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1
Zhou, Yu, Qiong-Yao Tang, Xiao-Ming Xia, and Christopher J. Lingle. "Glycine311, a determinant of paxilline block in BK channels: a novel bend in the BK S6 helix." Journal of General Physiology 135, no. 5 (April 26, 2010): 481–94. http://dx.doi.org/10.1085/jgp.201010403.
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The tremorogenic fungal metabolite, paxilline, is widely used as a potent and relatively specific blocker of Ca2+- and voltage-activated Slo1 (or BK) K+ channels. The pH-regulated Slo3 K+ channel, a Slo1 homologue, is resistant to blockade by paxilline. Taking advantage of the marked differences in paxilline sensitivity and the homology between subunits, we have examined the paxilline sensitivity of a set of chimeric Slo1/Slo3 subunits. Paxilline sensitivity is associated with elements of the S5–P loop–S6 module of the Slo1 channel. Replacement of the Slo1 S5 segment or the second half of the P loop results in modest changes in paxilline sensitivity. Replacing the Slo1 S6 segment with the Slo3 sequence abolishes paxilline sensitivity. An increase in paxilline affinity and changes in block kinetics also result from replacing the first part of the Slo1 P loop, the so-called turret, with Slo3 sequence. The Slo1 and Slo3 S6 segments differ at 10 residues. Slo1-G311S was found to markedly reduce paxilline block. In constructs with a Slo3 S6 segment, S300G restored paxilline block, but most effectively when paired with a Slo1 P loop. Other S6 residues differing between Slo1 and Slo3 had little influence on paxilline block. The involvement of Slo1 G311 in paxilline sensitivity suggests that paxilline may occupy a position within the central cavity or access its blocking position through the central cavity. To explain the differences in paxilline sensitivity between Slo1 and Slo3, we propose that the G311/S300 position in Slo1 and Slo3 underlies a structural difference between subunits in the bend of S6, which influences the occupancy by paxilline.
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Tian, Yutao, Florian Ullrich, Rong Xu, Stefan H. Heinemann, Shangwei Hou, and Toshinori Hoshi. "Two distinct effects of PIP2 underlie auxiliary subunit-dependent modulation of Slo1 BK channels." Journal of General Physiology 145, no. 4 (March 30, 2015): 331–43. http://dx.doi.org/10.1085/jgp.201511363.
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Phosphatidylinositol 4,5-bisphosphate (PIP2) plays a critical role in modulating the function of numerous ion channels, including large-conductance Ca2+- and voltage-dependent K+ (BK, Slo1) channels. Slo1 BK channel complexes include four pore-forming Slo1 (α) subunits as well as various regulatory auxiliary subunits (β and γ) that are expressed in different tissues. We examined the molecular and biophysical mechanisms underlying the effects of brain-derived PIP2 on human Slo1 BK channel complexes with different subunit compositions that were heterologously expressed in human embryonic kidney cells. PIP2 inhibited macroscopic currents through Slo1 channels without auxiliary subunits and through Slo1 + γ1 complexes. In contrast, PIP2 markedly increased macroscopic currents through Slo1 + β1 and Slo1 + β4 channel complexes and failed to alter macroscopic currents through Slo1 + β2 and Slo1 + β2 Δ2–19 channel complexes. Results obtained at various membrane potentials and divalent cation concentrations suggest that PIP2 promotes opening of the ion conduction gate in all channel types, regardless of the specific subunit composition. However, in the absence of β subunits positioned near the voltage-sensor domains (VSDs), as in Slo1 and probably Slo1 + γ1, PIP2 augments the negative surface charge on the cytoplasmic side of the membrane, thereby shifting the voltage dependence of VSD-mediated activation in the positive direction. When β1 or β4 subunits occupy the space surrounding the VSDs, only the stimulatory effect of PIP2 is evident. The subunit compositions of native Slo1 BK channels differ in various cell types; thus, PIP2 may exert distinct tissue- and divalent cation–dependent modulatory influences.
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Yang, Xiaoli, Duanlu Hou, Jianjun Liu, Tianyao Wang, Yufan Luo, Wenbo Sun, Chen Li, Liwei Shen, Wenpeng Liu, and Danhong Wu. "Soluble Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Level is Related to Clinical Prognosis In Patients with Acute Atherosclerosis-related Ischemic Stroke." Clinical and Applied Thrombosis/Hemostasis 27 (January 2021): 107602962110595. http://dx.doi.org/10.1177/10760296211059500.
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To investigate the associations between soluble Lectin-like Oxidized Low-density lipoprotein receptor-1 (sLOX-1) and clinical prognosis, especially infarct volume in patients with acute atherosclerosis-related ischemic stroke. We recruited acute ischemic stroke patients within 3 days after onset. Patients were stratified into 3 groups by sLOX-1 level. Initial stroke severity was assessed using the National Institutes of Health Stroke Scale scores, and infarct volume was measured using DWI by ITK-SNAP software. The clinical prognosis was evaluated by DWI volume, clinical response at discharge, and functional outcome at 90 days. Spearman rank correlation analysis was used to examine associations between circulating sLOX-1 levels and infarct volumes. Logistic regression was used to explore the relationship between sLOX-1 levels and clinical prognosis. A total of 207 patients were included in our study. The median DWI volume in the lowest sLOX-1 tertile was 1.98 cm3, smaller than 4.26 cm3 in the highest sLOX-1 group. The Spearman rank correlation coefficient between sLOX-1 levels and DWI volume was 0.47 ( P < .01). Compared with the highest sLOX-1 tertiles, patients in the lowest sLOX-1 tertile had a higher risk of favorable functional outcome at 90 days (OR = 3.47, 95% CI, 1.21-9.96) after adjusting traditional risk factors. However, there was no difference between sLOX-1 level and clinical response at discharge. For patients with acute atherosclerosis-related ischemic stroke, circulating sLOX-1 level is correlated with DWI volume in the acute phase and favorable functional outcome at 90 days, but not with the clinical response at discharge.
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Zhao, Zi-wen, Yi-wei Xu, Shu-mei Li, Jin-jian Guo, Tao Yi, and Liang-long Chen. "Higher serum lectin-like oxidized low-density lipoprotein receptor-1 in patients with stable coronary artery disease is associated with major adverse cardiovascular events: A multicentre pilot study." Biochemia medica 29, no. 1 (December 24, 2018): 84–93. http://dx.doi.org/10.11613/bm.2019.010705.
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Introduction: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is involved in the pathophysiology of atherosclerosis and acute coronary syndromes (ACS). Circulating soluble LOX-1 (sLOX-1) has been linked to the risk of coronary artery disease (CAD). Our aim was to test if baseline serum sLOX-1 was associated with major adverse cardiovascular events (MACE) in patients with stable CAD. Materials and methods: This multicentre pilot study enrolled 833 stable CAD patients. All patients were followed for two years. Serum sLOX-1 concentrations were detected by enzyme-linked immunosorbent assay (ELISA). The association between sLOX-1 concentrations and MACE was assessed by logistic regression, Kaplan-Meier survival curves and Cox proportional hazards analyses. Logistic regression analysis was employed to assess the predictors of complex lesion. Results: Multivariate logistic regression analysis revealed that sLOX-1 concentration was an independent predictor of MACE (OR 2.07, 95%CI 1.52 - 2.82; P < 0.001). Kaplan-Meier cumulative survival curves showed that the incidence of MACE in patients with a high sLOX-1 concentration was significantly higher than in patients with an intermediate or low sLOX-1 concentration (P < 0.001). Soluble LOX-1 concentrations were independently correlated with coronary complex lesions (OR 2.32, 95%CI 1.81 - 2.97; P < 0.001). Conclusions: Baseline sLOX-1 concentrations were correlated with 2-year MACE in stable CAD patients. Furthermore, patients with high serum sLOX-1 concentrations had higher cumulative incidence of MACE compared to those with low serum sLOX-1 concentrations.
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Li, Huilin, Weinong Guo, Kathryn A. Yamada, and Jeanne M. Nerbonne. "Selective elimination of IK,slow1 in mouse ventricular myocytes expressing a dominant negative Kv1.5α subunit." American Journal of Physiology-Heart and Circulatory Physiology 286, no. 1 (January 2004): H319—H328. http://dx.doi.org/10.1152/ajpheart.00665.2003.
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Although previous studies have revealed a role for the voltage-gated K+ channel α-subunit Kv1.5 ( KCNA5) in the generation of the 4-aminopyridine (4-AP)-sensitive component of delayed rectification in mouse ventricles ( IK,slow1), the phenotypic consequences of manipulating IK,slow1 expression in vivo in different (mouse) models are distinct. In these experiments, point mutations were introduced in the pore region of Kv1.5 to change the tryptophan (W) at position 461 to phenylalanine (F) to produce a nonconducting subunit, Kv1.5W461F, that is shown to function as a Kv1 subfamily-specific dominant negative (Kv1.5DN). With the use of the α-myosin heavy chain promoter to direct cardiac-specific expression, three lines of Kv1.5DN-expressing (C57BL6) transgenic mice were generated and characterized. Electrophysiological recordings from Kv1.5-DN-expressing left ventricular myocytes revealed that the micromolar 4-AP sensitive IK,slow1 is selectively eliminated. The attenuation of IK,slow1 is accompanied by increased ventricular action potential durations and marked QT prolongation. In contrast to previous findings in mice expressing a truncated (DN) Kv1.1 transgene; however, no electrical remodeling is evident in Kv1.5DN-expressing ventricular myocytes, and the (Kv1.5DN-induced) elimination of IK,slow1 does not result in spontaneous ventricular arrhythmias.
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Zhao, Zi-wen, Yi-wei Xu, Shu-mei Li, Jin-jian Guo, Jian-min Sun, Ju-chang Hong, and Liang-long Chen. "Baseline Serum sLOX-1 Concentrations Are Associated with 2-Year Major Adverse Cardiovascular and Cerebrovascular Events in Patients after Percutaneous Coronary Intervention." Disease Markers 2019 (October 20, 2019): 1–8. http://dx.doi.org/10.1155/2019/4925767.
