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Biology of Sport  2014;31(1):69-72.
The beneficial effect of magnesium supplementation on exercise performance has been reported by many researchers. In the present study, the effect of nigari, a concentrate of deep seawater containing high magnesium levels, on exercise performance, was examined. Gerbils were given double-distilled water or nigari (18 mg · kg−1, po) orally 30 min before exercise. All animals were subjected to forced exercise on a treadmill for 90 min at three successive speeds of 10, 15, and 20 m · min−1. The retention numbers were recorded. The retention numbers were 85.0 ± 21.0, 46.0 ± 9.7, and 48.0 ± 14.2 in the control group, and 44.0 ± 10.9, 23.0 ± 8.4, and 13.0 ± 4.8 in the nigari-treated group at the three speeds, respectively. The retention numbers were significantly reduced at higher speeds (by 50% at 15 and 73% at 20 m · min−1, respectively) in the nigari-treated group when compared to those of the control group, respectively. Thus, nigari administration appeared to reduce retention numbers and enhance exercise performance in gerbils.
PMCID: PMC3994588  PMID: 24917692
Nigari; concentrated deep seawater; Mg2+; retention number; treadmill exercise
2.  NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease 
British Journal of Pharmacology  2012;168(2):432-444.
Background and Purpose
The KCa3.1 channel is a potential target for therapy of immune disease. We identified a compound from a new chemical class of KCa3.1 inhibitors and assessed in vitro and in vivo inhibition of immune responses.
Experimental Approach
We characterized the benzothiazinone NS6180 (4-[[3-(trifluoromethyl)phenyl]methyl]-2H-1,4-benzothiazin-3(4H)-one) with respect to potency and molecular site of action on KCa3.1 channels, selectivity towards other targets, effects on T-cell activation as well as pharmacokinetics and inflammation control in colitis induced by 2,4-dinitrobenzene sulfonic acid, a rat model of inflammatory bowel disease (IBD).
Key Results
NS6180 inhibited cloned human KCa3.1 channels (IC50 = 9 nM) via T250 and V275, the same amino acid residues conferring sensitivity to triarylmethanes such as like TRAM-34. NS6180 inhibited endogenously expressed KCa3.1 channels in human, mouse and rat erythrocytes, with similar potencies (15–20 nM). NS6180 suppressed rat and mouse splenocyte proliferation at submicrolar concentrations and potently inhibited IL-2 and IFN-γ production, while exerting smaller effects on IL-4 and TNF-α and no effect on IL-17 production. Antibody staining showed KCa3.1 channels in healthy colon and strong up-regulation in association with infiltrating immune cells after induction of colitis. Despite poor plasma exposure, NS6180 (3 and 10 mg·kg−1 b.i.d.) dampened colon inflammation and improved body weight gain as effectively as the standard IBD drug sulfasalazine (300 mg·kg−1 q.d.).
Conclusions and Implications
NS6180 represents a novel class of KCa3.1 channel inhibitors which inhibited experimental colitis, suggesting KCa3.1 channels as targets for pharmacological control of intestinal inflammation.
PMCID: PMC3572569  PMID: 22891655
IK channel; KCNN4; KCa3.1; Gárdos channel; TRAM-34; IBD; DNBS-induced colitis; autoimmune disease; NS6180; T-cell activation
3.  Mechanoelectrical feedback regulates the arrhythmogenic activity of pulmonary veins 
Heart  2006;93(1):82-88.
Atrial fibrillation is commonly associated with dilated pulmonary veins. Stretch has been shown to have mechano‐electrical effects.
To investigate whether stretch can increase the arrhythmogenic activity of the pulmonary veins.
The transmembrane action potentials were recorded from rabbit pulmonary veins before and after stretch (100 and 300 mg). Gadolinium and streptomycin (stretch‐activated ion channel blockers) were each perfused into the pulmonary veins under a 300‐mg stretch.
