Mast cells: the missing source of cardiac renin?

The renin-angiotensin system (RAS) acts to regulate blood volume and arterial pressure, and has direct effects on the heart. Renin, released by the kidney, circulates and acts-in the rate-limiting step of angiotensin II (Ang II) production-to convert angiotensinogen to inactive angiotensin I (Ang I). Ang II constricts vessels, leading to increased arterial pressure, among other effects. Components of the RAS have been found in a number of extra-renal tissues. Recent research indicates that mast cells in the heart may produce renin, creating a cardiac-specific RAS that acts locally to produce Ang II. These results, however, are not without controversy. Others have searched for sites of renin production and have found no other significant source that was physiologically important or that could not be completely ruled out as a possible contaminant. How important is mast cell-synthesized renin for direct cardiac-related effects?     

Cardiac intracrine renin angiotensin system. Part of genetic reprogramming?

The hypothesis that intracrine renin-angiotensin system activated during heart failure is part of the tendency of the heart to return to embryological conditions when organogenesis is possible is presented and discussed. The hypothesis proposes that the change in genetic makeup, which is known to occur during heart failure, includes a drastic change of intercellular chemical and electrical communication such as second messengers and other signal molecules which are involved in cell proliferation and growth. The role of angiotensin II, which is a growth factor, reduces cell coupling in the failing heart through the activation of AT1 receptors and intracellular pathways, such as PKC, MAPK family and increment of intracellular calcium, might play a key role in the genetic reprogramming of the failing heart.     

Involvement of placental peptidases associated with renin–angiotensin systems in preeclampsia

Preeclampsia is characterized by pregnancy-induced hypertension accompanied with protein urea and generalized edema. Preeclampsia develops during the second half of pregnancy and resolves postpartum promptly, implicating the placenta as a primary cause in the disorder. Normal pregnancy is associated with reductions in arterial pressure and attenuated pressor response to exogenous infused angiotensin II (ANG II). In contrast, women with preeclampsia show the similar sensitivity to the pressor effect of ANG II as do non-pregnant women. To elucidate the involvement of placental peptidases associated with renin–angiotensin systems, we determined the localization of angiotensin-converting enzyme (ACE) and aminopeptidase A (AP-A), ANG II degrading enzyme, in the placenta and compared the expression of mRNA and protein in uncomplicated and preeclamptic placenta. In addition, AP-A expression in trophoblastic cells treated with ANG II and ACE expression in HUVECs under hypoxic condition were analyzed, respectively. The expression of both peptidases in the preeclamptic placenta was significantly higher than those from uncomplicated. ACE was primarily localized to venous endothelial cells of stem villous whereas AP-A expression was recognized in the trophoblast and pericytes of fetal arterioles and venules within stem villous. Hypoxia induced ACE expression in HUVECs while both hypoxia and ANG II evoked AP-A expression in trophoblast. These results suggested that hypoxic condition in preeclampsia induces ACE activation in feto-placental unit to maintain the fetal hemodynamics and placental AP-A plays a role as a component of the barrier of ANG II between mother and fetus.     

Specific cleavage of synthetic renin substrate by mouse γ-nerve growth factor

Results of the present investigation indicate that mouseγ-nerve growth factor (γ-NGF), which belongs to the kallikrein family of proteins, specifically cleaves the Phe-His bond of a synthetic renin substrate and exhibits rat-tonin-like activity. Since other mouse kallikreins do not cleave this bond,γ-NGF may play a regulatory role in the generation of antiogensin-II.     