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Background. Soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) may be a potential biomarker of coronary artery disease (CAD) and stroke. Objective. We aimed to investigate the association and prognostic value of elevated sLOX-1 concentrations with regard to long-term major adverse cardiovascular and cerebrovascular events (MACCEs) in patients with CAD undergoing primary percutaneous coronary intervention (PCI). Methods. A total of 1011 patients were enrolled. Serum sLOX-1 concentrations were detected by the enzyme-linked immunosorbent assay (ELISA). Patients were followed for 2 years. Multivariate Cox regression and Kaplan-Meier survival curve were explored to assess the association between sLOX-1 and MACCEs. A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic efficacy of sLOX-1. Results. Two-year MACCEs were associated with serum sLOX-1 concentrations (HR 1.278, 95% CI 1.019-1.604, P=0.034), left main disease (HR 2.938, 95% CI 1.246-6.925, P=0.014), small-caliber stents used (HR 2.207, 95% CI 1.189-4.095, P=0.012), and total stent length (HR 1.057, 95% CI 1.005-1.112, P=0.030). Serum sLOX-1 concentration≥1.10 ng/ml had maximum sensitivity and specificity in predicting the occurrence of 2-year MACCEs (P<0.001). Patients with higher serum sLOX-1 concentrations showed a significantly higher incidence of MACCEs in the Kaplan-Meier curve (P<0.001). The combination of any of the risk factors identified in multiple Cox regression was associated with a stepwise increase in MACCE rate (P<0.001). Conclusions. High baseline serum sLOX-1 concentration predicts 2-year MACCEs and shows an additional prognostic value to conventional risk factors in patients after primary PCI. sLOX-1 determination might play a complementary role in the risk stratification of patients with CAD treated with PCI.
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Hao, Fangfang, Jinliang Chen, Jinnan Wu, Xin Ge, Xuedong Lv, Dongmei Zhang, and Jianrong Chen. "Expression of Serum sLOX-1 in Patients with Non-Small-Cell Lung Cancer and Its Correlation with Lipid Metabolism." Canadian Respiratory Journal 2022 (April 11, 2022): 1–9. http://dx.doi.org/10.1155/2022/6619331.
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Objective. The aim of this study was to investigate the expression level of soluble LOX-1 (sLOX-1) in the serum of non-small-cell lung cancer (NSCLC) patients and its correlation with lipid metabolism. Methods. 99 inpatients with NSCLC and 81 healthy controls were enrolled in this study. The levels of serum sLOX-1 were compared between the two groups, and the correlation of sLOX-1 with clinicopathological characteristics, blood lipid indices, and carcinoembryonic antigen was analyzed. Results. Compared with the healthy controls, sLOX-1, low-density lipoprotein, triglyceride, and carcinoembryonic antigen in the patients with NSCLC were significantly higher ( p < 0.05), while the expression level of high-density lipoprotein was lower ( p < 0.05). The expression level of sLOX-1 in the serum of patients with healthy controls was positively correlated with low-density lipoprotein (r = 0.72, p < 0.05). The levels of sLOX-1 and low-density lipoprotein in the serum of patients with NSCLC were closely related to the lymph node metastasis, distant metastasis, and TNM stage ( p < 0.05). Compared with a single index, when the sLOX-1 was combined with the CEA, its specificity increased significantly to 97.5% (AUC = 0.995, p < 0.01, 95% CI: 0.989–1.000). Conclusion. sLOX-1 and low-density lipoprotein were overexpressed in the serum of patients with NSCLC, positively correlated, and closely related to the TNM stage and metastasis. This result suggested that lipid metabolic disorders may promote the progression of NSCLC through sLOX-1, which could be a potential serological marker with diagnostic value for NSCLC.
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Li, Bo, Li-hua Zhang, Xin-guo Yang, Xiong-tao Liu, and Yin-gang Ren. "Serum sLOX-1 levels are associated with the presence and severity of angiographic coronary artery disease in patients with metabolic syndrome." Clinical & Investigative Medicine 33, no. 6 (December 1, 2010): 398. http://dx.doi.org/10.25011/cim.v33i6.14591.
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Purpose: Patients with metabolic syndrome are at high-risk for development of atherosclerosis and cardiovascular events. Serum soluble lectin-like oxidized low-density lipoprotein receptor-1(sLOX-1) is associated with coronary artery disease (CAD) and metabolic disorders. We sought to assess whether serum sLOX-1 levels are correlated with the presence and severity of CAD in patients with metabolic syndrome (MetS) undergoing coronary angiography. Methods: Serum sLOX-1 levels were measured in 112 consecutive patients with MetS, undergoing coronary angiography for the evaluation of CAD. The severity of CAD was assessed by angiographic Gensini score system. Results: Serum sLOX-1 levels were significantly higher in MetS patients with CAD (n=69) than in those without CAD (n=43) (0.925 [range 0.137 to 1.432] ng/ml vs. 0.207 [range 0.063 to 0.774] ng/ml, P < 0.01). Multivariate logistic regression analysis revealed that serum sLOX-1 level was independently associated with the presence of CAD (odds ratio 2.489, 95% confidence interval 1.290-4.802; P < 0.01). Serum sLOX-1 levels were positively correlated with the Gensini score (ρ: 0.394, P < 0.01) after adjusting for other clinical characteristics. Conclusions: High sLOX-1 levels are associated with the presence and severity of CAD in patients with MetS. The measurement of serum sLOX-1may be potentially useful in predicting the presence and severity of CAD in patients with MetS.
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Coulon, Stéphane, Pierre-Henri L. Gaillard, Charly Chahwan, William Hayes McDonald, John R. Yates, and Paul Russell. "Slx1-Slx4 Are Subunits of a Structure-specific Endonuclease That Maintains Ribosomal DNA in Fission Yeast." Molecular Biology of the Cell 15, no. 1 (January 2004): 71–80. http://dx.doi.org/10.1091/mbc.e03-08-0586.
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In most eukaryotes, genes encoding ribosomal RNAs (rDNA) are clustered in long tandem head-to-tail repeats. Studies of Saccharomyces cerevisiae have indicated that rDNA copy number is maintained through recombination events associated with site-specific blockage of replication forks (RFs). Here, we describe two Schizosaccharomyces pombe proteins, homologs of S. cerevisiae Slx1 and Slx4, as subunits of a novel type of endonuclease that maintains rDNA copy number. The Slx1-Slx4–dependent endonuclease introduces single-strand cuts in duplex DNA on the 3′ side of junctions with single-strand DNA. Deletion of Slx1 or Rqh1 RecQ-like DNA helicase provokes rDNA contraction, whereas simultaneous elimination of Slx1-Slx4 endonuclease and Rqh1 is lethal. Slx1 associates with chromatin at two foci characteristic of the two rDNA repeat loci in S. pombe. We propose a model in which the Slx1–Slx4 complex is involved in the control of the expansion and contraction of the rDNA loci by initiating recombination events at stalled RFs.
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Ali Sheikh, Md Sayed. "Plasma soluble lectin-like oxidized low-density lipoprotein receptor-1 acts as a new biomarker for NSTEMI and STEMI patients." African Health Sciences 22, no. 3 (October 28, 2022): 349–58. http://dx.doi.org/10.4314/ahs.v22i3.37.
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Objective: The diagnostic significance of plasma soluble lectin-like oxidized low-density lipoprotein receptor-1(sLOX-1) for non-ST segment elevated myocardial infarction (NSTEMI) and ST segment elevated myocardial infarction (STEMI) were explored by this study.
Methods: In this study, 107 acute NSTEMI, 223 acute STEMI and 107 healthy subjects, and hypoxic (1%02) ventricular cardiomyocytes H9c2 were used.
Results: The significantly up-regulated plasma sLOX-1 levels in acute NSTEMI and STEMI patients compared to healthy subjects (p<0.001). Both male and female NSTEMI and STEMI groups had remarkably higher concentrations of plasma sLOX-1 levels than controls (p<0.001). The circulating levels of sLOX-1 expression obviously elevated in elderly aging (60-75 years) than younger aging (30-45 years) both male and female in healthy subjects as well as NSTEMI and STEMI (p<0.001). Altered levels of sLOX-1 in blood plasma revealed a significant discrimination with high sensitivity and specificity between healthy with NSTEMI and STEMI subjects with AUC= 0.916 and AUC= 0.925 respectively. Moreover, LOX-1 levls were highly released from 6hour, 12hour and 18hour hypoxic injured H9c2 cells than normoxic cell (p<0.001),reflected circulating plasma sLOX-1 in AMI patients.
Conclusion: Elevated levels of plasma sLOX-1concentrations might be used as a clinical biomarker for early recognition of NSTEMI and STEMI patients. Multicenter larger scale studies are necessary before use in clinical practice.
Keywords: Myocardial infarction; sLOX-1; biomarker; H9c2 cells.
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Balin, Mehmet, Ahmet Çelik, M. Ali Kobat, and Adil Baydas. "Pregnancy Followed by Delivery May Affect Circulating Soluble Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Levels in Women of Reproductive Age." Mediators of Inflammation 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/837375.
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Background/Objective. It is known that menopause or lack of endogenous estrogen is a risk factor for endothelial dysfunction and CAD. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is involved inmultiple phases of vascular dysfunction.The purpose of the current study was to determine the association between soluble LOX-1 (sLOX-1) and pregnancy followed by delivery in women of reproductive age.Materials/Methods. Sixty-eight subjects with pregnancy followed by delivery (group 1) and 57 subjects with nongravidity (group 2) were included in this study. Levels of sLOX-1 were measured in serum by EL SA.Results. Plasma levels of sLOX-1 were significantly lower in Group 1 than Group 2 in women of reproductive age ( ng/mL and , resp., ). There were strong correlations between sLOX-1 levels and the number of gravida (, ). The levels of sLOX-1 highly correlated with the number of parous (, ).Conclusion. Our study demonstrated that serum sLOX-1 levels were associated with pregnancy followed by delivery that might predict endothelial dysfunction. We conclude that pregnancy followed by delivery may delay the beginning and progress of arteriosclerosis and its clinical manifestations in women of reproductive age.
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Xu, Xiang, Mingzhu Wang, Jixue Sun, Zhenyu Yu, Guohong Li, Na Yang, and Rui-Ming Xu. "Structure specific DNA recognition by the SLX1–SLX4 endonuclease complex." Nucleic Acids Research 49, no. 13 (June 28, 2021): 7740–52. http://dx.doi.org/10.1093/nar/gkab542.
