European journal of medicinal chemistry, Apr 1, 1992
... IJ Chen 1 , JM Yang 2 , JL Yeh 1 , BN Wu 1 , YC Lo 1 and SJ Chen 1. ... This study was suppor... more ... IJ Chen 1 , JM Yang 2 , JL Yeh 1 , BN Wu 1 , YC Lo 1 and SJ Chen 1. ... This study was supported by research grants from ihe National Science Council of the Renublic of China of Taiwan (NSC 780412 B03729 and NSC ?90412B0375 1) References 1) Toh CC, Lee TS, Kiang ...
Rationale: CD93, a C-type lectin-like transmembrane glycoprotein, can be shed in a soluble form (... more Rationale: CD93, a C-type lectin-like transmembrane glycoprotein, can be shed in a soluble form (sCD93) upon inflammatory stimuli. sCD93 effectively enhances apoptotic cell clearance and has been proposed as an inflammatory disease biomarker. The function of sCD93 involved directly in inflammation remains to be determined. Herein, we attempted to examine the hypothesis that sCD93 might sequester proinflammatory high-mobility group box 1 protein (HMGB1), exerting anti-inflammatory properties. Methods: Different forms of soluble recombinant human CD93 (rCD93) were prepared by a mammalian protein expression system. rCD93-HMGB1 interaction was assessed using co-immunoprecipitation and solid-phase binding assays. Effects of soluble rCD93 were evaluated in HMGB1-induced macrophage and vascular smooth muscle cells (VSMC) activation and receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, CaCl2-induced and angiotensin II-infused abdominal aortic aneurysm (AAA) formation and ovariectomized-induced osteoporosis in mice. Results: Protein binding studies revealed that soluble rCD93, via the lectin-like domain (D1), can bind to HMGB1 and intercept HMGB1-receptor interaction. Soluble rCD93 containing D1 inhibited HMGB1-induced proinflammatory cytokine production and intracellular mitogen-activated protein kinase (MAPK)/nuclear factor (NF)-κB activation in macrophages and VSMCs, thereby attenuating CaCl2-induced and angiotensin II-infused AAA models. During osteoclastogenesis, RANKL stimulated HMGB1 secretion that promoted RANKL-induced osteoclastogenesis in return. Soluble rCD93 containing D1 impeded RANKL-induced osteoclastogenic marker gene expression and intracellular MAPK/NF-κB signaling, thereby mitigating ovariectomized-induced osteoporosis. Conclusion: These findings demonstrate the therapeutic potential of soluble recombinant CD93 containing D1 in inflammatory diseases. Our study highlights a novel anti-inflammatory mechanism, i.e., sequestration of HMGB1, through which sCD93 prevents HMGB1-receptor interaction on effector cells and alleviates inflammation.
Background. Severe burns result in hypercatabolic state and concomitant muscle atrophy that persi... more Background. Severe burns result in hypercatabolic state and concomitant muscle atrophy that persists for several months, thereby limiting patient recovery. However, the effects of burns on the corresponding spinal dermatome remain unknown. This study aimed to investigate whether burns induce apoptosis of spinal cord ventral horn motor neurons (VHMNs) and consequently cause skeletal muscle wasting. Methods. Third-degree hindpaw burn injury with 1% total body surface area (TBSA) rats were euthanized 4 and 8 weeks after burn injury. The apoptosis profiles in the ventral horns of the lumbar spinal cords, sciatic nerves, and gastrocnemius muscles were examined. The Schwann cells in the sciatic nerve were marked with S100. The gastrocnemius muscles were harvested to measure the denervation atrophy. Result. The VHMNs apoptosis in the spinal cord was observed after inducing third-degree burns in the hindpaw. The S100 and TUNEL double-positive cells in the sciatic nerve increased significantly after the burn injury. Gastrocnemius muscle apoptosis and denervation atrophy area increased significantly after the burn injury. Conclusion. Local hindpaw burn induces apoptosis in VHMNs and Schwann cells in sciatic nerve, which causes corresponding gastrocnemius muscle denervation atrophy. Our results provided an animal model to evaluate burn-induced muscle wasting, and elucidate the underlying mechanisms.
The effect of five lignans, epi-aschantin, epi-magnolin, epi-yangambin, deoxypodophyllotoxin and ... more The effect of five lignans, epi-aschantin, epi-magnolin, epi-yangambin, deoxypodophyllotoxin and yatein, isolated from Hernandia nymphaeifolia on Ca(2+) signaling in Madin-Darby canine kidney cells was examined using fura-2 as a Ca(2+) indicator. These lignans at concentrations between 10 and 100 microM increased [Ca(2+)](i) in a concentration-dependent manner. Removal of extracellular Ca(2+) abolished the Ca(2+) signals evoked by 50 microM of the lignans. La(3+)(50 microM) abolished the Ca(2+) signals induced by 100 microM of epi-aschantin, epi-magnolin and epi-yangambin, and 20 microM deoxypodophyllotoxin, but inhibited by 60% 50 microM yatein-induced responses. All five lignans (50-100 microM) inhibited by 42-65% thapsigargin-induced capacitative Ca(2+) entry, and inhibited by 23-61% thapsigargin-induced intracellular Ca(2+) release. Epi-yangambin (100 microM), epi-magnolin (100 microM), and epi-aschantin (100 microM) inhibited by 8-38% 10 microM ATP-induced Ca(2+) release. Trypan blue exclusion revealed that incubation with deoxypodophyllotoxin or yatein (but not the other lignans) decreased cell viability in a concentration-dependent manner. Together, the results suggest that, in renal tubular cells, these lignans exert multiple actions on Ca(2+) signaling. They caused Ca(2+) influx but reduced thapsigargin-induced capacitative Ca(2+) entry and also thapsigargin- and ATP-induced Ca(2+) release. Additionally, deoxypodophyllotoxin and yatein may be cytotoxic.
Journal of Cardiovascular Pharmacology, Mar 1, 2005
Labedipinedilol-A, a novel dihydropyridine-type calcium antagonist, has been shown to induce hypo... more Labedipinedilol-A, a novel dihydropyridine-type calcium antagonist, has been shown to induce hypotension and vasorelaxation. The objective of the present study was to investigate the effect of labedipinedilol-A on vascular function of rat aortic rings and cultured human umbilical vein endothelial cells (HUVECs). Labedipinedilol-A induced vasorelaxation in rat aortic rings that had been precontracted with phenylephrine in a concentration-dependent manner. This labedipinedilol-A-induced relaxation was significantly reduced by endothelium removal and by exposure to L-N Gnitroarginine methyl ester (L-NAME), methylene blue, or 1H-[1,2,4]oxadiazolol[4,3,a]quinoxalin-1-one (ODQ). In addition, the cyclic GMP content was significantly increased by labedipinedilol-A, which was inhibited by L-NAME in aorta. In cultured HUVECs, labedipinedilol-A induced concentration-dependent formation of NO and Ca 2+ influx, and it increased the abundance of endothelial NO synthase (eNOS) protein. Furthermore, labedipinedilol-A suppressed basal, 10% FBS-and thrombin-stimulated endothelin-1 production, which were reversed by pretreatment with L-NAME, demonstrating that NO was able to inhibit production of ET-1 in HUVECs. Labedipinedilol-A significantly protected cultured HUVECs against dihydroxyfumarate/iron ion-induced decrease of glutathione and cell death. Moreover, labedipinedilol-A also inhibited iron-induced lipid peroxidation in rat brain homogenate and scavenged 2,2#-azobis (2amidinopropane) dihydrochloride-derived peroxy radicals. Labedipinedilol-A acts as lacidipine with additional antioxidant effects and can protect endothelial cells against free radical-induced lipid peroxidation and cell injury. Our results indicate that the endotheliumdependent vasorelaxation by labedipinedilol-A is mediated through Ca 2+-dependent activation of NO synthase and stimulation of NO/cyclic GMP pathway.
