scholarly journals APS8 Delays Tumor Growth in Mice by Inducing Apoptosis of Lung Adenocarcinoma Cells Expressing High Number of α7 Nicotinic Receptors

Marine Drugs ◽  
2018 ◽  
Vol 16 (10) ◽  
pp. 367
Author(s):  
Sabina Berne ◽  
Maja Čemažar ◽  
Robert Frangež ◽  
Polona Juntes ◽  
Simona Kranjc ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
A549 Cells ◽  
Lung Fibroblasts ◽  
Normal Lung ◽  
Dependent Manner ◽  
Α7 Nachr ◽  
Α7 Nachrs

The alkylpyridinium polymer APS8, a potent antagonist of α7 nicotinic acetylcholine receptors (nAChRs), selectively induces apoptosis in non-small cell lung cancer cells but not in normal lung fibroblasts. To explore the potential therapeutic value of APS8 for at least certain types of lung cancer, we determined its systemic and organ-specific toxicity in mice, evaluated its antitumor activity against adenocarcinoma xenograft models, and examined the in-vitro mechanisms of APS8 in terms of apoptosis, cytotoxicity, and viability. We also measured Ca2+ influx into cells, and evaluated the effects of APS8 on Ca2+ uptake while siRNA silencing of the gene for α7 nAChRs, CHRNA7. APS8 was not toxic to mice up to 5 mg/kg i.v., and no significant histological changes were observed in mice that survived APS8 treatment. Repetitive intratumoral injections of APS8 (4 mg/kg) significantly delayed growth of A549 cell tumors, and generally prevented regrowth of tumors, but were less effective in reducing growth of HT29 cell tumors. APS8 impaired the viability of A549 cells in a dose-dependent manner and induced apoptosis at micro molar concentrations. Nano molar APS8 caused minor cytotoxic effects, while cell lysis occurred at APS8 >3 µM. Furthermore, Ca2+ uptake was significantly reduced in APS8-treated A549 cells. Observed differences in response to APS8 can be attributed to the number of α7 nAChRs expressed in these cells, with those with more AChRs (i.e., A549 cells) being more sensitive to nAChR antagonists like APS8. We conclude that α7 nAChR antagonists like APS8 have potential to be used as therapeutics for tumors expressing large numbers of α7 nAChRs.

scholarly journals Tonic engagement of nicotinic receptors bidirectionally controls striatal spiny projection neuron spike timing

2021 ◽  
Author(s):  
Lior Matityahu ◽  
Jeffrey Malgady ◽  
Meital Schirelman ◽  
Yvonne Johansson ◽  
Jennifer Wilking ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Gaba Release ◽  
Projection Neuron ◽  
Spike Timing ◽  
Projection Neurons ◽  
Striatal Slices ◽  
Cholinergic Interneurons ◽  
Α7 Nachr ◽  
Α7 Nachrs

Striatal spiny projection neurons (SPNs) transform convergent excitatory corticostriatal inputs into an inhibitory signal that shapes basal ganglia output. This process is fine-tuned by striatal GABAergic interneurons (GINs), which receive overlapping cortical inputs and mediate rapid corticostriatal feedforward inhibition of SPNs. Adding another level of control, cholinergic interneurons (CINs), which are also vigorously activated by corticostriatal excitation, can 1) disynaptically inhibit SPNs by activating α4β2 nicotinic acetylcholine receptors (nAChRs) on various GINs and 2) directly modulate corticostriatal synaptic strength via pre-synaptic α7 nAChR receptors. Measurements of the disynaptic inhibitory pathway, however, indicate that it is too slow to compete with direct GIN-mediated feed-forward inhibition. Moreover, functional nAChRs are also present on populations of GINs that do not respond to phasic activation of CINs, such as parvalbumin-positive fast-spiking interneurons (PV-FSIs), making the overall role of nAChRs in shaping striatal synaptic integration unclear. Using acute striatal slices we show that upon synchronous optogenetic activation of corticostriatal projections, blockade of α7 nAChRs delayed SPN spikes, whereas blockade of α4β2 nAChRs advanced SPN spikes and increased postsynaptic depolarizations. The nAChR-dependent inhibition was mediated by downstream GABA release, and data suggest that the GABA source was not limited to GINs that respond to phasic CIN activation. In particular, the observed spike-advancement caused by nAChR blockade was associated with a diminished frequency of spontaneous inhibitory postsynaptic currents in SPNs, and a parallel hyperpolarization of PV-FSIs. Taken together, we describe opposing roles for tonic (as opposed to phasic) engagement of nAChRs in striatal function. We conclude that tonic activation of nAChRs by CINs both sharpens the temporal fidelity of corticostriatal signaling via pre-synaptic α7 nAChRs and maintains a GABAergic brake on cortically-driven striatal output, processes that may shape SPN spike timing, striatal processing and synaptic plasticity.

