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Eicosapentaenoic acid (EPA), an omega-3 fatty acid abundant in fish oil, protects endothelial cells (EC) from lipotoxicity and triggers EC NO release. The latter is related to an elevation of cytosolic Ca.sup.2+. Although EPA has been shown to cause human EC cytosolic Ca.sup.2+ elevation, the mechanism is unclear. Microfluorimetric imaging was used here to measure free cytosolic Ca.sup.2+ concentration. EPA was shown to cause intracellular Ca.sup.2+ release in mouse cerebral cortex endothelial bEND.3 cells; interestingly, the EPA-sensitive intracellular Ca.sup.2+ pool(s) appeared to encompass and was larger than the Ca.sup.2+ pool mobilized by sarcoplasmic-endoplasmic reticulum Ca.sup.2+-ATPase inhibition by cyclopiazonic acid. EPA also opened a Ca.sup.2+ influx pathway pharmacologically distinct from store-operated Ca.sup.2+ influx. Surprisingly, EPA-triggered Ca.sup.2+ influx was Ni.sup.2+-insensitive; and EPA did not trigger Mn.sup.2+ influx. Further, EPA-triggered Ca.sup.2+ influx did not involve Na.sup.+-Ca.sup.2+ exchangers. Thus, our results suggest EPA triggered unusual mechanisms of Ca.sup.2+ release and Ca.sup.2+ influx in EC. Keywords: Eicosapentaenoic acid, Endothelial cells, Ca.sup.2+ release, Ca.sup.2+ influx, Author(s): King-Chuen Wu[sup.1,2], Kar-Lok Wong[sup.3], Mei-Ling Wang[sup.4], Lian-Ru Shiao[sup.4], Iat-Lon Leong[sup.5], Chi-Li Gong[sup.4], Ka-Shun Cheng[sup.3,6], Paul Chan[sup.7] and Yuk-Man Leung[sup.4] Introduction Eicosapentaenoic acid (EPA), an omega-3 fatty acid, is a [...]

Abstract: Magnolol, a polyphenolic compound isolated from Houpu, a Chinese herb from the bark of Magnolia officinalis, has been reported to have in vitro and in vivo neuroprotective effects. In spite of these reported beneficial effects, studies on the direct impact of magnolol on neuronal ion channels have been scarce. Whether magnolol affects voltage-gated Na+ channels (VGSC) and voltage-gated K+ (Kv) channels is unknown. Using the whole-cell voltage-clamp method, we studied the effects of magnolol on voltage-gated ion channels in neuronal NG108-15 cells. Magnolol inhibited VGSC channels with mild state-dependence (IC50 of 15 and 30μM, at holding potentials of −70 and −100mV, respectively). No frequency-dependence was observed in magnolol block. Magnolol caused a left-shift of 18mV in the steady-state inactivation curve but did not affect the voltage-dependence of activation. Magnolol inhibited Kv channels with an IC50 of 21μM, and it caused a 20-mV left-shift in the steady-state inactivation curve without affecting the voltage-dependence of activation. In conclusion, magnolol is an inhibitor of both VGSC and Kv channels and these inhibitory effects may in part contribute to some of the reported neuroprotective effects of magnolol. [Copyright &y& Elsevier]

Abstract: During prolonged depolarization, voltage-gated K+ (Kv) channels display C-type inactivation, a process which is due to selectivity filter destabilization and serves to limit K+ flux. Here we reported that coumarsabin, a coumarin derivative isolated from Juniperus Sabina, could hasten C-type inactivation and thus cause block of Kv channels in neuronal NG108-15 cells and Kv1.2 channels heterologously expressed in lung epithelial H1355 cells. In NG108-15 cells, extracellular, but not intracellular, coumarsabin (30μM) strongly speeded up Kv current decay and caused a left-shift in the steady-state inactivation curve. Coumarsabin inhibited end-of-pulse Kv currents with an IC50 of 13.4μM. The kinetics and voltage-dependence of activation were not affected by coumarsabin. The degree of block by coumarsabin was not enhanced by a reduction in intracellular K+ concentration. Data reveal that coumarsabin was a closed channel blocker and it displayed a frequency-independent mode of inhibition. Coumarsabin did not accelerate current decay in a Kv1.2 mutant (V370G) defective in C-type inactivation. Taken together, our data suggest that Kv channel inhibition by coumarsabin did not appear to result from a direct obstruction of the outer pore but relied on C-type inactivation. [Copyright &y& Elsevier]

