scholarly journals Hypotensive and Vasorelaxant Effects of Sericin-Derived Oligopeptides in Rats

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Amnart Onsa-ard ◽  
Dawan Shimbhu ◽  
Jiraporn Tocharus ◽  
Manote Sutheerawattananonda ◽  
Rungusa Pantan ◽  
...  
Keyword(s):  
Barium Chloride ◽  
Underlying Mechanism ◽  
Hypotensive Effect ◽  
Hypotensive Activity ◽  
Dependent Manner ◽  
Free Medium ◽  
Concentration Dependent Manner ◽  
Relaxant Effect ◽  
Rat Thoracic Aorta

Sericin-derived oligopeptides obtained from silk cocoons were investigated for the in vivo hypotensive effect and investigated for the underlying mechanism involved in vasodilation in isolated rat thoracic aorta. In normotensive anesthetized rats, oligopeptides induced an immediate and transient hypotensive activity. In rat aortic rings, oligopeptides induced a concentration-dependent vasorelaxation in vessels precontracted with both KCl and phenylephrine (PE) with endothelium-intact or endothelium-denuded rings. In endothelium-intact rings, pretreatment with Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME, 100 µM), an inhibitor of the NO synthase (NOS) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 µM), a selective inhibitor of the guanylyl cyclase enzyme, significantly reduced the relaxant effect of oligopeptides. However, indomethacin, an inhibitor of the cyclooxygenase, had no effect on oligopeptides-induced relaxation. In addition, pretreatment with tetraethylammonium (TEA, 5 mM) reduced the maximal relaxant effect induced by oligopeptides. By contrast, relaxation was not affected by 4-aminopyridine (4-AP, 1 mM), glibenclamide (10 µM), or barium chloride (BaCl2, 1 mM). In depolarization Ca2+-free solution, oligopeptides inhibited calcium chloride- (CaCl2-) induced contraction in endothelium-denuded rings in a concentration-dependent manner. Nevertheless, oligopeptides attenuated transient contractions in Ca2+-free medium containing EGTA (1 mM) induced by 1 µM PE, but they were not affected by 20 mM caffeine. It is obvious that potent vasodilation effect of oligopeptides is mediated through both the endothelium and the vascular smooth muscle.

Role of CYP27A1 in progesterone metabolism in vitro and in vivo

2009 ◽  
Vol 297 (4) ◽  
pp. E949-E955 ◽  
Author(s):  
Geneviève Escher ◽  
Isabelle Vögeli ◽  
Robert Escher ◽  
Robert C. Tuckey ◽  
Sandra Erickson ◽  
...  
Keyword(s):  
Gene Knockout ◽  
Human Kidney ◽  
Underlying Mechanism ◽  
Expression Cloning ◽  
Dependent Manner ◽  
Expression Library ◽  
Concentration Dependent Manner ◽  
Adrenodoxin Reductase

In the kidney, progesterone is inactivated to 20α-dihydro-progesterone (20α-DH-progesterone) to protect the mineralocorticoid receptor from progesterone excess. In an attempt to clone the enzyme with 20α-hydroxysteroid activity using expression cloning in CHOP cells and a human kidney expression library, serendipitously cDNA encoding CYP27A1 was isolated. Overexpression of CYP27A1 in CHOP cells decreased progesterone conversion to 20α-DH-progesterone in a dose-dependent manner, an effect enhanced by cotransfection with adrenodoxin and adrenodoxin reductase. Incubation of CHOP cells with 27-hydroxycholesterol, a product of CYP27A1, increased the ratio of progesterone to 20α-DH-progesterone in a concentration-dependent manner, indicating that the effect of CYP27A1 overexpression was mediated by 27-hydroxycholesterol. To analyze whether these observations are relevant in vivo, progesterone and 20α-DH-progesterone were measured by gas chromatography-mass spectometry in 24-h urine of CYP27A1 gene knockout (ko) mice and their control wild-type and heterozygote littermates. In CYP27A1 ko mice, urinary progesterone concentrations were decreased, 20α-DH-progesterone increased, and the progesterone-to-20α-DH-progesterone ratio decreased threefold ( P < 0.001). Thus CYP27A1 modulates progesterone concentrations. The underlying mechanism is inhibition of 20α-hydroxysteroid dehydrogenase by 27-hydroxycholesterol.

