scholarly journals Retroviral Glycoprotein-Mediated Immune Suppression via the potassium Channel KCa3.1- A new strategy for treatment of Inflammatory Bowel Diseases.

2022 ◽  
Author(s):  
Magdalena Laska ◽  
Jesper Bonnet Møller ◽  
Jonas Heilskov Graversen ◽  
Dorte Strøbæk ◽  
Linda Blomster ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Envelope Protein ◽  
Calcium Influx ◽  
Human Endogenous Retrovirus ◽  
Channel Blockers ◽  
Mice Model ◽  
Acute Colitis ◽  
Wide Range ◽  
Peptide Treatment

Background and Purpose: Peptides derived from retroviral envelope proteins have been shown to possess a wide range of immunosuppressive and anti-inflammatory activities. We have previously reported identification of such a peptide derived from the envelope protein coded by a human endogenous retrovirus (HERV). In this study we assessed effects of this peptide treatment on inhibition of immune response in the DSS-induced mice model of colitis. Furthermore, we identified that in vitro the peptide inhibits the KCa3.1 potassium channel, a potential target for therapy of immune diseases. Experimental Approach: We characterized an immunosuppressive peptide ENV59, from a specific HERV envelope protein, in vivo effects on inflammation control in acute colitis mice model and in vitro on the production of pro-inflammatory cytokines. Furthermore, we described in vitro ENV59-GP3 effects with respect to potency of inhibition on KCa3.1 channels and calcium influx. Key Results: ENV59-GP3 peptide treatment showed reduction of the disease score in the DSS-induced acute colitis mice model, which was comparable to effects of the KCa3.1 channel blocker NS6180. Analysis of cytokine production from DSS-mice model treated animals revealed equipotent inhibitory effects of the ENV59-GP3 and NS6180 compounds on the production of IL-6, TNF-α, IL-1β. Patch clamp studies show that the peptide ENV59-GP3 is a blocker of the potassium channel KCa3.1. Conclusion and Implications: Env59-GP3 represents KCa3.1 channel inhibitor underlining the implications of using virus derived channel blockers for treatment of autoimmune diseases. There are no drugs with a similar mechanism of action currently on the market.

scholarly journals Potassium channel contributions to afferent arteriolar tone in normal and diabetic rat kidney

2008 ◽  
Vol 295 (1) ◽  
pp. F171-F178 ◽  
Author(s):  
Carmen M. Troncoso Brindeiro ◽  
Rachel W. Fallet ◽  
Pascale H. Lane ◽  
Pamela K. Carmines
Keyword(s):  
Potassium Channel ◽  
Rat Kidney ◽  
The Other ◽  
Diabetic Rat ◽  
Channel Blockers ◽  
Juxtamedullary Nephron ◽  
Afferent Arterioles ◽  
Arteriolar Tone ◽  
Constrictor Response

We previously reported an enhanced tonic dilator impact of ATP-sensitive K+ channels in afferent arterioles of rats with streptozotocin (STZ)-induced diabetes. The present study explored the hypothesis that other types of K+ channel also contribute to afferent arteriolar dilation in STZ rats. The in vitro blood-perfused juxtamedullary nephron technique was utilized to quantify afferent arteriolar lumen diameter responses to K+ channel blockers: 0.1–3.0 mM 4-aminopyridine (4-AP; KV channels), 10–100 μM barium (KIR channels), 1–100 nM tertiapin-Q (TPQ; Kir1.1 and Kir3.x subfamilies of KIR channels), 100 nM apamin (SKCa channels), and 1 mM tetraethylammonium (TEA; BKCa channels). In kidneys from normal rats, 4-AP, TEA, and Ba2+ reduced afferent diameter by 23 ± 3, 8 ± 4, and 18 ± 2%, respectively, at the highest concentrations employed. Neither TPQ nor apamin significantly altered afferent diameter. In arterioles from STZ rats, a constrictor response to TPQ (22 ± 4% decrease in diameter) emerged, and the response to Ba2+ was exaggerated (28 ± 5% decrease in diameter). Responses to the other K+ channel blockers were similar to those observed in normal rats. Moreover, exposure to either TPQ or Ba2+ reversed the afferent arteriolar dilation characteristic of STZ rats. Acute surgical papillectomy did not alter the response to TPQ in arterioles from normal or STZ rats. We conclude that 1) KV, KIR, and BKCa channels tonically influence normal afferent arteriolar tone, 2) KIR channels (including Kir1.1 and/or Kir3.x) contribute to the afferent arteriolar dilation during diabetes, and 3) the dilator impact of Kir1.1/Kir3.x channels during diabetes is independent of solute delivery to the macula densa.

