Reverse switching from the biosimilar SB2 to the originator infliximab in previously switched patients with inflammatory bowel diseases: results of a prospective long-term cohort study.

Background: Data regarding multiple switches including reverse switching between infliximab and its biosimilars are scarce in the field of inflammatory bowel diseases (IBD).

Objectives: We investigated the clinical effectiveness as primary outcome measure after repeated switches. Secondary endpoints included C-reactive protein (CRP) levels, immunogenicity (trough levels (TL); anti-drug antibodies (ADA), safety and drug persistence.

NLRP3 Inhibition Leads to Impaired Mucosal Fibroblast Function in Patients with Inflammatory Bowel Diseases.

Background And Aims: Inflammatory bowel diseases (IBD) are characterized by mucosal inflammation and sequential fibrosis formation, but the exact role of the hyperactive NLRP3 inflammasome in these processes is unclear. Thus, we studied the expression and function of the NLRP3 inflammasome in the context of inflammation and fibrosis in IBD.

Methods: We analysed intestinal NLRP3 expression in mucosal immune cells and fibroblasts from IBD patients and NLRP3-associated gene expression via single-cell RNA sequencing and microarray analyses.

Bistacrine derivatives as new potent antimalarials.

Linking two tacrine molecules results in a tremendous increase of activity against Plasmodia in comparison to the monomer. This finding prompted the synthesis of a library of monomeric and dimeric tacrine derivatives in order to derive structure-activity relationships. The most active compounds towards chloroquine sensitive Plasmodium strain 3D7 and chloroquine resistant strain Dd2 show IC50 values in the nanomolar range of concentration, low cytotoxicity and target the cysteine protease falcipain-2, which is essential for parasite growth.

Malaria proteases mediate inside-out egress of gametocytes from red blood cells following parasite transmission to the mosquito.

Malaria parasites reside in human erythrocytes within a parasitophorous vacuole. The parasites are transmitted from the human to the mosquito by the uptake of intraerythrocytic gametocytes during a blood meal, which in the midgut become activated by external stimuli and subsequently egress from the enveloping erythrocyte. Gametocyte egress is a crucial step for the parasite to prepare for fertilization, but the molecular mechanisms of egress are not well understood.

Thiostrepton and derivatives exhibit antimalarial and gametocytocidal activity by dually targeting parasite proteasome and apicoplast.

Ribosome-targeting antibiotics exert their antimalarial activity on the apicoplast of the malaria parasite, an organelle of prokaryote origin having essential metabolic functions. These antibiotics typically cause a delayed-death phenotype, which manifests in parasite killing during the second replication cycle following administration. As an exception, treatment with the antibiotic thiostrepton results in an immediate killing.

Malaria parasites form filamentous cell-to-cell connections during reproduction in the mosquito midgut.

Physical contact is important for the interaction between animal cells, but it can represent a major challenge for protists like malaria parasites. Recently, novel filamentous cell-cell contacts have been identified in different types of eukaryotic cells and termed nanotubes due to their morphological appearance. Nanotubes represent small dynamic membranous extensions that consist of F-actin and are considered an ancient feature evolved by eukaryotic cells to establish contact for communication.

The bisnaphthalimides as new active lead compounds against Plasmodium falciparum.

The bisquaternary bisnaphthalimides are a versatile class of compounds being active against the malaria parasite Plasmodium falciparum in the lower nanomolar range of concentration combined with no cytotoxicity. The series of compounds is designed as choline analogues and interfering agents of the phosphatidylcholine biosynthesis. The qualitative analysis of the structure-activity relationships (SAR) revealed the importance of a long methylene middle chain of at least 8 methylene groups between the two bisquaternary naphthalimides or a monoquaternary naphthalimide consisting of a long alkyl chain attached to the positively charged nitrogen atom.

[Insulin-degrading neutral protease from plasma membranes of rat liver cells and erythrocytes].

Insulin-degrading neutral proteinase with molecular weight of 70 kDa was partly purified from the rat liver and erythrocyte plasma membranes. Incubation of membranes with [gamma-32P]ATP resulted in the enzyme phosphorylation. Intensity of this process greatly increased in the presence of insulin (100 microU/ml), and correlated with the elevation of the insulin-degrading activity in proteinase.

[Phosphorylation of lactate dehydrogenase by purified plasma membranes of loach liver cells: stimulation with insulin].

It is established that insulin enhances the ability of the loach liver plasma membranes to phosphorylate lactate dehydrogenase. In the case of insulin-treated plasma membranes the amount of incorporated 32P is more than 4 times higher than that of the basal level. It is concluded that insulin-stimulated plasma membrane-dependent phosphorylation of the enzyme is one of the possible molecular mechanisms of hormone action on intracellular metabolism.

[Insulin-degrading neutral proteinases of the plasma membrane of loach liver and embryo cells].

Insulin-degrading, Ca2+-activated, neutral proteinases of molecular weight about 150 kDa and 70 kDa were purified from plasma membranes of the loach liver and embryo cells. It was shown that dithiothreitol and cysteine enhanced the enzyme activity, whereas p-chloromercuribenzoate and iodoacetic acid inhibited its level. Incubation of isolated plasma membranes with 5'[gamma 32P]ATP resulted in phosphorylation of these proteinases.