The effects of nonivamide on the cardiovascular system were examined and compared with the effect... more The effects of nonivamide on the cardiovascular system were examined and compared with the effects of substance P (SP) in rats. Intravenous (IV) injection (10 @kg) of nonivamide produced triphasic pressure responses (A; depressor, B; pressor, and C; depressor) and biphasic bradycardia responses (f; fast bradycardia and s; slow bradycardia). IA injection (10 &kg) into the epigastric artery caused hypotension and mild tachycardia. The effects of atropine, vagotomy, SP antagonist, propranolal, and clonidine on these responses were examined and mechanisms responsible for the nonivamide-induced responses are postulated as follows. A and f are due to vagal reflex resulting from the excitation of afferent sensory neurons in the heart and are parasympathetic efferent effects from the nucleus solitarius. B is involved in sympathetic activation, partly caused by the release of SP in the spinal cord. C is due to the vasodilatory effect of SP released from perivascular stores. s was diminished by vagotomy and is due to the bradycardiac effect of acetylcholine, released by SP, from cardiac stores. The activation of the autonomic system is inhibited by clonidine and involved in the wide spectrum of nonivamide-induced cardiovascular effects.
Objective: Inflammation is an important molecular basis of atherosclerosis. Recent studies have s... more Objective: Inflammation is an important molecular basis of atherosclerosis. Recent studies have shown that dihydropyridine calcium channel blockers (CCBs) can exert potent anti-inflammatory effects in models of vascular dysfunction. The purpose of the present study was to evaluate anti-inflammatory effects and mechanisms of lercanidipine and labedipinedilol-A, new generation dihydropyridine CCBs, in rat vascular smooth muscle cells (VSMCs) exposed to lipopolysaccharide (LPS) and interferon-g (IFN-g). Methods and results: MTT, Griess reagent, RT-PCR, ELISA, gelatin zymography, immunocytochemistry and Western blotting were employed. We found that lercanidipine and labedipinedilol-A attenuated production of NO, ROS and TNF-a from LPS/IFN-g-stimulated VSMCs. In addition, they both diminished the LPS/IFN-g-induced expression of iNOS protein and mRNA, with attenuation of HMGB1 cytosolic translocation and subsequent extracellular release. Furthermore, they down-regulated MMP-2/MMP-9 activities, whereas expression of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), an inhibitor of MMP-9, was up-regulated. Finally, we found that lercanidipine and labedipinedilol-A inhibited the nuclear translocation of NF-kB and suppressed the phosphorylation of JNK, p38 MAPK and Akt. Conclusion: Lercanidipine and labedipinedilol-A can exert their anti-inflammatory effects through suppression of NO, ROS and TNF-a through down-regulation of iNOS, MMP-2/MMP-9, and HMGB1, with inhibition of signaling transduction of MAPKs, Akt/IkB-a and NF-kB pathways. These findings implicate a valuable role of new generation dihydropyridine CCBs lercanidipine and labedipinedilol-A for the treatment of inflammatory vascular diseases.
ABSTRACT Calcium channel and β-adrenoceptor blockade have proved highly useful in antihypertensiv... more ABSTRACT Calcium channel and β-adrenoceptor blockade have proved highly useful in antihypertensive therapy. Studies of the mechanisms of action of vanidipinedilol that combine these effects within a single molecule are described here. Intravenous injection of vanidipinedilol (0.1, 0.25, 0.5, 1.0, and 2.0 mg/kg) produced dose-dependent hypotensive and bradycardic responses, significantly different from nifedipine-induced (0.5 mg/kg, i.v.) hypotensive and reflex tachycardic effects in pentobarbital-anesthetized Wistar rats. A single oral administration of vanidipinedilol at doses of 10, 25, and 50 mg/kg dose-dependently reduced blood pressure with a decrease in heart rate in conscious spontaneously hypertensive rats (SHRs). In the isolated Wistar rat atrium, vanidipinedilol (10-7, 10-6, and 10-5 M) competitively antagonized the (-)isoproterenol-induced positive chronotropic and inotropic effects and inhibited the increase in heart rate induced by Ca2+ (3.0-9.0 mM) in a concentration-dependent manner. The parallel shift to the right of the concentration-response curve of (-)isoproterenol and CaCl2 suggested that vanidipinedilol possessed β-adrenoceptor-blocking and calcium entry-blocking activities. On tracheal strips of reserpinized guinea pig, cumulative doses of vanidipinedilol (10-10 to 3 × 10-6 M) produced dose-dependent relaxant responses. Preincubating the preparation with ICI 118,551 (10-10, 10-9, 10-8 M), a β2-adrenoceptor antagonist, shifted the vanidipinedilol concentration-relaxation curve significantly to a region of higher concentrations. These results implied that vanidipinedilol had a partial β2-agonist activity. In the isolated thoracic aorta of rat, vanidipinedilol had a potent effect inhibiting high-K+-induced contractions. KCl-induced intracellular calcium changes of blood vessel smooth muscle cell (A7r5 cell lines) determined by laser cytometry also was decreased after administration of vanidipinedilol (10-8, 10-7, 10-6 M). Furthermore, the binding characteristics of vanidipinedilol and various antagonists were evaluated in [3H]CGP-12177 binding to ventricle and lung and [3H]nitrendipine binding to cerebral cortex membranes in rats. The order of potency of β1- and β2-adrenoceptor antagonist activity against [3H]CGP-12177 binding was (-)propranolol (pKi, 8.59 for β1 and 8.09 for β2) > vanidipinedilol (pKi, 7.09 for β1 and 6.64 for β2) > atenolol (pKi, 6.58 for β1 and 5.12 for β2). The order of potency of calcium channel antagonist activity against [3H]nitrendipine binding was nifedipine (pKi, 9.36) > vanidipinedilol (pKi, 8.07). The ratio of β1-adrenergic-blocking/calcium entry-blocking selectivity is 0.1 and indicated that vanidipinedilol revealed more in calcium entry-blocking than in β-adrenergic-blocking activities. It has been suggested that vanidipinedilol-induced smooth muscle relaxation may involve decreased entry of Ca2+ and partial β2-agonist activities. In conclusion, vanidipinedilol is a nonselective β-adrenoceptor antagonist with calcium channel blocking and partial β2-agonist associated vasorelaxant and tracheal relaxant activities. Particularly, the vasodilator effects of vanidipinedilol are attributed to a synergism of its calcium entry blocking and partial β2-agonist activities in the blood vessel. A sustained bradycardic effect results from β-adrenoceptor blocking and calcium entry blocking, which blunts the sympathetic activation-associated reflex tachycardia in the heart.