Stretch (0, 100 and 300 mg) force dependently increased the incidence of spontaneous activity (22%, 48% and 83%; p<0.05), mean (standard deviation (SD)) firing rates of spontaneous activity (1.7 (0.2), 2.1 (0.3) and 3 (0.2) Hz; p<0.05) and incidence of early post‐depolarisations (9%, 26% and 61%; p<0.05) and delayed post‐depolarisations (0%, 4% and 30%; p<0.05) in 23 pulmonary veins. In the seven preparations with spontaneous activity after the 300‐mg stretch, gadolinium (1, 3 and 10 μmol/l) decreased the incidence of spontaneous activity by 43%, 29% and 14%, respectively (p<0.05), and decreased the firing rate from 2.9 (0.1) Hz to 0.8 (0.4), 0.3 (0.1) and 0.1 (0.1) Hz, respectively (p<0.05). Streptomycin (10 and 40 μmol/l) decreased the incidence of spontaneous activity by 71% and 29%, respectively (p<0.05), and decreased the firing rate from 2.9 (0.1) Hz to 1.6 (0.4) and 0.5 (0.3) Hz, respectively (p<0.05).
Stretch is an important factor in the electrical activity of the pulmonary vein. Stretch‐induced arrhythmogenic activity of the pulmonary vein may contribute to the genesis of atrial fibrillation.
PMCID: PMC1861344  PMID: 16905626
4.  Aberrant FHIT transcripts in hepatocellular carcinomas. 
British Journal of Cancer  1998;77(3):417-420.
To study abnormalities of the FHIT gene in human hepatocellular carcinoma (HCC), eight liver cancer cell lines, 18 matched tumorous and non-tumorous tissues from patients with HCC and three normal liver tissues were analysed by microsatellite polymorphism analysis and reverse transcription of FHIT mRNA followed by polymerase chain reaction (PCR) amplification and sequencing of the products. No loss of heterozygosity at chromosome 3p14.2 as defined by markers D3S1300 and D3S1312 was detected in any of the specimens. In addition, a normal transcript of the gene without any sequence change was found to be expressed in all the cell lines, 17 of the 18 tumorous and all 21 non-tumorous liver tissues tested. Although five out of eight liver cancer cell lines (62.5%), 12 out of 18 HCC tissues (66.7%) and 8 out of 18 paired non-tumorous liver tissues (44.4%) displayed abnormal faint bands of smaller size, sequence analysis revealed that they were aberrant FHIT transcripts lacking three or more exons and might represent alternatively spliced transcripts only. In conclusion, these studies indicate that abnormalities of the FHIT gene transcripts occur in a fairly high frequency of tumorous and non-tumorous liver tissues. However, it might not be causally related to the hepatocarcinogenesis.
PMCID: PMC2151291  PMID: 9472637
5.  Peptidyl-prolyl cis/trans isomerase Pin1 is critical for the regulation of PKB/Akt stability and activation phosphorylation 
Oncogene  2009;28(26):2436-2445.
The serine/threonine protein kinase B (PKB, also known as Akt) plays a pivotal role in diverse cellular functions. Elevated expression of activated Akt has been detected in a wide variety of human cancers; however, the mechanism of Akt protein stability regulation remains unclear. In this study, we showed a strong correlation between the expression levels of an oncogenic peptidyl-prolyl cis/trans isomerase Pin1 and levels of Akt phosphorylation at S473 in multiple cancer types (P<0.0001). Akt-pS473 status combined with Pin1 expression levels predicted a poorer prognosis than did either one alone in patients with breast cancer (P = 0.0052). We further showed that Pin1 regulated Akt stability and phosphorylation on S473 through the phosphorylated Thr-Pro motifs of Akt. These motifs are conserved evolutionary and are required for the maintenance of Akt stability and its interaction with Pin1. In addition, repressing Pin1 expression through either homologue Pin1 knockout or small interfering RNA-mediated knockingdown compromised its ability to protect Akt from degradation. Our results show how Akt protein stability is regulated by the peptidyl-prolyl cis/trans isomerase Pin1 and highlight the importance of this oncogenic network in human disease pathogenesis.
PMCID: PMC2748248  PMID: 19448664
PKB/Akt; Pin1; peptidyl-prolyl cis/trans isomerase; breast cancer
6.  Effect of K201, a novel antiarrhythmic drug on calcium handling and arrhythmogenic activity of pulmonary vein cardiomyocytes 
British Journal of Pharmacology  2007;153(5):915-925.
