Background and purpose:
Cinnamophilin, a thromboxane A
2
receptor antagonist, has been identified as a prominent anti‐arrhythmic agent in rat heart. This study aimed to determine its ...electromechanical and anti‐arrhythmic effects in guinea‐pig hearts.
Experimental approach:
Microelectrodes were used to study action potentials in ventricular papillary muscles. Fluo‐3 fluorimetric ratio and whole‐cell voltage‐clamp techniques were used to record calcium transients and membrane currents in single ventricular myocytes, respectively. Intracardiac electrocardiograms were obtained and the anti‐arrhythmic efficacy was determined from isolated perfused hearts.
Key results:
In papillary muscles, cinnamophilin decreased the maximal rate of upstroke (
V
max
) and duration of action potential, and reduced the contractile force. In single ventricular myocytes, cinnamophilin reduced Ca
2+
transient amplitude. Cinnamophilin decreased the L‐type Ca
2+
current (
I
Ca,L
)(IC
50
=7.5 μM) with use‐dependency, induced a negative shift of the voltage‐dependent inactivation and retarded recovery from inactivation. Cinnamophilin also decreased the Na
+
current (
I
Na
) (IC
50
=2.7 μM) and to a lesser extent, the delayed outward (
I
K
), inward rectifier (
I
K1
), and ATP‐sensitive (
I
K,ATP
) K
+
currents. In isolated perfused hearts, cinnamophilin prolonged the AV nodal conduction interval and Wenckebach cycle length and the refractory periods of the AV node, His‐Purkinje system and ventricle, while shortening the ventricular repolarization time. Additionally, cinnamophilin reduced the occurrence of reperfusion‐induced ventricular fibrillation.
Conclusions and implications:
These results suggest that the promising anti‐arrhythmic effect and the changes in the electromechanical function induced by cinnamophilin in guinea‐pig heart can be chiefly accounted for by inhibition of
I
Ca,L
and
I
Na
.
British Journal of Pharmacology
(2008)
153
, 110–123; doi:
10.1038/sj.bjp.0707541
; published online 29 October 2007
Plasma, the soluble component of the human blood, is believed to harbor thousands of distinct proteins, which originate from a variety of cells and tissues through either active secretion or leakage ...from blood cells or tissues. The dynamic range of plasma protein concentrations comprises at least nine orders of magnitude. Proteins involved in coagulation, immune defense, small molecule transport, and protease inhibition, many of them present in high abundance in this body fluid, have been functionally characterized and associated with disease processes. For example, protein sequence mutations in coagulation factors cause various serious disease states. Diagnosing and monitoring such diseases in blood plasma of affected individuals has typically been conducted by use of enzyme‐linked immunosorbent assays, which using a specific antibody quantitatively measure only the affected protein in the tested plasma samples. The discovery of protein biomarkers in plasma for diseases with no known correlations to genetic mutations is challenging. It requires a highly parallel display and quantitation strategy for proteins. We fractionated blood serum proteins prior to display on two‐dimensional electrophoresis (2‐DE) gels using immunoaffinity chromatography to remove the most abundant serum proteins, followed by sequential anion‐exchange and size‐exclusion chromatography. Serum proteins from 74 fractions were displayed on 2‐DE gels. This approach succeeded in resolving approximately 3700 distinct protein spots, many of them post‐translationally modified variants of plasma proteins. About 1800 distinct serum protein spots were identified by mass spectrometry. They collapsed into 325 distinct proteins, after sequence homology and similarity searches were carried out to eliminate redundant protein annotations. Although a relatively insensitive dye, Coomassie Brillant Blue G‐250, was used to visualize protein spots, several proteins known to be present in serum in < 10 ng/mL concentrations were identified such as interleukin‐6, cathepsins, and peptide hormones. Considering that our strategy allows highly parallel protein quantitation on 2‐DE gels, it holds promise to accelerate the discovery of novel serum protein biomarkers.