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Abstract The SLX1–SLX4 structure-specific endonuclease complex is involved in processing diverse DNA damage intermediates, including resolution of Holliday junctions, collapse of stalled replication forks and removal of DNA flaps. The nuclease subunit SLX1 is inactive on its own, but become activated upon binding to SLX4 via its conserved C-terminal domain (CCD). Yet, how the SLX1–SLX4 complex recognizes specific DNA structure and chooses cleavage sites remains unknown. Here we show, through a combination of structural, biochemical and computational analyses, that the SAP domain of SLX4 is critical for efficient and accurate processing of 5′-flap DNA. It binds the minor groove of DNA about one turn away from the flap junction, and the 5′-flap is implicated in binding the core domain of SLX1. This binding mode accounts for specific recognition of 5′-flap DNA and specification of cleavage site by the SLX1–SLX4 complex.
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Kumar, Sandeep, Wahid Ali, Sridhar Mishra, Akshyaya Pradhan, Rishi Sethi, Rashmi Kushwaha, Uma Shankar Singh, and Marco Alfonso Perrone. "Circulating Soluble Lectin-like Oxidized Low-Density Lipoprotein Receptor-1 (sLOX-1): A Diagnostic Indicator across the Spectrum of Acute Coronary Syndrome." Journal of Clinical Medicine 10, no. 23 (November 26, 2021): 5567. http://dx.doi.org/10.3390/jcm10235567.
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Background: Cardiac troponin is the best marker to diagnose acute coronary syndrome (ACS). However, early diagnosis using markers for plaque instability may be of significance. Soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) plays an important role in the pathogenesis of atherosclerosis plaque rupture and may be a potential biomarker of coronary artery disease (CAD), including ACS. The current study aims to evaluate sLOX-1 levels in the sera of patients with ACS as an independent marker of CAD with other established diagnostic markers and assess its level before and after percutaneous intervention (PCI) in predicting the risk of future recurrence of ACS. Methods: Peripheral blood was obtained from a total of 160 patients, including patients who underwent coronary angiography (n = 18, group I), patients of stable CAD who underwent percutaneous intervention (n = 50, group II), patients of the acute coronary syndrome (n = 64, group III), and healthy controls (n = 28, group IV). A serum sLOX-1 concentration was measured by the enzyme-linked immunosorbent assay (ELISA). Results: The results obtained showed a statistically significant raised level of sLOX-1 in pre/post PCI patients of stable CAD/ACS with male preponderance. The area under the curve for sLOX-1 was 0.925 for cases that are discriminated from controls with sensitivity and specificity of 87.88 and 100%, respectively. SLOX-1 showed 100% sensitivity and specificity in the discrimination of the stable CAD that underwent PCI vs. control with an AUC of 1.00. The recurrence of coronary artery disease was observed in 9 out of 132 (6.8%) cases. The post-interventional sLOX-1 level was significantly different and higher in recurrent cases (p = 0.027) of ACS/CAD. Conclusions: sLOX-1 was a useful biomarker of stable CAD/ACS and has a potential in the risk prediction of a future recurrence of coronary artery disease.
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Gaur, Vineet, Weronika Ziajko, Shivlee Nirwal, Aleksandra Szlachcic, Marta Gapińska, and Marcin Nowotny. "Recognition and processing of branched DNA substrates by Slx1–Slx4 nuclease." Nucleic Acids Research 47, no. 22 (October 4, 2019): 11681–90. http://dx.doi.org/10.1093/nar/gkz842.
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Abstract Structure-selective endonucleases cleave branched DNA substrates. Slx1 is unique among structure-selective nucleases because it can cleave all branched DNA structures at multiple sites near the branch point. The mechanism behind this broad range of activity is unknown. The present study structurally and biochemically investigated fungal Slx1 to define a new protein interface that binds the non-cleaved arm of branched DNAs. The DNA arm bound at this new site was positioned at a sharp angle relative to the arm that was modeled to interact with the active site, implying that Slx1 uses DNA bending to localize the branch point as a flexible discontinuity in DNA. DNA binding at the new interface promoted a disorder-order transition in a region of the protein that was located in the vicinity of the active site, potentially participating in its formation. This appears to be a safety mechanism that ensures that DNA cleavage occurs only when the new interface is occupied by the non-cleaved DNA arm. Models of Slx1 that interacted with various branched DNA substrates were prepared. These models explain the way in which Slx1 cuts DNA toward the 3′ end away from the branch point and elucidate the unique ability of Slx1 to cleave various DNA structures.
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Alioua, Abderrahmane, Rong Lu, Yogesh Kumar, Mansoureh Eghbali, Pallob Kundu, Ligia Toro, and Enrico Stefani. "Slo1 Caveolin-binding Motif, a Mechanism of Caveolin-1-Slo1 Interaction Regulating Slo1 Surface Expression." Journal of Biological Chemistry 283, no. 8 (December 12, 2007): 4808–17. http://dx.doi.org/10.1074/jbc.m709802200.
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Stankova, Teodora R., Ginka T. Delcheva, Ana I. Maneva, and Stefka V. Vladeva. "Serum Levels of Carbamylated LDL, Nitrotyrosine and Soluble Lectin-like Oxidized Low-density Lipoprotein Receptor-1 in Poorly Controlled Type 2 Diabetes Mellitus." Folia Medica 61, no. 3 (September 30, 2019): 419–25. http://dx.doi.org/10.3897/folmed.61.e39343.
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Introduction: Carbamylated low-density lipoprotein (cLDL) has profound proatherogenic properties. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) has been identified as the primary cLDL receptor. The soluble form of LOX-1 (sLOX-1) and 3-nitrotyrosine (NT) have recently been suggested as biomarkers of vascular disease. Although type 2 diabetes mellitus (T2DM) is characterised by an increased atherosclerotic risk, the clinical data on cLDL, NT and sLOX-1 levels in T2DM are limited. Aim: To explore the possible role of cLDL, NT and sLOX-1 as potential biomarkers for disease progression and complications in poorly controlled T2DM patients with and without microalbuminuria. Materials and methods: The serum concentrations of cLDL, NT and sLOX-1 were measured by ELISA in a cross-sectional study of 60 T2DM patients and 35 nondiabetic controls.Results: Both the normoalbuminuric (n = 34) and the microalbuminuric (n = 26) patients had significantly higher serum levels of cLDL and NT than the healthy controls, but sLOX-1 was only elevated in the microalbuminuric subgroup (p < 0.05). Carbamylated LDL correlated positively with NT in the diabetic subjects (rs = 0.266, p = 0.04) while it correlated with urea only in the control group (rs = 0.475, p = 0.004). The serum concentration of sLOX-1 correlated significantly with fasting glucose (rs = 0.441, p < 0.001), HbA1c (rs = 0.328, p = 0.01) and microalbuminuria (rs = 0.272, p = 0.035) in the whole diabetic cohort. Conclusions: The present study highlights the potential of cLDL, NT and sLOX-1 as possible markers of diabetic complications.
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Kim, Eun Young, Yu-Hsin Chiu, and Stuart E. Dryer. "Neph1 regulates steady-state surface expression of Slo1 Ca2+-activated K+ channels: different effects in embryonic neurons and podocytes." American Journal of Physiology-Cell Physiology 297, no. 6 (December 2009): C1379—C1388. http://dx.doi.org/10.1152/ajpcell.00354.2009.
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Large-conductance Ca2+-activated K+ (BKCa) channels encoded by the Slo1 gene are often components of large multiprotein complexes in excitable and nonexcitable cells. Here we show that Slo1 proteins interact with Neph1, a member of the immunoglobulin superfamily expressed in slit diaphragm domains of podocytes and in vertebrate and invertebrate nervous systems. This interaction was established by reciprocal coimmunoprecipitation of endogenous proteins from differentiated cells of a podocyte cell line, from parasympathetic neurons of the embryonic chick ciliary ganglion, and from HEK293T cells heterologously expressing both proteins. Neph1 can interact with all three extreme COOH-terminal variants of Slo1 (Slo1VEDEC, Slo1QEERL, and Slo1EMVYR) as ascertained by glutathione S-transferase (GST) pull-down assays and by coimmunoprecipitation. Neph1 is partially colocalized in intracellular compartments with endogenous Slo1 in podocytes and ciliary ganglion neurons. Coexpression in HEK293T cells of Neph1 with any of the Slo1 extreme COOH-terminal splice variants suppresses their steady-state expression on the cell surface, as assessed by cell surface biotinylation assays, confocal microscopy, and whole cell recordings. Consistent with this, small interfering RNA (siRNA) knockdown of endogenous Neph1 in embryonic day 10 ciliary ganglion neurons causes an increase in steady-state surface expression of Slo1 and an increase in whole cell Ca2+-dependent K+ current. Surprisingly, a comparable Neph1 knockdown in podocytes causes a decrease in surface expression of Slo1 and a decrease in whole cell BKCa currents. In podocytes, Neph1 siRNA also caused a decrease in nephrin, even though the Neph1 siRNA had no sequence homology with nephrin. However, we could not detect nephrin in ciliary ganglion neurons.
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Sagar, Divya, Ranjitha Gaddipati, Emily Ongstad, Saifur Rahman, Mehdi Belkhodja, Nicholas Bhagroo, Ling-Ling An, et al. "Soluble LOX-1: A Potential biomarker for SLE and Cardiovascular Comorbidity." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 45.1. http://dx.doi.org/10.4049/jimmunol.200.supp.45.1.
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Abstract Cardiovascular disease is the leading cause of mortality among systemic lupus erythematosus (SLE) patients. LOX-1 is a scavenger receptor strongly implicated in plaque formation, progression and destabilization. It gets upregulated during vascular inflammation on endothelial cells, monocytes, macrophages, smooth muscle cells and platelets. Soluble LOX-1 (sLOX-1) can serve as a potential biomarker for identifying SLE patients with increased cardiovascular risk. In a 120 SLE patient cohort, circulating sLOX-1 levels were 2-fold higher compared to healthy controls, particularly in those14–40 years of age. Patients with high sLOX-1 had elevated proinflammatory HDL, oxLDL, CRP and SAA levels; known markers for vascular injury. High sLOX-1 patient HDL had higher cholesterol content and lower efflux capacity compared to healthy and low sLOX-1 HDL. Both patient derived monocytes and low-density granulocytes (LDGs) express significant levels of membrane LOX-1 compared to controls. Monocytes when conditioned with oxLDL and stimulated with immune complexes, release significant levels of sLOX-1 and cytokines through the LOX-1 receptor. SLE HDL failed to nuclear colocalize the inflammation resolution factor ATF3, in monocyte derived macrophages. Additionally, patient LDGs underwent rapid NETosis in the presence of immune complexes when primed with oxLDL, through the LOX-1 receptor. Disease modified lipoproteins in SLE function as LOX-1 ligand contributing to inflammatory immune activation adding to cardiovascular risk. Hence, sLOX-1 can be predictive of increased cardiovascular risk and LOX-1 receptor blockade may be a promising target for ameliorating cardiovascular damage in SLE.
