Comparison of metabolic and mitogenic response in vitro of the rapid-acting insulin lispro product SAR342434, and US- and EU-approved Humalog®

Abstract Kynurenic acid (KYNA), an endogenous neuroprotectant formed along the kynurenine pathway of tryptophan degradation, is a selective ligand of the GPR35 receptor, which can be found on the surface of various populations of human immune cells. In infections and inflammations, KYNA produces an anti-inflammatory effect through this receptor, by depressing the synthesis of reactive oxygen species and pro-inflammatory cytokines. However, it is still unrecognized whether receptors for kynurenic acid are also localized on immune cells of poikilothermic animals, or whether KYNA is able to affect these cells. The objective of this study has been to determine the effect of different concentrations of kynurenic acid (12.5 μM to 10 mM) on the viability and mitogenic response of lymphocytes and on the activity of phagocytic cells isolated from blood and the spleen of rainbow trout. The results imply low toxicity of kynurenic acid towards fish immune cells, and the proliferative effect observed at the two lowest concentrations of KYNA (12.5 μM and 25 μM) seems indicative of endogenous kynurenic acid being capable of activating fish lymphocytes. Non-toxic, micromole concentrations of KYNA, however, had no influence on the mitogenic response of lymphocytes nor on the activity of phagocytes in rainbow trout under in vitro conditions. There is some likelihood that such an effect could be observed at lower, nanomole concentrations of KYNA.

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Protamine enhances the proliferative activity of hepatocyte growth factor in rats

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1998.274.1.g21 ◽

1998 ◽

Vol 274 (1) ◽

pp. G21-G28 ◽

Cited By ~ 1

Author(s):

Ke-Xin Liu ◽

Yukio Kato ◽

Tai-Ichi Kaku ◽

Kunio Matsumoto ◽

Toshikazu Nakamura ◽

...

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Proliferative Activity ◽

Plasma Clearance ◽

Mitogenic Response ◽

Enhancing Effect ◽

A Cell ◽

Hepatocyte Growth

The effect of protamine on the proliferative activity of hepatocyte growth factor (HGF) was examined in α-naphthyl isothiocyanate-intoxicated rats. Protamine preinjection increased the hepatocyte labeling index induced by HGF four- to fivefold. A similar effect was also observed in partially hepatectomized rats. Because a cell surface heparin-like substance can bind to HGF and protamine has an affinity for heparin, protamine may affect HGF pharmacokinetics. In fact, protamine injection caused a transient increase in plasma HGF concentrations after administration of HGF and, in vitro, protamine eluted HGF prebound to heparin-Sepharose. Protamine also reduced the plasma clearance of HGF and increased 2.5-fold the exposure of hepatocytes to HGF in vivo. The enhancing effect of protamine on the mitogenic response of hepatocytes to HGF was also observed in vitro (∼2-fold after protamine pretreatment compared with HGF alone), suggesting that the enhancing effect of protamine on HGF-induced liver regeneration results from dual effects exerted by protamine 1) lowering the overall elimination of HGF and 2) directly stimulating hepatocyte mitosis induced by HGF.

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An ultrafast insulin formulation enabled by high-throughput screening of engineered polymeric excipients

Science Translational Medicine ◽

10.1126/scitranslmed.aba6676 ◽

2020 ◽

Vol 12 (550) ◽

pp. eaba6676 ◽

Cited By ~ 3

Author(s):

Joseph L. Mann ◽

Caitlin L. Maikawa ◽

Anton A. A. Smith ◽

Abigail K. Grosskopf ◽

Sam W. Baker ◽

...