scholarly journals Phosphorylation of α-dystrobrevin is essential for αkap accumulation and acetylcholine receptor stability

2020 ◽  
Vol 295 (31) ◽  
pp. 10677-10688
Author(s):  
Po-Ju Chen ◽  
Diego Zelada ◽  
Dina Cheryne Belhasan ◽  
Mohammed Akaaboune
Keyword(s):  
Acetylcholine Receptor ◽  
Muscle Cells ◽  
Underlying Mechanism ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Tyrosine Residues ◽  
C Terminus ◽  
The Stability ◽  
High Level

The maintenance of a high density of the acetylcholine receptor (AChR) is the hallmark of the neuromuscular junction. Muscle-specific anchoring protein (αkap) encoded within the calcium/calmodulin-dependent protein kinase IIα (CAMK2A) gene is essential for the maintenance of AChR clusters both in vivo and in cultured muscle cells. The underlying mechanism by which αkap is maintained and regulated remains unknown. Here, using human cell lines, fluorescence microscopy, and pulldown and immunoblotting assays, we show that α-dystrobrevin (α-dbn), an intracellular component of the dystrophin glycoprotein complex, directly and robustly promotes the stability of αkap in a concentration-dependent manner. Mechanistically, we found that the phosphorylatable tyrosine residues of α-dbn are essential for the stability of α-dbn itself and its interaction with αkap, with substitution of three tyrosine residues in the α-dbn C terminus with phenylalanine compromising the αkap–α-dbn interaction and significantly reducing both αkap and α-dbn accumulation. Moreover, the αkap–α-dbn interaction was critical for αkap accumulation and stability. We also found that the absence of either αkap or α-dbn markedly reduces AChRα accumulation and that overexpression of α-dbn or αkap in cultured muscle cells promotes the formation of large agrin-induced AChR clusters. Collectively, these results indicate that the stability of αkap and α-dbn complex plays an important role in the maintenance of high-level expression of AChRs.

Comparison of Antiplatelet Effects of Two Nitric Oxide-donating Agents, FR146801 and FK409

1998 ◽  
Vol 79 (03) ◽  
pp. 620-624 ◽  
Author(s):  
Yasuko Kato ◽  
Shinichi Fukuyama ◽  
Mitsuko Ohno ◽  
Shigetaka Nishino ◽  
Masayuki Kato ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Platelet Aggregation ◽  
Thrombus Formation ◽  
Hypotensive Effect ◽  
Cgmp Level ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Antiplatelet Effect

SummaryIn the present study, we examined the antiplatelet effects of the two nitric oxide (NO)-donating agents, (±)-N -[(E)-4-ethyl-3-[(Z)hydroxyimino]-6-methyl-5-nitro-3-heptenyl]-3-pyridinecarboxamide (FR146801), a more stable analog of FK409 ((±)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide), and FK409 in in vitro and in vivo experiments. FR146801 and FK409 inhibited ADP- and collagen-induced platelet aggregation in human and rat platelet-rich plasma in a concentration-dependent manner, however, the inhibitory effect of FR146801 was weaker than that of FK409. In human washed platelets (WP), FR146801 and FK409 inhibited collagen-induced platelet aggregation in a concentration-dependent manner. The inhibitory effects of FR146801 and FK409 on platelet aggregation were closely reflected by the increase in the intraplatelet cGMP level. This intensely suggests that the antiplatelet activities of FR146801 and FK409 are due to NO-released from them. In the rat extracorporeal shunt model, FR146801 inhibited thrombus formation dose-dependently and its inhibition was significant at 10 mg/kg, p.o. FK409 suppressed thrombus formation significantly at 1.0 mg/kg, p.o., at which it induced significant hypotension, whereas FR146801 did not show any significant hypotensive effect even at 10 mg/kg, p.o. These results suggest that FR146801 has desirable antiplatelet effects both in vitro and in vivo and that its in vivo antiplatelet effect is more selective than its hypotensive effect, while FK409 does not show a selective antiplatelet effect in vivo.