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Intravenous injection of nonivamide or nonivamide succinate (25, 250 nmol/kg) into Wistar rats in... more Intravenous injection of nonivamide or nonivamide succinate (25, 250 nmol/kg) into Wistar rats induced bradycardia, hypotension, apnea and a triphasic blood pressure response: an initial short fall (effect A), an intermediate rise (effect B), and a subsequent delayed fall (effect C) of blood pressure. This blood pressure response remained unchanged after treatment with propranolol or phentolamine. In atropine-pretreatment rats the initial effect A was markedly decreased and effect C was slight increased. Effect A was absent after bilateral vagotomy. Unilateral microinjection of nonivamide succinate (3, 30 fmol) into the nucleus tractus solitarii produced a marked reduction in blood pressure and heart rate. In the isolated aorta of the guinea pig, application of either nonivamide or its succinate (10(-8) to 10(-5) M) eliminated the smooth muscle tone produced by phenylephrine (10(-6) M). Re-exposure to these agents, however, produced an immediate tachyphylactic relaxing response and prolonged rebound contractile response. Both compounds induced a vascular contraction rather than relaxation during tachyphylaxis. The potency of nonivamide succinate was found to be slightly greater than that of nonivamide.
Thallium-201 myocardial perfusion imaging is wildly used to detect and assess the extent of jeopa... more Thallium-201 myocardial perfusion imaging is wildly used to detect and assess the extent of jeopardized myocardial ischemia in the coronary artery disease and the viability of myocardium post infarction. In recent years, there has been a great deal of pharmacological development of blockers and openers of potassium channel. In this study, we will discuss the interference of uptake of thallium-201 ion in cultured neonatal rat myocytes with existence of a variety of pharmacological agents. The cultures of neonatal rat myocardial cells were incubated with different agents such as potassium chloride, sodium-potassium ATPase pump inhibitor (ouabain), cesium compound, variable potassium channel blockers (4 AP, TEA and glibenclamide) and their openers (minoxidil, and cromakalim). The radioactivity of intracellular thallium-201 that could enter rat myocardial cells was detected by gamma counter sixty minutes after thallium-201 was added. In this study we found that thallium and potassium ions behave in an analogous manner in cultured rat myocardial cells. Both 2.5 mM and 5 mM concentration of extracellular potassium ion significantly result in reduction of thallium-201 ion influx in rat myocardial cells. 0.5 mM ouabain, an inhibitor of sodium-potassium ATPase pump, reduced about 40% of influx of thallium-201 ion in cultured rat myocardial cells via active transport. Combination of both potassium ion and ouabain inhibit most of thallium-201 ions influx in myocardial cells, but it is not completely inhibited. Cesium, a potassium antagonist, also interferes with the uptake of thallium-201 in cultured rat myocytes in our study. The most interesting finding in our investigation is that potassium channel blockers such as TEA and glibenclamide, inhibit the influx of thallium-201 in myocytes. However, potassium channel openers have no overt effect on influx of thallium-201 in cultured rat myocytes. We indirectly observe about 60% of influx of thallium-201 ion into cultured rat myocardial cells via active sodium-potassium ATPase pump. Potassium, cesium and potassium channel blockers, such as TEA and glibenclamide, inhibited the different percentage of influx of thallium-201 in cultured rat myocardial cells in this study.
General Pharmacology-the Vascular System, Aug 1, 1998
1. Capsinolol (1.0-30.0 microM) in a cumulating manner decreased the maximum upstroke velocity (V... more 1. Capsinolol (1.0-30.0 microM) in a cumulating manner decreased the maximum upstroke velocity (Vmax), the action potential amplitude and twitch tension in isolated guinea-pig atria and papillary muscle, rabbit papillary muscle, dog Purkinje fibers and human ventricle tissues. 2. In the isolated guinea-pig atrium, perfusing with capsinolol at 3 microM for 3 min temporarily increased the twitch force and decreased spontaneous cycle length; however, the results were reversed after longer exposure of the tissue. 3. Capsinolol prolonged the duration of action potential in the guinea-pig atrium and rabbit papillary muscles. The maximum diastolic potential was shifted to a less-negative level in dog Purkinje fibers and human ventricular muscles.
International Journal of Molecular Sciences, Jul 4, 2020
The ductus arteriosus (DA) is a shunt vessel between the aorta and the pulmonary artery during th... more The ductus arteriosus (DA) is a shunt vessel between the aorta and the pulmonary artery during the fetal period that is essential for the normal development of the fetus. Complete closure usually occurs after birth but the vessel might remain open in certain infants, as patent ductus arteriosus (PDA), causing morbidity or mortality. The mechanism of DA closure is a complex process involving an orchestration of cell-matrix interaction between smooth muscle cells (SMC), endothelial cells, and extracellular matrix (ECM). ECM is defined as the noncellular component secreted by cells that consists of macromolecules such as elastin, collagens, proteoglycan, hyaluronan, and noncollagenous glycoproteins. In addition to its role as a physical scaffold, ECM mediates diverse signaling that is critical in development, maintenance, and repair in the cardiovascular system. In this review, we aim to outline the current understandings of ECM and its role in the pathophysiology of PDA, with emphasis on DA remodeling and highlight future outlooks. The molecular diversity and plasticity of ECM present a rich array of potential therapeutic targets for the management of PDA.