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Pirillo, Angela, and Alberico Luigi Catapano. "Soluble Lectin-Like Oxidized Low Density Lipoprotein Receptor-1 as a Biochemical Marker for Atherosclerosis-Related Diseases." Disease Markers 35 (2013): 413–18. http://dx.doi.org/10.1155/2013/716325.
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Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1), the main oxidized low-density lipoprotein (OxLDL) in endothelial cells, is upregulated in atherosclerotic lesions and is involved in several cellular processes that regulate the pathogenesis of atherosclerosis. The LOX-1 expressed on the cell surface can be proteolytically cleaved and released in a soluble form (sLOX-1) in the circulation under pathological conditions. Serum levels of sLOX-1, in fact, are elevated at the early stages of acute coronary syndrome and are associated with coronary plaque vulnerability and with the presence of multiple complex coronary lesions. Moreover, in subjects with stable CAD, levels of serum sLOX-1 are associated with the presence of lesions in the proximal and mid-segments of the left anterior descending artery that are the most prone to rupture; in subjects undergoing percutaneous coronary intervention, baseline preprocedural serum sLOX-1 levels are associated with the incidence of periprocedural myocardial infarction. Altogether, these findings suggest that circulating levels of sLOX-1 might be a diagnostic and prognostic marker for atherosclerotic-related events.
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Coulon, Stéphane, Eishi Noguchi, Chiaki Noguchi, Li-Lin Du, Toru M. Nakamura, and Paul Russell. "Rad22Rad52-dependent Repair of Ribosomal DNA Repeats Cleaved by Slx1-Slx4 Endonuclease." Molecular Biology of the Cell 17, no. 4 (April 2006): 2081–90. http://dx.doi.org/10.1091/mbc.e05-11-1006.
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Slx1 and Slx4 are subunits of a structure-specific DNA endonuclease that is found in Saccharomyces cerevisiae, Schizosaccharomyces pombe, and other eukaryotic species. It is thought to initiate recombination events or process recombination structures that occur during the replication of the tandem repeats of the ribosomal DNA (rDNA) locus. Here, we present evidence that fission yeast Slx1-Slx4 initiates homologous recombination events in the rDNA repeats that are processed by a mechanism that requires Rad22 (Rad52 homologue) but not Rhp51 (Rad51 homologue). Slx1 is required to generate ∼50% of the spontaneous Rad22 DNA repair foci that occur in cycling cells. Most of these foci colocalize with the nucleolus, which contains the rDNA repeats. The increased fork pausing at the replication fork barriers in the rDNA repeats in a strain that lacks Rqh1 DNA helicase is further increased by expression of a dominant negative form of Slx1. These data suggest that Slx1-Slx4 cleaves paused replication forks in the rDNA, leading to Rad22-dependent homologous recombination that is used to maintain rDNA copy number.
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Stankova, Delcheva, Maneva, and Vladeva. "Serum Levels of Carbamylated LDL and Soluble Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 are Associated with Coronary Artery Disease in Patients with Metabolic Syndrome." Medicina 55, no. 8 (August 15, 2019): 493. http://dx.doi.org/10.3390/medicina55080493.
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Background and objectives: Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) has been recognized as the primary receptor for carbamylated low-density lipoproteins (cLDL) and is increasingly being viewed as a critical mediator of vascular inflammation and atherosclerosis. The aim of the current study was to evaluate the possible role of circulating cLDL and soluble LOX-1 (sLOX-1) as potential biomarkers of metabolic syndrome (MetS) as well as of coronary artery disease (CAD) among MetS patients. Materials and Methods: The serum levels of cLDL and sLOX-1 were measured by ELISA in 30 MetS patients without CAD, 30 MetS patients with CAD, and 30 healthy controls. Results: Patients with MetS had significantly higher serum levels of both cLDL and sLOX-1 than the healthy controls but lower in comparison to MetS + CAD subjects. Serum sLOX-1 concentration correlated significantly with fasting glucose (rs = 0.414, p = 0.001) and high-density lipoprotein (HDL)-cholesterol (rs = −0.273, p = 0.035) in the whole MetS cohort, whereas it correlated with cLDL only in the MetS + CAD subgroup (rs = 0.396, p = 0.030). The receiver-operating characteristic (ROC) curves of cLDL and sLOX-1 for MetS diagnosis had area under the curve (AUC) values of 0.761 and 0.692, respectively. AUC values of cLDL and sLOX-1 for CAD diagnosis among MetS patients were 0.811 and 0.739. Elevated serum levels of cLDL and sLOX-1 were associated with a higher risk of MetS development [odds ratio (OR) 24.28, 95% confidence interval (CI): 5.86–104.61, p < 0.001 and OR 4.75; 95% CI: 1.58–14.25, p = 0.009] as well as with presence of CAD among MetS subjects (OR 11.23; 95% CI: 3.10–40.71, p < 0.001 and OR 4.03; 95% CI: 1.73–11.84, p = 0.019, respectively). Conclusions: The present study underscores the potential of cLDL and sLOX-1 as promising biomarkers for diagnosis and risk assessment of MetS and CAD among the MetS population.
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Roberts, Tania M., Michael S. Kobor, Suzanne A. Bastin-Shanower, Miki Ii, Sonja A. Horte, Jennifer W. Gin, Andrew Emili, Jasper Rine, Steven J. Brill, and Grant W. Brown. "Slx4 Regulates DNA Damage Checkpoint-dependent Phosphorylation of the BRCT Domain Protein Rtt107/Esc4." Molecular Biology of the Cell 17, no. 1 (January 2006): 539–48. http://dx.doi.org/10.1091/mbc.e05-08-0785.
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RTT107 (ESC4, YHR154W) encodes a BRCA1 C-terminal-domain protein that is important for recovery from DNA damage during S phase. Rtt107 is a substrate of the checkpoint protein kinase Mec1, although the mechanism by which Rtt107 is targeted by Mec1 after checkpoint activation is currently unclear. Slx4, a component of the Slx1-Slx4 structure-specific nuclease, formed a complex with Rtt107. Deletion of SLX4 conferred many of the same DNA-repair defects observed in rtt107Δ, including DNA damage sensitivity, prolonged DNA damage checkpoint activation, and increased spontaneous DNA damage. These phenotypes were not shared by the Slx4 binding partner Slx1, suggesting that the functions of the Slx4 and Slx1 proteins in the DNA damage response were not identical. Of particular interest, Slx4, but not Slx1, was required for phosphorylation of Rtt107 by Mec1 in vivo, indicating that Slx4 was a mediator of DNA damage-dependent phosphorylation of the checkpoint effector Rtt107. We propose that Slx4 has roles in the DNA damage response that are distinct from the function of Slx1-Slx4 in maintaining rDNA structure and that Slx4-dependent phosphorylation of Rtt107 by Mec1 is critical for replication restart after alkylation damage.
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Kim, Eun Young, Kyoung-Jae Choi, and Stuart E. Dryer. "Nephrin binds to the COOH terminus of a large-conductance Ca2+-activated K+ channel isoform and regulates its expression on the cell surface." American Journal of Physiology-Renal Physiology 295, no. 1 (July 2008): F235—F246. http://dx.doi.org/10.1152/ajprenal.00140.2008.
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We carried out a yeast two-hybrid screen to identify proteins that interact with large-conductance Ca2+-activated K+ (BKCa) channels encoded by the Slo1 gene. Nephrin, an essential adhesion and scaffolding molecule expressed in podocytes, emerged in this screen. The Slo1-nephrin interaction was confirmed by coimmunoprecipitation from the brain and kidney, from HEK-293T cells expressing both proteins, and by glutathione S-transferase pull-down assays. We detected nephrin binding to the Slo1VEDEC splice variant, which is typically retained in intracellular stores, and to the β4-subunit. However, we did not detect significant binding of nephrin to the Slo1QEERL or Slo1EMVYR splice variants. Coexpression of nephrin with Slo1VEDEC increased expression of functional BKCa channels on the surface of HEK-293T cells but did not affect steady-state surface expression of the other COOH-terminal Slo1 variants. Nephrin did not affect the kinetics or voltage dependence of channel activation in HEK-293T cells expressing Slo1. Stimulation of Slo1VEDEC surface expression in HEK-293T cells was also observed by coexpressing a small construct encoding only the distal COOH-terminal domains of nephrin that interact with Slo1. Reduction of endogenous nephrin expression by application of small interfering RNA to differentiated cells of an immortalized podocyte cell line markedly reduced the steady-state surface expression of Slo1 as assessed by electrophysiology and cell-surface biotinylation assays. Nephrin therefore plays a role in organizing the surface expression of ion channel proteins in podocytes and may play a role in outside-in signaling to allow podocytes to adapt to mechanical or neurohumoral stimuli originating in neighboring cells.
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Ridgway, Lon D., Eun Young Kim, and Stuart E. Dryer. "MAGI-1 interacts with Slo1 channel proteins and suppresses Slo1 expression on the cell surface." American Journal of Physiology-Cell Physiology 297, no. 1 (July 2009): C55—C65. http://dx.doi.org/10.1152/ajpcell.00073.2009.