4969Enhanced gap junction coupling organised and terminated acute ventricular fibrillation in ex-vivo perfused hearts

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
B S Handa ◽  
X Li ◽  
C Roney ◽  
D Pitcher ◽  
R A Chowdhury ◽  
...  
Keyword(s):  
Ventricular Fibrillation ◽  
Ex Vivo ◽  
Electrical Coupling ◽  
Underlying Mechanism ◽  
Dominant Frequency ◽  
Diffuse Fibrosis ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Concentration Dependent Manner

Abstract Background The underlying mechanism of ventricular fibrillation (VF) remains unclear. There are both experimental and clinical data to support the existence of rotational drivers (RDs), though other opposing studies suggest that VF is the result of disorganized myocardial activation. Abnormal electrical coupling between cardiomyocytes through gap junctions (GJ) has been considered an important factor in the genesis and maintenance of VF and pre-treatment with GJ couplers, rotigaptide (RTG), has been shown to reduce VF inducibility. Purpose We hypothesized that the degree of GJ coupling determines the underlying mechanism of VF, and that changes in GJ coupling can shift or modify the predominant mechanism of fibrillation along the spectrum between disorganised activity and organised drivers. We proposed that increased organisation of VF is critical to its termination. Methods Thirty Sprague-Dawley rat hearts were explanted, perfused ex-vivo and acute VF was induced with burst pacing and 30μM pinacidil. Optical mapping of transmembrane potential was performed at baseline and the effects of GJ coupling on VF dynamics were studied in an acute VF model by perfusing with increasing concentrations of a GJ uncoupler; carbenoxolone (0–50μM, CBX, n=10) or a GJ coupling-enhancer; RTG (0–80nM, n=10). A chronic diffuse fibrosis model (n=10) was generated with 4 weeks of in-vivo angiotensin infusion (500nm/kg/min). Fibrillation dynamics were quantified using phase analysis, phase singularity (PS) tracking and our novel method of global fibrillation organisation quantification, frequency dominance index (FDI), which is a power ratio of highest amplitude dominant frequency in the frequency spectrum. Results RTG increased average rotations per RD (Baseline: 2.86±0.10 vs 80nM: 5.66±0.43, p<0.001) whilst CBX caused a reduction (Baseline: 3.77±0.39 vs 50μM: 0.26±0.26, p<0.001). Maximum rotations for a RD increased with RTG (5.4±0.45 vs 48.20±12.32, p<0.001) and decreased with CBX (8.0±1.3 vs 0.3±0.3, p<0.001). Proportion of time PSs were detected in VF increased with RTG (0.44±0.06 vs 0.93±0.02, p<0.001) and decreased with CBX (0.61±0.9 vs 0.03±0.02, p<0.001). RTG reduced meander of longest duration RD (20.6±1.68 vs 11.51±0.77 pixels, p<0.001) for PS >5 rotations. FDI increased with RTG (0.53±0.04 vs 0.78±0.3, p<0.001) and decreased with CBX (0.60±0.05 vs 0.17±0.03, p<0.001). In the diffuse fibrosis group, in comparison to baseline RTG 80nM increased FDI (0.35 vs 0.65, p<0.001) and terminated VF in 40% of hearts. Conclusion The degree of GJ coupling is a key determinant of the underlying mechanism of VF. RTG organised fibrillation and stabilised RDs in a concentration-dependent manner whilst CBX disorganised VF. Enhancing GJ coupling with RTG in diseased hearts with fibrosis can terminate VF and may be a potential therapeutic target in acute VF. Acknowledgement/Funding BHF Programme Grant PG/16/17/32069

scholarly journals Prunetin Relaxed Isolated Rat Aortic Rings by Blocking Calcium Channels