Trans-resveratrol, a phytoalexin found at high levels in grapes and in grape products such as red wine, has been shown to prevent carcinogenesis or antitumor growth in murine models. Here we dissect ...the detailed signaling pathway involved in resveratrol-induced apoptosis. Our data showed that treatment with resveratrol-induced activation of apoptosis signal-regulating kinase 1, a mitogen-activated protein kinase kinase kinase, in turn, activated the downstream kinases c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, but not extracellular signal-regulated kinase. Transfection with a dominant-negative c-Jun N-terminal kinase expression vector reduced FasL expression and DNA fragmentation induced by resveratrol. However, inhibition of p38 mitogen-activated protein kinase activity by treatment with SB203580 (p38 mitogen-activated protein kinase specific inhibitor) or expression of mutant p38 mitogen-activated protein kinase expression vector did not alter the apoptosis and FasL expression in response to resveratrol. Furthermore, genetic inhibition of apoptosis signal-regulating kinase 1 signaling inhibited not only the activation of c-Jun N-terminal kinase, but also the expression of FasL and apoptosis. Similarly, over-expression of wild-type apoptosis signal-regulating kinase 1 strengthened the resveratrol-induced c-Jun N-terminal kinase activation, FasL expression and subsequent apoptosis. These results suggest the possible involvement of apoptosis signal-regulating kinase 1/c-Jun N-terminal kinase signaling in the regulation of FasL expression and subsequent apoptosis induced by resveratrol in HL-60 cells. Resveratrol also activated the small GTP-binding protein Cdc42, rather than other members such as RhoA or Rac1. Expression of a mutant Cdc42 (N17 Cdc42) dramatically reduced resveratrol-induced c-Jun N-terminal kinase activity, FasL expression and apoptotic cell death. These results showed that resveratrol induced apoptosis through the Cdc42/apoptosis signal-regulating kinase 1/c-Jun N-terminal kinase/FasL signaling cascade in HL-60 cells.
This study assessed the efficacy of endoscopic hemorrhoidal ligation for treatment of patients with symptoms caused by internal hemorrhoids.
A total of 576 consecutive patients with symptoms caused ...by internal hemorrhoids were enrolled in the study. Symptoms were rectal bleeding (239 patients) and prolapse (337 patients). The severity of the hemorrhoids was classified by using the grading system of Goligher.
All patients were treated by the same operator. Mean follow-up was 17.5 months (range 8 to 24 months). The mean number of band ligations per session was 2.86. The mean number of treatment sessions was 1.24. At least one grade reduction in the severity of the hemorrhoids was achieved in most patients (93.58%). Moreover, rectal bleeding was controlled in 228 patients (95.4%), and rectal prolapse was reduced in 310 patients (91.99%). After treatment, 85 patients experienced anal pain, 37 had mild bleeding, 4 developed external hemorrhoidal thrombosis, and one had a peri-anal abscess. The latter 5 patients were treated surgically and recovered uneventfully.
Endoscopic hemorrhoidal ligation is a simple, safe, and effective treatment for patients with symptoms caused by internal hemorrhoids.
We report a polymer-stabilized liquid crystal (LC) microlens array with a large dynamic range and fast response time. The top substrate has a planar indium-tin oxide (ITO) electrode, while the bottom ...substrate has two patterned ITO electrodes for generating a fringing field and uniform longitudinal field. The fringing field is utilized to create the desired gradient refractive index profile in the LC/monomer layer, which is later stabilized by UV curing to form polymer networks. To tune the focal length, we apply a longitudinal field to change the lens shape. This microlens array offers several attractive features, such as large dynamic range, fast response time, and good mechanical stability.
To determine the proportion of adults with hypertension who reported: (i) having been previously diagnosed with hypertension; (ii) taking blood pressure-lowering medication; and (iii) having achieved ...hypertension control, in five health and demographic surveillance system sites across five countries in Asia.
Data were collected during household surveys conducted between 2016 and 2020 in the five surveillance sites in Bangladesh, India, Indonesia, Malaysia and Viet Nam. We defined hypertension as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg or taking blood pressure-lowering medication. We defined hypertension control as systolic blood pressure < 140 mmHg and diastolic blood pressure < 90 mmHg. We disaggregated hypertension awareness, treatment and control by surveillance site, and within each site by sex, age group, education, body mass index and smoking status.
Of 22 142 participants, 11 137 had hypertension (Bangladesh: 211; India: 487; Indonesia: 1641; Malaysia: 8164; and Viet Nam: 634). The mean age of participants with hypertension was 60 years (range: 19-101 years). Only in the Malaysian site were more than half of individuals with hypertension aware of their condition. Hypertension treatment ranged from 20.8% (341/1641; 95% CI: 18.8-22.8%) in the Indonesian site to 44.7% (3649/8164; 95% CI: 43.6-45.8%) in the Malaysian site. Less than one in four participants with hypertension had achieved hypertension control in any site. Hypertension awareness, treatment and control were generally higher among women and older adults.
While hypertension awareness and treatment varied widely across surveillance sites, hypertension control was low in all sites.
