Introducing the Biosimilar Paradigm to Neurology: The Totality of Evidence for the First Biosimilar Natalizumab.

A biosimilar medicine is a successor to a reference ('originator'/'original-brand') biologic medicine brought to market once the patent and exclusive marketing rights for the reference have expired. Biosimilar natalizumab (PB006 [biosim-NTZ]; developed by Polpharma Biologics S.A.

Göttingen pigs as a potential model for natalizumab pharmacokinetics, pharmacodynamics, and immunogenicity evaluation.

Natalizumab is a recombinant, humanized form of a monoclonal antibody that binds to CD49d. The presented study was conducted to explore the suitability of Göttingen pigs as a pharmacokinetic/pharmacodynamic model in the preclinical phase of biosimilar natalizumab development. The minipigs were treated with 1.

Ustekinumab pharmacokinetics after subcutaneous administration in swine model.

Background: Due to multiple similarities in the structure and physiology of human and pig skin, the pig model is extremely useful for biological drug testing after subcutaneous administration. Knowledge of the differences between subcutaneous injection sites could have a significant impact on the absorption phase and pharmacokinetic profiles of biological drugs.

Objectives: This study aimed to analyze the impact of administration site on pharmacokinetics and selected biochemical and hematological parameters after a single subcutaneous administration of ustekinumab in pigs.

Myoblast-conditioned media improve regeneration and revascularization of ischemic muscles in diabetic mice.

Introduction: Diabetes is associated with reduced expression of heme oxygenase-1 (HO-1), a heme-degrading enzyme with cytoprotective and proangiogenic properties. In myoblasts and muscle satellite cells HO-1 improves survival, proliferation and production of proangiogenic growth factors. Induction of HO-1 in injured tissues facilitates neovascularization, the process impaired in diabetes.

PPARγ activation but not PPARγ haplodeficiency affects proangiogenic potential of endothelial cells and bone marrow-derived progenitors.

Background: Peroxisome proliferator-activated receptor-γ (PPARγ) agonists, which have been used as insulin sensitizers in diabetic patients, may improve functions of endothelial cells (ECs). We investigated the effect of PPARγ on angiogenic activities of murine ECs and bone marrow-derived proangiogenic cells (PACs).

Methods: PACs were isolated from bone marrow of 10-12 weeks old, wild type, db/db and PPARγ heterozygous animals.

Proinsulin C-peptide potentiates the inhibitory action of insulin on glucose synthesis in primary cultured rabbit kidney-cortex tubules: metabolic studies.

Effects of equimolar concentrations of proinsulin C-peptide and insulin on glucose synthesis were studied in primary cultures of rabbit kidney-cortex tubules grown in the presence of alanine, glycerol, and octanoate. The rhodamine-labeled C-peptide entered renal tubular cells and localized in nuclei, both in the presence and absence of insulin; preincubations with the unlabeled compound inhibited internalization. C-peptide did not affect glucose formation when added alone but potentiated the inhibitory action of insulin by about 20% due to a decrease in flux through glucose-6-phosphate isomerase (GPI) and (or) glucose-6-phosphatase (G6Pase).

Molecular identification of carnosine N-methyltransferase as chicken histamine N-methyltransferase-like protein (hnmt-like).

Anserine (beta-alanyl-N(Pi)-methyl-L-histidine), a naturally occurring derivative of carnosine (beta-alanyl-L-histidine), is an abundant constituent of skeletal muscles and brain of many vertebrates. Although it has long been proposed to serve as a proton buffer, radicals scavenger and transglycating agent, its physiological function remains obscure. The formation of anserine is catalyzed by carnosine N-methyltransferase which exhibits unknown molecular identity.

[Nuclear receptors PPAR as a drug target in metabolic disorders].

Nuclear receptors regulate many basic cellular processes and their malfunction can lead to serious consequences including metabolic disorders, obesity and type 2 diabetes. Among many nuclear receptor families, the best known for their therapeutic use are the PPARs. These are key transcription factors determining, proper cellular metabolism of glucose and lipids, tissue sensitivity to insulin, appropriate immune responses including inflammatory processes and finally cell division and differentiation.

[The mechanism of insulin resistance in peripheral tissues].