Effect of combination of renin inhibitor and Mas-receptor agonist in DOCA–salt-induced hypertension in rats

To investigate the combined effect of aliskiren, a renin inhibitor, and AVE 0991, a Mas-receptor agonist, in experimental hypertension (HT) in rats. HT was produced by administration of deoxycorticosterone acetate (DOCA) and mean arterial blood pressure (MABP) was assessed by tail-cuff method. Treatments were started from 4th week onwards and were continued for 9 days. A significant increase in MABP was noted after 1 week in DOCA control rats, as compared with the base line value. A stable HT developed after 4 weeks of DOCA administration. Treatments with aliskiren and AVE 0991 alone, dose-dependently decreased MABP in DOCA-treated rats. Further, combination of low doses of aliskiren and AVE 0991 significantly reduced MABP, as compared with DOCA control rats and with either drug alone in low doses. It may be concluded that treatment with aliskiren produced down-regulation of both harmful Ang II–AT1-receptor and survival Ang(1–7)/Mas-receptor axis of RAAS. Treatment with combination of low doses of aliskiren and AVE 0991, for the first time, has been shown to produce synergistic blood pressure lowering effect. Therefore, combination of renin inhibitor with Mas-receptor agonist may prove beneficial for the treatment of hypertensive patients.     

The potential therapeutic use of renin–angiotensin system inhibitors in the treatment of inflammatory diseases

Inflammation is a normal part of the immune response to injury or infection but its dysregulation promotes the development of inflammatory diseases, which cause considerable human suffering. Nonsteroidal anti-inflammatory agents are the most commonly prescribed agents for the treatment of inflammatory diseases, but they are accompanied by a broad range of side effects, including gastrointestinal and cardiovascular events. The renin–angiotensin system (RAS) is traditionally known for its role in blood pressure regulation. However, there is increasing evidence that RAS signaling is also involved in the inflammatory response associated with several disease states. Angiotensin II increases blood pressure by binding to angiotensin type 1 (AT₁) receptor, and direct renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors and AT₁ receptor blockers (ARBs) are clinically used as antihypertensive agents. Recent data suggest that these drugs also have anti-inflammatory effects. Therefore, this review summarizes these recent findings for the efficacy of two of the most widely used antihypertensive drug classes, ACE inhibitors and ARBs, to reduce or treat inflammatory diseases such as atherosclerosis, arthritis, steatohepatitis, colitis, pancreatitis, and nephritis.     

Does heparin inhibit renin activity?

Although heparin was reported in the 1960s to inhibit renin activity, this has not always been confirmed by other investigators. Hence, we re-examined whether heparin really inhibits renin or not. Renin activities were determined by radioimmunoassay of angiotensin I generated at pH 7.4. (i) No significant difference was found between the two kinds of plasma samples obtained with heparin and with EDTA as anticoagulant, in ARC (renin activity with addition of sheep renin substrate), TRC (ARC after activation of inactive renin by trypsin), or PRA (plasma renin activity without additional substrate). (ii) Even in higher concentrations of heparin up to 500 U/mL, neither PRA, ARC, nor TRC of plasma was affected significantly. (iii) Heparin, in concentrations up to 500 U/mL, exerted no significant effect on TRC of the media of human vascular smooth muscle cell culture. In conclusion, heparin does not exert any significant inhibitory effect on human renin nor does it affect activation of inactive renin by trypsin in the range of concentration of practical use, under the conditions employed in this study.     

Subtyping of haptoglobin — Presentation of a new method

Summary A method is described for large scale routine phenotyping of haptoglobin (Hp) which allows complete subtyping without prior purification of the Hp molecule. The procedure includes polyacrylamide gel isoelectric focusing of reduced, neuraminidase treated serum or plasma samples, and nitrocellulose blots developed with the immunoperoxidase technique. Different variables including sample treatment, electrofocusing, blotting procedures, and immunoperoxidase visualization are discussed.Characteristic -chain patterns allow identification of the common allotypes 2FS, 2SS, 2FF, IS, IF, and Johnson. Isoelectric variations in the -chain may also be recognized. For comparison, two-dimensional Hp-patterns are presented. The results from concurrent typing of 600 samples by ordinary starch gel electrophoresis and by the described isofocusing technique, are evaluated.     

Epigenomics of cancer – emerging new concepts

The complexity of the mammalian genome is regulated by heritable epigenetic mechanisms, which provide the basis for differentiation, development and cellular homeostasis. These mechanisms act on the level of chromatin, by modifying DNA, histone proteins and nucleosome density/composition. During the last decade it became clear that cancer is defined by a variety of epigenetic changes, which occur in early stages of disease and parallel genetic mutations. With the advent of new technologies we are just starting to unravel the cancer epigenome and latest mechanistic findings provide the first clue as to how altered epigenetic patterns might occur in different cancers. Here we review latest findings on chromatin related mechanisms and hypothesize how their impairment might contribute to the altered epigenome of cancer cells.     