Direct cell–cell interactions are fundamental for tissue development and differentiation. We have studied the expression and function of cadherins in human osteoblasts during in vitro ...differentiation. Using reverse transcription‐polymerase chain reaction and mRNA hybridization, we found that human trabecular bone osteoblasts (HOBs), osteoprogenitor marrow stromal cells (BMCs), and the osteogenic sarcoma lines, SaOS‐2 and MG‐63, expressed mRNA for cadherin‐11 (C11) and N‐cadherin (N‐cad). HOBs and BMCs also expressed low levels of cadherin‐4 (C4) mRNA. C11 was the most abundant cadherin protein present in human osteoblasts, and its expression was unaffected by bone morphogenetic protein‐2 (BMP‐2) treatment of either BMCs or HOBs. Likewise, N‐cad mRNA did not change during BMP‐2 incubation. Conversely, C4 protein, undetectable in transformed cell lines, was down‐regulated by BMP‐2 treatment of normal cells. Both C11 and C4 were localized to sites of cell–cell contact in both HOBs and BMCs, colocalized with β‐catenin, and bands corresponding to cadherins were coimmunoprecipitated by a β‐catenin antibody, findings indicative of functional cadherins. A decapeptide containing the HAV motif of human N‐cad partially inhibited Ca2+‐dependent cell–cell adhesion and completely prevented BMP‐2–induced stimulation of alkaline phosphatase activity by BMCs. Thus, human osteoblasts and their progenitor cells express a repertoire of multiple cadherins. Cadherin‐mediated cell‐to‐cell adhesion is critical for normal human osteoblast differentiation.
White shrimp
Litopenaeus vannamei injected with saline, and injected with tryptic soy broth (TSB)-grown
Vibrio alginolyticus at 1.0 × 10
5 and 1.8 × 10
5 colony-forming units (cfu) shrimp
−1 were ...examined for hyaline cell (HC) counts, granular cell (GC) counts, total haemocyte counts (THCs), phenoloxidase (PO) activity, respiratory burst (RB) and superoxide dismutase (SOD) activity after 1–168 h. Shrimp that received no injection served as the control. The shrimps which received
V. alginolyticus at both doses showed significant decreases in these parameters after 6–96 h. The values for HC and SOD activity decreased earlier and then RB. The time to cause maximum depletion of haemocytes (haemocytopenia), PO activity, RB, and SOD activity were 12, 72, 48, and 24 h post-injection, respectively. The HC, GC, and RB returned to the original values earlier at 72 h, followed by SOD activity at 96 h, and then PO activity at 168 h post-infection. It was concluded that an injection of
V. alginolyticus rapidly reduced the shrimp's immunity by decreasing HC, GC, SOD activity, RB, and PO activity within 3–24 h, followed by a slow recovery during 72–168 h post-injection. Furthermore, white shrimp
L. vannamei which received
V. alginolyticus showed a 6–9 h later response in PO activity, and a 72–96 h later recovery of PO activity, compared to the responses in RB and SOD activity indicating their roles in shrimp defence and immunity.
One hundred eighty-four serum samples from patients with ovarian cancer (n = 109), patients with benign tumors (n = 19), and healthy donors (n = 56) were analyzed on strong anion-exchange surfaces ...using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry technology. Univariate and multivariate statistical analyses applied to protein-profiling data obtained from 140 training serum samples identified three biomarker protein panels. The first panel of five candidate protein biomarkers, termed the screening biomarker panel, effectively diagnosed benign and malignant ovarian neoplasia 95.7% sensitivity, 82.6% specificity, 89.2% accuracy, and receiver operating characteristic (ROC) area under the curve of 0.94. The other two panels, consisting of five and four candidate protein biomarkers each, effectively distinguished between benign and malignant ovarian neoplasia and were therefore referred to as validation biomarker panel I (81.5% sensitivity, 94.9% specificity, 88.2% accuracy, and ROC = 0.94) and validation biomarker panel II (72.8% sensitivity, 94.9% specificity, 83.9% accuracy, and ROC = 0.90). The three ovarian cancer biomarker protein panels correctly diagnosed 41 of the 44 blinded test samples: 21 of 22 malignant ovarian neoplasias 10 of 11 early-stage ovarian cancer (I/II) and 11 of 11 advanced-stage ovarian cancer (III/IV), 6 of 6 low malignant potential, 5 of the 6 benign tumors, and 9 of 10 normal patient samples. In conclusion, we have discovered three ovarian cancer biomarker protein panels that, when used together, effectively distinguished serum samples from healthy controls and patients with either benign or malignant ovarian neoplasia.
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