Chronic metabolic and cardiovascular diseases, described as the epidemics of XXI century, are connected to the resistance of peripheral tissues, such as liver, muscle and fat, to insulin. Insulin resistance, which precedes the development of type 2 diabetes by several years, is difficult to diagnose, mainly because of practical limitations to the use of "gold standard" hyperinsulinemic euglycemic clamp technique for screening. It is also begins a certain vicious circle, in which insulin resistant peripheral tissues force pancreatic beta cells to increased insulin release, and sustained high concentrations of insulin cause further development of insulin resistance.

Heme oxygenase-1 inhibits myoblast differentiation by targeting myomirs.

Aims: Heme oxygenase-1 (HMOX1) is a cytoprotective enzyme degrading heme to biliverdin, iron ions, and carbon monoxide, whose expression is induced in response to oxidative stress. Its overexpression has been suggested as a strategy improving survival of transplanted muscle precursors.

Results: Here we demonstrated that HMOX1 inhibits differentiation of myoblasts and modulates miRNA processing: downregulates Lin28 and DGCR8, lowers the total pool of cellular miRNAs, and specifically blocks induction of myomirs.

Combined vascular endothelial growth factor-A and fibroblast growth factor 4 gene transfer improves wound healing in diabetic mice.

Background: Impaired wound healing in diabetes is related to decreased production of growth factors. Hence, gene therapy is considered as promising treatment modality. So far, efforts concentrated on single gene therapy with particular emphasis on vascular endothelial growth factor-A (VEGF-A).

PPAR-gamma-independent inhibitory effect of rosiglitazone on glucose synthesis in primary cultured rabbit kidney-cortex tubules.

Therapeutic effect of rosiglitazone has been reported to result from an improvement of insulin sensitivity and inhibition of glucose synthesis. As the latter process occurs in both liver and kidney cortex the aim of this study was to elucidate the rosiglitazone action on glucose formation in both tissues. Primary cultured cells of both liver and kidney cortex grown in defined medium were use throughout.

Differential effects of selegiline on glucose synthesis in rabbit kidney-cortex tubules and hepatocytes. In vitro and in vivo studies.

The action of selegiline, a selective and irreversible inhibitor of monoamine oxidase B, commonly applied in the therapy of Parkinson's disease, on glucose formation was investigated in isolated rabbit hepatocytes and kidney-cortex tubules, maintaining the whole body glucose homeostasis via gluconeogenic pathway activity. An intensive hepatic metabolism of selegiline resulted in formation of selegiline-N-oxide, desmethylselegiline, methamphetamine and amphetamine, whereas during slow degradation of the drug in freshly isolated renal tubules selegiline-N-oxide was mainly produced. At 100 microM concentration selegiline markedly diminished glucose synthesis in isolated renal tubules incubated with dihydroxyacetone or alanine+glycerol+octanoate (by about 60 and 30%, respectively), while at 5 microM concentration a similar degree of inhibition was achieved in renal tubules grown in primary culture under the same conditions (about 40 and 60%, respectively).

Expression of murine DNA methyltransferases Dnmt1 and Dnmt3a in the yeast Saccharomyces cerevisiae.

Murine DNA methyltransferases Dnmt1 and Dnmt3a were expressed in the yeast Saccharomyces cerevisiae. Adjustment to yeast preferences of the nucleotide sequences upstream and downstream of the translation initiation sites of both cDNAs was needed to obtain significant levels of the methyltransferases. Both proteins were correctly localized to the nucleus and their presence had no measurable influence on the functioning of yeast cells.

Melatonin is more effective than taurine and 5-hydroxytryptophan against hyperglycemia-induced kidney-cortex tubules injury.