Nonanoyl vanillylamide-4-o-glycerol (glyceryl nonivamide, GLNVA) a nonpungent ether-linked deriva... more Nonanoyl vanillylamide-4-o-glycerol (glyceryl nonivamide, GLNVA) a nonpungent ether-linked derivative of nonanoyl vanillylamide (nonivamide, NVA) was compared to capsaicin (CAP) and NVA with regard to its depressor response in rats. IV injection of CAP and NVA (IO-' to lo-' mg/kg) in Wistar rats elicit a triphasic blood pressure response, bradycardia, and aponea. However, IV injection of GLNVA results in a monophasic reduction in blood pressure, with little effect on heart rate and respiration. The depressor response to GLNVA was not diminished by bilateral vagotomy or by systemic pretreatment with atropine. Following the CAP pretreatment, the delayed hypotension induced by CAP, NVA, and the hypotension of GLNVA was almost abolished. Injection of CAP, NVA (10 &kg), or GLNVA (100 fig/kg) into one femoral artery elicited a fall in blood pressure in the rat. This effect was abolished following intrathecal injection of substance P antagonist [D-Pro2, D-Trp7,9]-SP. Microejections of CAP, NVA, or GLNVA into the nucleus tractus solitarii (NTS) evoked hypotension, the bradycardia following microejection of CAP and NVA into the NTS occurred only at higher doses of GLNVA. From these results it is suggested that GLNVA appears to act more exclusively than CAP by stimulating peripheral perivascular small diameter C-fiber sensory nerves. Capsaicin Substance P antagonist Cardiovascular actions Nucleus tractus solitari Vagus reflex Arterial pressure Intrathecal injection CAPSAICIN (CAP, 8-methyl-N-vanillyl-6-nonenamide;
Aim-As the global population has reached 7 billion and the baby boom generation reaches old age, ... more Aim-As the global population has reached 7 billion and the baby boom generation reaches old age, thrombosis has become the major contributor to the global disease burden. It has been reported that, in moderate doses, beer may protect against thrombosis. Xanthohumol (XN), an antioxidant, is found at high concentrations in hop cones (Humulus lupulus L.) and is a common ingredient of beer. Here, the aim of the present work was to investigate the effects of XN on antithrombotic and antiplatelet activities, and study its mechanism. Approach and Results-Using ferric chloride-induced carotid artery injury, inferior vena cava ligation model, and platelet function tests, we demonstrated that XN uniquely prevents both venous and arterial thrombosis by inhibiting platelet activation. Interestingly, in tail bleeding time studies, XN did not increase bleeding risk, which is recognized as a major limitation of current antithrombotic therapies. We also demonstrated that XN induces Sirt1 expression and thereby decreases reactive oxygen species (ROS) overload, prevents mitochondrial dysfunction, and reduces activated platelet-induced mitochondrial hyperpolarization, respiratory disorders, and associated membrane damage at low concentrations. In mitochondrial function assays designed to detect amounts of extracellular mitochondrial DNA (mtDNA), we found that XN prevents mtDNA release, which induces platelet activation in a DC-SIGN-dependent manner. Conclusions-XN exemplifies a promising new class of antiplatelet agents that are highly effective at inhibiting platelet activation by decreasing ROS accumulation and platelet mtDNA release without incurring a bleeding risk. This study has also provided novel insights into mechanisms of thrombotic diseases with possible therapeutic implications.
In this research, we conducted an in vitro analysis to evaluate the prostate cancer cells respons... more In this research, we conducted an in vitro analysis to evaluate the prostate cancer cells response to labedipinedilol-A in order to determine the effect of this selective alpha(1)-adrenoceptor antagonist to suppress prostate cancer cell growth by affecting cell proliferation and apoptosis. Here, we report that treatment of androgen-sensitive (LNCaP) and androgen-insensitive (PC-3) prostate cancer cells with labedipinedilol-A inhibited cell proliferation in concentration-dependent and time-dependent manners. Moreover, norepinephrine-stimulated proliferation of both cell lines are markedly inhibited by labedipinedilol-A. The probable involvement of alpha(1)-adrenoceptors in this cellular response is suggested. Labedipinedilol-A-induced growth inhibition was associated with G(0)/G(1) arrest, and G(2)/M arrest depending upon concentrations. Cell cycle blockade was associated with reduced amounts of cyclin D1/2, cyclin E, Cdk2, Cdk4, and Cdk6 and increased levels of the Cdk inhibitory proteins (Cip1/p21 and Kip1/p27). In addition, labedipinedilol-A also induced apoptosis in PC-3 cells, as determined by using Hoechst 33342 staining, DNA fragmentation, and Annexin V staining assay. Furthermore, labedipinedilol-A triggered the mitochondrial apoptotic pathway, as indicated by increasing the expression of Bax, but decreasing the level of Bcl-2, resulting in mitochondrial membrane potential loss, cytochrome c release, and activation of caspase-9 and -3. We further investigated the role of MAPK cascades in the anti-proliferative and apoptosis effects of labedipinedilol-A, and confirmed that labedipinedilol-A could activate JNK1/2 but not p38 in both cell lines. Unlike JNK1/2, however, labedipinedilol-A treatment resulted in down-regulation of phospho-ERK1/2 expression. We concluded that labedipinedilol-A possessed the growth-suppressive and apoptotic effects on LNCaP and PC-3 cells by its alpha(1)-adrenoceptor blockade, and the apoptotic effects of labedipinedilol-A primarily through caspases and MAPKs mediated pathways.
Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabete... more Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. However, its effect on pulmonary arterial hypertension (PAH) is unknown. In this study, we investigated its effects on rats with monocrotaline (MCT)-induced PAH and mechanisms on rat pulmonary artery smooth muscle cells (PASMCs). Liraglutide was investigated for both prevention and treatment of MCTinduced PAH. The hemodynamic and body weight changes, right heart hypertrophy, lung morphology, immune-reactivity of endothelial nitric oxide synthase (eNOS), endothelin-1 and cyclic guanosine monophosphate (cGMP) levels, protein expressions of eNOS, soluble guanylyl cyclase (sGCα), protein kinase G (PKG) and Rho kinase (ROCK) II pathway were measured in both in vivo and in vitro. Cell migration and cell cycle were also determined. Liraglutide both prevented and reversed MCT-induced PAH, right ventricle hypertrophy and pulmonary vascular wall remodeling. Protein expression of ROCK II was increased while eNOS, sGC and PKG were decreased. Pretreatment with liraglutide inhibited platelet-derived growth factor (PDGF)-BB stimulated PASMCs migration, which were associated with cell-cycle arrest at G 0 /G 1 phase. Liraglutide may have both preventive and therapeutic effects on MCTinduced PAH, through the eNOS/sGC/PKG and Rho kinase pathways. Thus, liraglutide may have a therapeutic role in pulmonary vascular remodelling. Recent studies suggest that diabetes is a risk factor for pulmonary arterial hypertension (PAH) 1. Endothelial dysfunction, classically characterized by a reduced capacity of endothelial cells to induce vasodilatation via the release of nitric oxide (NO), is an early and independent predictor of a poor prognosis of PAH 2,3. The signaling pathway of NO, cGMP, and cGMP-dependent protein kinases has been shown to be down regulated under diabetic conditions and to contribute to the development of diabetic vascular complications 4. PAH is a disease often considered to be driven by vasoconstriction. It is well established that the endothelin, NO and prostacyclin pathways play important roles in the development of PAH. Endothelin-1 (ET-1) is a key mediator of PAH, released from the endothelium, driving pathological changes in the lung that lead to pulmonary vascular remodeling 5. PAH is associated with impaired production of the endothelium-derived vasodilator, NO 6. eNOS is a nitric oxide synthase that generates NO in blood vessels and is involved with regulating vascular tone by inhibiting smooth muscle contraction and platelet aggregation. In healthy individuals, NO acts on smooth muscle cells to induce vasodilation and inhibit proliferation by increasing production of the secondary
European journal of medicinal chemistry, Apr 1, 1992
... IJ Chen 1 , JM Yang 2 , JL Yeh 1 , BN Wu 1 , YC Lo 1 and SJ Chen 1. ... This study was suppor... more ... IJ Chen 1 , JM Yang 2 , JL Yeh 1 , BN Wu 1 , YC Lo 1 and SJ Chen 1. ... This study was supported by research grants from ihe National Science Council of the Renublic of China of Taiwan (NSC 780412 B03729 and NSC ?90412B0375 1) References 1) Toh CC, Lee TS, Kiang ...