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2372 ◽  
Author(s):  
Bumjung Kim ◽  
Cheolmin Jo ◽  
Ho-Young Choi ◽  
Kyungjin Lee
Keyword(s):  
Blood Pressure ◽  
Calcium Channels ◽  
Herbal Medicines ◽  
Hypotensive Effect ◽  
Treated Group ◽  
Hypotensive Activity ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Vasorelaxant Effect ◽  
Isolated Rat

Prunetin, a component of herbal medicines and various foods, such as pea, peach, cherry, and Prunus yedoensis, is a useful pharmacological compound. We previously reported the potent vasorelaxant effect of the bark of P. yedoensis. Therefore, we investigated the vasorelaxant activities of prunetin on isolated rat aortic rings and hypotensive activity on spontaneously hypertensive rats (SHR) in this study. In the present study, prunetin (1–30 μg/mL) relaxed isolated rat aortic rings pre-contracted by phenylephrine (PE) in a concentration-dependent manner. Pre-incubation with prunetin (3 and 10 μg/mL) inhibited vasoconstriction induced by the supply of Ca2+ in rat aortic rings pre-contracted with PE or KCl in a Ca2+-free Krebs–Henseleit (KH) buffer. Prunetin (10 μg/mL) pre-treatment also inhibited caffeine-induced contraction of aortic rings in a Ca2+-free KH buffer. To investigate the hypotensive effect of prunetin, the systolic blood pressure (SBP) of the SHR was measured by using a tail cuff assay. The SBP of SHR was significantly lower in the prunetin (25 mg/kg)-treated group. These results suggested that prunetin decreased blood pressure and relaxed blood vessels by blocking receptor-operated calcium channels, voltage-dependent calcium channels, and ryanodine receptor channels.

Chickpea (Cicer arietinum L.) Lectin Exhibit Inhibition of ACE-I, α-amylase and α-glucosidase Activity

2019 ◽  
Vol 26 (7) ◽  
pp. 494-501 ◽  
Author(s):  
Sameer Suresh Bhagyawant ◽  
Dakshita Tanaji Narvekar ◽  
Neha Gupta ◽  
Amita Bhadkaria ◽  
Ajay Kumar Gautam ◽  
...  
Keyword(s):  
Biological Effects ◽  
Exchange Chromatography ◽  
Health Concern ◽  
Carbohydrate Binding ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Ic50 Values ◽  
Chickpea Lectin

Background: Diabetes and hypertension are the major health concern and alleged to be of epidemic proportions. This has made it a numero uno subject at various levels of investigation. Glucosidase inhibitor provides the reasonable option in treatment of Diabetes Mellitus (DM) as it specifically targets post prandial hyperglycemia. The Angiotensin Converting Enzyme (ACE) plays an important role in hypertension. Therefore, inhibition of ACE in treatment of elevated blood pressure attracts special interest of the scientific community. Chickpea is a food legume and seeds contain carbohydrate binding protein- a lectin. Some of the biological properties of this lectin hitherto been elucidated. Methods: Purified by ion exchange chromatography, chickpea lectin was tested for its in vitro antioxidant, ACE-I inhibitory and anti-diabetic characteristic. Results: Lectin shows a characteristic improvement over the synthetic drugs like acarbose (oral anti-diabetic drug) and captopril (standard antihypertensive drug) when, their IC50 values are compared. Lectin significantly inhibited α-glucosidase and α-amylase in a concentration dependent manner with IC50 values of 85.41 ± 1.21 ҝg/ml and 65.05 ± 1.2 µg/ml compared to acarbose having IC50 70.20 ± 0.47 value of µg/ml and 50.52 ± 1.01 µg/ml respectively. β-Carotene bleaching assay showed antioxidant activity of lectin (72.3%) to be as active as Butylated Hydroxylanisole (BHA). In addition, lectin demonstrated inhibition against ACE-I with IC50 value of 57.43 ± 1.20 µg/ml compared to captopril. Conclusion: Lectin demonstrated its antioxidant character, ACE-I inhibition and significantly inhibitory for α-glucosidase and α-amylase seems to qualify as an anti-hyperglycemic therapeutic molecule. The biological effects of chickpea lectin display potential for reducing the parameters of medically debilitating conditions. These characteristics however needs to be established under in vivo systems too viz. animals through to humans.