scholarly journals Statins Prevent β-Amyloid Inhibition of Sympathetic α7-nAChR-Mediated Nitrergic Neurogenic Dilation in Porcine Basilar Arteries

2005 ◽  
Vol 25 (12) ◽  
pp. 1573-1585 ◽  
Author(s):  
Min-Liang Si ◽  
Chen Long ◽  
Ding-I Yang ◽  
Mei-Fang Chen ◽  
Tony Jer-Fu Lee
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Early Phase ◽  
Calcium Influx ◽  
Cerebral Hypoperfusion ◽  
Α7 Nachr ◽  
Inward Currents ◽  
Basilar Arteries ◽  
Β Amyloid ◽  
Α7 Nachrs

The exact mechanism underlying regional cerebral hypoperfusion in the early phase of Alzheimer's disease (AD) is not understood. We have shown in isolated porcine cerebral arteries that stimulation of sympathetic α7-nicotinic acetylcholine receptors (α7-nAChRs) causes release of nitric oxide in parasympathetic nitrergic nerves and vasodilation. We therefore examined if β-amyloid peptides (Aβs), which play a key role in pathogenesis of AD, blocked sympathetic α7-nAChRs leading to reduced neurogenic nitrergic dilation in isolated porcine basilar arteries, using in vitro tissue bath, calcium image, and patch clamping techniques. The results indicated that Aβ1–40, but not Aβ40–1, blocked relaxation of endothelium-denuded basilar arterial rings induced by nicotine (100μ;mol/L) and choline (1 mmol/L) without affecting that induced by sodium nitroprusside or isoproterenol. In cultured superior cervical ganglion (SCG) cells, Aβ1–40, but not Aβ40–1, blocked choline- and nicotine-induced calcium influx and inward currents. The Aβ blockade of the nitrergic vasodilation and inward currents, but not that of calcium influx, was prevented by acute pretreatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors mevastatin and lovastatin. These results suggest that Aβ1–40 blocks cerebral perivascular sympathetic α7-nAChRs, resulting in the attenuation of cerebral nitrergic neurogenic vasodilation. This effect of Aβ may be responsible in part for cerebral hypoperfusion occurred in the early phase of the AD, which may be prevented by statins most likely because of their effects independent of cholesterol lowering. Statins may offer an alternative strategy in the prevention and treatment of AD.

Extract from the Leaves of Toona sinensis Roemor Exerts Potent Antiproliferative Effect on Human Lung Cancer Cells

2002 ◽  
Vol 30 (02n03) ◽  
pp. 307-314 ◽  
Author(s):  
Hui-Chiu Chang ◽  
Wen-Chun Hung ◽  
Ming-Shyan Huang ◽  
Hseng-Kuang Hsu
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Human Lung ◽  
Apoptotic Cell ◽  
A549 Cells ◽  
Lung Cancer Cells ◽  
Lung Fibroblasts ◽  
Human Lung Cancer ◽  
Toona Sinensis

Recent study indicated that the components of Toona sinensis Roemor have potent anti-inflammatory and analgesic effects. These components have also been reported to inhibit the growth of boils in vivo. In this study, we investigated the effect of crude extract from the leaves of Toona sinensis Roemor on the proliferation of A549 lung cancer cells. We found that the extract effectively blocked cell cycle progression by inhibiting the expression of cyclin D1 and E in A549 cells. Additionally, incubation of the extract led to activation of caspase-3-like proteases and apoptotic cell death. Conversely, the extract did not show any significant cytotoxic effect on primarily cultured human foreskin fibroblasts or MRC-5 human lung fibroblasts. Therefore, antiproliferative action of the extract is specific for tumor cells. Our results suggest that the components of Toona sinensis Roemor have potent anticancer effects in vitro and identification of the useful components in the extract may lead to the development of a novel class of anticancer drugs.

