Search

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.

The aim of this study was to determine the chemical composition of Salvia tomentosa (Miller) essential oil and to examine its inhibitory effect on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), tyrosinase, α-amylase and α-glucosidase in vitro. In this study, the interaction between the main components of essential oil and the enzymes in question was analyzed through molecular docking analyses. The presence of 60 compounds representing 98.2% of the essential oil was determined. The major compounds of the oil were camphor (9.35%), γ-muurolene (8.37%), α-pinene (7.59%), α-caryophyllene (6.25%), viridiflorol (5.13), δ-cadinene (5.01%), and terpinene-4-ol (5.01 %). The oil exhibited higher inhibitory activity on BChE than on AChE. The BChE inhibitory activity of the oil was determined to be 16.48 mg GALAEs/g. The oil showed 47.13 mg KAEs/g inhibitory activity on tyrosinase. The inhibitory activities of the essential oil on α-glucosidase and α-amylase were determined as 703.29 and 694.75 mg ACEs/g, respectively. Based on docking binding energies, δ-cadinene, viridiflorol, γ-muurolene and α-caryophyllene were determined to be the most promising ligands showing the highest affinity (min. -6.90 kcal/mol; max. -8.40 kcal/mol) against α-amylase, AChE and BChE. However, all four ligands were found to exhibit low affinity (min. -5.50 kcal/mol; max. -5.90 kcal/mol) against tyrosinase. Considering in silico physicochemical properties, drug-like features (Lipinski's rule of 5) and intracellular targets, δ-cadinene, viridiflorol, γ-muurolene and α-caryophyllene possess hit features and do not show non-specific enzyme or protein affinity. Ligand binding assays (LBA) to be performed between the monoterpenes and enzymes in question may constitute the next step in confirming their competitive inhibitory capacity.

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.

The novel corona virus has infected nearly 163 million people globally as of May 2021 and caused death of more than 3.3 million patients. Despite intense efforts, however, a small molecule with full therapeutic potential has not been developed in the treatment of SARS-CoV-2. The aim of this study was to investigate the inhibitory potentials of oleuropein and its hydrolysis product 3-hydroxytyrosol against spike glycoprotein, papain-like protease, main protease and RNA-dependent RNA polymerase of SARS-CoV-2 using molecular modelling simulations. Compared to 3-hydroxytyrosol, oleuropein showed stronger binding affinity to all targets in docking, and its affinity to Mpro (-7.0 kcal mol-1) and RdRp (-8.0 kcal mol-1) was quite high. Despite the Mpro-oleuropein complex, the RdRp-oleuropein complex showed a highly stable binding in 15-ns molecular dynamics based on root-mean-square-deviation (0.14 - 0.32 nm) and hydrogen bond numbers (6.85). The intracellular targets of oleuropein covered various proteases (17%), enzymes (16%), family A G protein-coupled receptors (11%), kinases (10%) and other cytosolic proteins (10%), however, probabilistic analysis showed that oleuropein was unlikely (p = 0 - 0.22) to bind these targets. ADMET profile showed that, with few exceptions, oleuropein has the physicochemistry that should be present in a drug molecule. In conclusion, oleuropein binds tightly to the active site of RdRp and could inhibit this enzyme. Oleuropein may be used alone or in combination with replicase inhibitors such as remdesivir or favipiravir in the treatment of COVID-19. Additional in vitro binding assays and in vivo efficacy studies are needed to prove our findings., Yeni tip korona virüsü Mayıs 2021 itibariyle dünya genelinde yaklaşık 163 milyon kişiyi enfekte etmiş ve 3.3 milyondan fazla hastanın ölümüne neden olmuştur. Yoğun çalışmalara rağmen SARS-CoV-2 tedavisinde tam koruma sağlayan terapötik potansiyelli bir ilaç geliştirilememiştir. Bu çalışmanın amacı, moleküler modelleme simülasyonları kullanarak oleuropein ve onun hidroliz ürünü 3-hidroksitirosol’ün SARS-CoV-2 spike glikoproteini, papain-benzeri proteazı (PLpro), ana proteazı (Mpro) ve RNA-bağımlı RNA polimerazına (RdRp) karşı inhibitör potansiyellerini araştırmaktır. 3-hidroksitirosol ile karşılaştırıldığında oleuropein, moleküler doking analizinde tüm protein hedeflere daha yüksek bağlanma afinitesi göstermekle beraber Mpro (-7.0 kcal/mol) ve RdRp'ye (-8.0 kcal/mol) karşı afinitesi oldukça yüksek bulunmuştur. Kök-ortalama-kare-sapması (0.14 - 0.32 nm) ve hidrojen bağı sayısı (6.85) göz önüne alındığında, Mpro-oleuropein kompleksinin aksine, RdRp-oleuropein kompleksi 15 nanosaniyelik moleküler dinamik analizinde oldukça kararlı bir bağlanma sergilemiştir. Oleuropein’in intraselüler hedefleri arasında çeşitli proteazlar (%17), enzimler (%16), G protein-bağlı reseptörler (%11), kinazlar (%10) ve diğer sitozolik proteinler (%10) bulunmasına rağmen, olasılık analizlerine göre oleuropein’in bu hedeflere bağlanma olasılığı oldukça düşük bulunmuştur (p = 0 - 0.22). Birkaç istisna dışında oleuropein'in absorbsiyon-dağılım-metabolizma-atılım-toksisite (ADMET) profili, bir ilaç molekülünde bulunması gereken fizikokimyasal özelliklere sahip olduğunu göstermiştir. Sonuç olarak oleuropein, RdRp'nin aktif bölgesine sıkıca bağlanma ve bu enzimi inhibe etme potansiyeline sahiptir. Oleuropein, COVID-19 tedavisinde tek başına ya da remdesivir veya favipiravir gibi replikaz inhibitörleri ile birlikte kullanılabilir. Bulgularımızın kanıtlanması için ilave in vitro ilaç-bağlanma ve in vivo etkinlik çalışmalarına ihtiyaç duyulmaktadır.