scholarly journals Influence of icariin on inflammation, apoptosis, invasion, and tumor immunity in cervical cancer by reducing the TLR4/MyD88/NF-κB and Wnt/β-catenin pathways

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chunyang Li ◽  
Shuangqing Yang ◽  
Huaqing Ma ◽  
Mengjia Ruan ◽  
Luyan Fang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Underlying Mechanism ◽  
Tissue Growth ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Siha Cells ◽  
Cervical Cancer Cells

Abstract Background Cervical cancer is a type of the most common gynecology tumor in women of the whole world. Accumulating data have shown that icariin (ICA), a natural compound, has anti-cancer activity in different cancers, including cervical cancer. The study aimed to reveal the antitumor effects and the possible underlying mechanism of ICA in U14 tumor-bearing mice and SiHa cells. Methods The antitumor effects of ICA were investigated in vivo and in vitro. The expression of TLR4/MyD88/NF-κB and Wnt/β-catenin signaling pathways were evaluated. Results We found that ICA significantly suppressed tumor tissue growth and SiHa cells viability in a dose-dependent manner. Also, ICA enhanced the anti-tumor humoral immunity in vivo. Moreover, ICA significantly improved the composition of the microbiota in mice models. Additionally, the results clarified that ICA significantly inhibited the migration, invasion capacity, and expression levels of TGF-β1, TNF-α, IL-6, IL-17A, IL-10 in SiHa cells. Meanwhile, ICA was revealed to promote the apoptosis of cervical cancer cells by down-regulating Ki67, survivin, Bcl-2, c-Myc, and up-regulating P16, P53, Bax levels in vivo and in vitro. For the part of mechanism exploration, we showed that ICA inhibits the inflammation, proliferation, migration, and invasion, as well as promotes apoptosis and immunity in cervical cancer through impairment of TLR4/MyD88/NF-κB and Wnt/β-catenin pathways. Conclusions Taken together, ICA could be a potential supplementary agent for cervical cancer treatment.

scholarly journals Modulatory Effects of Osthole on Lipopolysaccharides-Induced Inflammation in Caco-2 Cell Monolayer and Co-Cultures with THP-1 and THP-1-Derived Macrophages

Nutrients ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 123
Author(s):  
Natalia K. Kordulewska ◽  
Justyna Topa ◽  
Małgorzata Tańska ◽  
Anna Cieślińska ◽  
Ewa Fiedorowicz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Reaction ◽  
Wide Spectrum ◽  
Cell Monolayer ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Tnf Α

Lipopolysaccharydes (LPS) are responsible for the intestinal inflammatory reaction, as they may disrupt tight junctions and induce cytokines (CKs) secretion. Osthole has a wide spectrum of pharmacological effects, thus its anti-inflammatory potential in the LPS-treated Caco-2 cell line as well as in Caco-2/THP-1 and Caco-2/macrophages co-cultures was investigated. In brief, Caco-2 cells and co-cultures were incubated with LPS to induce an inflammatory reaction, after which osthole (150–450 ng/mL) was applied to reduce this effect. After 24 h, the level of secreted CKs and changes in gene expression were examined. LPS significantly increased the levels of IL-1β, -6, -8, and TNF-α, while osthole reduced this effect in a concentration-dependent manner, with the most significant decrease when a 450 ng/mL dose was applied (p < 0.0001). A similar trend was observed in changes in gene expression, with the significant osthole efficiency at a concentration of 450 ng/μL for IL1R1 and COX-2 (p < 0.01) and 300 ng/μL for NF-κB (p < 0.001). Osthole increased Caco-2 monolayer permeability, thus if it would ever be considered as a potential drug for minimizing intestinal inflammatory symptoms, its safety should be confirmed in extended in vitro and in vivo studies.

