Characterization and Functions of Protease-Activated Receptor 2 in Obesity, Diabetes, and Metabolic Syndrome: A Systematic Review

Proteinase-activated receptor 2 (PAR2) is a cell surface receptor activated by serine proteinases or specific synthetic compounds. Interest in PAR2 as a pharmaceutical target for various diseases is increasing. Here we asked two questions relevant to endothelial dysfunction and diabetes: How is PAR2 function affected in blood vessels? What role does PAR2 have in promoting obesity, diabetes, and/or metabolic syndrome, specifically via the endothelium and adipose tissues? We conducted a systematic review of the published literature in PubMed and Scopus (July 2015; search terms: par2, par-2, f2lr1, adipose, obesity, diabetes, and metabolic syndrome). Seven studies focused on PAR2 and vascular function. The obesity, diabetes, or metabolic syndrome animal models differed amongst studies, but each reported that PAR2-mediated vasodilator actions were preserved in the face of endothelial dysfunction. The remaining studies focused on nonvascular functions and provided evidence supporting the concept that PAR2 activation promoted obesity. Key studies showed that PAR2 activation regulated cellular metabolism, and PAR2 antagonists inhibited adipose gain and metabolic dysfunction in rats.We conclude that PAR2 antagonists for treatment of obesity indeed show early promise as a therapeutic strategy; however, endothelial-specific PAR2 functions, which may offset mechanisms that produce vascular dysfunction in diabetes, warrant additional study

Preserved arterial vasodilatation via endothelial protease-activated receptor-2 in obese type 2 diabetic mice

BACKGROUND AND PURPOSE In non-obese diabetic animals, protease-activated receptor-2 (PAR2) agonists are more effective vasodilators, which is attributed to increased COX-2 and endothelial NOS (eNOS) activities. Under conditions of diabetes and obesity, the effectiveness of PAR2 agonists is unknown. We compared the vasodilator responses of small calibre mesenteric arteries from obese diabetic B6.BKS(D)-Leprdb/J (db/db) induced by PAR2-activating agonists 2-furoyl-LIGRLO-amide (2fly) and trypsin to those obtained in controls [C57BL/6J (C57)], and assessed the contributions of COX, NOS and calcium-activated potassium channels (KCa) to these responses. EXPERIMENTAL APPROACH Arteries mounted in wire myographs under isometric tension conditions were contracted submaximally by U46619 then exposed to vasodilators. mRNA and protein expression of PAR2, eNOS and soluble GC (sGC) were determined by real-time PCR and Western blots. KEY RESULTS ACh- and nitroprusside-induced relaxations were attenuated in db/db compared with C57. In contrast, 2fly- and trypsin-induced relaxations were largely retained in db/db. A NOS inhibitor partly inhibited ACh- and 2fly-induced relaxations in C57, but not those in db/db. Inhibitors of the COX-cAMP pathway (FR122044, SC560, NS398, SC58125, SQ22536, CAY10441) did not affect these relaxation responses in either strain. Charybdotoxin (BKCa, SK3.1 blocker), but not iberiotoxin (BKCa blocker), inhibited responses to the PAR2 agonists in db/db. In db/db protein levels of eNOS were higher, whereas those of sGC were lower than in C57. PAR2 mRNA expression in db/db was higher than in C57. CONCLUSIONS AND IMPLICATIONS PAR2-mediated vasodilatation is protected against the negative effects of obesity and diabetes in mice. In diabetic vascular dysfunction, preserved PAR2 vasodilatation was linked to activation of SK3.1

Tracking the Heavy Metal Contaminants Entrained with the Flow into a Trickle Bed Hydrotreating Reactor Packed with Different Catalyst Shapes using Newly Developed Noninvasive Dynamic Radioactive Particle Tracking

A newly developed modified Dynamic Radioactive Particle Tracking system (DRPT) was used to investigate the heavy metal contaminants deposition locations in different catalyst beds, sphere, cylinder, trilobe, and quadrilobed in Trickle Bed Reactors. In the present paper, Kernel Density Estimator (KDE) was used to estimate the probability density distributions of heavy metal contaminants depositions in terms of bed radius height. The result shows that the four cases have similar probability density distribution in terms of radius, while the spherical catalyst has the larger distribution range in terms of bed height. The heavy metal deposition is directly related to the pressure drops along the bed height which indicate the bed porosity and intricate bed structure in catalyst packed beds. Heavy metals have more chance to deposit at higher levels of packed beds with higher pressure drops

過酸化ベンゾイルの一般薬理学的研究

The pharmacological actions of benzoyl peroxide were investigated using the screening methods of general pharmacology. The results obtained in the present study were as follows: (1) In in vivo study, benzoyl peroxide did not exhibit analgesic, anti-convulsive, muscle-relaxant or hypnotic effects in mice. (2) Benzoyl peroxide did not affect the twitch response to electrical stimulation in isolated phrenic nerve-diaphragm preparation of rats. (3) Benzoyl peroxide did not affect the contractile response to acetylcholine in the isolated bronchus of rats, but significantly depressed the contractile responses to acetylcholine and Ba^ in isolated ileum of rats. (4) Benzoyl peroxide did not exhibit diuretic effects or hemolytic effects in rabbits. The in vivo results indicated that benzoyl peroxide has no effect on the central nervous system or the somatic nervous system of rats. However, at higher concentrations benzoyl peroxide depressed the contractile response of ileal smooth muscles. Therefore, our results suggest that excess benzoyl peroxide changes some physiological functions of smooth muscle tissue without changing the behavior or external appearance in vivo experiments