Çağdaş yaşamın dezavantajların biri raf ömrü olan besinlere yönelmektir. Bu maddelerin teklikeli sınıfına giren yapay bir renklendirici olan kömür katranı olarak da bilinen Brown HT (E155)’dir. Çalışmada Brown HT’nin genotoksik ve sitotoksik etkilerini araştırılmıştır. Bu etkiler genotoksik olarak mikronukleus testi ile, sitotoksik olarak da nukleus bölünme indeksi parametresi ile saptanmıştır. Brown HT 24 ve 48 saatlik muameleli kültürlerin hepsinde MN oluşumunu önemli derecede artırmıştır. Bazı binükleer hücrede bir mikronükleus ya da iki mikronükleuslara rastlanmıştır. İki nükleuslardaki MN yüzdesi yine 24 ve 48 saatlik kültürlerde kontrole nazaran artmıştır. Brown HT ile 24 saatlik muameleli kültürlerde NBI’ya bir etkisi olmamış fakat 48 saatlik kültürlerin 25µg/mL konsantrasyondaki NBI önemli derece de azalmıştır.

Yaptığımız çalışmada, klastojenik ve anojenik etki (genotoksik) MN testi ile, sitotoksik etki ise nukleus bölünme indeksi (NBI) ile saptanmaya çalışılmıştır. Test maddesi 24 saatlik muamelede en yüksek konsantrasyon hariç binukleuslu mikronukleus (BNMN) düzeyinde herhangi bir artışa neden olmazken, 48 saatlik PBV muamelesi BNMN’lerin artışında önemli derecede (50 ve 100 µg/ml dozlarda MMC kadar), etkili olmuştur. MN yüzdesi incelendiğinde BNMN bulgularıyla korelasyon göstermektedir. PBV’nin muameleleri NBI’de hafif düşüşlere neden olmakla birlikte bu azalmaların istatistiksel olarak önemli olmadığı bulunmuştur.

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.

Sertraline (SRT) is an antidepressant agent used as a neuronal selective serotonin-reuptake inhibitor (SSRI). SRT blocks serotonin reuptake and increases serotonin stimulation of somatodendritic serotonin 1A receptor (5-HT1AR) and terminal autoreceptors in the brain. Although numerous studies on SSRIs indicate that many of those agents possess genotoxic risk, the genotoxic effect of SRT in human peripheral blood lymphocytes has not been investigated so far. In the present study, the genotoxic potential of SRT was evaluated using cytokinesis-block micronucleus (CBMN) cytome assay in peripheral blood lymphocytes of healthy human subjects. In addition, biochemical parameters of total antioxidant status (TAS) and total oxidant status (TOS) were measured to quantitate oxidative stress. Human peripheral blood lymphocytes were exposed to four different concentrations (1.25, 2.5, 3.75 and 5 μg/mL) of SRT for 24- and 48-h treatment periods. In this study, SRT was not found to induce MN formation either in 24- or 48-h treatment periods. In contrast, SRT induced a concentration-dependent decrease (r= - 0.979, p ≤ 0.01) in the MN when it was present for the last 48 hr (48-h treatment) of the culture period. The application of various concentrations of SRT did not increase TAS levels in either 24- or 48-h treatment periods when compared to control. However, SRT caused significant oxidative stress in both 24- or 48-h treatment periods. The increase in TOS was potent as the positive control MMC at both treatment times. In addition, exposing cells to SRT caused significant decreases in the nuclear division index at 1.25, 2.50 and 3.75 μg/mL in 24-h and at the highest concentration (5 μg/mL) in 48-h treatment periods. Our results suggest that SRT may have nucleotoxic effect on cultured human peripheral blood lymphocytes.

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.

Azospermi santrifüje edilen semen örneğinde hiç spermatozoa saptanmaması olarak tanımlanır. Azospermi tüm erkeklerin yaklaşık % 1’inde bulunurken infertil erkeklerin ise yaklaşık %15’inde saptanmaktadır. Azospermili erkeklerin değerlendirilmesinde altta yatan etyolojinin belirlenmesi tedavi planı açısından önemlidir. Etyoloji nonobstrüktif ve obstrüktif azospermi olarak gruplanabilir. Nonobstrüktif azospermi hipotalamik-hipofizer-gonadal aksta sorun nedeniyle oluşurken, obstrüktif azospermide rete testis ile ejakulator kanal arasındaki herhangi bir seviyede obstrüksiyona bağlı sprem transportunda bozulma vardır. Testis kaynaklı azospermi genellikle düzeltilemez. Primer testiküler yetmezlik nedeniyle oluşan azospermide muhtemel kromozomal anomali açısından genetik testler yapılmalıdır. Genetik analiz sonucu t4;22 (q21;p13) resiprokal translokasyon saplanan bir azospermi olgusu sunulmuştur.