scholarly journals RASSF1A inhibits PDGFB-driven malignant phenotypes of nasopharyngeal carcinoma cells in a YAP1-dependent manner

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Ying-Ying Liang ◽  
Xu-Bin Deng ◽  
Xian-Tao Lin ◽  
Li-Li Jiang ◽  
Xiao-Ting Huang ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Underlying Mechanism ◽  
Carcinoma Cells ◽  
Dependent Manner ◽  
Transcriptional Coactivator ◽  
Actin Remodeling ◽  
Aggressive Tumor ◽  
Subunit B

Abstract Nasopharyngeal carcinoma (NPC) is a highly aggressive tumor characterized by distant metastasis. Deletion or down-regulation of the tumor suppressor protein ras-association domain family protein1 isoform A (RASSF1A) has been confirmed to be a key event in NPC progression; however, little is known about the effects or underlying mechanism of RASSF1A on the malignant phenotype. In the present study, we observed that RASSF1A expression inhibited the malignant phenotypes of NPC cells. Stable silencing of RASSF1A in NPC cell lines induced self-renewal properties and tumorigenicity in vivo/in vitro and the acquisition of an invasive phenotype in vitro. Mechanistically, RASSF1A inactivated Yes-associated Protein 1 (YAP1), a transcriptional coactivator, through actin remodeling, which further contributed to Platelet Derived Growth Factor Subunit B (PDGFB) transcription inhibition. Treatment with ectopic PDGFB partially increased the malignancy of NPC cells with transient knockdown of YAP1. Collectively, these findings suggest that RASSF1A inhibits malignant phenotypes by repressing PDGFB expression in a YAP1-dependent manner. PDGFB may serve as a potential interest of therapeutic regulators in patients with metastatic NPC.

Roscovitine, a specific inhibitor of cyclin-dependent protein kinases, reversibly inhibits chromatin condensation during in vitro maturation of porcine oocytes

Zygote ◽  
2001 ◽  
Vol 9 (4) ◽  
pp. 309-316 ◽  
Author(s):  
Carsten Krischek ◽  
Burkhard Meinecke
Keyword(s):  
Map Kinase ◽  
Protein Kinases ◽  
Chromatin Condensation ◽  
Specific Inhibitor ◽  
Histone H1 ◽  
Dependent Manner ◽  
Free Medium ◽  
Concentration Dependent Manner ◽  
Dependent Protein

In the present study the effects of roscovitine on the in vitro nuclear maturation of porcine oocytes were investigated. Roscovitine, a specific inhibitor of cyclin-dependent protein kinases, prevented chromatin condensation in a concentration-dependent manner. This inhibition was reversible and was accompanied by non-activation of p34cdc2/histone H1 kinase. It also decreased enzyme activity of MAP kinase, suggesting a correlation between histone H1 kinase activation and the onset of chromatin condensation. The addition of roscovitine (50 μM) to extracts of metaphase II oocytes revealed that the MAP kinase activity was not directly affected by roscovitine, which indicates a possible link between histone H1 and MAP kinase. Chromatin condensation occurred between 20 and 28 h of culture of cumulus-oocyte complexes (COCs) in inhibitor-free medium (germinal vesicle stage I, GV1: 74.6% and 13.7%, respectively). Nearly the same proportion of chromatin condensation was detected in COCs incubated initially in inhibitor-free medium for 20-28 h and subsequently in roscovitine-supplemented medium (50 μM) for a further 2-10 h (GV I: 76.2% and 18.8%, respectively). This observation indicates that roscovitine prevents chromatin condensation even after an initial inhibitor-free cultivation for 20 h. Extending this initial incubation period to ≥22 h led to an activation of histone H1 and MAP kinase and increasing proportions of oocytes exhibiting chromatin condensation in the presence of roscovitine. It is concluded that histone H1 kinase is involved in the induction of chromatin condensation during in vitro maturation of porcine oocytes.

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