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Large conductance Ca2+-activated K+ (BKCa) channels encoded by the Slo1 gene (also known as KCNMA1) are physiologically important in a wide range of cell types and form complexes with a number of other proteins that affect their function. We performed a yeast two-hybrid screen to identify proteins that interact with BKCa channels using a bait construct derived from domains in the extreme COOH-terminus of Slo1. A protein known as membrane-associated guanylate kinase with inverted orientation protein-1 (MAGI-1) was identified in this screen. MAGI-1 is a scaffolding protein that allows formation of complexes between certain transmembrane proteins, actin-binding proteins, and other regulatory proteins. MAGI-1 is expressed in a number of tissues, including podocytes and the brain. The interaction between MAGI-1 and BKCa channels was confirmed by coimmunoprecipitation and glutathione S-transferase pull-down assays in differentiated cells of a podocyte cell line and in human embryonic kidneys (HEK)293T cells transiently coexpressing MAGI-1a and three different COOH-terminal Slo1 variants. Coexpression of MAGI-1 with Slo1 channels in HEK-293T cells results in a significant reduction in the surface expression of Slo1, as assessed by cell-surface biotinylation assays, confocal microscopy, and whole cell recordings. Partial knockdown of endogenous MAGI-1 expression by small interfering RNA (siRNA) in differentiated podocytes increased the surface expression of endogenous Slo1 as assessed by electrophysiology and cell-surface biotinylation assays, whereas overexpression of MAGI-1a reduced steady-state voltage-evoked outward current through podocyte BKCa channels. These data suggest that MAGI-1 plays a role in regulation of surface expression of BKCa channels in the kidney and possibly in other tissues.
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Ren, Kaixuan, Huayun Jiang, Tiantian Li, Chengqun Qian, Li Zhu, and Tianle Wang. "Correlation of sLOX-1 Levels and MR Characteristics of Culprit Plaques in Intracranial Arteries with Stroke Recurrence." Diagnostics 13, no. 4 (February 20, 2023): 804. http://dx.doi.org/10.3390/diagnostics13040804.
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(1) Background: Symptomatic intracranial artery atherosclerosis (sICAS) is an important cause of acute ischaemic stroke (AIS) and is associated with a high risk of stroke recurrence. High-resolution magnetic resonance vessel wall imaging (HR-MR-VWI) is an effective method for evaluating atherosclerotic plaque characteristics. Soluble lectin-like oxidised low-density lipoprotein receptor-1 (sLOX-1) is closely associated with plaque formation and rupture. We aim to explore the correlation between sLOX-1 levels and culprit plaque characteristics, based on HR-MR-VWI, with stroke recurrence in patients with sICAS. (2) Methods: A total of 199 patients with sICAS underwent HR-MR-VWI between June 2020 and June 2021 in our hospital. The culprit vessel and plaque characteristics were assessed according to HR-MR-VWI, and sLOX-1 levels were measured by ELISA (enzyme linked immunosorbent assay). Outpatient follow-up was performed 3, 6, 9, and 12 months after discharge. (3) Results: sLOX-1 levels were significantly higher in the recurrence group than in the non-recurrence group (p < 0.001). The culprit plaque thickness, degree of stenosis and plaque burden were higher in the recurrence group than in the non-recurrence group (p = 0.003, p = 0.014 and p = 0.010, respectively). The incidence of hyperintensity on T1WI, positive remodelling and significant enhancement (p < 0.001, p = 0.003 and p = 0.027, respectively) was higher in the recurrence group than in the non-recurrence group. Kaplan–Meier curves showed that patients with sLOX-1 levels > 912.19 pg/mL and hyperintensity on T1WI in the culprit plaque had a higher risk of stroke recurrence (both p < 0.001). Multivariate Cox regression analysis showed that sLOX-1 > 912.19 pg/mL (HR = 2.583, 95%CI 1.142, 5.846, p = 0.023) and hyperintensity on T1WI in the culprit plaque (HR = 2.632, 95% CI 1.197, 5.790, p = 0.016) were independent risk factors for stroke recurrence. sLOX-1 levels were significantly associated with the culprit plaque thickness (r = 0.162, p = 0.022), degree of stenosis (r = 0.217, p = 0.002), plaque burden (r = 0.183, p = 0.010), hyperintensity on T1WI (F = 14.501, p < 0.001), positive remodelling (F = 9.602, p < 0.001), and significant enhancement (F = 7.684, p < 0.001) (4) Conclusions: sLOX-1 levels were associated with vulnerability of the culprit plaque and can be used as a supplement to HR-MR-VWI to predict stroke recurrence.
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Qian, Xiang, Crina M. Nimigean, Xiaowei Niu, Brenda L. Moss, and Karl L. Magleby. "Slo1 Tail Domains, but Not the Ca2+ Bowl, Are Required for the β1 Subunit to Increase the Apparent Ca2+ Sensitivity of BK Channels." Journal of General Physiology 120, no. 6 (November 25, 2002): 829–43. http://dx.doi.org/10.1085/jgp.20028692.
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Functional large-conductance Ca2+- and voltage-activated K+ (BK) channels can be assembled from four α subunits (Slo1) alone, or together with four auxiliary β1 subunits to greatly increase the apparent Ca2+ sensitivity of the channel. We examined the structural features involved in this modulation with two types of experiments. In the first, the tail domain of the α subunit, which includes the RCK2 (regulator of K+ conductance) domain and Ca2+ bowl, was replaced with the tail domain of Slo3, a BK-related channel that lacks both a Ca2+ bowl and high affinity Ca2+ sensitivity. In the second, the Ca2+ bowl was disrupted by mutations that greatly reduce the apparent Ca2+ sensitivity. We found that the β1 subunit increased the apparent Ca2+ sensitivity of Slo1 channels, independently of whether the α subunits were expressed as separate cores (S0-S8) and tails (S9-S10) or full length, and this increase was still observed after the Ca2+ bowl was mutated. In contrast, β1 subunits no longer increased Ca2+ sensitivity when Slo1 tails were replaced by Slo3 tails. The β1 subunits were still functionally coupled to channels with Slo3 tails, as DHS-I and 17 β-estradiol activated these channels in the presence of β1 subunits, but not in their absence. These findings indicate that the increase in apparent Ca2+ sensitivity induced by the β1 subunit does not require either the Ca2+ bowl or the linker between the RCK1 and RCK2 domains, and that Slo3 tails cannot substitute for Slo1 tails. The β1 subunit also induced a decrease in voltage sensitivity that occurred with either Slo1 or Slo3 tails. In contrast, the β1 subunit–induced increase in apparent Ca2+ sensitivity required Slo1 tails. This suggests that the allosteric activation pathways for these two types of actions of the β1 subunit may be different.
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Hou, Shangwei, Rong Xu, Joseph F. Clark, William L. Wurster, Stefan H. Heinemann, and Toshinori Hoshi. "Bilirubin Oxidation End Products Directly Alter K+ Channels Important in the Regulation of Vascular Tone." Journal of Cerebral Blood Flow & Metabolism 31, no. 1 (April 28, 2010): 102–12. http://dx.doi.org/10.1038/jcbfm.2010.54.
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The exact etiology of delayed cerebral vasospasm following cerebral hemorrhage is not clear, but a family of compounds termed ‘bilirubin oxidation end products (BOXes)’ derived from heme has been implicated. As proper regulation of vascular smooth muscle tone involves large-conductance Ca2+- and voltage-dependent Slo1 K+ (BK, maxiK, KCa1.1) channels, we examined whether BOXes altered functional properties of the channel. Electrophysiological measurements of Slo1 channels heterologously expressed in a human cell line and of native mouse BK channels in isolated cerebral myocytes showed that BOXes markedly diminished open probability. Biophysically, BOXes specifically stabilized the conformations of the channel with its ion conduction gate closed. The results of chemical amino-acid modifications and molecular mutagenesis together suggest that two specific lysine residues in the structural element linking the transmembrane ion-permeation domain to the carboxyl cytosolic domain of the Slo1 channel are critical in determining the sensitivity of the channel to BOXes. Inhibition of Slo1 BK channels by BOXes may contribute to the development of delayed cerebral vasospasm following brain hemorrhage.
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Hoshi, Toshinori, Rong Xu, Shangwei Hou, Stefan H. Heinemann, and Yutao Tian. "A point mutation in the human Slo1 channel that impairs its sensitivity to omega-3 docosahexaenoic acid." Journal of General Physiology 142, no. 5 (October 14, 2013): 507–22. http://dx.doi.org/10.1085/jgp.201311061.
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Long-chain polyunsaturated omega-3 fatty acids such as docosahexaenoic acid (DHA) at nanomolar concentrations reversibly activate human large-conductance Ca2+- and voltage-gated K+ (Slo1 BK) channels containing auxiliary β1 or β4 subunits in cell-free patches. Here we examined the action of DHA on the Slo1 channel without any auxiliary subunit and sought to elucidate the biophysical mechanism and the molecular determinants of the DHA sensitivity. Measurements of ionic currents through human Slo1 (hSlo1) channels reveal that the stimulatory effect of DHA does not require activation of the voltage or Ca2+ sensors. Unlike gating of the hSlo1 channel, that of the Drosophila melanogaster Slo1 (dSlo1) channel is unaltered by DHA. Our mutagenesis study based on the differential responses of human and dSlo1 channels to DHA pinpoints that Y318 near the cytoplasmic end of S6 in the hSlo1 channel is a critical determinant of the stimulatory action of DHA. The mutation Y318S in hSlo1, which replaces Y with S as found in dSlo1, greatly diminishes the channel’s response to DHA with a 22-carbon chain whether β1 or β4 is absent or present. However, the responses to α-linolenic acid, an omegea-3 fatty acid with an 18-carbon chain, and to arachidonic acid, an omega-6 fatty acid with a 20-carbon chain, remain unaffected by the mutation. Y318 in the S6 segment of hSlo1 is thus an important determinant of the electrophysiological response of the channel to DHA. Furthermore, the mutation Y318S may prove to be useful in dissecting out the complex lipid-mediated modulation of Slo1 BK channels.
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Uransilp, Nattaphol, Pannawat Chaiyawatthanananthn, and Sombat Muengtaweepongsa. "Efficacy of High-Dose and Low-Dose Simvastatin on Vascular Oxidative Stress and Neurological Outcomes in Patient with Acute Ischemic Stroke: A Randomized, Double-Blind, Parallel, Controlled Trial." Neurology Research International 2018 (2018): 1–6. http://dx.doi.org/10.1155/2018/7268924.
