Betula pendula Leaf Extract Targets the Interplay between Brain Oxidative Stress, Inflammation, and NFkB Pathways in Amyloid Aß1-42-Treated Rats.

Alzheimer's disease (AD) is known as the primary and most common cause of dementia in the middle-aged and elderly population worldwide. Chemical analyses of B. pendula leaf extract (BPE), performed using spectrophotometric and chromatographic methods (LC/MS), revealed high amounts of polyphenol carboxylic acids (gallic, chlorogenic, caffeic, trans-p-coumaric, ferulic, and salicylic acids), as well as flavonoids (apigenin, luteolin, luteolin-7-O-glucoside, naringenin, hyperoside, quercetin, and quercitrin). Four groups of Wistar rats were used in this experiment (n = 7/group): control (untreated), Aß1-42 (2 µg/rat intracerebroventricular (i.c.v.), Aß1-42 + BPE (200 mg/Kg b.w.), and DMSO (10 µL/rat). On the first day, one dose of Aß1-42 was intracerebroventricularly administered to animals in groups 2 and 3. Subsequently, BPE was orally administered for the next 15 days to group 3. On the 16th day, behavioral tests were performed. Biomarkers of brain oxidative stress Malondialdehyde (MDA), (Peroxidase (PRx), Catalase (CAT), and Superoxid dismutase (SOD) and inflammation (cytokines: tumor necrosis factor -α (TNF-α), Interleukin 1ß (IL-1ß), and cyclooxygenase-2 (COX 2)) in plasma and hippocampus homogenates were assessed. Various protein expressions (Phospho-Tau (Ser404) (pTau Ser 404), Phospho-Tau (Ser396) (pTau Ser 396), synaptophysin, and the Nuclear factor kappa B (NFkB) signaling pathway) were analyzed using Western blot and immunohistochemistry in the hippocampus. The results show that BPE diminished lipid peroxidation and neuroinflammation, modulated specific protein expression, enhanced the antioxidant capacity, and improved spontaneous alternation behavior, suggesting that it has beneficial effects in AD.

Association between Human Leukocyte Antigen and End-Stage Renal Disease in Patients from Transylvania, Romania.

End-stage renal disease (ESRD) is the final stage of chronic kidney disease. This study explored the association between human leukocyte antigen (HLA) and ESRD. The interaction between genetic and environmental factors may also play a role in the development of ESRD. The study included 2392 ESRD patients who were awaiting renal transplantation. Blood samples were genotyped by SSOP and SSP-PCR methods. Multivariate logistic regression analysis showed that HLA-A*11 (p = 0.027), HLA-A*34 (p = 0.017), HLA-A*69 (p = 0.012), HLA-B*41 (p < 0.001), HLA-B*50 (p = 0.004), HLA-DRB1*10 (p = 0.027), and HLA-DRB1*14 (p = 0.004) were positively associated with ESRD (OR > 1); HLA-DRB1*07 (p < 0.001), HLA-DRB1*08 (p = 0.005), and HLA-DRB1*13 (p < 0.001) were protective against ESRD (OR < 1); and the three-locus haplotype HLA-A*02-B*41-DRB1*03, containing one susceptible allele, was strongly associated with ESRD (p < 0.001, OR = 3.15). In conclusion, this retrospective analysis of HLA typing in patients with ESRD of various etiologies suggests that molecular data on the HLA polymorphism should be collected in order to identify high-risk ESRD patients and to improve graft survival after kidney transplantation.

New Copper Complexes with Antibacterial and Cytotoxic Activity.

The discovery of a new non-toxic metal complex with biological activity represents a very active area of research. Two Cu+2 complexes, [Cu4(L1)4(OH)4(DMF)2(H2O)] (C1) (HL1 = N-(5-ethyl-[1,3,4]-thiadiazole-2-yl)-benzenesulfonamide) and [Cu(L2)2(phen)(H2O)] (C2) (HL2 = N-(5-(4-methylphenyl)-[1,3,4]-thiadiazole-2-yl)-naphtalenesulfonamide), with two new ligands were synthesized. The X-ray crystal structures of the complexes were determined. In both complexes, Cu+2 is five-coordinated, forming a CuN2O3 and CuN4O chromophore, respectively. The ligands act as monodentate, coordinating the metal ion through a single Nthiadiazole atom; for the two complexes, the molecules from the reaction medium (phenantroline, dimethylformamide and water) are also involved in the coordination of Cu+2. The complexes have a distorted square pyramidal square-planar geometry. The compounds were characterized by FT-IR and UV-Vis spectroscopy. Using the microdilution method, the antibacterial activity of the complexes was determined against four Gram-positive and two Gram-negative bacteria, with Gentamicin as the positive control. Cytotoxicity studies were carried out on two tumor cell lines (HeLa, DLD-1) and on a normal cell line (HFL1) using the MTT method and Cisplatin as a positive control. Flow cytometric assessment of apoptosis induced by the complexes on the three cell lines was also performed. Both complexes present in vitro biological activities but complex C2 is more active.

