Docking-based virtual screening, ADMET, and network pharmacology prediction of anthocyanidins against human alpha-amylase and alpha-glucosidase enzymes as potential antidiabetic agents

Diabetes mellitus (DM) characterized by high blood sugar concentration is a major global public health problem and untreated DM results in blindness, kidney failure, heart attack, stroke, and lower extremity amputation. In this structure-based drug design (SBDD) study, the potential inhibitory effects of twelve anthocyanidins (aglycon unit of anthocyanins) components on human pancreatic α-amylase and intestinal α-glucosidase enzymes were investigated using the molecular docking method and a novel approach developed by our research group was used to rank the global binding potentials of ligands to a series of different enzymes simultaneously. In addition, drug-likeness, absorption-distribution-metabolism-excretion-toxicity (ADMET) predictions, and intracellular target-component interaction network analyses of twelve anthocyanidin components were performed using the search tool for interactions of chemicals (STITCH). Petunidin, peonidin, and aurantinidin were determined as 'hit' phytochemicals according to the docking binding energy and relative binding capacity index (RBCI) analyses, whereas, based on the RBCI index, petunidin was found to be the most effective ligand in terms of binding capacity to both enzymes that play an important role in DM. The more accessible and large-volume active site of α-amylase compared to α-glucosidase caused petunidin to bind with higher affinity against α-amylase. Promisingly, petunidin did not violate any of the criteria for drug-likeness consisting of a combination of the Lipinski's rule of 5, Ghose and Veber filters, showed no cytochrome (CYP) P450 or hERG I-II inhibitory activity in the ADMET analysis, however, it was found to have a low gastrointestinal absorption profile. In intracellular target-component network analysis using the STITCH online platform, it was determined that petunidin did not show negative functional interactions with any enzyme in the human protein network. Considering these results, it is recommended that petunidin be advanced to further in vitro and in vivo assays as a potential α-amylase and α-glucosidase inhibitory agent in the treatment of DM. However, the intestinal absorption profile of petunidin must be enhanced by molecular optimization without compromising its pharmacological activity

Assessment of apigenin-7-glucoside and luteolin-7-glucoside as multi-targeted agents against Alzheimer's disease: a molecular docking study

Although the incidence of Alzheimer's disease (AD) is increasing in society, unfortunately, no definite progress has been made in treating this disease yet. In this study, the potential of apigenin-7-glucoside (A7G) and luteolin-7-glucoside (L7G) to be used as multi-targeted agents in AD was investigated by molecular docking calculations against the acetylcholinesterase (AChE), butyrylcholinesterase (BChE), amyloid precursor protein (APP) and 42-residue beta-amyloid peptide (Aβ). A7G and L7G exhibited very high binding affinity (-9.42 and -9.60 kcal/mol for A7G; -9.30 and -9.90 kcal/mol for L7G) to AChE and BChE, respectively, while the affinities of these two flavonoid glycosides towards APP and Aβ peptide (-6.10 and -6.0 kcal/mol for A7G; -6.30 and -6.10 kcal/mol for L7G) were moderately strong. Compared to rivastigmine, A7G and L7G exhibited a highly significant binding affinity, even stronger than rivastigmine, for AChE and BChE. Although A7G showed a more drug-like physicochemical character than L7G, both ligands were within the normal range for ADMET and did not show high affinity for cellular proteins, according to the results of SwissTarget analysis. According to the STITCH interaction analysis, both ligands had the potential to inhibit enzymes predominantly in the inflammatory pathway (ADIPOQ, NOS1, NOS2 and NOS3). As a result, A7G and L7G exhibit multi-targeted agent properties in AD. Our results should also be verified by experimental enzyme inhibition studies, which may be performed simultaneously on AChE, BChE, APP, and Aβ peptides

Cell Division, Cytotoxicity, and the Assays Used in the Detection of Cytotoxicity

Cell division is a phenomenon that is encountered in all cells in nature. While normal cell division results in proliferation in single-celled organisms, and development and repair in multicellular organisms, aberrant and untimely cell division results in tumor formation. Therefore, the understanding of the cell division is hidden in identifying the details of the molecular mechanisms that govern cellular division at the exact time and under right conditions. Sometimes these molecular mechanisms are distorted by both intrinsic and extracellular factors, and the division process halts or deviates to an abnormal pathway. At this point, it is essential that the abnormal cells are removed from the tissue by an appropriate mechanism. In this context, in this review, general and specific information about cell division and its molecular control mechanisms were discussed, and different types of cell death mechanisms were mentioned accordingly. In addition, chemical, biological, and physical cytotoxic agents that negatively affect cell division and their mechanisms of action are explained. Finally, a brief review of the principles of different cytotoxicity (cell viability and proliferation) test systems has been performed to provide a source of information for investigators who study cell viability, proliferation, or different types of cellular death pathways

Preliminary in Silico Studies of the Interactions of Certain Genotoxic Azo Dyes with Different Double-Stranded DNA Conformations