Praziquantel and the benzodiazepine Ro 11-3128 do not compete for the same binding sites in schistosomes

Parasitology ◽  
2007 ◽  
Vol 135 (1) ◽  
pp. 47-54 ◽  
Author(s):  
L. PICA-MATTOCCIA ◽  
A. RUPPEL ◽  
C. M. XIA ◽  
D. CIOLI
Keyword(s):  
Calcium Channel ◽  
Binding Sites ◽  
Calcium Influx ◽  
Cytochalasin D ◽  
The Other ◽  
Channel Blockers ◽  
Spastic Paralysis ◽  
Receptor Sites

SUMMARYThe benzodiazepine Ro 11-3128 (methyl-clonazepam) presents several similarities with praziquantel with regard to its anti-schistosomal mode of action, since both drugs cause spastic paralysis, calcium influx and tegumental disruption in the parasites. In order to know whether the two compounds share the same binding sites in the schistosomes, we performed in vivo and in vitro competition experiments. We took advantage of the fact that Ro 11-3128 is active against immature Schistosoma mansoni (whereas praziquantel is inactive), and praziquantel is active against S. japonicum (which is insensitive to Ro 11-3128). An excess of praziquantel did not inhibit the activity of Ro 11-3128 against immature S. mansoni and an excess of Ro 11-3128 did not inhibit the activity of praziquantel against S. japonicum, suggesting that the schistosome binding sites of the two drugs are different. On the other hand, cytochalasin D, an agent known to perturb – among other things – calcium channel function, was capable of inhibiting the schistosomicidal activity of both praziquantel and Ro 11-3128, thus adding another element of similarity between the two anti-schistosomal agents. A similar, albeit partial, inhibition of the schistosomicidal activity of the two drugs was exerted by some of the classical calcium channel blockers. Taken together, these results suggest that praziquantel and Ro 11-3128, although binding to different schistosome receptor sites, may use the same basic anti-schistosomal effector mechanisms.

Excitation of cutaneous sensory nerve endings in the rat by 4-aminopyridine and tetraethylammonium

1992 ◽  
Vol 67 (1) ◽  
pp. 125-131 ◽  
Author(s):  
C. Kirchhoff ◽  
J. D. Leah ◽  
S. Jung ◽  
P. W. Reeh
Keyword(s):  
Potassium Channel ◽  
Sensory Nerve ◽  
Low Frequency ◽  
Threshold Concentration ◽  
Nerve Endings ◽  
Channel Blockers ◽  
C Fibers ◽  
Sensory Nerve Endings ◽  
Potassium Channel Blockers

1. The effects of the potassium channel blockers 4-aminopyridine (4-AP) and tetraethylammonium (TEA) on cutaneous sensory nerve endings have been investigated with the use of an in vitro skin-nerve preparation from the rat. 2. Direct application of these compounds to the nerve endings, but not to the axons, induced continuous discharges in most A beta, A delta, and C fibers. There was no relationship between the fibers' responsiveness or the threshold concentration required to induce discharges and either the conduction velocity or sensory properties of the fibers. 3. The rate of induced discharges increased linearly with increasing concentrations of 4-AP. At threshold concentrations of 10(-6)-10(-5) M, low-frequency, irregular discharges developed; but at the highest concentration of 10(-3) M, a characteristic doublet or bursting discharges usually emerged. 4. During and after the induced discharges there did not appear to be an alteration in the sensitivity of the sensory nerve endings to mechanical or thermal stimuli. 5. It is concluded that the induced activity arises from an action of these potassium channel blockers at or near the action potential generator region at the nerve endings.

Inhibitory effects of potassium channel blockers on tetramethylpyrazine-induced relaxation of rat aortic strip in vitro

Life Sciences ◽  
2002 ◽  
Vol 71 (11) ◽  
pp. 1321-1330 ◽  
Author(s):  
Chin-Chuan Tsai ◽  
Tung-Yuan Lai ◽  
Wei-Chan Huang ◽  
I-Min Liu ◽  
Juei-Tang Cheng
Keyword(s):  
Potassium Channel ◽  
Channel Blockers ◽  
Inhibitory Effects ◽  
Aortic Strip ◽  
Potassium Channel Blockers

scholarly journals Potassium Channel Blockers Attenuate Hypoxia- and Ischemia-Induced Neuronal Death In Vitro and In Vivo