Full textAbstract:
Backgrounds. Stroke is the leading cause of death and long-term disability. Oxidative stress is elevated during occurrence of acute ischemic stroke (AIS). Soluble LOX-1 (sLOX-1) and NO are used as biomarkers for vascular oxidative stress that can reflect stabilization of atherosclerotic plaque. Previous study showed that simvastatin can reduce oxidative stress and LOX-1 expression. Objectives. To evaluate neurological outcomes and serum sLOX-1 and NO levels in patients with AIS treatment with low dose 10 mg/day and high dose 40 mg/day of simvastatin. Methods. 65 patients with AIS within 24 hours after onset were randomized to treatment with simvastatin 10 mg/day or 40 mg/day for 90 days. Personal data and past history of all patients were recorded at baseline. The blood chemistries were measured by standard laboratory techniques. Serum sLOX-1 and NO levels and neurological outcomes including NIHSS, mRS, and Barthel index were tested at baseline and Day 90 after simvastatin therapy. Results. Baseline characteristics were not significantly different in both groups except history of hypertension. Serum sLOX-1 and NO levels significantly reduce in both groups (sLOX-1 = 1.19±0.47 and 0.98±0.37 ng/ml; NO = 49.28±7.21 and 46.59±9.36 μmol/l) in 10 mg/day and 40 mg/day simvastatin groups, respectively. Neurological outcomes including NIHSS, mRS, and Barthel index significantly improve in both groups. However, no difference in NO level and neurological outcomes was found at 90 days after treatment as compared between low dose 10 mg/day and high dose 40 mg/day of simvastatin. Conclusion. High-dose simvastatin might be helpful to reduce serum sLOX-1. But no difference in clinical outcomes was found between high- and low-dose simvastatin. Further more intensive clinical trial is needed to confirm the appropriate dosage of simvastatin in patients with acute ischemic stroke. This trial is registered with ClinicalTrials.gov ID: NCT03402204.
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Zhang, Xue, Xuhui Zeng, and Christopher J. Lingle. "Slo3 K+ Channels: Voltage and pH Dependence of Macroscopic Currents." Journal of General Physiology 128, no. 3 (August 28, 2006): 317–36. http://dx.doi.org/10.1085/jgp.200609552.
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The mouse Slo3 gene (KCNMA3) encodes a K+ channel that is regulated by changes in cytosolic pH. Like Slo1 subunits responsible for the Ca2+ and voltage-activated BK-type channel, the Slo3 α subunit contains a pore module with homology to voltage-gated K+ channels and also an extensive cytosolic C terminus thought to be responsible for ligand dependence. For the Slo3 K+ channel, increases in cytosolic pH promote channel activation, but very little is known about many fundamental properties of Slo3 currents. Here we define the dependence of macroscopic conductance on voltage and pH and, in particular, examine Slo3 conductance activated at negative potentials. Using this information, the ability of a Horrigan-Aldrich–type of general allosteric model to account for Slo3 gating is examined. Finally, the pH and voltage dependence of Slo3 activation and deactivation kinetics is reported. The results indicate that Slo3 differs from Slo1 in several important ways. The limiting conductance activated at the most positive potentials exhibits a pH-dependent maximum, suggesting differences in the limiting open probability at different pH. Furthermore, over a 600 mV range of voltages (−300 to +300 mV), Slo3 conductance shifts only about two to three orders of magnitude, and the limiting conductance at negative potentials is relatively voltage independent compared to Slo1. Within the context of the Horrigan-Aldrich model, these results indicate that the intrinsic voltage dependence (zL) of the Slo3 closed–open equilibrium and the coupling (D) between voltage sensor movement are less than in Slo1. The kinetic behavior of Slo3 currents also differs markedly from Slo1. Both activation and deactivation are best described by two exponential components, both of which are only weakly voltage dependent. Qualitatively, the properties of the two kinetic components in the activation time course suggest that increases in pH increase the fraction of more rapidly opening channels.
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Yeste, Marc, Marc Llavanera, Guillermo Pérez, Fabiana Scornik, Josep Puig-Parri, Ramon Brugada, Sergi Bonet, and Elisabeth Pinart. "Elucidating the Role of K+ Channels during In Vitro Capacitation of Boar Spermatozoa: Do SLO1 Channels Play a Crucial Role?" International Journal of Molecular Sciences 20, no. 24 (December 15, 2019): 6330. http://dx.doi.org/10.3390/ijms20246330.
Full textAbstract:
This study sought to identify and localize SLO1 channels in boar spermatozoa by immunoblotting and immunofluorescence, and to determine their physiological role during in vitro sperm capacitation. Sperm samples from 14 boars were incubated in a capacitation medium for 300 min in the presence of paxilline (PAX), a specific SLO1-channel blocker, added either at 0 min or after 240 min of incubation. Negative controls were incubated in capacitation medium, and positive controls in capacitation medium plus tetraethyl ammonium (TEA), a general K+-channel blocker, also added at 0 min or after 240 min of incubation. In all samples, acrosome exocytosis was triggered with progesterone after 240 min of incubation. Sperm motility and kinematics, integrity of plasma and acrosome membranes, membrane lipid disorder, intracellular calcium levels and acrosin activity were evaluated after 0, 60, 120, 180, 240, 250, 270 and 300 min of incubation. In boar spermatozoa, SLO1 channels were found to have 80 kDa and be localized in the anterior postacrosomal region and the mid and principal piece of the tail; their specific blockage through PAX resulted in altered calcium levels and acrosome exocytosis. As expected, TEA blocker impaired in vitro sperm capacitation, by altering sperm motility and kinematics and calcium levels. In conclusion, SLO1 channels are crucial for the acrosome exocytosis induced by progesterone in in vitro capacitated boar spermatozoa.
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Flott, Sonja, and John Rouse. "Slx4 becomes phosphorylated after DNA damage in a Mec1/Tel1-dependent manner and is required for repair of DNA alkylation damage." Biochemical Journal 391, no. 2 (October 10, 2005): 325–33. http://dx.doi.org/10.1042/bj20050768.
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Members of the RecQ family of DNA helicases, mutated in several syndromes associated with cancer predisposition, are key regulators of genome stability. The Saccharomyces cerevisiae SLX4 gene is required for cell viability in the absence of Sgs1, the only yeast RecQ helicase. SLX4 encodes one subunit of the heterodimeric Slx1–Slx4 endonuclease, although its cellular function is not clear. Slx1–Slx4 was reported to preferentially cleave replication fork-like structures in vitro, and cells lacking SLX4 are hypersensitive to DNA alkylation damage. Here we report that Slx4 becomes phosphorylated in cells exposed to a wide range of genotoxins. Even though it has been proposed that the role of Slx4 is restricted to S-phase, Slx4 phosphorylation is observed in cells arrested in G1 or G2 phases of the cell cycle, but not during an unperturbed cell cycle. Slx4 phosphorylation is completely abolished in cells lacking the Mec1 and Tel1 protein kinases, critical regulators of genome stability, but is barely affected in the absence of both Rad53 and Chk1 kinases. Finally we show that, whereas both Slx1 and Slx4 are dispensable for activation of cell-cycle checkpoints, Slx4, but not Slx1, is required for repair of DNA alkylation damage in both aynchronously growing cells and in G2-phase-arrested cells. These results reveal Slx4 as a new target of the Mec1/Tel1 kinases, with a crucial role in DNA repair that is not restricted to the processing of stalled replisomes.
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Zheng, Yangmin, Yuyou Huang, Lingzhi Li, Pingping Wang, Rongliang Wang, Zhen Tao, Junfen Fan, et al. "sLOX-1: A Molecule for Evaluating the Prognosis of Recurrent Ischemic Stroke." Neural Plasticity 2021 (August 28, 2021): 1–9. http://dx.doi.org/10.1155/2021/6718184.
Full textAbstract:
Several clinical parameters and biomarkers have been proposed as prognostic markers for stroke. However, it has not been clarified whether the risk factors affecting the prognosis of patients with recurrent and first-ever stroke are similar. In this study, we aimed to explore the relationship between soluble lectin-like oxidized low-density lipoprotein receptor 1 (sLOX-1) levels and the prediction of the functional outcome in patients with recurrent and first-ever stroke. A total of 266 patients with recurrent and first-ever stroke, who underwent follow-up for 3 months, were included in this study. Plasma samples were collected within 24 h after onset. The results showed that biomarkers for the prognosis of patients with recurrent stroke were different from that of those with first-ever stroke. sLOX-1 levels were correlated with modified Rankin Scale scores of patients with recurrent stroke alone ( r = 0.3232 , p = 0.001 ). sLOX-1 levels were also associated with an increased risk of unfavorable outcomes in patients with recurrent stroke with an adjusted odds ratio of 1.489 (95% confidence interval, 1.204–1.842, p < 0.0001 ). Combining the risk factors showed greater accuracy for prognosis, yielding a sensitivity of 93.2% and a specificity of 75%, with an area under the curve of 0.916, evaluated by the receiver operating characteristic curve. These findings suggest that the diagnosis and prognosis are different between patients with recurrent stroke and those with first-ever stroke, and sLOX-1 level is an independent prognostic marker in patients with recurrent stroke.
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Horrigan, Frank T., Stefan H. Heinemann, and Toshinori Hoshi. "Heme Regulates Allosteric Activation of the Slo1 BK Channel." Journal of General Physiology 126, no. 1 (June 13, 2005): 7–21. http://dx.doi.org/10.1085/jgp.200509262.
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Large conductance calcium-dependent (Slo1 BK) channels are allosterically activated by membrane depolarization and divalent cations, and possess a rich modulatory repertoire. Recently, intracellular heme has been identified as a potent regulator of Slo1 BK channels (Tang, X.D., R. Xu, M.F. Reynolds, M.L. Garcia, S.H. Heinemann, and T. Hoshi. 2003. Nature. 425:531–535). Here we investigated the mechanism of the regulatory action of heme on heterologously expressed Slo1 BK channels by separating the influences of voltage and divalent cations. In the absence of divalent cations, heme generally decreased ionic currents by shifting the channel's G–V curve toward more depolarized voltages and by rendering the curve less steep. In contrast, gating currents remained largely unaffected by heme. Simulations suggest that a decrease in the strength of allosteric coupling between the voltage sensor and the activation gate and a concomitant stabilization of the open state account for the essential features of the heme action in the absence of divalent ions. At saturating levels of divalent cations, heme remained similarly effective with its influence on the G–V simulated by weakening the coupling of both Ca2+ binding and voltage sensor activation to channel opening. The results thus show that heme dampens the influence of allosteric activators on the activation gate of the Slo1 BK channel. To account for these effects, we consider the possibility that heme binding alters the structure of the RCK gating ring and thereby disrupts both Ca2+- and voltage-dependent gating as well as intrinsic stability of the open state.