Rationale: CD93, a C-type lectin-like transmembrane glycoprotein, can be shed in a soluble form (... more Rationale: CD93, a C-type lectin-like transmembrane glycoprotein, can be shed in a soluble form (sCD93) upon inflammatory stimuli. sCD93 effectively enhances apoptotic cell clearance and has been proposed as an inflammatory disease biomarker. The function of sCD93 involved directly in inflammation remains to be determined. Herein, we attempted to examine the hypothesis that sCD93 might sequester proinflammatory high-mobility group box 1 protein (HMGB1), exerting anti-inflammatory properties. Methods: Different forms of soluble recombinant human CD93 (rCD93) were prepared by a mammalian protein expression system. rCD93-HMGB1 interaction was assessed using co-immunoprecipitation and solid-phase binding assays. Effects of soluble rCD93 were evaluated in HMGB1-induced macrophage and vascular smooth muscle cells (VSMC) activation and receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, CaCl2-induced and angiotensin II-infused abdominal aortic aneurysm (AAA) formation and ovariectomized-induced osteoporosis in mice. Results: Protein binding studies revealed that soluble rCD93, via the lectin-like domain (D1), can bind to HMGB1 and intercept HMGB1-receptor interaction. Soluble rCD93 containing D1 inhibited HMGB1-induced proinflammatory cytokine production and intracellular mitogen-activated protein kinase (MAPK)/nuclear factor (NF)-κB activation in macrophages and VSMCs, thereby attenuating CaCl2-induced and angiotensin II-infused AAA models. During osteoclastogenesis, RANKL stimulated HMGB1 secretion that promoted RANKL-induced osteoclastogenesis in return. Soluble rCD93 containing D1 impeded RANKL-induced osteoclastogenic marker gene expression and intracellular MAPK/NF-κB signaling, thereby mitigating ovariectomized-induced osteoporosis. Conclusion: These findings demonstrate the therapeutic potential of soluble recombinant CD93 containing D1 in inflammatory diseases. Our study highlights a novel anti-inflammatory mechanism, i.e., sequestration of HMGB1, through which sCD93 prevents HMGB1-receptor interaction on effector cells and alleviates inflammation.
Background. Severe burns result in hypercatabolic state and concomitant muscle atrophy that persi... more Background. Severe burns result in hypercatabolic state and concomitant muscle atrophy that persists for several months, thereby limiting patient recovery. However, the effects of burns on the corresponding spinal dermatome remain unknown. This study aimed to investigate whether burns induce apoptosis of spinal cord ventral horn motor neurons (VHMNs) and consequently cause skeletal muscle wasting. Methods. Third-degree hindpaw burn injury with 1% total body surface area (TBSA) rats were euthanized 4 and 8 weeks after burn injury. The apoptosis profiles in the ventral horns of the lumbar spinal cords, sciatic nerves, and gastrocnemius muscles were examined. The Schwann cells in the sciatic nerve were marked with S100. The gastrocnemius muscles were harvested to measure the denervation atrophy. Result. The VHMNs apoptosis in the spinal cord was observed after inducing third-degree burns in the hindpaw. The S100 and TUNEL double-positive cells in the sciatic nerve increased significantly after the burn injury. Gastrocnemius muscle apoptosis and denervation atrophy area increased significantly after the burn injury. Conclusion. Local hindpaw burn induces apoptosis in VHMNs and Schwann cells in sciatic nerve, which causes corresponding gastrocnemius muscle denervation atrophy. Our results provided an animal model to evaluate burn-induced muscle wasting, and elucidate the underlying mechanisms.
The effect of five lignans, epi-aschantin, epi-magnolin, epi-yangambin, deoxypodophyllotoxin and ... more The effect of five lignans, epi-aschantin, epi-magnolin, epi-yangambin, deoxypodophyllotoxin and yatein, isolated from Hernandia nymphaeifolia on Ca(2+) signaling in Madin-Darby canine kidney cells was examined using fura-2 as a Ca(2+) indicator. These lignans at concentrations between 10 and 100 microM increased [Ca(2+)](i) in a concentration-dependent manner. Removal of extracellular Ca(2+) abolished the Ca(2+) signals evoked by 50 microM of the lignans. La(3+)(50 microM) abolished the Ca(2+) signals induced by 100 microM of epi-aschantin, epi-magnolin and epi-yangambin, and 20 microM deoxypodophyllotoxin, but inhibited by 60% 50 microM yatein-induced responses. All five lignans (50-100 microM) inhibited by 42-65% thapsigargin-induced capacitative Ca(2+) entry, and inhibited by 23-61% thapsigargin-induced intracellular Ca(2+) release. Epi-yangambin (100 microM), epi-magnolin (100 microM), and epi-aschantin (100 microM) inhibited by 8-38% 10 microM ATP-induced Ca(2+) release. Trypan blue exclusion revealed that incubation with deoxypodophyllotoxin or yatein (but not the other lignans) decreased cell viability in a concentration-dependent manner. Together, the results suggest that, in renal tubular cells, these lignans exert multiple actions on Ca(2+) signaling. They caused Ca(2+) influx but reduced thapsigargin-induced capacitative Ca(2+) entry and also thapsigargin- and ATP-induced Ca(2+) release. Additionally, deoxypodophyllotoxin and yatein may be cytotoxic.
Journal of Cardiovascular Pharmacology, Mar 1, 2005
Labedipinedilol-A, a novel dihydropyridine-type calcium antagonist, has been shown to induce hypo... more Labedipinedilol-A, a novel dihydropyridine-type calcium antagonist, has been shown to induce hypotension and vasorelaxation. The objective of the present study was to investigate the effect of labedipinedilol-A on vascular function of rat aortic rings and cultured human umbilical vein endothelial cells (HUVECs). Labedipinedilol-A induced vasorelaxation in rat aortic rings that had been precontracted with phenylephrine in a concentration-dependent manner. This labedipinedilol-A-induced relaxation was significantly reduced by endothelium removal and by exposure to L-N Gnitroarginine methyl ester (L-NAME), methylene blue, or 1H-[1,2,4]oxadiazolol[4,3,a]quinoxalin-1-one (ODQ). In addition, the cyclic GMP content was significantly increased by labedipinedilol-A, which was inhibited by L-NAME in aorta. In cultured HUVECs, labedipinedilol-A induced concentration-dependent formation of NO and Ca 2+ influx, and it increased the abundance of endothelial NO synthase (eNOS) protein. Furthermore, labedipinedilol-A suppressed basal, 10% FBS-and thrombin-stimulated endothelin-1 production, which were reversed by pretreatment with L-NAME, demonstrating that NO was able to inhibit production of ET-1 in HUVECs. Labedipinedilol-A significantly protected cultured HUVECs against dihydroxyfumarate/iron ion-induced decrease of glutathione and cell death. Moreover, labedipinedilol-A also inhibited iron-induced lipid peroxidation in rat brain homogenate and scavenged 2,2#-azobis (2amidinopropane) dihydrochloride-derived peroxy radicals. Labedipinedilol-A acts as lacidipine with additional antioxidant effects and can protect endothelial cells against free radical-induced lipid peroxidation and cell injury. Our results indicate that the endotheliumdependent vasorelaxation by labedipinedilol-A is mediated through Ca 2+-dependent activation of NO synthase and stimulation of NO/cyclic GMP pathway.