Monoamine uptake inhibitors block α7-nAChR-mediated cerebral nitrergic neurogenic vasodilation

2006 ◽  
Vol 291 (1) ◽  
pp. H202-H209 ◽  
Author(s):  
Cheng Long ◽  
Mei-Fang Chen ◽  
Susan J. Sarwinski ◽  
Po-Yi Chen ◽  
Minliang Si ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Sympathetic Neurons ◽  
Monoamine Uptake ◽  
Uptake Inhibitors ◽  
Α7 Nachr ◽  
Inward Currents ◽  
Monoamine Uptake Inhibitors ◽  
Α7 Nachrs ◽  
Neurogenic Vasodilation

We have proposed that activation of cerebral perivascular sympathetic α7-nicotinic acetylcholine receptors (α7-nAChRs) by nicotinic agonists releases norepinephrine, which then acts on parasympathetic nitrergic nerves, resulting in release of nitric oxide and vasodilation. Using patch-clamp electrophysiology, immunohistochemistry, and in vitro tissue bath myography, we tested this axo-axonal interaction hypothesis further by examining whether blocking norepinephrine reuptake enhanced α7-nAChR-mediated cerebral nitrergic neurogenic vasodilation. The results indicated that choline- and nicotine-induced α7-nAChR-mediated nitrergic neurogenic relaxation in endothelium-denuded isolated porcine basilar artery rings was enhanced by desipramine and imipramine at lower concentrations (0.03–0.1 μM) but inhibited at higher concentrations (0.3–10 μM). In cultured superior cervical ganglion (SCG) neurons of the pig and rat, choline (0.1–30 mM)-evoked inward currents were reversibly blocked by 1–30 μM mecamylamine, 1–30 μM methyllycaconitine, 10–300 nM α-bungarotoxin, and 0.1–10 μM desipramine and imipramine, providing electrophysiological evidence for the presence of similar functional α7-nAChRs in cerebral perivascular sympathetic neurons of pigs and rats. In α7-nAChR-expressing Xenopus oocytes, choline-elicited inward currents were attenuated by α-bungarotoxin, imipramine, and desipramine. These monoamine uptake inhibitors appeared to directly block the α7-nAChR, resulting in diminished nicotinic agonist-induced cerebral nitrergic vasodilation. The enhanced nitrergic vasodilation by lower concentrations of monoamine uptake inhibitors is likely due to a greater effect on monoamine uptake than on α7-nAChR blockade. These results further support the hypothesis of axo-axonal interaction in nitrergic regulation of cerebral vascular tone.

scholarly journals A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine

Marine Drugs ◽  
2020 ◽  
Vol 18 (2) ◽  
pp. 106 ◽  
Author(s):  
Hong Xing ◽  
Sunil Keshwah ◽  
Anne Rouchaud ◽  
William R. Kem
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Radioligand Binding ◽  
Partial Agonist ◽  
Secondary Compounds ◽  
Piperidine Ring ◽  
Medical Disorders ◽  
In Vitro Investigation ◽  
Α7 Nachrs

Many organisms possess “secondary” compounds to avoid consumption or to immobilize prey. While the most abundant or active compounds are initially investigated, more extensive analyses reveal other “minor” compounds with distinctive properties that may also be of biomedical and pharmaceutical significance. Here, we present an initial in vitro investigation of the actions of two isomeric tetrahydropyridyl ring-containing anabasine analogs: isoanatabine, an alkaloid isolated from a marine worm, and anatabine, a relatively abundant minor alkaloid in commercial tobacco plants. Both compounds have a double bond that is distal to the piperidine ring nitrogen of anabasine. Racemic isoanatabine and anatabine were synthesized and their S- and R-enantiomers were isolated by chiral high pressure liquid chromatography (HPLC). Both isoanatabines displayed higher efficacies at α4β2 nicotinic acetylcholine receptors (nAChRs) relative to the anatabines; R-isoanatabine was most potent. Radioligand binding experiments revealed similar α4β2 nAChR binding affinities for the isoanatabines, but R-anatabine affinity was twice that of S-anatabine. While the two anatabines and S-isoanatabine were highly efficacious agonists at α7 nAChRs, R-isoanatabine was only a weak partial agonist. The four compounds share an ability to stimulate both α4β2 and α7 nAChRs, a property that may be useful in developing more efficacious drugs to treat neurodegenerative and other medical disorders.