Towards a new politics of migration?

This paper reconsiders Stephen Castle’s classic paper Why Migration Policies Fail. Beginning with the so-called migration crisis of 2015 it considers the role of numbers is assessing success or failure. It argues that in the UK public debates about immigration changed with European Union (EU) Enlargement in 2004, when the emphasis shifted from concerns about asylum to concerns about EU mobility. Concerns were exacerbated by the government’s failure to meet its promise to reduce net migration. This policy is hampered by the general problem of definition of “migrant” and the gap between statistical measures and popular usage in which “migration” signifies problematic mobility. In fact, concern about migration has become a placeholder for concerns about globalization and democratic accountability. A new politics of migration must make connections between migrants and citizens, but also between migration and other global processes, particularly outsourcing and the exploitation of labour and resources in the global south.     

Synthesis of new α-heterocyclic α-aminoesters

alpha-Heterocyclic alpha-aminoesters were obtained in good yields by reaction of a glycine cation equivalent and different heterocyclic nucleophiles; diastereoselectivity using a carbohydrate (galactopyranose) as N-protecting group was modest.     

Acanthochlamydoideae—A new subfamily of Amaryllidaceae

Acanthochlamydoideae, a new subfamily of Amaryllidaceae, is proposed in the present paper, based upon the monotypic genus Acanthochlamys which was detected by the writer in 1979 and named Didymocolpus as a new genus but was preceded by P. C. Kao in 1980 under the former name. The genus is indeed of great morphological interest. It has semicylindric leaves with a deep furrow on the ventral and dorsal sides respectively. The lower part of the leaf is connate with, or adnate to, the lower midrib of a rather large and membranous vagina . Such a feature, as far as we know, is very rare in the monocotyledons. The flower resembles that of Amaryllidaceae in having inferior ovary, six stamens and corolla-like perianth with a rather long tube. But it is quite different in other characters, such as head-like cyme, leaf-like bracts and bisulcate leaves, which all are foreign to any taxon known in the Amaryllidaceae. On the other hand, it bears some resemblance particularly in habit and inflorescence to Campynemanthe of the Hypoxidaceae, and also to Borya and Bartlingia of the Liliaceae (in the tribe Johnsonieae), but differs in its long perianth-tube and curious leaf structure. It is highly probable that the resemblance between them is only superficial and not indicative of direct or close relationship. This is no doubt a very curious plant of which we still know incompletely, and for which an appropriate place in the monocotyledons has not yet been found. Considering its floral characters, however, it seems safe for the present to place it as a separate subfamily in the Amaryllidaceae and is juxtaposed with the Ixiolirioideae and Amaryllidoideae, the only two subfamilies of Amaryllidaceae according to H. Melchior (1964), and, of course, to either of them it is not directly related. Its true affinity remains problematic. The only species, Acanthochlamys bracteata, is found in Mar-er-kan (102°12'N, 31°47'E), Qian-ning (101°30'N, 30°33'E), Xiang-cheng (99°39'N, 28°54'E) and Dau cheng (100°10'N, 29°03'E) in western Sichuan of southwest China, in open bushland or grassland at an altitude between 2700—3500 meters. Its geographical distribution is mapped and its morphological details are illustrated to facilitate its identification.     