Keyword(s):

High Throughput ◽

Insulin Lispro ◽

High Throughput Screening ◽

Amyloid Fibrils ◽

Tight Glycemic Control ◽

Duration Of Action ◽

Acting Insulin ◽

Insulin Formulation ◽

Patients With Diabetes ◽

Aging Conditions

Insulin has been used to treat diabetes for almost 100 years; yet, current rapid-acting insulin formulations do not have sufficiently fast pharmacokinetics to maintain tight glycemic control at mealtimes. Dissociation of the insulin hexamer, the primary association state of insulin in rapid-acting formulations, is the rate-limiting step that leads to delayed onset and extended duration of action. A formulation of insulin monomers would more closely mimic endogenous postprandial insulin secretion, but monomeric insulin is unstable in solution using present formulation strategies and rapidly aggregates into amyloid fibrils. Here, we implement high-throughput–controlled radical polymerization techniques to generate a large library of acrylamide carrier/dopant copolymer (AC/DC) excipients designed to reduce insulin aggregation. Our top-performing AC/DC excipient candidate enabled the development of an ultrafast-absorbing insulin lispro (UFAL) formulation, which remains stable under stressed aging conditions for 25 ± 1 hours compared to 5 ± 2 hours for commercial fast-acting insulin lispro formulations (Humalog). In a porcine model of insulin-deficient diabetes, UFAL exhibited peak action at 9 ± 4 min, whereas commercial Humalog exhibited peak action at 25 ± 10 min. These ultrafast kinetics make UFAL a promising candidate for improving glucose control and reducing burden for patients with diabetes.

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The in vitro effects of Bordetella pertussis lymphocytosis-promoting factor on murine lymphocytes: II. Nature of the responding cells.

Journal of Experimental Medicine ◽

10.1084/jem.145.1.163 ◽

1977 ◽

Vol 145 (1) ◽

pp. 163-174 ◽

Cited By ~ 12

Author(s):

A S Kong ◽

S I Morse

Keyword(s):

T Cells ◽

Bordetella Pertussis ◽

T Cell Response ◽

Adherent Cells ◽

Phagocytic Cells ◽

Mitogenic Response ◽

Con A ◽

Surface Receptors ◽

In Vitro Effects

The mitogenic response of murine lymphocytes to the lymphocytosis-promoting factor of Bordetella pertussis has been shown to be due to activation of T cells. The selectivity of responsiveness to LPF with respect to the population of T cells which is stimllated, differs from that of PHA as well as Con A, and the surface receptors are different. A population of adherent cells, which does not appear to consist of macrophages or other phagocytic cells, is required for the T-cell response.

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Effect of Karasurin-A on Nitric Oxide Production by Murine Macrophages and Mitogenic Response of Murine Splenocytes in Vitro.

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.20.435 ◽

1997 ◽

Vol 20 (4) ◽

pp. 435-437 ◽

Cited By ~ 5

Author(s):

Kiyoshi TERAWAKI ◽

Mitsuhiko NOSE ◽

Toshiya KONDO ◽

Keisuke KOJIMA ◽

Hajime MIZUKAMI ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Production ◽

Mitogenic Response ◽

Murine Splenocytes ◽

Murine Macrophages ◽

Oxide Production

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PROMOTION OF REPLICATION IN LYMPHOID CELLS BY SPECIFIC THIOLS AND DISULFIDES IN VITRO

Journal of Experimental Medicine ◽

10.1084/jem.138.3.574 ◽

1973 ◽

Vol 138 (3) ◽

pp. 574-592 ◽

Cited By ~ 164

Author(s):

J. D. Broome ◽

M. W. Jeng

Keyword(s):

Culture Media ◽

Growth Promotion ◽

Lymphoid Cells ◽

Splenic Lymphocytes ◽

Mitogenic Response ◽

Lymphoma Cells ◽

Structure Activity ◽

Standard Culture ◽

Increased Sensitivity

Numerous lines of mouse lymphoid tumors (13 of 22 tested) showed, with increased sensitivity, a property of normal mouse splenic lymphocytes, the potential for growth promotion in vitro by specific thiols added to standard culture media. For lymphoma L1210 (V), structure activity relationships were examined; 9 of 30 thiols promoted growth; the most active was α-thioglycerol, effective at 0.2 µM. Thiols became oxidized under conditions of tissue culture and had half-lives of less than 8 h. Disulfides of active thiols promoted growth of lymphoma cells. The mitogenic response of splenic lymphocytes to lectins was increased by thiols-disulfides which promoted the growth of lymphoma cells, but the response varied with the mitogen preparation used and under some conditions thiols-disulfides were inhibitory.

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