Image1_Gasdermin B (GSDMB) in psoriatic patients–a preliminary comprehensive study on human serum, urine and skin.pdf

Psoriasis is one of the most common skin diseases and a crucial issue to manage in contemporary dermatology. The search for the details of its pathogenesis, markers and treatment is continuously ongoing. Our aim was to investigate the role of gasdermin B (GSDMB) in psoriasis, the second protein from the gasdermin family, involved in cell death and proliferation. GSDMB serum and urinary concentrations have never been studied in psoriatics, neither tissue expression of GSDMB by immunohistochemistry. The study included 60 psoriatic patients and 30 volunteers without dermatoses as controls. The serum and urinary GSDMB were evaluated by ELISA. Tissue expression of GSDMB was analyzed by immunohistochemistry. The serum and absolute urine concentrations of GSDMB were significantly higher in psoriatic patients than controls without skin diseases (p = 0.0137, p = 0.039 respectively). Urinary GSDMB/creatinine concentration ratio was significantly lower in patients compared to controls (p = 0.0241). The expression of GSDMB in the dermis and epidermis was significantly more prevalent in psoriatic plaque compared to the non-lesional skin and healthy skin of controls (p = 0.0012, p = 0.017, respectively). Serum GSDMB correlated positively with the age of patients (R = 0.41; p = 0.001). Our study adds to the current state of knowledge about psoriasis concerning the potential involvement of GSDMB. Possibly it could be engaged in keratinocytes migration, which requires further research. Elevated serum GSDMB and decreased urinary GSDMB/creatinine concentration ratio could potentially be investigated as psoriasis biomarkers. GSDMB could be investigated in the future as a potential therapeutic target.</p

Femoral length and biomechanical properties of the femur of control and chronic kidney disease (CKD) rats evaluated by the three-point bending test (A) and the bending test of the femoral neck (B).

<p>Femoral length and biomechanical properties of the femur of control and chronic kidney disease (CKD) rats evaluated by the three-point bending test (A) and the bending test of the femoral neck (B).</p

¹⁷⁷Lu Labeled Cyclic Minigastrin Analogues with Therapeutic Activity in CCK2R Expressing Tumors: Preclinical Evaluation of a Kit Formulation

Minigastrin (MG) analogues specifically target cholecystokinin-2 receptors (CCK2R) expressed in different tumors and enable targeted radiotherapy of advanced and disseminated disease when radiolabeled with a beta emitter such as ¹⁷⁷Lu. Especially truncated MG analogues missing the penta-Glu sequence are associated with low kidney retention and seem therefore most promising for therapeutic use. Based on [d-Glu¹,desGlu^2–6]­MG (MG11) we have designed the two cyclic MG analogues cyclo^1,9[γ-d-Glu¹,desGlu^2–6,d-Lys⁹]­MG (cyclo-MG1) and cyclo^1,9[γ-d-Glu¹,desGlu^2–6,d-Lys⁹,Nle¹¹]­MG (cyclo-MG2). In the present work we have developed and preclinically evaluated a pharmaceutical kit formulation for the labeling with ¹⁷⁷Lu of the two DOTA-conjugated cyclic MG analogues. The stability of the kits during storage as well as the stability of the radiolabeled peptides was investigated. A cell line stably transfected with human CCK2R and a control cell line without receptor expression were used for <i>in vitro</i> and <i>in vivo</i> studies with the radioligands prepared from kit formulations. In terms of stability ¹⁷⁷Lu-DOTA-cyclo-MG2 showed advantages over ¹⁷⁷Lu-DOTA-cyclo-MG1. Still, for both radioligands a high receptor-mediated cell uptake and favorable pharmacokinetic profile combining receptor-specific tumor uptake with low unspecific tissue uptake and low kidney retention were confirmed. Investigating the therapy efficacy and treatment toxicity in xenografted BALB/c nude mice a receptor-specific and comparable therapeutic effect could be demonstrated for both radioligands. A 1.7- to 2.6-fold increase in tumor volume doubling time was observed for receptor-positive tumors in treated versus untreated animals, which was 39–73% higher when compared to receptor-negative tumors. The treatment was connected with transient bone marrow toxicity and minor signs of kidney toxicity. All together the obtained results support further studies for the clinical translation of this new therapeutic approach

Body weight and biochemical parameters in controls and chronic kidney disease (CKD) rats after one and three months of disease progression.