Organic azo dyes, which are widely used in industrial, health and cosmetic fields, pose genotoxic risks due to their chemical structures; however, the molecular details of the undesirable effects of these dyes on DNA have been poorly or insufficiently clarified. In this computational molecular docking study, the DNA binding modes and binding affinities of 14 azo dyes, previously determined to show DNA clastogenicity, were characterized using 2 different double-stranded DNA (dsDNA) conformations (an intact dsDNA and dsDNA with an intercalation gap). In this study, it was determined that 10 out of the 14 genotoxic azo dyes were strong dsDNA minor groove binders, while the remaining ones formed tight binding complexes with dsDNA through intercalation or threading intercalation modes. The azo, nitro, hydroxyl, ammonium, sulfonate, naphthalene, methoxyphenyl, bromine, nitrophenyl, imidazole, amino-phenylethanol and chloro-nitrophenyl groups were found to play primary role in the most favorable binding conformations of these dyes on dsDNA with an affinity ranging from −6.35 kcal/mol to −9.42 kcal/mol. It was determined that dsDNA sequences containing GT dinucleotides are frequently preferred in binding by these dyes, and that rings and polar groups are important features for tight binding with dsDNA. It was concluded that these dyes may be banned, or non-genotoxic congeners should be manufactured with appropriate molecular optimization for the genetic health of the human population and for future generations

In vitro genotoxic effects of pemetrexed and cefixime as single-agent or combination form on human peripheral blood lymphocytes.

TEZ9387Tez (Doktora) -- Çukurova Üniversitesi, Adana, 2014.Kaynakça (s. 133-146) var.xxii, 147 s. : res. (bzs. rnk.), tablo ; 29 cm.Bu çalışmada, küçük hücreli olmayan akciğer kanserinin tedavisinde yaygın olarak kullanılan pemetrexed (PMX) ve bir sefalosporin grubu antibiyotik olan cefixime (CFX)’nin insanlar için genotoksik risk oluşturup oluşturmadığı, insan periferal lenfositlerinde in vitro kardeş kromatid değişimi (KKD), kromozom anormalliği (KA) ve mikronukleus (MN) testleri ile araştırılmıştır. Hücreler, 25, 50, 75, 100 ?g/ml PMX’le; 900, 1600, 2300, 3000 ?g/ml CFX’le; tek başlarına ve bu konsantrasyonların yarısı kadar konsantrasyonlarda bir araya getirilerek karışım (PMX+CFX) halinde 24 ve 48 saat muamele edilmiştir. Bu çalışmada, PMX 24 saatlik muamelede tüm konsantrasyonlarda KA oluşumunu istatistiksel olarak önemli derecede artırırken, 48 saatlik muamelede KA’nı uyarmamıştır. PMX 24 ve 48 saatlik muamelelerde KKD ve MN oluşumunu uyarmamıştır. Ancak, bütün süre ve konsantrasyonlarda mitotik indeks (MI), proliferasyon indeksi (PI) ve nukleus bölünme indeksini (NBI)’yı önemli derecede düşürmüştür. CFX bütün süre ve konsantrasyonlarda KA ve MN oluşumunu uyarmaz iken, 24 saatlik muamele süresinde en yüksek iki konsantrasyonda (2300 ve 3000 ?g/ml), 48 saatlik muamelede tüm konsantrasyonlarda kontrollerdekine (kontrol ve eritici kontrol) nazaran KKD oluşumunu artırmış, fakat bu artış önemli bulunmamıştır. CFX MI ve PI’nı her iki süre ve tüm konsantrasyonlarda önemli derecede düşürmüştür. CFX her iki muamele süresinde de NBI’nı önemli derecede düşürmemiştir, ancak, 48 saatlik muameledeki düşüş konsantrasyona bağlı durum göstermiştir (r = -0,979, P < 0.05). PMX+CFX’in karışım hali ise genotoksik olmamalarına karşılık ilaçların tek başlarına muamele edilen hallerinden daha fazla sitotoksik olduğu saptanmıştır.The aim of this study was to investigate the genotoxic effects of pemetrexed (PMX) (an antifolate for the treatment of lung cancer and mesothelioma) and cefixime (CFX) (a cephalosporin antibiotic) separately or in combination on human peripheral lymphocytes by using sister chromatid exchange (SCE), chromosomal aberrations (CA) and micronucleus (MN) tests. Cells were treated separately with 25, 50, 75, 100 ?g/ml PMX; 900, 1600, 2300, 3000 ?g/ml CFX and with their combinations at their half concentrations for 24 and 48 hr. In this study, PMX significantly increased the formation of CAs in 24-hr treatment period, but not in 48-hr treatment. PMX did not induce the formation of SCE or MN either in 24- or 48-hr treatment periods. On the other hand, PMX significantly decreased the MI, PI and NDI at all concentrations and treatment times. No significant increase was detected in CA or MN in cultures treated with CFX for both treatment times. Although CFX induced the SCE at the two concentrations (2300 and 3000 ?g/ml) for 24-hr treatment; and at all concentrations for 48-hr, the detected increases were not significant when compared to control and solvent control. CFX significantly decreased the MI and PI at all concentrations and treatment times. Although not statistically significant when compared to controls (negative and solvent control), CFX induced a concentration-dependent decrease in the NDI for 48-hr treatment (r = -0,979, P < 0.05). Combinations of PMX+CFX were detected to be more cytotoxic as compared to their separate treatments, but not genotoxic, in human peripheral lymphocytes.Bu çalışma Ç.Ü. Bilimsel Araştırma Projeleri Birimi tarafından desteklenmiştir. Proje No: FEF2011D8

