No abstract

We have developed a method for obtaining pneumococcal lipoteichoic acid (LTA) with none, one, or two acyl chains. Anion-exchange chromatography at pH 9.5 yields pneumococcal LTA (labeled LTA-9.5) that has a mass spectrum identical to that of pre-ion-exchange LTA and loses 500 mass units after deacylation by alkali hydrolysis. Anion exchange at pH 10.5 produces LTA (labeled LTA-10.5) with mass peaks that are 264 mass units lower than those of pre-ion-exchange LTA, and deacylation of LTA-10.5 by alkali hydrolysis reduces the mass by only 239 mass units. This result indicates that LTA-10.5 has lost one of the two acyl chains, whereas LTA-9.5 has both acyl chains. When the biological properties of LTA-9.5 and LTA-10.5 are examined with mouse cells, only LTA-9.5 (and not LTA-10.5) is able to stimulate mouse cells to produce tumor necrosis factor alpha, interleukin-1␤, and nitric oxide. In contrast, both LTA-9.5 and LTA-10.5 can stimulate human cells. LTA became inactive when both acyl chains were removed. Thus, acyl chains are critical for LTA function, and small variations in acyl chains can alter biological properties of LTA.Lipoteichoic acid (LTA) is an important component of the cell walls of gram-positive bacteria. LTA is a polyphosphate polymer that is linked to a glycerol backbone with two acyl chains (10). The acyl chains anchor the molecule to the bacterial plasma membrane. The resulting LTA structure is amphipathic, which is also true of the lipopolysaccharide (LPS) of gram-negative bacteria. Also, like LPS, LTA is considered to be an important pathogen-associated molecular pattern capable of stimulating innate immunity and responsible for grampositive bacterial sepsis. However, the biological properties of LTA are only beginning to be elucidated because the LTA used in previous studies may have contained biologically active contaminants (12) or may have been altered in structure (25). The biological properties of LTA have been investigated mostly with staphylococcal LTA, which stimulates platelet-activating factor receptor (24) and TLR2 (9, 30). Staphylococcal LTA has been shown to induce the production of tumor necrosis factor alpha (TNF-␣) (9) and nitric oxide (NO) (7,22). It has also been shown to induce sepsis in rats when peptidoglycan is coadministered (8,23,26). Thus, staphylococcal LTA may be as important in causing gram-positive bacterial sepsis as LPS is in causing gram-negative bacterial sepsis.Along with staphylococci, pneumococci are responsible for most cases of gram-positive bacterial sepsis, which accounts for about half of all cases of bacterial sepsis (6, 35). Pneumococcal LTA has also been shown to stimulate cells via TLR2 (16,29). Yet to date, pneumococcal LTA has not been studied as extensively as has staphylococcal LTA. Also, it is difficult to extrapolate biological properties of staphylococcal LTA to those of pneumococcal LTA, since the two LTAs have significant structural differences. For instance, the polyphosphate polymer of staphylococcal LTA is composed of 20 to 50 small and va...

Fimasartan (Kanarb®), an angiotensin II receptor antagonist with selectivity for the AT1 receptor subtype, is a pyrimidinone-related heterocyclic compound that was developed by Boryung Pharm. Co., Ltd. Among numerous synthetic derivatives, fimasartan was chosen as a new drug candidate through in vitro and in vivo screening studies. Pharmadynamic-pharmacokinetic properties and safety profiles were determined in a series of nonclinical and clinical studies. Fimasartan is a new angiotensin receptor blocker, and the first new molecular entity acting on cardiovascular system approved by Korean Food and Drug Administration for the treatment of essential hypertension in September 2010. Further development process for combination therapy and overseas registration is currently ongoing.

given orally at 1 and 3 mg/kg reduced blood pressure in conscious renal hypertensive rats. Taken together, these findings indicate that BR-A-657 is a potent and specific antagonist of Ang II at the AT 1 receptor subtype, and reveal the molecular basis responsible for the marked lowering of blood pressure in conscious rats.Key words BR-A-657; losartan; AT 1 receptor; angiotensin II pressor; renal hypertensive rat Hypertension is important not only because of its prevalence but also because it is a major modifiable risk factor of associated cardiovascular and renal complications. 1) Current guidelines emphasize the importance of managing hypertension to reduce substantial morbidity and mortality associated with cardiovascular events. 2-4)The renin angiotensin system (RAS) plays a pivotal role in cardiovascular regulation by blood pressure and fluid-electrolyte balance control. Angiotensin II (Ang II) circulates in the blood stream and is the principal mediator of the RAS system, stimulates vasoconstriction and the retention of salt and water, releases aldosterone from the adrenal glands, and modulates central effects such as drinking.5) The haemodynamic and cardiovascular effects of Ang II are all mediated by its binding to receptors on the surfaces of target cells within central and peripheral blood vessels, and within the heart and other organs.6) There are two distinct receptor subtypes, namely, AT 1 and AT 2 , and AT 1 receptors are thought to mediate the major effects of Ang II in cardiovascular, renal, neuronal, endocrine, hepatic, and other target cells. Many studies have shown that Ang II produces its biological activities by stimulating AT 1 receptors, especially in its blood pressure regulatory effect. Therefore, an Ang II receptor blocker (ARB) that blocks AT 1 receptors is considered to provide potential therapeutic strategies for the managements of hypertension and cardiovascular and renal diseases, and to date, several nonpeptide AT 1 receptor antagonists have been developed for the treatment of hypertension and heart failure. 7,8)