[Protein fractions of the ova, embryos and skeletal muscles of the loach affecting the stability and activity of lactate dehydrogenase].

When lactate dehydrogenase obtained from Misgurnus muscles and purified to the homogeneous state is incubated for 16 hat 38 degrees C, its activity lowers down to 10% of the initial value. Extracts of egg cells, embryos or skeletal muscles of the mentioned fish species added to the enzyme solution decrease considerably its inactivation. Proteins stabilizing the activity of lactate dehydrogenase are revealed in the supernatant liquid obtained after salting out of the above extracts with 60% sulphate ammonium saturation.

[Proteolysis in the cells of malignant human and animal tumors].

The data concerning proteolytic enzymes in human and animal malignant tumours are reviewed. The activity of these proteinases, its changes in the course of the disease, intracellular localization and secretion into the extracellular space and blood are discussed. The role of proteolytic enzymes including the role of plasminogen activator in tumour progress and during the metastasis development is considered.

[Properties of cathepsin D from unfertilized eggs, embryos and skeletal muscles of the loach].

The action and some properties of cathepsin D, partly purified from unfertilized loach eggs, embryos and skeletal muscles were determined. The enzyme from embryo cells displays the activity maximum at pH 3.0 and pH 4.

[Insulin and 17-oxycorticosteroids in unfertilized eggs and in embryos of the loach].

Loach eggs are stated to possess some quantities of insulin or insulin-like substances with a positive reaction to antiinsulin antiserum. The level of these components is five times as high 30 minutes after fertilization, and does not change for the next 20 hours of the embryo development. No 17-oxycorticosteroids were detected in loach eggs and embryos during first four hours of the development; they appeared only at the blastula stage and at the state of gastrula their level increases considerably.

[Effect of extracts from loach eggs and embryos exposed to insulin on glucose-6-phosphate dehydrogenase activity].

It is established that the incubation of glucose-6-phosphate dehydrogenase solution (33 micrograms of enzymic protein per 1 ml) with extracts of unfertilized loach eggs and embryos results in a marked stabilization of the enzyme with respect to its inactivation. Extracts from the embryos preliminary affected by insulin possessed a lower stabilizing ability, the hormonal effect being removed to a considerable extent by actinomycin D and cycloheximide.

[Proteolytic activity in unfertilized eggs and embryos of the loach under the effect of insulin].

The paper deals with studies in proteolytic activity of loach eggs and embryos incubated in water and in insulin solutions. It is established that after fertilization the above-mentioned activity level increased considerably, but even at the cleavage stage of embryo development it is 7-10 times as low as in the liver and 3-5 times as low as in the skeletal muscle tissue of the adults. After incubation of unfertilized eggs in insulin solutions at relatively low concentrations (0.

[Influence of loach egg- and embryo-extract on the activity of lactate dehydrogenase in the presence of insulin].

Studies of the pig muscle lactate dehydrogenase (LDH) activity were permormed after incubating the enzyme solution with extracts of loach (Misgurnus fossilis) eggs and embryos, which were subjected to the influence of insulin hydrocortisone as well as to insulin combination with actinomycin D, cycloheximide or puromycin. The insulin alone is established to decrease the inactivating ability of the investigated extracts on the lactate dehydrogenase activity, when antibiotics removed to a considerable extent the influence of hormone. In the eggs and embryos there are proteins activating and stabilizing the LDH molecule.

[Effect of insulin on activity of carbohydrate metabolism enzymes in loach embryos in early development].

It is established that in embryos incubated until the early blastula stage in the solution of insulin with addition of cycloheximide or puromycin, there is neither a decrease in the hexokinase and glucose-61 phosphate dehydrogenase activities nor an increase in the phosphofructokinase activity, as it is shown under the influence of insulin only. Puromycin removes an inhibitory effect of insulin on the glucose-6-phosphatase activity, and actinomycin D removes this influence with respect to glucose-6-phosphate dehydrogenase and glucose-6-phosphatase activities. The addition of antibiotics removes inhibition of the hexokinase, glucose-6-phosphate dehydrogenase and glucose-6-phosphatase activities by the hormone in the unfertilized eggs as well.

[Activity of carbohydrate metabolism enzymes in loach embryos under the influence of hormones].

The activities of hexokinase, glucokinase, phosphofructokinase, glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, and fructose-1,6-diphosphatase were determined in loach embryos developed in solutions of insulin, hydrocortisone, estrone and thyroxin at different stages of embryogenesis. Glucokinase and fructose-1,6-diphosphatase activties are shown not to change markedly under the influence of the above-mentioned hormones. During some periods of early development the hexokinase activity is inhibited by insulin, estrone and thyroxin.

[State of the sympathetic-adrenal system in newborn infants (clinico-biochemical comparisons)].

A study was made of urinary catecholamine excretion in 102 newborn boys on the 1st-8th day after birth. Depending on the state at birth neonates were divided into 2 groups: the 1st group included babies born in satisfactory condition (60), and the 2nd group - at the state of mild asphyxia. Catecholamines were determined on the 1st-2nd, 3rd-5th, and 6th-8th days after birth.