Amoxicillin antibiyotiğinin insan feriferal lenfositlerinde in vitro genotoksik etkileri

TEZ7401Tez (Yüksek Lisans) -- Çukurova Üniversitesi, Adana, 2009.Kaynakça (s.89-99) var.xvii, 100 s. : rnk.res. ; 29 cm.The aim of the present study was to investigate the genotoxic effects of amoxicillin, a commonly prescribed ?-lactam antibiotic for the treatment of bacterial infections, on human peripheral lymphocytes by using sister chromatid Exchange (SCE), chromosomal aberration (CA) and micronucleus (MN) tests. Cells were treated with 400, 600, 800, 1000 ?g/ml amoxicillin for 24 and 48 hours in the absence of a metabolic activation system and 400, 600, 800, 1000 ?g/ml amoxicillin for 3 hours in the presence of a metabolic activation system...Bu çalışma, penisillin türevi bir beta-laktam antibiyotik olan amoxicillin'in insanlar için genotoksik risk oluşturup oluşturmadığını, insan periferal kan lenfositlerinde eksojen metabolik aktivatör varlığında ve yokluğunda in vitro kardeş kromatid değişimi (KKD), kromozom anormalliği (KA) ve mikronukleus (MN) testleri ile araştırmak amacıyla yürütülmüştür. Hücreler, eksojen metabolik aktivatör yokluğunda, 400, 600, 800, 1000 ?g/ml amoxicillin ile 24 ve 48 saat, eksojen metabolik aktivatör varlığında ise 3 saat boyunca 400, 600, 800, 1000 ?g/ml amoxicillin ile muamele edilmişlerdir...Bu çalışma Ç.Ü. Bilimsel Araştırma Projeleri Birimi Tarafından Desteklenmiştir. Proje No:FEF2007YL3

Characterization of an Interstitial 4q32 Deletion in a Patient with Mental Retardation and a Complex Chromosome Rearrangement

Interstitial deletions of chromosome band 4q32 are rare. We report on a 22-year-old female patient with a de novo interstitial deletion of chromosome 4q32 and a balanced translocation t(2;5)(p21;q12.1). Clinical problems of the patient comprised mild to moderate mental retardation, psychosis, obesity, broad nasal root, sparse lateral eyebrows, thin upper lip, short philtrum, micrognathia, and strabismus. Analysis by whole genome array CGH using an Agilent 244K oligonucleotide array and subsequent FISH using BAC clones from the 4q32 region revealed an unexpectedly complex rearrangement comprising a deletion of approximately 10 Mb in 4q32.1q32.3 and the insertion of two small fragments of 0.8 and 0.11 Mb originating from the derivative chromosome 4q32 into derivative chromosome 5q. The breakpoints of the t(2;5) translocation were mapped by BAC-FISH; no genes were disrupted by these breakpoints. The deleted interval in 4q32 harbored more than 30 genes, and haploinsufficiency of one or several of these genes is likely to have caused the clinical problems of the patient. Candidate genes for cognitive defects are GRIA2, GLRB, NPY1R, and NPY5R. In conclusion, this patient increases our knowledge about the phenotypic consequences of interstitial 4q32 deletions. Reports of patients with overlapping deletions will be needed to elucidate the role of individual genes and to establish genotype–phenotype correlations.Grant sponsor: German Nationales Genomforschungsnetzwerk; Grantnumber: 01GR0203

Lymphocytes

Although all the features of the immune system have not been fully resolved yet, the knowledge we have gained from studies on lymphocytes, the basic elements of the immune system, is quite lucid. For this reason, the significance of lymphocytes (the cells that are the source of most of the information we have obtained about the human genome, the negative effects of drugs on the genetic system, the development and behavior of immune system, antigen-antibody association, cytotoxic adaptive immunity, antibody-driven adaptive immunity, cancer and autoimmune diseases) is clear. Studies on lymphocytes will not only help us develop tools to combat human diseases more effectively in the future, but will also help us understand how evolution shapes the immune system in living organisms

Cytotoxicity - Definition, Identification, and Cytotoxic Compounds

Compensating for cytotoxicity in the multicellular organism by a certain level of cellular proliferation is the primary aim of homeostasis. In addition, the loss of cellular proliferation control (tumorigenesis) is at least as important as cytotoxicity, however, it is a contrasting trauma. With the disruption of the delicate balance between cytotoxicity and proliferation, confrontation with cancer can inevitably occur. This book presents important information pertaining to the molecular control of the mechanisms of cytotoxicity and cellular proliferation as they relate to cancer. It is designed for students and researchers studying cytotoxicity and its control