A New Isoxazolic Compound Acts as α7 Nicotinic Receptor Agonist in Human Umbilical Vein Endothelial Cells

2014 ◽  
Vol 69 (7-8) ◽  
pp. 291-299 ◽  
Author(s):  
Magdalena P. Cortés ◽  
Rocío Alvarez ◽  
Evelyn Sepúlveda ◽  
Felipe Jiménez-Aspee ◽  
Luis Astudillo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Umbilical Vein ◽  
Therapeutic Angiogenesis ◽  
Dependent Manner ◽  
Human Umbilical Vein ◽  
Α7 Nachr ◽  
Significant Difference ◽  
Umbilical Vein Endothelial Cells

Recent evidence suggests that the α7 nicotinic acetylcholine receptors (α7 nAChRs) participate in the development of angiogenesis and could be a new endothelial target for revascularization in therapeutic angiogenesis. It has been shown that in human umbilical vein endothelial cells (HUVECs) α7 nAChR agonists increase the intracellular calcium concentration ([Ca2+]i), thus inducing proliferation and vessel formation which are important stages of angiogenesis. In the present study we evaluated the effect of new isoxazole compounds on the cytosolic Ca2+ signal in HUVECs using the fluorescent Ca2+ indicator Fluo-3AM and probing the involvement of α7 nAChR by means of pharmacological tools. HUVECs expressed mainly α7 nAChR, since there was no significant difference in the increase in [Ca2+]i induced by nicotine, a non-selective nicotinic agonist, in relation to choline, a selective α7 nAChR agonist. The increase in [Ca2+]i induced by 1 mM choline was inhibited significantly (p = 0.014) in cells which had been pre-incubated for 15 min with methyllycaconitine (MLA), a selective α7 nAChR antagonist. The studied compounds 1, 2, and 3 induced an increase in [Ca2+]i in a dose-dependent manner. Compound 1 at 10 mM induced a greater increase in [Ca2+]i than compounds 2 and 3. The increase in [Ca2+]i induced by compound 1 was significantly inhibited by MLA (p = 0.013) and completely inhibited by mecamylamine, a non-selective nAChR antagonist, indicating that the isoxazolic compound 1 acts as an α7 nAChR agonist.

scholarly journals EVALUATION OF IN VITRO CYTOTOXIC EFFECT OF VIOLACEIN PRODUCED BY NOVEL ISOLATE CHROMOBACTERIUM VACCINII CV5 AGAINST THE CERVICAL AND LUNG CANCER CELL

2017 ◽  
Vol 10 (10) ◽  
pp. 227 ◽  
Author(s):  
Vishnu T Santhosh ◽  
Palaniswamy Muthusamy
Keyword(s):  
Lung Cancer ◽  
Anticancer Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
A549 Cells ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Cytotoxicity Activity ◽  
Ic50 Values

  Objectives: This study investigates the in vitro anticancer activity of the violacein extracted from the Chromobacterium vaccinii CV5.Methods: Natural colorants or dyes derived from flora to fauna are believed to be safe because of nontoxic, noncarcinogenic, and biodegradable in nature. There are a number of natural pigments, but only a few are available in sufficient quantities for industrial production. The cytotoxicity activity of pigment was assessed against the cervical (HeLa) and lung cancer (A549) cell lines using the MTT assay and there by potential cytotoxic activity exhibited by the pigment was identified.Results: The result of the pigment shows potent anticancer activity on the two cancer cell lines tested in a concentration dependent manner. The potent anticancer activity was observed with the pigment with IC50 values of 26 μg/mL on HeLa and 31 μg/mL on A549 cells, respectively.Conclusion: The study is pioneering report for determining the better in vitro anticancer activity of violacein from the novel isolate C. vaccinii CV5.

Downregulation of CPA4 to suppress NSCLC proliferation by inducing apoptosis and G1 arrest.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20074-e20074
Author(s):  
Yangyang Fu ◽  
Xiaoying Huang ◽  
Liangxing Wang
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
A549 Cells ◽  
Lung Cancer Cells ◽  
Normal Lung ◽  
G1 Arrest ◽  
Cancer Aggressiveness

e20074 Background: Carboxypepidase A4 (CPA4) is a member of the metallocarboxypeptidase family. Previous study discovered that CPA4 may participate in cell growth and differentiation of prostate epithelial cells. Meanwhile, CPA4 is a printed gene and thought to be involved in prostate cancer aggressiveness. As is reported, CPA4 was increased in NSCLC tissues compared to normal lung tissues and high expression of CPA4 was correlated with poor prognosis of NSCLC patients. However, the role of CPA4 play in lung tumorigenesis is still unclear. Methods: We examined the mRNA and protein expression level of CPA4 via real-time PCR and immunohistochemistry in NSCLC tissues and adjacent tissues. Growth assays both in vitro and in vivo were performed to elucidate the role of CPA4 may play in lung cancer and Fluorescence Activated Cell Sorter was conducted to uncover the putative mechanism. Results: CPA4 expression was increased both in mRNA and protein levels in NSCLC tissues compared to adjacent tissues. MTT and colony formation assays showed that downregulation of CPA4 in H1299 and A549 cells inhibited lung cancer cells proliferation. We further confirmed this result by using cellomics and celligo. Depleting CPA4 also suppressed tumor growth in mice. Mechanically, we found that suppressing CPA4 expression in lung cancer cells could induce apoptosis and G1 arrest. We supposed that CPA4 expression may be associated with caspase family and it needs further studies. Conclusions: Collectively, we demonstrate that decreased CPA4 inhibits NSCLC proliferation via inducing apoptosis and G1 arrest.