Metallo-Drugs in Cancer Therapy: Past, Present and Future.

Cancer treatments which include conventional chemotherapy have not proven very successful in curing human malignancies. The failures of these treatment modalities include inherent resistance, systemic toxicity and severe side effects. Out of 50% patients administrated to chemotherapy, only 5% survive. For these reasons, the identification of new drug designs and therapeutic strategies that could target cancer cells while leaving normal cells unaffected still continues to be a challenge. Despite advances that have led to the development of new therapies, treatment options are still limited for many types of cancers. This review provides an overview of platinum, copper and ruthenium metal based anticancer drugs in clinical trials and in vitro/in vivo studies. Presumably, copper and ruthenium complexes have greater potential than Pt(II) complexes, showing reduced toxicity, a new mechanism of action, a different spectrum of activity and the possibility of non-cross-resistance. We focus the discussion towards past, present and future aspects.

New Cu+2 Complexes with N-Sulfonamide Ligands: Potential Antitumor, Antibacterial, and Antioxidant Agents.

Nowadays, the discovery of a new non-toxic metal complex with biological activity represents a very active area of research. Two Cu+2 complexes, [Cu(L1)2(H2O)3] (C1) (HL1= N-(5-(4-methylphenyl)-[1,3,4]-thiadiazole-2-yl)-naphtalenesulfonamide) and [Cu(L2)2(py)2(H2O)] (C2) (HL2= N-(5-ethyl-[1,3,4]-thiadiazole-2-yl)-naphtalenesulfonamide), with two new ligands were synthesized. The X-ray crystal structures of the complexes were determined. In both complexes, Cu+2 is five-coordinated, forming a CuN2O3 and CuN4O chromophore, respectively. The ligands act as monodentate, coordinating the metal ion through a single Nthiadiazole atom; for the C2 complex, the molecules from the reaction medium (pyridine and water) are also involved in the coordination of Cu+2. The complexes have a distorted square pyramidal square-planar geometry. The compounds were characterized by FT-IR, electronic EPR spectroscopy, and magnetic methods. The nuclease activity studies confirm the complexes' capacity to cleave the DNA molecule. Using a xanthine-xanthine oxydase system, the SOD mimetic activity of the complexes was demonstrated. Cytotoxicity studies were carried out on two tumor cell lines (HeLa, WM35) and on a normal cell line (HFL1) using the MTT method, with cisplatin used as a positive control. The antibacterial activity of the complexes was investigated against two Gram-positive and two Gram-negative bacteria, and compared with Amoxicillin and Norfloxacin using the disk diffusion method. Both complexes showed in vitro biological activity but the C2 complex was more active. A lack of in vivo toxicity was demonstrated for the C2 complex by performing hepatic, renal, and hematological studies on Swiss mice.

Platinum derivatives: a multidisciplinary approach.

Cancer is one of the most difficult diseases to be treated. The particularities regarding the tumors' occurrence mechanism, their evolution under chemotherapy, disease-free interval, but also the increasing number of patients make cancer an intensively studied health domain. Although introduced in therapy since the early 80s, platinum derivatives play an essential role in anticancer therapy. Their use in therapy resulted in improving the patient quality of life and prolonging disease-free interval, which makes them still a benchmark for other anticancer compounds. However, adverse reactions and allergic reactions are a major impediment in therapy with platinum derivatives. This paper summarizes data about platinum derivatives through a multidisciplinary approach, starting from a chemical point of view and on to their mechanism of action, mechanism of cellular resistance, predictive factors for the outcome of chemotherapy such as micro RNAs (miRNAs), tumor suppressor protein p53, and the excision repair cross-complementing 1 protein (ERCC1).

The importance of the granulocyte-colony stimulating factor in oncology.