Structure optimization of a new class of PPARγ antagonists

Peroxisome proliferator-activated receptor gamma (PPARγ) modulators have found wide application for the treatment of cancers, metabolic disorders and inflammatory diseases. Contrary to PPARγ agonists, PPARγ antagonists have been much less studied and although they have shown immunomodulatory effects, there is still no therapeutically useful PPARγ antagonist on the market. In contrast to non-competitive, irreversible inhibition caused by 2-chloro-5-nitrobenzanilide (GW9662), the recently described (E)-2-(5-((4-methoxy-2-(trifluoromethyl)quinolin-6-yl)methoxy)-2-((4-(trifluoromethyl)benzyl)oxy)-benzylidene)-hexanoic acid (MTTB, T-10017) is a promising prototype for a new class of PPARγ antagonists. It exhibits competitive antagonism against rosiglitazone mediated activation of PPARγ ligand binding domain (PPARγLBD) in a transactivation assay in HEK293T cells with an IC₅₀ of 4.3 µM against 1 µM rosiglitazone. The aim of this study was to investigate the structure-activity relationships (SAR) of the MTTB scaffold focusing on improving its physicochemical properties. Through this optimization, 34 new derivatives were prepared and characterized. Two new potent compounds (T-10075 and T-10106) with much improved drug-like properties and promising pharmacokinetic profile were identified.     

The renin–angiotensin system plays a major role in voiding dysfunction of ovariectomized rats

Aims

The renin–angiotensin system (RAS) plays a major role in cardiovascular diseases in postmenopausal women, but little is known about its importance to lower urinary tract symptoms. In this study we have used the model of ovariectomized (OVX) estrogen-deficient rats to investigate the role of RAS in functional and molecular alterations in the urethra and bladder.

Main methods

Responses to contractile and relaxant agents in isolated urethra and bladder, as well as cystometry were evaluated in 4-month OVX Sprague–Dawley rats. Angiotensin-converting enzyme activity and Western blotting for AT1/AT2 receptors were examined.

Key findings

Cystometric evaluations in OVX rats showed increases in basal pressure, capacity and micturition frequency, as well as decreased voiding pressure. Angiotensin II and phenylephrine produced greater urethral contractions in OVX compared with Sham group. Carbachol-induced bladder contractions were significantly reduced in OVX group. Relaxations of urethra and bladder to sodium nitroprusside and BAY 41-2272 were unaffected by OVX. Angiotensin-converting enzyme activity was 2.6-fold greater (p < 0.05) in urethral tissue of OVX group, whereas enzyme activity in plasma and bladder remained unchanged. Expressions of AT1 and AT2 receptors in the urethra were markedly higher in OVX group. In bladder, AT1 receptors were not detected, whereas AT2 receptor expression was unchanged between groups. 17β-Estradiol replacement (0.1 mg/kg, weekly) or losartan (30 mg/kg/day) largely attenuated most of the alterations seen in OVX group.

Significance

Prolonged estrogen deprivation leads to voiding dysfunction and urethral hypercontractility that are associated with increased ACE activity and up-regulation of angiotensin AT1/AT2 receptor in the urethral tissue.     

Muribasidiospora — A new genus of the exobasidiaceae

Summary A new genus under the Exobasidiaceae namelyMuribasidiospora gen. nov.Kamat, M. N. &Rajendren, R. B. has been established to accommodate such species ofExobasidium producing muriform basidiospores in their life cycle. Accordingly the two species viz.Exobasidium hesperidium Maire andE. celtidis Ramakrishnan, T. S. & K. are proposed to be transferred to the new genus under new combinations.     

‘Kumanasamuha’ a new genus of dematiaceae

Summary Kumanasamuha a new genus of Dematiaceae is described, collected growing as saprophyte on unidentified wood, from Pakhal forest, withK. sundara as type.     

Three new rare variants of α1-Antitrypsin

Summary Three new rare genetic variants of the serum protein ₁-antitrypsin (₁-protease inhibitor) have been identified in a Caucasian population. The new alleles in the PI system are PI ^*EFRA, PT^*PCAS, and PI ^*XALB. When compared with the normal type M by isoelectric focusing in polyacrylamide, Efranklin (EFRA) is anodal, and Pcastoria (PCAS) and Xalban (XALB) are cathodal. These variants have been compared with previously described variants by isoelectric focusing and by electrophoresis in agarose and acid starch gels. All three variant alleles appear to be associated with normal amounts of ₁-antitrypsin, assayed both by functional and immunological methods.This work was supported by a grant from the Medical Research Council of Canada