The effects of nonivamide on the cardiovascular system were examined and compared with the effect... more The effects of nonivamide on the cardiovascular system were examined and compared with the effects of substance P (SP) in rats. Intravenous (IV) injection (10 @kg) of nonivamide produced triphasic pressure responses (A; depressor, B; pressor, and C; depressor) and biphasic bradycardia responses (f; fast bradycardia and s; slow bradycardia). IA injection (10 &kg) into the epigastric artery caused hypotension and mild tachycardia. The effects of atropine, vagotomy, SP antagonist, propranolal, and clonidine on these responses were examined and mechanisms responsible for the nonivamide-induced responses are postulated as follows. A and f are due to vagal reflex resulting from the excitation of afferent sensory neurons in the heart and are parasympathetic efferent effects from the nucleus solitarius. B is involved in sympathetic activation, partly caused by the release of SP in the spinal cord. C is due to the vasodilatory effect of SP released from perivascular stores. s was diminished by vagotomy and is due to the bradycardiac effect of acetylcholine, released by SP, from cardiac stores. The activation of the autonomic system is inhibited by clonidine and involved in the wide spectrum of nonivamide-induced cardiovascular effects.
Objective: Inflammation is an important molecular basis of atherosclerosis. Recent studies have s... more Objective: Inflammation is an important molecular basis of atherosclerosis. Recent studies have shown that dihydropyridine calcium channel blockers (CCBs) can exert potent anti-inflammatory effects in models of vascular dysfunction. The purpose of the present study was to evaluate anti-inflammatory effects and mechanisms of lercanidipine and labedipinedilol-A, new generation dihydropyridine CCBs, in rat vascular smooth muscle cells (VSMCs) exposed to lipopolysaccharide (LPS) and interferon-g (IFN-g). Methods and results: MTT, Griess reagent, RT-PCR, ELISA, gelatin zymography, immunocytochemistry and Western blotting were employed. We found that lercanidipine and labedipinedilol-A attenuated production of NO, ROS and TNF-a from LPS/IFN-g-stimulated VSMCs. In addition, they both diminished the LPS/IFN-g-induced expression of iNOS protein and mRNA, with attenuation of HMGB1 cytosolic translocation and subsequent extracellular release. Furthermore, they down-regulated MMP-2/MMP-9 activities, whereas expression of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), an inhibitor of MMP-9, was up-regulated. Finally, we found that lercanidipine and labedipinedilol-A inhibited the nuclear translocation of NF-kB and suppressed the phosphorylation of JNK, p38 MAPK and Akt. Conclusion: Lercanidipine and labedipinedilol-A can exert their anti-inflammatory effects through suppression of NO, ROS and TNF-a through down-regulation of iNOS, MMP-2/MMP-9, and HMGB1, with inhibition of signaling transduction of MAPKs, Akt/IkB-a and NF-kB pathways. These findings implicate a valuable role of new generation dihydropyridine CCBs lercanidipine and labedipinedilol-A for the treatment of inflammatory vascular diseases.
ABSTRACT Calcium channel and β-adrenoceptor blockade have proved highly useful in antihypertensiv... more ABSTRACT Calcium channel and β-adrenoceptor blockade have proved highly useful in antihypertensive therapy. Studies of the mechanisms of action of vanidipinedilol that combine these effects within a single molecule are described here. Intravenous injection of vanidipinedilol (0.1, 0.25, 0.5, 1.0, and 2.0 mg/kg) produced dose-dependent hypotensive and bradycardic responses, significantly different from nifedipine-induced (0.5 mg/kg, i.v.) hypotensive and reflex tachycardic effects in pentobarbital-anesthetized Wistar rats. A single oral administration of vanidipinedilol at doses of 10, 25, and 50 mg/kg dose-dependently reduced blood pressure with a decrease in heart rate in conscious spontaneously hypertensive rats (SHRs). In the isolated Wistar rat atrium, vanidipinedilol (10-7, 10-6, and 10-5 M) competitively antagonized the (-)isoproterenol-induced positive chronotropic and inotropic effects and inhibited the increase in heart rate induced by Ca2+ (3.0-9.0 mM) in a concentration-dependent manner. The parallel shift to the right of the concentration-response curve of (-)isoproterenol and CaCl2 suggested that vanidipinedilol possessed β-adrenoceptor-blocking and calcium entry-blocking activities. On tracheal strips of reserpinized guinea pig, cumulative doses of vanidipinedilol (10-10 to 3 × 10-6 M) produced dose-dependent relaxant responses. Preincubating the preparation with ICI 118,551 (10-10, 10-9, 10-8 M), a β2-adrenoceptor antagonist, shifted the vanidipinedilol concentration-relaxation curve significantly to a region of higher concentrations. These results implied that vanidipinedilol had a partial β2-agonist activity. In the isolated thoracic aorta of rat, vanidipinedilol had a potent effect inhibiting high-K+-induced contractions. KCl-induced intracellular calcium changes of blood vessel smooth muscle cell (A7r5 cell lines) determined by laser cytometry also was decreased after administration of vanidipinedilol (10-8, 10-7, 10-6 M). Furthermore, the binding characteristics of vanidipinedilol and various antagonists were evaluated in [3H]CGP-12177 binding to ventricle and lung and [3H]nitrendipine binding to cerebral cortex membranes in rats. The order of potency of β1- and β2-adrenoceptor antagonist activity against [3H]CGP-12177 binding was (-)propranolol (pKi, 8.59 for β1 and 8.09 for β2) > vanidipinedilol (pKi, 7.09 for β1 and 6.64 for β2) > atenolol (pKi, 6.58 for β1 and 5.12 for β2). The order of potency of calcium channel antagonist activity against [3H]nitrendipine binding was nifedipine (pKi, 9.36) > vanidipinedilol (pKi, 8.07). The ratio of β1-adrenergic-blocking/calcium entry-blocking selectivity is 0.1 and indicated that vanidipinedilol revealed more in calcium entry-blocking than in β-adrenergic-blocking activities. It has been suggested that vanidipinedilol-induced smooth muscle relaxation may involve decreased entry of Ca2+ and partial β2-agonist activities. In conclusion, vanidipinedilol is a nonselective β-adrenoceptor antagonist with calcium channel blocking and partial β2-agonist associated vasorelaxant and tracheal relaxant activities. Particularly, the vasodilator effects of vanidipinedilol are attributed to a synergism of its calcium entry blocking and partial β2-agonist activities in the blood vessel. A sustained bradycardic effect results from β-adrenoceptor blocking and calcium entry blocking, which blunts the sympathetic activation-associated reflex tachycardia in the heart.