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Zhou, Yu, Huanghe Yang, Jianmin Cui, and Christopher J. Lingle. "Threading the biophysics of mammalian Slo1 channels onto structures of an invertebrate Slo1 channel." Journal of General Physiology 149, no. 11 (October 12, 2017): 985–1007. http://dx.doi.org/10.1085/jgp.201711845.
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For those interested in the machinery of ion channel gating, the Ca2+ and voltage-activated BK K+ channel provides a compelling topic for investigation, by virtue of its dual allosteric regulation by both voltage and intracellular Ca2+ and because its large-single channel conductance facilitates detailed kinetic analysis. Over the years, biophysical analyses have illuminated details of the allosteric regulation of BK channels and revealed insights into the mechanism of BK gating, e.g., inner cavity size and accessibility and voltage sensor-pore coupling. Now the publication of two structures of an Aplysia californica BK channel—one liganded and one metal free—promises to reinvigorate functional studies and interpretation of biophysical results. The new structures confirm some of the previous functional inferences but also suggest new perspectives regarding cooperativity between Ca2+-binding sites and the relationship between voltage- and Ca2+-dependent gating. Here we consider the extent to which the two structures explain previous functional data on pore-domain properties, voltage-sensor motions, and divalent cation binding and activation of the channel.
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Çoner, Ali, Alp Aydınalp, and Haldun Müderrisoğlu. "Evaluation of hs-CRP and sLOX-1 Levels in Moderate-to-High Risk Acute Coronary Syndromes." Endocrine, Metabolic & Immune Disorders - Drug Targets 20, no. 1 (January 7, 2020): 96–103. http://dx.doi.org/10.2174/1871530319666190408145905.
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Objective: Risk stratification and prompt treatment are essential for the management of acute coronary syndromes (ACS) and prediction of future prognosis. Subclinical vascular inflammation and novel biomarkers play an important role in the clinical evaluation of ACS patients. Methods: We enrolled patients who were admitted to emergency service with unstable angina or non- ST segment elevated ACS (NSTE-ACS) in the study population. Coronary artery disease (CAD) complexity was determined via evaluation of angiographical views and peripheral venous blood samples were collected to measure highly sensitive C-reactive protein (hs-CRP) and soluble form of Lectin-like OxLDL receptor-1 (sLOX-1) levels. Results: A total of 40 patients were enrolled in the study population, mean age was 65.1±13.8 years and male gender percentage was 52.5%. Twenty-nine of patients had NSTE-ACS and 11 patients had unstable angina presentation. The modified Gensini scores were higher for patients with elevated hs- CRP and sLOX-1 levels. Conclusion: Vascular inflammation displays the onset of ACS and it is related to more complex CAD in these patients. An increase in sLOX-1 expression is closely related to anatomical complexity of CAD in ACS..
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Zhou, Xiaohong, Maria DeLucia, and Jinwoo Ahn. "SLX4-SLX1 Protein-independent Down-regulation of MUS81-EME1 Protein by HIV-1 Viral Protein R (Vpr)." Journal of Biological Chemistry 291, no. 33 (June 27, 2016): 16936–47. http://dx.doi.org/10.1074/jbc.m116.721183.
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Evolutionarily conserved structure-selective endonuclease MUS81 forms a complex with EME1 and further associates with another endonuclease SLX4-SLX1 to form a four-subunit complex of MUS81-EME1-SLX4-SLX1, coordinating distinctive biochemical activities of both endonucleases in DNA repair. Viral protein R (Vpr), a highly conserved accessory protein in primate lentiviruses, was previously reported to bind SLX4 to mediate down-regulation of MUS81. However, the detailed mechanism underlying MUS81 down-regulation is unclear. Here, we report that HIV-1 Vpr down-regulates both MUS81 and its cofactor EME1 by hijacking the host CRL4-DCAF1 E3 ubiquitin ligase. Multiple Vpr variants, from HIV-1 and SIV, down-regulate both MUS81 and EME1. Furthermore, a C-terminally truncated Vpr mutant and point mutants R80A and Q65R, all of which lack G2 arrest activity, are able to down-regulate MUS81-EME1, suggesting that Vpr-induced G2 arrest is not correlated with MUS81-EME1 down-regulation. We also show that neither the interaction of MUS81-EME1 with Vpr nor their down-regulation is dependent on SLX4-SLX1. Together, these data provide new insight on a conserved function of Vpr in a host endonuclease down-regulation.
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Chen, Mingyi, Xin Lin, Hannah Archibald, Ted Wun, and Ralph Green. "Increased Circulating Soluble Lectin-Like Oxidized Low-Density Lipoprotein Receptor (sLOX-1) and Increased Endothelial Cell Expression of LOX-1 in Sickle Cell Disease (SCD): A Novel Marker for SCD Vasculopathy?" Blood 120, no. 21 (November 16, 2012): 246. http://dx.doi.org/10.1182/blood.v120.21.246.246.
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Abstract Abstract 246 Introduction: Inflammation and abnormal adhesion of sickle red blood cells (RBCs), leukocytes and platelets to the vascular endothelium are postulated to play a central role in the pathogenesis of vaculopathy associated with sickle cell disease (SCD). Dysfunctional endothelial cells in the SCD vaso-occlusive process display vasoconstriction, proinflammatory and prothrombotic changes. Sickle RBCs may damage or activate the endothelium via enhanced expression of cell surface adhesion molecules such as vascular cell adhesion molecule (VCAM), intercellular adhesion molecules (ICAM), platelet endothelial cellular adhesion marker (PECAM), E- selectin, and P-selectin. In addition, SCD modulates high levels of circulating soluble adhesion molecules especially during the sickle cell crisis. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is an endothelial cell receptor for oxidized low-density lipoprotein. The enhanced expression of LOX-1 in endothelial cells has been identified in a variety of pathologic conditions including atherosclerosis, diabetic vasculopathy, hyperlipidemia and inflammation. The purpose of this study is to investigate changes in the expression of LOX-1 and its potential role in the pathogenesis of SCD vasculopathy. Methods: Using real time quantitative PCR, we analyzed LOX-1 gene expression in cultured human coronary endothelial cells (HCEC) following static incubation with sickle RBCs. We also measured circulating soluble LOX-1 (sLOX-1) concentrations by sandwich ELISA assay in SCD patient plasma. The statistical analysis was performed using Student's t-test. Results: LOX-1 gene expression in HCEC was significantly increased by incubation with sickle RBCs compared with normal RBCs. Upregulation was detected after 1 hour of incubation, and reached a peak after 6 hours. We studied 48 SCD (hemoglobin SS) patients (26 female, 22 male); vs 17 healthy (hemoglobin AA) control subjects (12 female, 5 male). The SCD cohort comprised pediatric and adult patients in steady-state (33 patients) and vaso-occlusive crisis (VOC; 15 patients). The concentration of circulating sLOX-1 protein in plasma of SCD patients (mean: 3.05±2.53 ng/mL; range 0.30 – 11.30 ng/mL) was significantly higher (p=0.0046) than in control healthy subjects (mean: 1.27±0.81 ng/mL). In the 15 SCD patients with VOC, sLOX-1 concentrations were higher, (mean: 3.65±2.40 ng/mL). Conclusions: Our study reveals that LOX-1 gene expression in endothelial cells is upregulated by incubation with SCD erythrocytes. Baseline circulating sLOX-1 levels are elevated in SCD patients compared with healthy controls. sLOX-1 levels are further elevated in VOC. Enhanced LOX-1 expression in endothelial cells may play a role in the pathophysiology of SCD vasculopathy. Studies of sLOX-1 in SCD may provide new insights into risk stratification, and may lead to novel therapeutic strategies for sickle cell patients with acute vascular complications. Disclosures: Green: Emisphere - Consultancy: Consultancy; Teva Pharmaceuticals - expert testimony: Consultancy.
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Magleby, Karl L. "Gating Mechanism of BK (Slo1) Channels." Journal of General Physiology 121, no. 2 (January 13, 2003): 81–96. http://dx.doi.org/10.1085/jgp.20028721.
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Tian, Yutao, Stefan H. Heinemann, and Toshinori Hoshi. "Large-conductance Ca2+- and voltage-gated K+channels form and break interactions with membrane lipids during each gating cycle." Proceedings of the National Academy of Sciences 116, no. 17 (April 9, 2019): 8591–96. http://dx.doi.org/10.1073/pnas.1901381116.
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Membrane depolarization and intracellular Ca2+promote activation of the large-conductance Ca2+- and voltage-gated (Slo1) big potassium (BK) channel. We examined the physical interactions that stabilize the closed and open conformations of the ion conduction gate of the human Slo1 channel using electrophysiological and computational approaches. The results show that the closed conformation is stabilized by intersubunit ion–ion interactions involving negative residues (E321 and E324) and positive residues (329RKK331) at the cytoplasmic ends of the transmembrane S6 segments (“RKK ring”). When the channel gate is open, the RKK ring is broken and the positive residues instead make electrostatic interactions with nearby membrane lipid oxygen atoms. E321 and E324 are stabilized by water. When the329RKK331residues are mutated to hydrophobic amino acids, these residues form even stronger hydrophobic interactions with the lipid tails to promote the open conformation, shifting the voltage dependence of activation to the negative direction by up to 400 mV and stabilizing the selectivity filter region. Thus, the RKK segment forms electrostatic interactions with oxygen atoms from two sources, other amino acid residues (E321/E324), and membrane lipids, depending on the gate status. Each time the channel opens and closes, the aforementioned interactions are formed and broken. This lipid-dependent Slo1 gating may explain how amphipathic signaling molecules and pharmacologically active agents influence the channel activity, and a similar mechanism may be operative in other ion channels.
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Kim, Yonghwan, Gabriella S. Spitz, Uma Veturi, Francis P. Lach, Arleen D. Auerbach, and Agata Smogorzewska. "Regulation of multiple DNA repair pathways by the Fanconi anemia protein SLX4." Blood 121, no. 1 (January 3, 2013): 54–63. http://dx.doi.org/10.1182/blood-2012-07-441212.