scholarly journals In vitro cytotoxic and genotoxic effects of donkey milk on lung cancer and normal cells lines

2019 ◽  
Vol 37 (No. 1) ◽  
pp. 29-35 ◽  
Author(s):  
Cetin Akca ◽  
Ozgur Vatan ◽  
Dilek Yilmaz ◽  
Huzeyfe HURIYET ◽  
Nilüfer Cinkilic ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Line ◽  
Micronucleus Test ◽  
A549 Cells ◽  
Tumor Cell Line ◽  
Normal Lung ◽  
Dna Breaks ◽  
Donkey Milk ◽  
Genotoxic Effects

In vitro cytotoxic and genotoxic effects of donkey milk on cancer (A549) and normal (BEAS-2B) lung cell lines were investigated. The XTT and WST-1 tests as well as clonogenic assays were used to evaluate cytotoxicity. The comet assay and micronucleus test were used as genotoxicity endpoints. Donkey milk showed lower cytotoxic effects against normal lung cell line BEAS-2B in comparison to the tumor cell line A549. Genotoxicity experiments revealed dose dependent increases in the frequencies of micronuclei and single stranded DNA breaks in A549 cells whereas no significant damage was observed in BEAS-2B cells. The results indicate that donkey milk has anti-proliferative and genotoxic effects on lung cancer cells at concentrations which are non-toxic to normal lung cells.

scholarly journals Procognitive effects of varenicline in the animal model of schizophrenia depend on α4β2- and α7-nicotinic acetylcholine receptors

2018 ◽  
Vol 33 (1) ◽  
pp. 62-73 ◽  
Author(s):  
Agnieszka Potasiewicz ◽  
Joanna Golebiowska ◽  
Piotr Popik ◽  
Agnieszka Nikiforuk
Keyword(s):  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Partial Agonist ◽  
Set Shifting ◽  
Nicotinic Acetylcholine ◽  
Α7 Nachr ◽  
Α7 Nicotinic Acetylcholine Receptors ◽  
Α7 Nachrs

Background: Varenicline, a partial agonist of the α4β2 nicotinic acetylcholine receptor (α4β2-nAChR), is currently used to facilitate smoking cessation. Preclinical and clinical studies have suggested that this compound may also be effective in treating cognitive impairments in schizophrenia. However, it is unclear which nicotinic acetylcholine receptor subtypes may be involved because varenicline is not only a partial agonist for α4β2-nAChRs but also a full agonist for α7 nicotinic acetylcholine receptors (α7-nAChRs). Aim: We investigated the effects of varenicline, compared to the α4β2-nAChR partial agonist TC-2403 and the α7-nAChR full agonist PNU-282987, in a ketamine-based model of schizophrenia-like cognitive deficits on the attentional set-shifting task in rats. The second goal was to elucidate whether the procognitive efficacy of varenicline was due to the compound’s action on α4β2-nAChRs or α7-nAChRs. Methods: Ketamine was administered to rats for 10 consecutive days and the test was performed 14 days following the last injection. The tested compounds were administered 30 min prior to the attentional set-shifting task. Results: Varenicline, TC-2403 and PNU-282987 ameliorated ketamine-evoked set-shifting deficits. While the α4β2-nAChR antagonist dihydro-β-erythroidine and the α7-nAChR antagonist methyllycaconitine completely prevented the procognitive actions of TC-2403 and PNU-282987, respectively, varenicline’s effect was only partially blocked by any given antagonist. Moreover, the combined treatment with TC-2403 and PNU-282987 more effectively facilitated rats’ set-shifting ability than activation of either type of nicotinic acetylcholine receptor alone. Conclusion: The present findings demonstrated that varenicline’s actions on both α7-nAChRs and α4β2-nAChRs may be necessary to produce its full procognitive effect in the present experimental setting.

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