アワ メイショ ズエ ニオケル ビザン ノ シゼン ト ケイカン

In this paper the nature and the landscape of the Mt. Bizan are investigated based on “Awa meisho zue” which was a guidebook of Awa (Tokushima) published about 200 years ago. In the picture entitled “Mt. Bizan” a tower at the Jimyoin Temple and two buildings are drawn in the mountain. The mountain is covered with pine trees, and there is a waterfall near the tower. Besides pine trees, three types of trees, Japanese cedar and/or Japanese cypress, trees that presumably cherry, and unknown broadleaf trees are drawn in Mt. Otakiyama that is a part of Mt. Bizan based on the picture entitled “Otakisan Jimyoin”. Other historical records in Edo era coincide with the composition of plant species in Mt. Bizan. Though the vegetation of Mt. Bizan was efended by laws throughout Edo era, it was deforested and the mountain became bald after the Meiji Restoration. Afterwards, it was protected by specifying it as the protection forest and by making it as a park. Now, pine trees and Japanese cedar and/or Japanese cypress have almost been lost, and pasania and live oak are well growing in the mountain. The tower at Jimyoin was burned down by the air raid in the World War II, and the waterfall has thinned. On the other hand, mountain trails and a ropeway were made, and a lot of buildings were built at the top of the mountain. Thus, the nature and the landscape of Mt. Bizan greatly changed in 200 years. However, citizens are still familiar with it as the symbol of Tokushima City

Fluorescence Dequenching Makes Haem-Free Soluble Guanylate Cyclase Detectable in Living Cells

In cardiovascular disease, the protective NO/sGC/cGMP signalling-pathway is impaired due to a decreased pool of NO-sensitive haem-containing sGC accompanied by a reciprocal increase in NO-insensitive haem-free sGC. However, no direct method to detect cellular haem-free sGC other than its activation by the new therapeutic class of haem mimetics, such as BAY 58-2667, is available. Here we show that fluorescence dequenching, based on the interaction of the optical active prosthetic haem group and the attached biarsenical fluorophor FlAsH can be used to detect changes in cellular sGC haem status. The partly overlap of the emission spectrum of haem and FlAsH allows energy transfer from the fluorophore to the haem which reduces the intensity of FlAsH fluorescence. Loss of the prosthetic group, e.g. by oxidative stress or by replacement with the haem mimetic BAY 58-2667, prevented the energy transfer resulting in increased fluorescence. Haem loss was corroborated by an observed decrease in NO-induced sGC activity, reduced sGC protein levels, and an increased effect of BAY 58-2667. The use of a haem-free sGC mutant and a biarsenical dye that was not quenched by haem as controls further validated that the increase in fluorescence was due to the loss of the prosthetic haem group. The present approach is based on the cellular expression of an engineered sGC variant limiting is applicability to recombinant expression systems. Nevertheless, it allows to monitor sGC's redox regulation in living cells and future enhancements might be able to extend this approach to in vivo conditions

Reactive oxygen-derived free radicals are key to the endothelial dysfunction of diabetes.

Vascular complications are an important pathological issue in diabetes that lead to the further functional deterioration of several organs. The balance between endothelium-dependent relaxing factors and endothelium-dependent contracting factors (EDCFs) is crucial in controlling local vascular tone and function under normal conditions. Diabetic endothelial dysfunction is characterized by reduced endothelium-dependent relaxations and/or enhanced endothelium-dependent contractions. Elevated levels of oxygen-derived free radicals are the initial source of endothelial dysfunction in diabetes. Oxygen-derived free radicals not only reduce nitric oxide bioavailability, but also facilitate the production and/or action of EDCFs. Thus, the endothelial balance tips towards vasoconstrictor responses over the course of diabetes. © 2009 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.postprin

ACE2 Deficiency Enhances Angiotensin II-Mediated Aortic Profilin-1 Expression, Inflammation and Peroxynitrite Production

Inflammation and oxidative stress play a crucial role in angiotensin (Ang) II-mediated vascular injury. Angiotensin-converting enzyme 2 (ACE2) has recently been identified as a specific Ang II-degrading enzyme but its role in vascular biology remains elusive. We hypothesized that loss of ACE2 would facilitate Ang II-mediated vascular inflammation and peroxynitrite production. 10-week wildtype (WT, Ace2+/y) and ACE2 knockout (ACE2KO, Ace2−/y) mice received with mini-osmotic pumps with Ang II (1.5 mg.kg−1.d−1) or saline for 2 weeks. Aortic ACE2 protein was obviously reduced in WT mice in response to Ang II related to increases in profilin-1 protein and plasma levels of Ang II and Ang-(1–7). Loss of ACE2 resulted in greater increases in Ang II-induced mRNA expressions of inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1β, and IL-6 without affecting tumor necrosis factor-α in aortas of ACE2KO mice. Furthermore, ACE2 deficiency led to greater increases in Ang II-mediated profilin-1 expression, NADPH oxidase activity, and superoxide and peroxynitrite production in the aortas of ACE2KO mice associated with enhanced phosphorylated levels of Akt, p70S6 kinase, extracellular signal-regulated kinases (ERK1/2) and endothelial nitric oxide synthase (eNOS). Interestingly, daily treatment with AT1 receptor blocker irbesartan (50 mg/kg) significantly prevented Ang II-mediated aortic profilin-1 expression, inflammation, and peroxynitrite production in WT mice with enhanced ACE2 levels and the suppression of the Akt-ERK-eNOS signaling pathways. Our findings reveal that ACE2 deficiency worsens Ang II-mediated aortic inflammation and peroxynitrite production associated with the augmentation of profilin-1 expression and the activation of the Akt-ERK-eNOS signaling, suggesting potential therapeutic approaches by enhancing ACE2 action for patients with vascular diseases