Background and purpose:
Pulmonary veins are the most important focus for the generation of atrial fibrillation. Abnormal calcium homeostasis with ryanodine receptor dysfunction may underlie the arrhythmogenic activity in pulmonary veins. The preferential ryanodine receptor stabilizer (K201) possesses antiarrhythmic effects through calcium regulation. The purpose of this study was to investigate the effects of K201 on the arrhythmogenic activity and calcium regulation of pulmonary vein cardiomyocytes.
Experimental approach:
The ionic currents and intracellular calcium were studied in isolated single cardiomyocytes from rabbit pulmonary vein before and after the administration of K201, by the whole-cell patch clamp and indo-1 fluorimetric ratio techniques.
Key results:
K201 (0.1, 0.3, 1 μM) reduced the firing rates in pulmonary vein cardiomyocytes, decreased the amplitudes of the delayed afterdepolarizations and prolonged the action potential duration. K201 decreased the L-type calcium currents, Na+/Ca2+ exchanger currents, transient inward currents and calcium transients. K201 (1 μM, but not 0.1 μM or 0.3 μM) also reduced the sarcoplasmic reticulum calcium content. Moreover, both the pretreatment and administration of K201 (0.3 μM) decreased the isoprenaline (10 nM)-induced arrhythmogenesis in pulmonary veins.
Conclusions and implications:
K201 reduced the arrhythmogenic activity of pulmonary vein cardiomyocytes and attenuated the arrhythmogenicity induced by isoprenaline. These findings may reveal the anti-arrhythmic potential of K201.
PMCID: PMC2267278  PMID: 17994112
atrial fibrillation; calcium handling; pulmonary vein; ryanodine receptor; triggered activity
7.  Hydroxychavicol, a novel betel leaf component, inhibits platelet aggregation by suppression of cyclooxygenase, thromboxane production and calcium mobilization 
British Journal of Pharmacology  2007;152(1):73-82.
Background and purpose:
Platelet hyperactivity is important in the pathogenesis of cardiovascular diseases. Betel leaf (PBL) is consumed by 200-600 million betel quid chewers in the world. Hydroxychavicol (HC), a betel leaf component, was tested for its antiplatelet effect.
Experimental approach:
We tested the effect of HC on platelet aggregation, thromboxane B2 (TXB2) and reactive oxygen species (ROS) production, cyclooxygenase (COX) activity, ex vivo platelet aggregation and mouse bleeding time and platelet plug formation in vivo. The pharmacokinetics of HC in rats was also assessed.
Key results:
HC inhibited arachidonic acid (AA) and collagen-induced platelet aggregation and TXB2 production. HC inhibited the thrombin-induced TXB2 production, but not platelet aggregation. SQ29548, suppressed collagen- and thrombin-induced TXB2 production, but not thrombin-induced platelet aggregation. HC also suppressed COX-1/COX-2 enzyme activity and the AA-induced ROS production and Ca2+ mobilization. HC further inhibited the ex vivo platelet aggregation of platelet-rich plasma (>100 nmole/mouse) and prolonged platelet plug formation (>300 nmole/mouse) in mesenteric microvessels, but showed little effect on bleeding time in mouse tail. Moreover, pharmacokinetics analysis found that more than 99% of HC was metabolized within 3 min of administration in Sprague-Dawley rats in vivo.
Conclusions and implications:
HC is a potent COX-1/COX-2 inhibitor, ROS scavenger and inhibits platelet calcium signaling, TXB2 production and aggregation. HC could be a potential therapeutic agent for prevention and treatment of atherosclerosis and other cardiovascular diseases through its anti-inflammatory and antiplatelet effects, without effects on haemostatic functions.
PMCID: PMC1978281  PMID: 17641677
betel leaf; hydroxychavicol; platelet aggregation; thromboxane; cyclooxygenase; calcium
8.  The prevalence and spectrum of α and β thalassaemia in Guangdong Province: implications for the future health burden and population screening 
Journal of Clinical Pathology  2004;57(5):517-522.
Aim: Thalassaemia is a good candidate disease for control by preventive genetic programmes in developing countries. Accurate population frequency data are needed for planning the control of thalassaemia in the high risk Guangdong Province of southern China.
Methods: In total, 13 397 consecutive samples from five geographical areas of Guangdong Province were analysed for both haematological and molecular parameters.