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Intravenous injection of nonivamide or nonivamide succinate (25, 250 nmol/kg) into Wistar rats in... more Intravenous injection of nonivamide or nonivamide succinate (25, 250 nmol/kg) into Wistar rats induced bradycardia, hypotension, apnea and a triphasic blood pressure response: an initial short fall (effect A), an intermediate rise (effect B), and a subsequent delayed fall (effect C) of blood pressure. This blood pressure response remained unchanged after treatment with propranolol or phentolamine. In atropine-pretreatment rats the initial effect A was markedly decreased and effect C was slight increased. Effect A was absent after bilateral vagotomy. Unilateral microinjection of nonivamide succinate (3, 30 fmol) into the nucleus tractus solitarii produced a marked reduction in blood pressure and heart rate. In the isolated aorta of the guinea pig, application of either nonivamide or its succinate (10(-8) to 10(-5) M) eliminated the smooth muscle tone produced by phenylephrine (10(-6) M). Re-exposure to these agents, however, produced an immediate tachyphylactic relaxing response and prolonged rebound contractile response. Both compounds induced a vascular contraction rather than relaxation during tachyphylaxis. The potency of nonivamide succinate was found to be slightly greater than that of nonivamide.
Thallium-201 myocardial perfusion imaging is wildly used to detect and assess the extent of jeopa... more Thallium-201 myocardial perfusion imaging is wildly used to detect and assess the extent of jeopardized myocardial ischemia in the coronary artery disease and the viability of myocardium post infarction. In recent years, there has been a great deal of pharmacological development of blockers and openers of potassium channel. In this study, we will discuss the interference of uptake of thallium-201 ion in cultured neonatal rat myocytes with existence of a variety of pharmacological agents. The cultures of neonatal rat myocardial cells were incubated with different agents such as potassium chloride, sodium-potassium ATPase pump inhibitor (ouabain), cesium compound, variable potassium channel blockers (4 AP, TEA and glibenclamide) and their openers (minoxidil, and cromakalim). The radioactivity of intracellular thallium-201 that could enter rat myocardial cells was detected by gamma counter sixty minutes after thallium-201 was added. In this study we found that thallium and potassium ions behave in an analogous manner in cultured rat myocardial cells. Both 2.5 mM and 5 mM concentration of extracellular potassium ion significantly result in reduction of thallium-201 ion influx in rat myocardial cells. 0.5 mM ouabain, an inhibitor of sodium-potassium ATPase pump, reduced about 40% of influx of thallium-201 ion in cultured rat myocardial cells via active transport. Combination of both potassium ion and ouabain inhibit most of thallium-201 ions influx in myocardial cells, but it is not completely inhibited. Cesium, a potassium antagonist, also interferes with the uptake of thallium-201 in cultured rat myocytes in our study. The most interesting finding in our investigation is that potassium channel blockers such as TEA and glibenclamide, inhibit the influx of thallium-201 in myocytes. However, potassium channel openers have no overt effect on influx of thallium-201 in cultured rat myocytes. We indirectly observe about 60% of influx of thallium-201 ion into cultured rat myocardial cells via active sodium-potassium ATPase pump. Potassium, cesium and potassium channel blockers, such as TEA and glibenclamide, inhibited the different percentage of influx of thallium-201 in cultured rat myocardial cells in this study.
General Pharmacology-the Vascular System, Aug 1, 1998
1. Capsinolol (1.0-30.0 microM) in a cumulating manner decreased the maximum upstroke velocity (V... more 1. Capsinolol (1.0-30.0 microM) in a cumulating manner decreased the maximum upstroke velocity (Vmax), the action potential amplitude and twitch tension in isolated guinea-pig atria and papillary muscle, rabbit papillary muscle, dog Purkinje fibers and human ventricle tissues. 2. In the isolated guinea-pig atrium, perfusing with capsinolol at 3 microM for 3 min temporarily increased the twitch force and decreased spontaneous cycle length; however, the results were reversed after longer exposure of the tissue. 3. Capsinolol prolonged the duration of action potential in the guinea-pig atrium and rabbit papillary muscles. The maximum diastolic potential was shifted to a less-negative level in dog Purkinje fibers and human ventricular muscles.
International Journal of Molecular Sciences, Jul 4, 2020
The ductus arteriosus (DA) is a shunt vessel between the aorta and the pulmonary artery during th... more The ductus arteriosus (DA) is a shunt vessel between the aorta and the pulmonary artery during the fetal period that is essential for the normal development of the fetus. Complete closure usually occurs after birth but the vessel might remain open in certain infants, as patent ductus arteriosus (PDA), causing morbidity or mortality. The mechanism of DA closure is a complex process involving an orchestration of cell-matrix interaction between smooth muscle cells (SMC), endothelial cells, and extracellular matrix (ECM). ECM is defined as the noncellular component secreted by cells that consists of macromolecules such as elastin, collagens, proteoglycan, hyaluronan, and noncollagenous glycoproteins. In addition to its role as a physical scaffold, ECM mediates diverse signaling that is critical in development, maintenance, and repair in the cardiovascular system. In this review, we aim to outline the current understandings of ECM and its role in the pathophysiology of PDA, with emphasis on DA remodeling and highlight future outlooks. The molecular diversity and plasticity of ECM present a rich array of potential therapeutic targets for the management of PDA.
