by doctor. The SCTs were classified using an integrated diagnostic method that included facial features, body shape, voice, and questionnaire responses. The association between the SCT and the incidence of HTN was investigated by Cox proportional hazard regression analysis and calculation of estimated survival functions. RESULTS: The Tae-eum (TE) type showed a significantly increased risk for HTN (hazard ratio [HR] = 1.55, 95% confidence interval [CI] 1.15-2.10; p = 0.005), even after adjusting for all possible confounders. In a stratified analysis by body mass index (BMI) conducted only in the TE type, even those in the TE type with normal BMI had a significantly higher risk for HTN (HR = 1.47, 95% CI 1.07-2.03; p = 0.016). Furthermore, survival analysis showed that the TE type had a higher rate of developing HTN than the So-eum and So-yang types had, regardless of obesity status. CONCLUSIONS: These results show that the TE type is an independent risk factor for HTN. Thus, early prevention and treatment for HTN in this type are needed.

Novel potent antagonists of transient receptor potential channel, vanilloid subfamily member 1: structure-activity relationship of 1,3-diarylalkyl thioureas possessing new vanilloid equivalents.

Recently, 1,3-diarylalkyl thioureas have merged as one of the promising nonvanilloid TRPV1 antagonists possessing excellent therapeutic potential in pain regulation. In this paper, the full structure-activity relationship for TRPV1 antagonism of a novel series of 1,3-diarylalky thioureas is reported. Exploration of the structure-activity relationship, by systemically modulating three essential pharmacophoric regions, led to six examples of 1,3-dibenzyl thioureas, which exhibit Ca(2+) uptake inhibition in rat DRG neuron with IC(50) between 10 and 100 nM.

Association of Sasang Constitutional Type with Sarcopenia.

Sasang constitutional medicine (SCM) is a unique Korean traditional medicine that classifies human beings as four distinct types named Sasang constitutional types (SCTs), based on physiologic, physical, and psychological traits. Accumulating evidence has demonstrated that specific constitutional types are associated with chronic diseases, but no study has investigated the relationship between SCTs and sarcopenia. The aim of this study was to examine the association in a large population-based study. Data from 1,204 participants who completed questionnaires for life style, anthropometric evaluation, and biochemical analysis were analyzed. Classification of the SCTs was done using an integrated diagnostic method. Sarcopenia was defined as appendicular skeletal muscle mass/height(2) less than one standard deviation below the gender-specific normal mean of a younger group. Dual-energy X-ray absorptiometry was used to assess whole body composition. The prevalence of sarcopenia was 8.6% in the Tae-eum (TE) type, 44.7% in the So-eum (SE) type, and 20.7% in the So-yang (SY) type. Multivariate analysis revealed that the SE and SY types had 9.22 (5.06-16.81; P < 0.0001) and 2.90 (1.76-4.76; P < 0.0001) greater odds of sarcopenia compared to the TE type, respectively. Our results show that the SE and SY types are significantly associated with increased prevalence of sarcopenia.

In vitro structure-activity relationship and in vivo studies for a novel class of cyclooxygenase-2 inhibitors: 5-aryl-2,2-dialkyl-4-phenyl-3(2H)furanone derivatives.

5-Aryl-2,2-dialkyl-4-phenyl-3(2H)furanone derivatives were studied as a novel class of selective cyclooxygenase-2 inhibitors with regard to synthesis, in vitro SAR, antiinflammatory activities, pharmacokinetic considerations, and gastric safety. 1f, a representative compound for methyl sulfone derivatives, showed a COX-2 IC(50) comparable to that of rofecoxib. In case of 20b, a representative compound for sulfonamide derivatives, a potent antiinflammatory ED(50) of 0.1 mg kg(-1) day(-1) was observed against adjuvant-induced arthritis by a preventive model, positioning 20b as one of the most potent COX-2 inhibitors ever reported. Furthermore, 20b showed strong analgesic activity as indicated by its ED(50) of 0.25 mg/kg against carrageenan-induced thermal hyperalgesia in the Sprague-Dawley rat. 3(2H)Furanone derivatives showed due gastric safety profiles as selective COX-2 inhibitors upon 7-day repeat dosing. A highly potent COX-2 inhibitor of the 3(2H)furanone scaffold could be considered suitable for a future generation COX-2 selective arthritis medication with improved safety profiles.

So-eum type as an independent risk factor for irritable bowel syndrome: a population-based study in Korea.

OBJECTIVES: It has been hypothesized that Sasang constitutional types (SCTs) have a specific hypoactive organ, which can account for vulnerability to related diseases or symptoms. This study examined the relationship between SCTs and irritable bowel syndrome (IBS). DESIGN: Cross-sectional study in a population-based cohort study in Korea. PARTICIPANTS: 1362 individuals (705 men and 657 women) who participated in the Korean Genome and Epidemiology Study. OUTCOME MEASURES: The participants were classified into SCTs by the integrated diagnostic model and asked about symptoms related to IBS using the Rome II criteria. RESULTS: The prevalence of IBS differed significantly among the SCTs, with 33 (18.3%) of the So-eum (SE) type, 74 (9.9%) of the Tae-eum (TE) type, and 57 (13.2%) of the So-yang (SY) type having IBS. Even after adjustment for possible confounders, the SE type for both sexes continued to show 1.82-fold (95% confidence interval [CI], 1.05-3.16) excess odds of having IBS. Men with SE type had a 2.97 times (95% CI, 1.34-6.58) and a 2.50 times (95% CI, 1.15-5.47) significantly higher odds of having IBS than the TE and SY types, respectively. In analysis for the joint effect of SCT and psychological stress, the multivariate odds ratio of IBS was 3.21 (95% CI, 1.33-7.75) for the SE type and Psychological Well-Being Index-Short Form (PWI-SF) score (<27), and 5.83 (95% CI, 1.80-18.88) for the SE type and PWI-SF (≥27) compared with the TE type and PWI-SF score (<27). CONCLUSIONS: The SE type of SCT is an independent risk factor for IBS. The findings support the hypothesis that persons with SE type are vulnerable to gastrointestinal diseases.

Design, synthesis, and structure-activity relationship of carbamate-tethered aryl propanoic acids as novel PPARalpha/gamma dual agonists.

We have developed a new class of PPARalpha/gamma dual agonists, which show excellent agonistic activity in PPARalpha/gamma transactivation assay. In particular, (R)-9d was identified as a potent PPARalpha/gamma dual agonist with EC(50)s of 0.377 microM in PPARalpha and 0.136 microM in PPARgamma, respectively. Interestingly, the structure-activity relationship revealed that the stereochemistry of the identified PPARalpha/gamma dual agonists significantly affects their agonistic activities in PPARalpha than in PPARgamma.

Biarylcarboxybenzamide derivatives as potent vanilloid receptor (VR1) antagonistic ligands.

Seventeen biarylcarboxybenzamide derivatives were prepared for the study of their agonistic/antagonistic activities to the vanilloid receptor (VR1) in rat DRG neurons. The replacement of the piperazine moiety of the lead compound 1 with phenyl ring showed quite enhanced antagonistic activity. Among the prepared derivatives, N-(4-tert-butylphenyl)-4-pyridine-2-yl-benzamide (2, IC(50)=31 nM) and N-(4-tert-butylphenyl)-4-(3-methylpyridine-2-yl)benzamide (3g, IC(50)=31 nM), showed 5-fold higher antagonistic activity than 1 in (45)Ca(2+)-influx assay.