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Abstract SLX4, the newly identified Fanconi anemia protein, FANCP, is implicated in repairing DNA damage induced by DNA interstrand cross-linking (ICL) agents, topoisomerase I (TOP1) inhibitors, and in Holliday junction resolution. It interacts with and enhances the activity of XPF-ERCC1, MUS81-EME1, and SLX1 nucleases, but the requirement for the specific nucleases in SLX4 function is unclear. Here, by complementing a null FA-P Fanconi anemia cell line with SLX4 mutants that specifically lack the interaction with each of the nucleases, we show that the SLX4-dependent XPF-ERCC1 activity is essential for ICL repair but is dispensable for repairing TOP1 inhibitor-induced DNA lesions. Conversely, MUS81-SLX4 interaction is critical for resistance to TOP1 inhibitors but is less important for ICL repair. Mutation of SLX4 that abrogates interaction with SLX1 results in partial resistance to both cross-linking agents and TOP1 inhibitors. These results demonstrate that SLX4 modulates multiple DNA repair pathways by regulating appropriate nucleases.
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Mullen, Janet R., Vivek Kaliraman, Samer S. Ibrahim, and Steven J. Brill. "Requirement for Three Novel Protein Complexes in the Absence of the Sgs1 DNA Helicase in Saccharomyces cerevisiae." Genetics 157, no. 1 (January 1, 2001): 103–18. http://dx.doi.org/10.1093/genetics/157.1.103.
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Abstract The Saccharomyces cerevisiae Sgs1 protein is a member of the RecQ family of DNA helicases and is required for genome stability, but not cell viability. To identify proteins that function in the absence of Sgs1, a synthetic-lethal screen was performed. We obtained mutations in six complementation groups that we refer to as SLX genes. Most of the SLX genes encode uncharacterized open reading frames that are conserved in other species. None of these genes is required for viability and all SLX null mutations are synthetically lethal with mutations in TOP3, encoding the SGS1-interacting DNA topoisomerase. Analysis of the null mutants identified a pair of genes in each of three phenotypic classes. Mutations in MMS4 (SLX2) and SLX3 generate identical phenotypes, including weak UV and strong MMS hypersensitivity, complete loss of sporulation, and synthetic growth defects with mutations in TOP1. Mms4 and Slx3 proteins coimmunoprecipitate from cell extracts, suggesting that they function in a complex. Mutations in SLX5 and SLX8 generate hydroxyurea sensitivity, reduced sporulation efficiency, and a slow-growth phenotype characterized by heterogeneous colony morphology. The Slx5 and Slx8 proteins contain RING finger domains and coimmunoprecipitate from cell extracts. The SLX1 and SLX4 genes are required for viability in the presence of an sgs1 temperature-sensitive allele at the restrictive temperature and Slx1 and Slx4 proteins are similarly associated in cell extracts. We propose that the MMS4/SLX3, SLX5/8, and SLX1/4 gene pairs encode heterodimeric complexes and speculate that these complexes are required to resolve recombination intermediates that arise in response to DNA damage, during meiosis, and in the absence of SGS1/TOP3.
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Rouse, John. "Control of genome stability by Slx protein complexes." Biochemical Society Transactions 37, no. 3 (May 20, 2009): 495–510. http://dx.doi.org/10.1042/bst0370495.
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The six Saccharomyces cerevisiae SLX genes were identified in a screen for factors required for the viability of cells lacking Sgs1, a member of the RecQ helicase family involved in processing stalled replisomes and in the maintenance of genome stability. The six SLX gene products form three distinct heterodimeric complexes, and all three have catalytic activity. Slx3–Slx2 (also known as Mus81–Mms4) and Slx1–Slx4 are both heterodimeric endonucleases with a marked specificity for branched replication fork-like DNA species, whereas Slx5–Slx8 is a SUMO (small ubiquitin-related modifier)-targeted E3 ubiquitin ligase. All three complexes play important, but distinct, roles in different aspects of the cellular response to DNA damage and perturbed DNA replication. Slx4 interacts physically not only with Slx1, but also with Rad1–Rad10 [XPF (xeroderma pigmentosum complementation group F)–ERCC1 (excision repair cross-complementing 1) in humans], another structure-specific endonuclease that participates in the repair of UV-induced DNA damage and in a subpathway of recombinational DNA DSB (double-strand break) repair. Curiously, Slx4 is essential for repair of DSBs by Rad1–Rad10, but is not required for repair of UV damage. Slx4 also promotes cellular resistance to DNA-alkylating agents that block the progression of replisomes during DNA replication, by facilitating the error-free mode of lesion bypass. This does not require Slx1 or Rad1–Rad10, and so Slx4 has several distinct roles in protecting genome stability. In the present article, I provide an overview of our current understanding of the cellular roles of the Slx proteins, paying particular attention to the advances that have been made in understanding the cellular roles of Slx4. In particular, protein–protein interactions and underlying molecular mechanisms are discussed and I draw attention to the many questions that have yet to be answered.
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Inoue, Nobutaka, Tomonori Okamura, Yoshihiro Kokubo, Yoshiko Fujita, Yuko Sato, Mamoru Nakanishi, Kazuki Yanagida, et al. "LOX Index, a Novel Predictive Biochemical Marker for Coronary Heart Disease and Stroke." Clinical Chemistry 56, no. 4 (April 1, 2010): 550–58. http://dx.doi.org/10.1373/clinchem.2009.140707.
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Abstract Background: Lectin-like oxidized LDL receptor 1 (LOX-1) is implicated in atherothrombotic diseases. Activation of LOX-1 in humans can be evaluated by use of the LOX index, obtained by multiplying the circulating concentration of LOX-1 ligands containing apolipoprotein B (LAB) times that of the soluble form of LOX-1 (sLOX-1) [LOX index = LAB × sLOX-1]. This study aimed to establish the prognostic value of the LOX index for coronary heart disease (CHD) and stroke in a community-based cohort. Methods: An 11-year cohort study of 2437 residents age 30–79 years was performed in an urban area located in Japan. Of these, we included in the analysis 1094 men and 1201 women without history of stroke and CHD. We measured LAB and sLOX-1 using ELISAs with recombinant LOX-1 and monoclonal anti–apolipoprotein B antibody and with 2 monoclonal antibodies against LOX-1, respectively. Results: During the follow-up period, there were 68 incident cases of CHD and 91 cases of stroke (with 60 ischemic strokes). Compared with the bottom quartile, the hazard ratio (HR) of the top quartile of LOX index was 1.74 (95% CI 0.92–3.30) for stroke and 2.09 (1.00–4.35) for CHD after adjusting for sex, age, body mass index, drinking, smoking, hypertension, diabetes, non-HDL cholesterol, and use of lipid-lowering agents. Compared with the bottom quartile of LOX index, the fully adjusted HRs for ischemic stroke were consistently high from the second to the top quartile: 3.39 (95% CI 1.34–8.53), 3.15 (1.22–8.13) and 3.23 (1.24–8.37), respectively. Conclusions: Higher LOX index values were associated with an increased risk of CHD. Low LOX index values may be protective against ischemic stroke.
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Cochet-Escartin, Olivier, Jason A. Carter, Milena Chakraverti-Wuerthwein, Joydeb Sinha, and Eva-Maria S. Collins. "Slo1 regulates ethanol-induced scrunching in freshwater planarians." Physical Biology 13, no. 5 (September 9, 2016): 055001. http://dx.doi.org/10.1088/1478-3975/13/5/055001.
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Liu, Jianxi, Anna N. Bukiya, Guruprasad Kuntamallappanavar, Aditya K. Singh, and Alex M. Dopico. "Distinct Sensitivity of Slo1 Channel Proteins to Ethanol." Molecular Pharmacology 83, no. 1 (October 23, 2012): 235–44. http://dx.doi.org/10.1124/mol.112.081240.
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Ando, Makoto, Takayuki Matsumoto, Shota Kobayashi, Maika Iguchi, Kumiko Taguchi, and Tsuneo Kobayashi. "Differential participation of calcium-activated potassium channel in endothelium-dependent hyperpolarization-type relaxation in superior mesenteric arteries of spontaneously hypertensive rats." Canadian Journal of Physiology and Pharmacology 96, no. 8 (August 2018): 839–44. http://dx.doi.org/10.1139/cjpp-2017-0557.
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The purpose of this study was to determine the relationship of KCa channels to endothelium-dependent hyperpolarizing factor (EDHF)-mediated relaxation induced by acetylcholine (ACh) in the superior mesenteric arteries of 7-month-old spontaneously hypertensive rats (SHR). Upon inhibition of nitric oxide synthase and cyclooxygenase, ACh-induced EDHF-mediated relaxation was found to be weaker in SHR than in age-matched Wistar Kyoto rats (WKY). These relaxations in both group were attenuated by combined treatment with small-conductance and intermediate-conductance Ca2+-activated K+ channels (SKCa and IKCa) inhibitors, with the exception of relaxation resistant to inhibition of these channels in SHR (vs. WKY). Treatment with large-conductance Ca2+-activated K+ channels (BKCa) inhibitor specifically attenuated relaxation in SHR, but not in WKY. Protein expression of IKCa and SKCa in the arteries did not differ between the 2 groups, whereas ratio of sloβ1 subunit to α subunit of BKCa was increased in SHR (vs. WKY). These results suggest that EDHF-mediated relaxations in superior mesenteric arteries are impaired in SHR, and utilize components of BKCa in addition to SKCa/IKCa channel activities, that the increased participation of BKCa may be attributable to alterations in α and sloβ1 subunit ratio, and that components unrelated to KCa activity may also contribute to the difference between SHR and WKY arteries.
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Contreras, Gustavo F., Karen Castillo, Nicolás Enrique, Willy Carrasquel-Ursulaez, Juan Pablo Castillo, Verónica Milesi, Alan Neely, et al. "A BK (Slo1) channel journey from molecule to physiology." Channels 7, no. 6 (November 2, 2013): 442–58. http://dx.doi.org/10.4161/chan.26242.
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Zakharov, Sergey I., John P. Morrow, Guoxia Liu, Lin Yang, and Steven O. Marx. "Activation of the BK (SLO1) Potassium Channel by Mallotoxin." Journal of Biological Chemistry 280, no. 35 (July 5, 2005): 30882–87. http://dx.doi.org/10.1074/jbc.m505302200.
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Avdonin, Vladimir, Xiang Dong Tang, and Toshinori Hoshi. "Stimulatory Action of Internal Protons on Slo1 BK Channels." Biophysical Journal 84, no. 5 (May 2003): 2969–80. http://dx.doi.org/10.1016/s0006-3495(03)70023-x.
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