<p>Body weight and biochemical parameters in controls and chronic kidney disease (CKD) rats after one and three months of disease progression.</p

The correlations between serum alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase form 5b (TRACP 5b) activities and biomechanical parameters of the femur of CKD rats: A–three-point bending test (n = 22), B–bending test of the femoral neck (n = 22).

<p>The correlations between serum alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase form 5b (TRACP 5b) activities and biomechanical parameters of the femur of CKD rats: A–three-point bending test (n = 22), B–bending test of the femoral neck (n = 22).</p

Representative images of the proximal tibia of controls and CKD rats after 1 and 3 months of CKD indication.

<p>(A) Spongy bone and (B) compact bone in tibia of the CON-1 rat; (C) Spongy bone of CKD-1 rat. Visible an increase in osteoclast surface and an increase in eroded surface of trabecular bone (arrow); (D) The increase in osteoclasts surface (arrows) in compact bone of CKD-1 rat; (E) Spongy bone and (F) compact bone in tibia of CON-3 rat; (G) The significant increase in the osteoclast surface (arrow) and the erosion of trabecular bone in CKD-3 rat; (H) areas of osteoclastic activity in compact bone (arrows) in CKD-3 rat (HE staining, magnification x200, x400).</p

The histological changes in the kidney tissue 4 weeks after subtotal nephrectomy.

<p>(A) The intact kidney from sham-operated rat; (B-E) the renal stump of subtotal nephrectomized rat 4 weeks after CKD induction; (B) moderate glomerulosclerosis (C), strong tubular atrophy (D), focal interstitial fibrosis (E) focal interstitial lymphocytic infiltration (HE staining, magnification x200, x400).</p

The Association between Elevated Levels of Peripheral Serotonin and Its Metabolite – 5-Hydroxyindoleacetic Acid and Bone Strength and Metabolism in Growing Rats with Mild Experimental Chronic Kidney Disease - Fig 3

<p><b>The changes in 5-HT (panel A), 5-HIAA (panel B) levels, the ratio of 5-HT/TRP (panel C), the ratio of 5-HIAA/5-HT (panel D) and the results of two-way ANOVA with Bonferroni post hoc test (panel E) in controls and appropriate chronic kidney disease (CKD) rats.</b> Data are mean ±SD, n = 11 in each group. Abbreviations: CKD = Chronic Kidney Disease, CON = Controls, 5-HT = serotonin, 5-HIAA = 5-hydroxyindoleacetic acid, TRP = tryptophan; *p<0.05, **p<0.01, *** p<0.001 controls versus appropriate CKD group; #p<0.05 CKD-1 versus CKD-3.</p

Anticoagulant Properties of Poly(sodium 2‑(acrylamido)-2-methylpropanesulfonate)-Based Di- and Triblock Polymers

Di- and triblock copolymers with low dispersity of molecular weight were synthesized using radical addition–fragmentation chain transfer polymerization. The copolymers contained anionic poly­(sodium 2-acrylamido-2-methylpropanesulfonate) (PAMPS) block as an anticoagulant component. The block added to lower the toxicity was either poly­(ethylene glycol) (PEG) or poly­(2-(methacryloyloxy)­ethyl phosphorylcholine) (PMPC). The polymers prolonged clotting times both in vitro and in vivo. The influence of the polymer architecture and composition on the efficacy of anticoagulation and safety parameters was evaluated. The polymer with the optimal safety/efficacy profile was PEG47-<i>b</i>-PAMPS108, i.e., a block copolymer with the degrees of polymerization of PEG and PAMPS blocks equal to 47 and 108, respectively. The anticoagulant action of copolymers is probably mediated by antithrombin, but it differs from that of unfractionated heparin. PEG47-<i>b</i>-PAMPS108 also inhibited platelet aggregation in vitro and increased the prostacyclin production but had no antiplatelet properties in vivo. PEG47-<i>b</i>-PAMPS108 anticoagulant activity can be efficiently reversed with a copolymer of PEG and poly­((3-(methacryloylamino)­propyl)­trimethylammonium chloride) (PMAPTAC) (PEG41-<i>b</i>-PMAPTAC53, HBC), which may be attributed to the formation of polyelectrolyte complexes with PEG shells without anticoagulant properties

Binding of UFH by the cationic polymers.

<p>Dependence of free UFH concentration on the concentration of Dex6-GTMAC expressed as the ratio of the Dex6-GTMAC mass and total UFH mass. Data for protamine are shown for comparison.</p