Nonanoyl vanillylamide-4-o-glycerol (glyceryl nonivamide, GLNVA) a nonpungent ether-linked deriva... more Nonanoyl vanillylamide-4-o-glycerol (glyceryl nonivamide, GLNVA) a nonpungent ether-linked derivative of nonanoyl vanillylamide (nonivamide, NVA) was compared to capsaicin (CAP) and NVA with regard to its depressor response in rats. IV injection of CAP and NVA (IO-' to lo-' mg/kg) in Wistar rats elicit a triphasic blood pressure response, bradycardia, and aponea. However, IV injection of GLNVA results in a monophasic reduction in blood pressure, with little effect on heart rate and respiration. The depressor response to GLNVA was not diminished by bilateral vagotomy or by systemic pretreatment with atropine. Following the CAP pretreatment, the delayed hypotension induced by CAP, NVA, and the hypotension of GLNVA was almost abolished. Injection of CAP, NVA (10 &kg), or GLNVA (100 fig/kg) into one femoral artery elicited a fall in blood pressure in the rat. This effect was abolished following intrathecal injection of substance P antagonist [D-Pro2, D-Trp7,9]-SP. Microejections of CAP, NVA, or GLNVA into the nucleus tractus solitarii (NTS) evoked hypotension, the bradycardia following microejection of CAP and NVA into the NTS occurred only at higher doses of GLNVA. From these results it is suggested that GLNVA appears to act more exclusively than CAP by stimulating peripheral perivascular small diameter C-fiber sensory nerves. Capsaicin Substance P antagonist Cardiovascular actions Nucleus tractus solitari Vagus reflex Arterial pressure Intrathecal injection CAPSAICIN (CAP, 8-methyl-N-vanillyl-6-nonenamide;
Aim-As the global population has reached 7 billion and the baby boom generation reaches old age, ... more Aim-As the global population has reached 7 billion and the baby boom generation reaches old age, thrombosis has become the major contributor to the global disease burden. It has been reported that, in moderate doses, beer may protect against thrombosis. Xanthohumol (XN), an antioxidant, is found at high concentrations in hop cones (Humulus lupulus L.) and is a common ingredient of beer. Here, the aim of the present work was to investigate the effects of XN on antithrombotic and antiplatelet activities, and study its mechanism. Approach and Results-Using ferric chloride-induced carotid artery injury, inferior vena cava ligation model, and platelet function tests, we demonstrated that XN uniquely prevents both venous and arterial thrombosis by inhibiting platelet activation. Interestingly, in tail bleeding time studies, XN did not increase bleeding risk, which is recognized as a major limitation of current antithrombotic therapies. We also demonstrated that XN induces Sirt1 expression and thereby decreases reactive oxygen species (ROS) overload, prevents mitochondrial dysfunction, and reduces activated platelet-induced mitochondrial hyperpolarization, respiratory disorders, and associated membrane damage at low concentrations. In mitochondrial function assays designed to detect amounts of extracellular mitochondrial DNA (mtDNA), we found that XN prevents mtDNA release, which induces platelet activation in a DC-SIGN-dependent manner. Conclusions-XN exemplifies a promising new class of antiplatelet agents that are highly effective at inhibiting platelet activation by decreasing ROS accumulation and platelet mtDNA release without incurring a bleeding risk. This study has also provided novel insights into mechanisms of thrombotic diseases with possible therapeutic implications.
In this research, we conducted an in vitro analysis to evaluate the prostate cancer cells respons... more In this research, we conducted an in vitro analysis to evaluate the prostate cancer cells response to labedipinedilol-A in order to determine the effect of this selective alpha(1)-adrenoceptor antagonist to suppress prostate cancer cell growth by affecting cell proliferation and apoptosis. Here, we report that treatment of androgen-sensitive (LNCaP) and androgen-insensitive (PC-3) prostate cancer cells with labedipinedilol-A inhibited cell proliferation in concentration-dependent and time-dependent manners. Moreover, norepinephrine-stimulated proliferation of both cell lines are markedly inhibited by labedipinedilol-A. The probable involvement of alpha(1)-adrenoceptors in this cellular response is suggested. Labedipinedilol-A-induced growth inhibition was associated with G(0)/G(1) arrest, and G(2)/M arrest depending upon concentrations. Cell cycle blockade was associated with reduced amounts of cyclin D1/2, cyclin E, Cdk2, Cdk4, and Cdk6 and increased levels of the Cdk inhibitory proteins (Cip1/p21 and Kip1/p27). In addition, labedipinedilol-A also induced apoptosis in PC-3 cells, as determined by using Hoechst 33342 staining, DNA fragmentation, and Annexin V staining assay. Furthermore, labedipinedilol-A triggered the mitochondrial apoptotic pathway, as indicated by increasing the expression of Bax, but decreasing the level of Bcl-2, resulting in mitochondrial membrane potential loss, cytochrome c release, and activation of caspase-9 and -3. We further investigated the role of MAPK cascades in the anti-proliferative and apoptosis effects of labedipinedilol-A, and confirmed that labedipinedilol-A could activate JNK1/2 but not p38 in both cell lines. Unlike JNK1/2, however, labedipinedilol-A treatment resulted in down-regulation of phospho-ERK1/2 expression. We concluded that labedipinedilol-A possessed the growth-suppressive and apoptotic effects on LNCaP and PC-3 cells by its alpha(1)-adrenoceptor blockade, and the apoptotic effects of labedipinedilol-A primarily through caspases and MAPKs mediated pathways.
Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabete... more Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. However, its effect on pulmonary arterial hypertension (PAH) is unknown. In this study, we investigated its effects on rats with monocrotaline (MCT)-induced PAH and mechanisms on rat pulmonary artery smooth muscle cells (PASMCs). Liraglutide was investigated for both prevention and treatment of MCTinduced PAH. The hemodynamic and body weight changes, right heart hypertrophy, lung morphology, immune-reactivity of endothelial nitric oxide synthase (eNOS), endothelin-1 and cyclic guanosine monophosphate (cGMP) levels, protein expressions of eNOS, soluble guanylyl cyclase (sGCα), protein kinase G (PKG) and Rho kinase (ROCK) II pathway were measured in both in vivo and in vitro. Cell migration and cell cycle were also determined. Liraglutide both prevented and reversed MCT-induced PAH, right ventricle hypertrophy and pulmonary vascular wall remodeling. Protein expression of ROCK II was increased while eNOS, sGC and PKG were decreased. Pretreatment with liraglutide inhibited platelet-derived growth factor (PDGF)-BB stimulated PASMCs migration, which were associated with cell-cycle arrest at G 0 /G 1 phase. Liraglutide may have both preventive and therapeutic effects on MCTinduced PAH, through the eNOS/sGC/PKG and Rho kinase pathways. Thus, liraglutide may have a therapeutic role in pulmonary vascular remodelling. Recent studies suggest that diabetes is a risk factor for pulmonary arterial hypertension (PAH) 1. Endothelial dysfunction, classically characterized by a reduced capacity of endothelial cells to induce vasodilatation via the release of nitric oxide (NO), is an early and independent predictor of a poor prognosis of PAH 2,3. The signaling pathway of NO, cGMP, and cGMP-dependent protein kinases has been shown to be down regulated under diabetic conditions and to contribute to the development of diabetic vascular complications 4. PAH is a disease often considered to be driven by vasoconstriction. It is well established that the endothelin, NO and prostacyclin pathways play important roles in the development of PAH. Endothelin-1 (ET-1) is a key mediator of PAH, released from the endothelium, driving pathological changes in the lung that lead to pulmonary vascular remodeling 5. PAH is associated with impaired production of the endothelium-derived vasodilator, NO 6. eNOS is a nitric oxide synthase that generates NO in blood vessels and is involved with regulating vascular tone by inhibiting smooth muscle contraction and platelet aggregation. In healthy individuals, NO acts on smooth muscle cells to induce vasodilation and inhibit proliferation by increasing production of the secondary
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