BK Channels Regulate LPS-induced CCL-2 Release from Human Pulmonary Endothelial Cells

Zyrianova, Tatiana; López, Benjamín; Liao, Andy; Gu, C. Charles; Wong, Leanne; Ottolia, Michela; Olcese, Riccardo; Schwingshackl, Andreas

doi:10.1165/rcmb.2020-0228oc

Cited by 14 publications

(15 citation statements)

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“…Human tumor incidence and death have been steadily rising in recent years, and the incidence of esophageal cancer, in particular, remains high. One of the main reasons for tumor recurrence or difficulty in treatment is the weak immunogenicity or lack of expression of tumor antigens, and the body's immune tolerance to the tumor can lead to escape response when the tumor is attacked by the body, resulting in treatment failure [14][15][16][17][18]. Therefore, reducing tumor drug resistance and improving tumor immunogenicity is the key to successful esophageal tumor treatment.…”

Section: Discussionmentioning

confidence: 99%

Lentinan Enhances the Function of Oxaliplatin on the Esophageal Tumors by Persuading Immunogenic Cell Death

Huo

Pei

Wang

et al. 2022

Computational and Mathematical Methods in Medicine

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Objective. The focus of this research was to look at the effects of the combination of the lentinan (LNT) and oxaliplatin (Oxa) on the apoptosis of human esophageal cancer cells, as well as the underlying mechanism. Methods. LNT and Oxa were used to treat EC-109 human esophageal cancerous cells at various doses, and the cell survival rate was measured using the Cell Counting Kit-8 (CCK-8) assay. In addition, 24 h after treatment of EC-109 cells with a combination of LNT and Oxa, flow cytometry was used to analyze their apoptotic effect on these cells. Additionally, LNT on EC-109 cell apoptotic upshot was assessed via measuring the consequence of LNT on the mRNA and protein expression levels pertaining to immunogenic cell death factors CALR, HSP90, and HSP70 by qPCR (quantitative real-time polymerase chain reaction) and western blot analysis, correspondingly. Results. Cell proliferation was inhibited only when EC-109 cells were added with LNT at 1,200 μg/mL to the maximum concentrations, but the combination of LNT and Oxa at a low dose (800 μg/mL and 20 μM, respectively) significantly increased their sensitivity to Oxa and reduced their proliferation ( P < 0.05 ), and their apoptosis was significantly increased by LNT ( P < 0.05 ). The immunogenic cell death-related genes CALR, HSP90, and HSP70 had dramatically enhanced mRNA and protein expression levels after therapy with a combination of LNT and Oxa ( P < 0.05 ). Conclusion. These data imply that LNT increases the susceptibility of esophageal cancerous cells to Oxa by driving EC-109 cells to display immunogenic death. Therefore, LNT combined with Oxa may be an effective method in esophageal cancer management.

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Section: Discussionmentioning

confidence: 99%

Lentinan Enhances the Function of Oxaliplatin on the Esophageal Tumors by Persuading Immunogenic Cell Death

Huo

Pei

Wang

et al. 2022

Computational and Mathematical Methods in Medicine

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“…The BKca channel provides an important negative-feedback system for calcium entry into neuronal cell. NS1619, a potent activator of the BKca channel, has demonstrated significant protection through preconditioning mediated oxidative stress regulation, anti-inflammation, stabilizing membrane potential, and regulating immunity [22][23][24][25]. However, the protective effect of NS1619 on BDEV mediated brain injury remains unclear.…”

Section: Introductionmentioning

confidence: 99%

NS1619 Alleviate Brain-Derived Extracellular Vesicle-Induced Brain Injury by Regulating BKca Channel and Nrf2/HO-1/NF-ĸB Pathway