Results: There was a high prevalence of carriers of α thalassaemia (8.53%), β thalassaemia (2.54%), and both α and β thalassaemia (0.26%). Overall, 11.07% of the population in this area were heterozygous carriers of α and β thalassaemia. The mutation spectrum of α and β thalassaemia and its constitution were fully described in this area. This study reports the true prevalence of silent α thalassaemia in the southern China population for the first time. In addition, two novel mutations that give rise to α thalassaemia, one deletion resulting in β thalassaemia, and a rare deletion (−−THAI allele) previously unreported in mainland China were detected. The frequency of the most common mutation, the Southeast Asian type of deletion (−−SEA, accounting for 48.54% of all α thalassaemias) was similar to the total of two α+ thalassaemia deletions (−α3.7 and −α4.2, accounting for 47.49% of α thalassaemia).
Conclusion: Both α and β thalassaemia are widely distributed in Guangdong Province of China. The knowledge gained in this study will enable the projected number of pregnancies at risk to be estimated and a screening strategy for control of thalassaemia to be designed in this area.
PMCID: PMC1770296  PMID: 15113860
thalassaemia; epidemiology; mutations; Hb H disease; genetic screening
9.  hTERT phosphorylation by PKC is essential for telomerase holoprotein integrity and enzyme activity in head neck cancer cells 
British Journal of Cancer  2006;94(6):870-878.
Telomerase activity is suppressed in normal somatic tissues but is activated in most cancer cells. We have previously found that all six telomerase subunit proteins, including hTERT and hsp90 are needed for full enzyme activity. Telomerase activity has been reported to be upregulated by protein kinase C (PKC), but the mechanism is not clear. In this study, we examined how PKC regulates telomerase activity in head and neck cancer cells. PKC inhibitor, bisindolylmaleimide I (BIS), inhibited telomerase activity but had no effect on the expressions of telomerase core subunits. RNA interference (RNAi) and in vitro phosphorylation studies revealed that PKC isoforms α, β, δ, ɛ, ζ specifically involved in telomerase regulation, and the phosphorylation target was on hTERT. Treatment with the hsp-90 inhibitor novobiocin dissociated hsp90 and hTERT as revealed by immunoprecipitation and immunoblot analysis and reduced telomerase activity. Treatment with the PKC activator SC-10 restored the association of hsp90 and hTERT and reactivate telomerase, suggesting that hTERT phosphorylation by PKC is essential for telomerase holoenzyme integrity and function. Analysis on clinical normal and tumour tissues reveal that the expressions of PKC α, β, δ, ɛ, ζ were higher in the tumour tissues, correlated with telomerase activity. Disruption of PKC phosphorylation by BIS significantly increased chemosensitivity to cisplatin. In conclusion, PKC isoenzymes α, β, δ, ɛ, ζ regulate telomerase activity in head and neck cancer cells by phosphorylating hTERT. This phosphorylation is essential for telomerase holoenzyme assembly, leading to telomerase activation and oncogenesis. Manipulation of telomerase activity by PKC inhibitors is worth exploring as an adjuvant therapeutic approach.
PMCID: PMC2361368  PMID: 16508638
hTERT; PKC isoenzymes; phosphorylation; telomerase
10.  Effect of aminophylline on brain stem auditory evoked potentials in preterm infants. 
To determine the neurophysiological effects of aminophylline on apnoea of prematurity, the brain stem auditory evoked potentials (BAEPs) of 30 apnoeic infants and 34 age matched controls were evaluated and compared. After six days of treatment with aminophylline, the brain stem conduction time (interpeak latency of I-V) in apnoeic infants decreased compared with controls of a similar postconceptional age. The mean latencies of the peaks and interpeaks of all waves except wave I were significantly lower in the apnoeic infants after than before receiving aminophylline. No significant differences were found in the latencies of BAEPs between the apnoeic infants who responded and those who did not respond to aminophylline treatment, however. These results suggest that aminophylline may enhance conduction along central auditory pathways and stimulate the regulatory effect on the respiratory centre of the brain stem.