Granulocyte-colony stimulating factor (G-CSF) is a glycoprotein, the second CSF, sharing some common effects with granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin-3 (IL-3) and interleukin-5 (IL-5). G-CSF is mainly produced by fibroblasts and endothelial cells from bone marrow stroma and by immunocompetent cells (monocytes, macrophages). The receptor for G-CSF (G-CSFR) is part of the cytokine and hematopoietin receptor superfamily and G-CSFR mutations cause severe congenital neutropenia. The main action of G-CSF - G-CSFR linkage is stimulation of the production, mobilization, survival and chemotaxis of neutrophils, but there are many other G-CSF effects: growth and migration of endothelial cells, decrease of norepinephrine reuptake, increase in osteoclastic activity and decrease in osteoblast activity. In oncology, G-CSF is utilized especially for the primary prophylaxis of chemotherapy-induced neutropenia, but it can be used for hematopoietic stem cell transplantation, it can produce monocytic differentiation of some myeloid leukemias and it can increase some drug resistance. The therapeutic indications of G-CSF are becoming more and more numerous: non neutropenic patients infections, reproductive medicine, neurological disturbances, regeneration therapy after acute myocardial infarction and of skeletal muscle, and hepatitis C therapy.

Hypersensitivity reactions to platinum derivatives: findings of new predictive markers.

PURPOSE: Platinum derivatives play a very important role in cancer therapy. Despite their outstanding results in the treatment of tumors with different locations, the occurrence of hypersensitivity reactions raises issues when it comes to therapy decision, because the changing of chemotherapy line could influence the tumor's evolution. Over the years the scientific community has paid particular attention to the mechanism by which this occurs and to identification of predictive factors. The purpose of this case-control, retrospective study was to find new predictive markers for the occurrence of allergic reactions to platinum derivatives. METHODS: We identified 59 cases of allergic reactions to platinum derivatives in the Oncology Institute "Prof. Dr. Ion Chiricuta" from Cluj-Napoca city in 2013. Blood tests data were analyzed before the administration of the cycle on which the allergic reaction occurred, along with the mandatory analyses for the patients and we focused on the values of neutrophils, lymphocytes, monocytes, eosinophils and basophils. RESULTS: When these values were compared with the values of the control group (,which was made at a ratio of 1:2 or 1:3, matched for age, tumor location and chemotherapy cycle) we found that each increase of lymphocytes or doses of platinum and each drop in monocytes number increased the risk for allergic reactions to occur. CONCLUSION: These findings are of a great value for the physicians and represent a starting point for more detailed studies.

Comparative study concerning mistletoe viscotoxins antitumor activity.

Viscum album L. (Santalaceae) (VA) - a parasitic plant that grows on various trees - has proved a significant anticancer effect in both experimental studies and clinical trials. The present study assesses the influence of oxidative stress in mistletoe induced cytotoxicity in tumor cells, in relation to classic cytostatic therapy. VA ethanolic extract was administered alone and combined with doxorubicin (chloride) in Swiss female mice previously intraperitoneally (i.p.) inoculated with Ehrlich tumor cells (1 × 106/animal) that consequently developed Ehrlich ascites carcinoma (EAC). The administered doses were of 50 mg/kg on the 1st, 3rd and 6th day for the VA extract, respectively of 2.5 mg/kg on the 1st and 6th day for doxorubicin, after tumor cell implantation. Fourteen days later all mice were euthanized, ascites of the EAC were collected in order to analyze the tumor proliferation parameters, as well as blood samples, in order to evaluate the antioxidant status in plasma. Tumor development was associated with increased activity of plasma enzymes; classic doxorubicin therapy not only prevents the accumulation of ascitic fluid, but also significantly reduces the activity of plasma antioxidant enzymes. Furthermore, in association with VA extract, the protective effect is improved. Oxidative changes in Ehrlich tumor cells consisted in decreased catalase activity and amplified xanthine oxidase and peroxidase activities.

Structure of N-(5-ethyl-[1,3,4]-thiadiazole-2-yl)toluenesulfonamide by combined X-ray powder diffraction, 13C solid-state NMR and molecular modelling.

The crystal structure solution of the title compound is determined from microcrystalline powder using a multi-technique approach that combines X-ray powder diffraction (XRPD) data analysis based on direct-space methods with information from (13)C solid-state NMR (SSNMR), and molecular modelling using the GIPAW (gauge including projector augmented-wave) method. The space group is Pbca with one molecule in the asymmetric unit. The proposed methodology proves very useful for unambiguously characterizing the supramolecular arrangement adopted by the N-(5-ethyl-[1,3,4]-thiadiazole-2-yl)toluenesulfonamide molecules in the crystal, which consists of extended double strands held together by C-H···π non-covalent interactions.