Gao

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Brain induced extracellular vesicle (BDEV) elevates after traumatic brain injury (TBI) and contributes to secondary brain injury. However, the role of BDEV in TBI remains unclear. In this study, we determined the mechanisms of BDEV in brain injury and explored whether neuroprotective drug BKca channel opener NS1619 may attenuate BDEV-induced brain injury. We injected BDEV and lactadherin, respectively, to mimic the up and downregulation of BDEV after TBI and illustrated the role of BDEV in vivo. In vitro, the membrane potential and calcium concentration of HT-22, bEnd3, and BV-2 were measured by fluorescent staining. The effects of BDEV and NS1619 on HT-22 were evaluated by CCK-8, LDH release assay, Na+/k+-ATPase activity, JC-1 staining, DHE staining, and 4-HNE staining, respectively. The role of BDEV and NS1619 on the Nrf2/HO-1/p65 pathway was also evaluated in HT-22. Finally, we administrated TBI mice with NS1619 to clarify the role of NS1619 against BDEV in vivo. Our results suggested that BDEV aggravated and lactadherin mitigated TBI-induced EB leakage, brain edema, neuronal degeneration, apoptosis, ROS level, microgliosis, MMP-9 activity, and NF-κB activation. In vitro, BDEV-caused depolarized membrane potential and calcium overload were significantly attenuated by NS1619 in HT-22, bEnd3, and BV-2. BDEV markedly decreased cell viability, Na+/k+-ATPase activity, and caused mitochondrial dysregulation, oxidative stress, and NF-ĸB activation. NS1619 pretreatment alleviated above process and enhanced antioxidant system Nrf2/HO-1 in HT-22. Finally, NS1619 administration significantly inhibited neuroinflammation response and improved TBI outcome after TBI. NS1619 treatment also reduced 4-HNE content and NF-ĸB activation and enhanced Nrf2/HO-1 pathway. Our data showed that BDEV aggravated brain injury by perturbing cell membrane potential, calcium homeostasis, oxidative stress, and neuroinflammation. The BKca channel opener NS1619 attenuated BDEV-induced pathological process in vitro and in vivo by modulating the BKca channel and Nrf2/HO-1/NF-ĸB pathway.

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“…In this model, the cytokine and TNF-α pathway sub-clusters interacted with each other via the proinflammatory CCL-2/TNF-α axis and their respective receptors, CCR-2 and TNFRSF-1B (dashed lines in Figure 2 B), which shared three out of four edges, suggested a high likelihood of interaction. Based on the currently available information, with the same input variables, the ion channel sub-cluster remained isolated from the rest of the PPI network, except for one previous report that linked the BK channels to the cytokine CCL-2 [ 18 ], highlighting the substantial lack of knowledge in this area.…”

Section: Resultsmentioning

confidence: 99%

Activation of Endothelial Large Conductance Potassium Channels Protects against TNF-α-Induced Inflammation

Zyrianova

Zou

López

et al. 2023

IJMS

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Elevated TNF-α levels in serum and broncho-alveolar lavage fluid of acute lung injury patients correlate with mortality rates. We hypothesized that pharmacological plasma membrane potential (Em) hyperpolarization protects against TNF-α-induced CCL-2 and IL-6 secretion from human pulmonary endothelial cells through inhibition of inflammatory Ca2+-dependent MAPK pathways. Since the role of Ca2+ influx in TNF-α-mediated inflammation remains poorly understood, we explored the role of L-type voltage-gated Ca2+ (CaV) channels in TNF-α-induced CCL-2 and IL-6 secretion from human pulmonary endothelial cells. The CaV channel blocker, Nifedipine, decreased both CCL-2 and IL-6 secretion, suggesting that a fraction of CaV channels is open at the significantly depolarized resting Em of human microvascular pulmonary endothelial cells (−6 ± 1.9 mV), as shown by whole-cell patch-clamp measurements. To further explore the role of CaV channels in cytokine secretion, we demonstrated that the beneficial effects of Nifedipine could also be achieved by Em hyperpolarization via the pharmacological activation of large conductance K+ (BK) channels with NS1619, which elicited a similar decrease in CCL-2 but not IL-6 secretion. Using functional gene enrichment analysis tools, we predicted and validated that known Ca2+-dependent kinases, JNK-1/2 and p38, are the most likely pathways to mediate the decrease in CCL-2 secretion.

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BK Channels Regulate LPS-induced CCL-2 Release from Human Pulmonary Endothelial Cells

Cited by 14 publications

References 50 publications

Lentinan Enhances the Function of Oxaliplatin on the Esophageal Tumors by Persuading Immunogenic Cell Death

Lentinan Enhances the Function of Oxaliplatin on the Esophageal Tumors by Persuading Immunogenic Cell Death

NS1619 Alleviate Brain-Derived Extracellular Vesicle-Induced Brain Injury by Regulating BKca Channel and Nrf2/HO-1/NF-ĸB Pathway

Activation of Endothelial Large Conductance Potassium Channels Protects against TNF-α-Induced Inflammation

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