The antioxidative effects of melatonin (Mel), 5-hydroxytryptophan (5-HTP) and taurine (TAU) on hyperglycemia-induced oxidative stress was investigated in primary cultures of kidney-cortex tubule cells grown in metabolically and hormonally defined medium. In the presence of 30 mm glucose (hyperglycemic conditions), cell viability was decreased by about 35% in comparison with that estimated in the glucose-depleted medium probably as a result of induction of apoptosis, as concluded from: (i) chromatin condensation and DNA fragmentation assays, (ii) a significant enhancement of reactive oxygen species (ROS) production, (iii) 8-hydroxydeoxyguanosine (8-OHdG) generation, (iv) an increased protein peroxidation and (v) a decline of reduced glutathione (GSH) levels leading to a disturbed glutathione redox state. The addition of 100 microm Mel to the hyperglycemic medium resulted in a twofold decrease in both 8-OHdG accumulation and protein peroxidation as well as restoration of the control intracellular ROS levels accompanied by a substantial increase in GSH/oxidized glutathione (GSSG) ratio due to a decline in GSSG content.

Differential effects of selenium compounds on glucose synthesis in rabbit kidney-cortex tubules and hepatocytes. In vitro and in vivo studies.

Although selenium is taken with diet mainly as selenoamino acids, its hypoglycaemic action on hepatic gluconeogenesis has been studied with the use of inorganic selenium derivatives. The aim of the present investigation was to compare relative efficacies of inorganic and organic selenium compounds in reducing glucose synthesis in hepatocytes and renal tubules, significantly contributing to the glucose homeostasis. In contrast to hepatocytes, both selenite and methylselenocysteine inhibited renal gluconeogenesis by about 40-45% in control rabbits.

Melatonin-induced modulation of glucose metabolism in primary cultures of rabbit kidney-cortex tubules.

The effect of melatonin on glucose metabolism in the presence and absence of insulin has been investigated in the primary cultures of renal tubules grown in a defined medium. In the absence of glucose in the medium containing 5 microg/mL of insulin and 2 mm alanine + 5 mm glycerol + 0.5 mm octanoate, 100 nm melatonin stimulated both glucose and lactate synthesis, while in the medium devoid of insulin melatonin action was negligible.

The role of intracellular cAMP in renal gluconeogenesis in view of differential action of various cAMP analogues.

Effects of various cAMP analogues on gluconeogenesis in isolated rabbit kidney tubules have been investigated. In contrast to N(6),2'-O-dibutyryladenosine-3',5'-cyclic monophosphate (db-cAMP) and cAMP, which accelerate renal gluconeogenesis, 8-bromoadenosine-3',5'-cyclic monophosphate (Br-cAMP) and 8-(4-chlorophenylthio)-cAMP (pCPT-cAMP) inhibit glucose production. Stimulatory action of cAMP and db-cAMP may be evoked by butyrate and purinergic agonists generated during their extracellular and intracellular metabolism resulting in an increase in flux through fructose-1,6-bisphosphatase and in consequence acceleration of the rate of glucose formation.

Amino-acid-dependent, differential effects of ethanol on glucose production in rabbit kidney-cortex tubules.

Aims: The effect of ethanol on glucose synthesis in kidney-cortex tubules of control and diabetic rabbits has been investigated.

Methods: Both freshly isolated and grown in primary cultures, kidney-cortex tubules were incubated with alanine or aspartate plus lactate or glycerol plus octanoate in the absence and presence of 100 mmol/l ethanol.

Results: In freshly isolated renal tubules incubated in the presence of alanine plus lactate or glycerol plus octanoate, and in tubules grown in primary culture in the medium containing alanine plus lactate plus octanoate alcohol, resulted in about 30% decrease in glucose formation.

Activation of human topoisomerase I by protein kinase CK2.

The enzymatic studies were performed to reveal a mode of activation of human topoisomerase I by a direct interaction with protein kinase CK2. In the absence of ATP CK2 kinase activated DNA relaxation about twofold. CK2alpha subunit was identified as solely responsible for the stimulation of relaxing activity by CK2 kinase.

Purinergic regulation of glucose and glutamine synthesis in isolated rabbit kidney-cortex tubules.

The effects of extracellular purinergic agonists and their breakdown products on glucose and glutamine synthesis in rabbit kidney-cortex tubules incubated with aspartate + glycerol or alanine + glycerol + octanoate were investigated. A rapid extracellular degradation of ATP was accompanied by an accumulation of AMP, inosine, and hypoxanthine. Extracellular ATP and its breakdown products accelerated glucose synthesis in renal tubules, while ammonium released from adenine-containing compounds enhanced glutamine synthesis and diminished the degree of gluconeogenesis stimulation.