PMCID: PMC1061062  PMID: 8092864
11.  A retrospective cohort study of leukemia and other cancers in benzene workers 
A retrospective cohort study was carried out in 1982–1983 among 28,460 benzene-exposed workers (15,643 males, 12,817 females) from 233 factories and 28,257 control workers (16,621 males, 12,366 females) from 83 factories in 12 large cities in China. All-cause mortality was significantly higher among the exposed (265.46/100,000 person-years) than among the unexposed (139.06/100,000 person-years), as was mortality from all malignant neoplasms (123.21/100,000 versus 54.7/100,000, respectively). For certain cancers, increased mortality was noted among benzene-exposed males in comparison with that among unexposed males; the standardized mortality ratios (SMR) were elevated for leukemia (SMR = 5.74), lung cancer (SMR = 2.31), primary hepatocarcinoma (SMR = 1.12), and stomach cancer (SMR = 1.22). For females only leukemia occurred in excess among the exposed. Risk of leukemia rose as duration to exposure to benzene increased up to 15 years, and then declined with additional years of exposure. Leukemia occurred among some workers with as little as 6 to 10 ppm average exposure and 50 ppm-years (or possibly less) cumulative lifetime exposure (based on all available measurements for the exposed work units). Among the 30 leukemia cases identified in the exposed cohort, the proportion of subjects with acute lymphocytic leukemia was substantially lower and the proportion with acute nonlymphocytic leukemias was higher than in the general population. During 1972 to 1981, the annual incidence of leukemia ranged from 5.83 to 28.33 per 100,000 with higher rates occurring in the interval 1977 to 1981 than in the earlier years of the study period. Future studies should evaluate more precisely the relationship between exposure levels, job title, and development of leukemia among cases and noncases within the exposed cohort.
PMCID: PMC1568128  PMID: 2792042
12.  Leukaemia in benzene workers: a retrospective cohort study. 
A retrospective cohort study was conducted in 233 benzene factories and 83 control factories in 12 cities in China. The benzene cohort and the control cohort consisted of 28,460 benzene exposed workers (178,556 person-years in 1972-81) and 28,257 control workers (199,201 person-years). Thirty cases of leukaemia (25 dead and 5 alive) were detected in the former and four cases (all dead) in the latter. The leukaemia mortality rate was 14/100,000 person-years in the benzene cohort and 2/100,000 person-years in the control cohort; the standardized mortality ratio was 5.74 (p less than 0.01 by U test). The average latency of benzene leukaemia was 11.4 years. Most (76.6%) cases of benzene leukaemia were of the acute type. The mortality due to benzene leukaemia was high in organic synthesis plants followed by painting and rubber synthesis industries. The concentration of benzene to which patients with a leukaemia were exposed ranged from 10 to 1000 mg/m3 (mostly from 50 to 500 mg/m3). Of the 25 cases of leukaemia, seven had a history of chronic benzene poisoning before the leukaemia developed.
PMCID: PMC1007793  PMID: 3814544
13.  Highly potent and specific siRNAs against E6 or E7 genes of HPV16- or HPV18-infected cervical cancers 
Cancer Gene Therapy  2010;17(12):827-836.
Infection with high-risk types (type 16 or type 18) of human papillomaviruses (HPVs) increases a patient's risk of cervical cancer. Given the importance of the cervix and the severe side effects resulting from traditional cancer therapies, this study aimed to achieve targeted inhibition of viral oncogenes in tumor cells using small interfering RNAs (siRNA). To accomplish this, we developed nine siRNAs against either the E6 or E7 genes of HPV-16 or HPV-18 in several combinations, yielding siRNAs targeting 16E6, 16E7, 18E6 and 18E7. We measured the effectiveness of the siRNAs by examining E6 or E7 mRNA expression after transfection of the siRNAs into HPV-positive CaSki (HPV-16) or HeLa (HPV-18) cell lines. We found that the HPV-siRNAs significantly reduced cell growth and colony formation in both cell lines. Flow cytometry analysis revealed a significant increase in apoptosis. The siRNAs had no effect on cell growth, colony formation or apoptosis in HPV-negative C33A cells, demonstrating a lack of off-target effects. In addition, an in vivo xenograft study showed that intra-tumoral injection of the siRNAs reduced tumor growth in BALB/c nude mice. In conclusion, we have developed highly specific and potent HPV-siRNAs that successfully suppress tumor growth and induce apoptosis in HPV-positive cervical cancer cells. siRNA treatment has potential for further development as an adjuvant therapy for cervical cancer.
PMCID: PMC2994641  PMID: 20885450
HPV; E6; E7; cervical cancer; siRNA silencing

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