Stroke ◽  
2003 ◽  
Vol 34 (5) ◽  
pp. 1281-1286 ◽  
Author(s):  
Ling Wei ◽  
Shan Ping Yu ◽  
Frank Gottron ◽  
B. Joy Snider ◽  
Gregory J. Zipfel ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Neuronal Death ◽  
Channel Blockers ◽  
Potassium Channel Blockers

Quantitative analysis of voltage-gated potassium currents from primary equine (Equus caballus) and elephant (Loxodonta africana) articular chondrocytes

2005 ◽  
Vol 289 (1) ◽  
pp. R172-R180 ◽  
Author(s):  
A. Mobasheri ◽  
T. C. Gent ◽  
M. D. Womack ◽  
S. D. Carter ◽  
P. D. Clegg ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Articular Chondrocytes ◽  
Polyclonal Antibodies ◽  
Electrophysiological Study ◽  
Activation Parameters ◽  
Electrophysiological Recording ◽  
Channel Blockers ◽  
Voltage Gated ◽  
K 12

In this comparative study, we have established in vitro models of equine and elephant articular chondrocytes, examined their basic morphology, and characterized the biophysical properties of their primary voltage-gated potassium channel (Kv) currents. Using whole cell patch-clamp electrophysiological recording from first-expansion and first-passage cells, we measured a maximum Kv conductance of 0.15 ± 0.04 pS/pF ( n = 10) in equine chondrocytes, whereas that in elephant chondrocytes was significantly larger (0.8 ± 0.4 pS/pF, n = 4, P ≤ 0.05). Steady-state activation parameters of elephant chondrocytes ( V = −22 ± 6 mV, k = 11.8 ± 3 mV, n = 4) were not significantly different from those of horse chondrocytes ( V = −12.5 ± 4.3 mV, k = 12 ± 2, n = 10). This suggests that there would be slightly more resting Kv activation in elephant chondrocytes than in their equine counterparts. Kinetic analysis revealed that both horse and elephant chondrocyte Kv currents had similar activation and inactivation parameters. Pharmacological investigation of equine chondrocyte Kv currents showed them to be powerfully inhibited by the potassium channel blockers tetraethylammonium and 4-aminopyridine but not by dendrotoxin-I. Immunohistochemical studies using polyclonal antibodies to Kv1.1–Kv1.5 provided evidence for expression of Kv1.4 in equine chondrocytes. This is the first electrophysiological study of equine or elephant chondrocytes. The data support the notion that voltage-gated potassium channels play an important role in regulating the membrane potential of articular chondrocytes and will prove useful in future modeling of electromechanotransduction of fully differentiated articular chondrocytes in these and other species.

scholarly journals MicroRNA-223 inhibits neutrophil extracellular traps formation through regulating calcium influx and small extracellular vesicles transmission

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tsai-Ling Liao ◽  
Yi-Ming Chen ◽  
Kuo-Tung Tang ◽  
Po-Ku Chen ◽  
Hung-Jen Liu ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Calcium Influx ◽  
Neutrophil Extracellular Traps ◽  
In Vitro Assays ◽  
Unknown Etiology ◽  
Channel Blockers ◽  
Healthy Controls ◽  
Extracellular Traps ◽  
Mitochondrial Ros

AbstractModulation of miRNAs and neutrophil extracellular traps (NETs) formation are both implicated in inflammatory disorders. Adult-onset Still’s disease (AOSD) is a systemic autoinflammatory disease with neutrophilic leukocytosis and unknown etiology. Although the NETs formation is elevated in AOSD patients, the regulatory roles of miRNAs in NETs formation in AOSD remains unclear. We revealed that the circulating levels of IL-18, NETs, and miR-223 were significantly higher in active AOSD patients, compared with inactive AOSD patients or healthy controls (P < 0.005). Moreover, IL-18 increased calcium influx into neutrophils, which led to mitochondrial ROS (mROS) production and NETs formation. Elevated levels of NETs-DNA could induce miR-223 expression in neutrophils through activating Toll-like receptor 9. The upregulated miR-223 expression in neutrophils suppressed mROS production by blocking calcium influx, and subsequently inhibited IL-18-mediated NETs formation. Besides, the increased neutrophil-derived exosomal miR-223 levels were observed in active AOSD patients compared with healthy controls (P < 0.005). Our in vitro assays demonstrated that the neutrophil-derived small extracellular vesicles carried miR-223, which could repress IL-18 production in macrophages. Together, these results suggest a fine-tuned mechanism between inflammatory (IL-18 induced NETs) and anti-inflammatory (miR-223) factors in AOSD. MiR-223, mROS inhibitors, and calcium channel blockers are the potential therapeutics for autoinflammatory diseases such as AOSD.