Background: The study aims to evaluate the contribution of excision repair cross-complementing group 1 (ERCC1), which plays an important role in genome integrity maintenance, to lung cancer risk., Materials and Methods: ERCC1 rs11615 and rs3212986 genotypes were identified by polymerase chain reaction-restriction fragment length polymorphism analysis and their association with lung cancer risk was examined among 358 lung cancer patients and 716 controls., Results: The proportions of CC, CT and TT for the rs11615 genotype were 43.6%, 41.6% and 14.8% in the case group and 50.0%, 41.1% and 8.9% in the control group, respectively (p for trend=0.0082). Allelic analysis showed that ERCC1 rs11615 T-allele carriers have a 1.32-fold higher risk of lung cancer than wild-type C-allele carriers [95%confidence interval (CI)=1.09-1.60, p=0.0039]. In addition, a significant interaction between the rs11615 genotype and smoking status was observed., Conclusion: The T allele of ERCC1 rs11615 jointly with smoking habits may contribute to a higher lung cancer risk in Taiwan., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Mounting evidence has shown that miRNAs play a critical role in the regulation of hematopoiesis of cell proliferation and apoptosis as well as in tumorigenesis. The miR146a rs2910164 polymorphism, which is closely responsive for its expression, has been reported to associate with the risk of several solid cancers. The study aimed at examining the association of the it with susceptibility to childhood acute lymphoblastic leukemia (ALL) in Taiwan., Materials and Methods: We recruited 266 patients with childhood ALL and 266 healthy controls, and rs2910164 genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism methodology., Results: The allele G was associated with decreased childhood ALL risk (OR=0.66, 95%CI=0.52-0.85, p=0.0011). Consistently, the GG genotype was associated with a decreased susceptibility (OR=0.40, 95%CI=0.23-0.67, p=0.0004). Patients with CG and GG genotypes were of earlier onset than those with CC genotype (p=0.0255 and p=0.0001)., Conclusion: MiR146a rs2910164 G allele serves as a protective marker for childhood ALL in Taiwan., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Matrix metalloproteinase 2 (MMP2) is up-regulated in many cancers. However, the association of MMP2 genotype to nasopharyngeal cancer (NPC) susceptibility in Taiwan remains elusive., Materials and Methods: In this study, the role of MMP2 promoter C-1306T (rs243865) and C-735T (rs2285053) genotypes were investigated among 208 NPC patients and 416 healthy controls, and their role in NPC staging and TNM classifications were examined., Results: There was no differential distribution as for the genotypic or allelic frequencies at MMP2 promoter C-1306T or C-735T between the control and case groups. Noticeably, those with MMP2 C-1306T CT+TT genotypes had a lower metastatic risk than those with CC (p=0.0295). As for staging, T and N classifications, there was no differential distribution in C-1306T genotypes (p>0.05). Also, there was no differential distribution of C-735T genotypes according to different behavioral/clinicopathological characteristics., Conclusion: CT and TT genotypes at MMP2 C-1306T were associated with a significantly decreased risk of NPC metastasis., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: Arsenic trioxide (As 2 O 3 ), known as pi-shuang and the most toxic compound in traditional Chinese medicine, has been used as an antitumor agent for thousands of years. Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a natural phenol that has significant anti-bacterial, anti-fungaI and antiaging activities. Our study aimed to examine the combined anticancer effects of As 2 O 3 and resveratrol against human neuroblastoma SK-N-SH cells, and elucidate the underlying intracellular signaling., Materials and Methods: SK-N-SH cells were treated with an extremely low-dose (2-4 μM) of As 2 O 3 alone or combined with 75 μg/ml resveratrol for further comparisons. Cell viability, apoptotic signaling as well as synergistic cytotoxic effects were estimated using the MTT assay, microscopy observation, flow cytometric analysis for loss of mitochondrial membrane potential (MMP) and reactive oxygen species (ROS), and typical quantitative western blotting analysis. Student's t-test, and one- and two-way analysis of variance (ANOVA) were used for examination of significant differences., Results: The combined treatment was more effective than single treatment of As 2 O 3 or resveratrol alone in suppressing cell viability, which correlated with the elevation of ROS levels. The intracellular mechanisms of cytotoxicity of As 2 O 3 plus resveratrol were revealed as ROS accumulation and relative decrease of MMP, leading to activation of caspase-3 and -9, but not of caspase-1, -7 and-8. Combination treatment reduced the expression of B-cell lymphoma 2 (BCL2), BH3 interacting domain death agonist (BID), and BCL-x/L., Conclusion: Combined treatment at extremely low concentration of two agents from natural products, As 2 O 3 and resveratrol, has high potential as a cocktail of anticancer drugs for neuroblastoma., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Pterygium is composed of proliferating fibrovascular tissue, and its formation and progression are closely related to the homeostasis of the extracellular microenvironment. However, few studies have examined the contribution of matrix metalloproteinases (MMP) to either diagnostic or prognostic potential in pterygium. In this study, we investigated the contribution of a polymorphism in the promoter region of MMP-8 (-799C/T) and two non-synonymous polymorphisms (Val436Ala and Lys460Thr) to pterygium., Materials and Methods: In this study, 134 patients with pterygium and 268 non-cancer controls patients were collected and the MMP-8 -799C/T, Val436Ala and Lys460Thr polymorphic genotypes of each subject were examined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)., Results: The results showed that the three polymorphisms investigated were not significantly associated with risk of pterygium. In addition, the stratified analysis showed that there was no interaction between MMP-8 genotype with age or gender on pterygium risk determination., Conclusion: Polymorphisms at MMP-8 -799C/T, Val436Ala and Lys460Thr may not mainly contribute to determining personal susceptibility to pterygium in the Taiwanese examined., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Accumulated evidence has supported the notion that matrix metalloproteinase (MMP) genotypes are associated with the susceptibility of many types of cancers. However, few reports have studied the contribution of MMP genotypes to either diagnostic or prognostic potential in non-solid tumors such as leukemia. In this study, we firstly investigated the contribution of a polymorphism in the promoter region of MMP-8 (-799C/T) and two non-synonymous polymorphisms (Val436Ala and Lys460Thr) to childhood leukemia., Patients and Methods: In this study, 266 patients with childhood acute lymphoblastic leukemia (ALL) and 266 non-cancer control patients were collected and the genomic DNA was isolated from their peripheral blood. MMP-8 -799C/T, Val436Ala and Lys460Thr polymorphic genotypes of each subject were determined by the typical polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)., Results: The results showed that the three polymorphisms were not significantly associated with an increased risk of childhood ALL in the overall investigated population. Furthermore, when the analyses were stratified by age and gender, no significant association between these genotypes and increased ALL risk was found., Conclusion: Our findings suggest that the polymorphisms at MMP-8 -799C/T, Val436Ala and Lys460Thr may not play a major role in determining the personal susceptibility to childhood ALL in Taiwan., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)