scholarly journals Preparation of serum capped silver nanoparticles for selective killing of microbial cells sparing host cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rehana Parveen ◽  
Prasanta Kumar Maiti ◽  
Nabendu Murmu ◽  
Alokmay Datta
Keyword(s):  
Silver Nanoparticles ◽  
Mammalian Cells ◽  
Vascular Endothelial Cells ◽  
Host Cells ◽  
Mice Model ◽  
Human Liver Cell ◽  
Wide Range ◽  
Stress Dependent

AbstractFollowing access into the cell, colloidal silver nanoparticles exhibit generalized cytotoxic properties, thus appear as omnipotent microbicidal, but not suitable for systemic use unless are free of toxic effects on host cells. The AgNP-Serum-18 when prepared from silver nitrate, using dextrose as reducing and group-matched homologous serum as a stabilizing agent, selective endocytosis, and oxidative stress-dependent bio-functional damages to the host are mostly eliminated. For their bio-mimicking outer coat, there is the least possibility of internalization into host cells or liberation of excess oxidants in circulation following interaction with erythrocytes or vascular endothelial cells. The presence of infection-specific antibodies in the serum can make such nano-conjugates more selective. A potent antimicrobial action and a wide margin of safety for mammalian cells in comparison with very similar PVA-capped silver nanoparticles have been demonstrated by the in-vitro challenge of such nanoparticles on different microbes, human liver cell-line, and in-vivo study on mice model. This may open up wide-range therapeutic prospects of colloidal nanoparticles.

scholarly journals Preparation of Serum Capped Silver Nanoparticles for Selective Killing of Microbial Cells Sparing Host Cells

2021 ◽  
Author(s):  
Rehana Parveen ◽  
Prasanta Kumar Maiti ◽  
Nabendu Murmu ◽  
Alokmay Datta
Keyword(s):  
Silver Nanoparticles ◽  
Mammalian Cells ◽  
Host Cells ◽  
Mice Model ◽  
Human Liver Cell ◽  
Wide Range ◽  
Margin Of Safety ◽  
Stress Dependent

Abstract Following access into cell, colloidal silver nanoparticles exhibit generalized cytotoxic properties, thus appear as omnipotent microbicidal, but not suitable for systemic use unless are free of toxic effects on host cells. The serum capped silver nanoparticles when prepared from silver nitrate, using dextrose as reducing and group-matched homologous serum as a stabilizing agent, selective endocytosis and oxidative stress dependent bio-functional damages to the host are mostly eliminated. For their bio-mimicking outer coat, there is least possibility of internalization into host-cells or liberation of excess oxidants in circulation following interaction with erythrocytes or vascμμμar endothelial cells. Presence of infection specific antibody in the serum can make such nano-conjugates more selective. A potent antimicrobial action and a wide margin of safety for mammalian cells in comparison with very similar PVA-capped silver nanoparticles have been demonstrated by in-vitro challenge of such nanoparticles on different microbes, human liver cell-line, and in-vivo study on mice model. This may open-up wide-range therapeutic prospects of colloidal nanoparticles.

Mucosal calcium uptake by rat cecum: identity with transcellular calcium absorption

1983 ◽  
Vol 244 (6) ◽  
pp. G618-G622
Author(s):  
H. N. Nellans ◽  
R. S. Goldsmith
Keyword(s):  
Calcium Binding ◽  
Calcium Uptake ◽  
Calcium Absorption ◽  
Calcium Influx ◽  
Maximal Velocity ◽  
Similar Reduction ◽  
High Calcium ◽  
Wide Range ◽  
Rat Cecum

Unidirectional intestinal calcium uptake (JCame) at the mucosal surface of rat cecum was investigated in vitro with intact tissue. Uptake is linear for 2–3 min with no indication of rapid calcium binding. Kinetic parameters reveal a maximal velocity of 333 nmol . cm-2 . h-1 with a half-maximal concentration of 0.98 mM. High-calcium diet decreased JCame by more than 60% with respect to both control and low-calcium diets; 1 mM N-ethylmaleimide caused a similar reduction. The activation energy of JCame is significantly less than that of transepithelial mucosal-to-serosal calcium absorption. Mucosal uptake was compared with transepithelial calcium fluxes in rat cecum and revealed a 1:1 correlation over a wide range of transport rates. These results are interpreted to implicate a feedback control system between basolateral calcium efflux and brush-border calcium influx.

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