A bifunctional antibody conjugate marks the location of DNA binding proteins on deproteinized DNA fibers.

Immunofluorescent foci of DNA Damage Response (DDR) proteins serve as surrogates for DNA damage and are frequently interpreted as denoting specific lesions. For example, Double Strand Breaks (DSBs) are potent inducers of the DDR, whose best-known factor is the phosphorylated histone variant H2AX (γ-H2AX). The association with DSBs is so well established that the reverse interpretation that γ-H2AX invariably implies DSBs is routine.

Repair of genomic interstrand crosslinks.

Genomic interstrand crosslinks (ICLs) are formed by reactive species generated during normal cellular metabolism, produced by the microbiome, and employed in cancer chemotherapy. While there are multiple options for replication dependent and independent ICL repair, the crucial step for each is unhooking one DNA strand from the other. Much of our insight into mechanisms of unhooking comes from powerful model systems based on plasmids with defined ICLs introduced into cells or cell free extracts.

To Evaluate Different Endodontic Instrumentation Systems Regarding Post-Operative Pain After Endodontic Therapy: A Clinical Study.

Background: Despite substantial breakthroughs in instrumentation systems and pharmaceutical interventions, pain following endodontic therapy remains a serious concern. The effect of the type of endodontic instrumentation system in post-operative pain after endodontic therapy has been a matter of debate.

Aim: To evaluate different endodontic instrumentation systems, namely Reciproc (GmbH, Munich), OneShape® (MicroMega, France), Protaper Gold (Dentsply Sirona, USA), and Hyflex® EDM (Coltène/Whaledent Inc.

A green bio-organic catalyst (taurine) promoted one-pot synthesis of (/)-2-thioxo-3,4-dihydropyrimidine(TDHPM)-5-carboxanilides: chiral investigations using circular dichroism and validation by computational approaches.

Owing to the massive importance of dihydropyrimidine (DHPMs) scaffolds in the pharmaceutical industry and other areas, we developed an effective and sustainable one-pot reaction protocol for the synthesis of (/)-2-thioxo-DHPM-5-carboxanilides the Biginelli-type cyclo-condensation reaction of aryl aldehydes, thiourea and various acetoacetanilide derivatives in ethanol at 100 °C. In this protocol, taurine was used as a green and reusable bio-organic catalyst. Twenty-three novel derivatives of (/)-TDHPM-5-carboxanilides and their structures were confirmed by various spectroscopy techniques.

Alcohol-induced hormonal and metabolic alterations in plasma and erythrocytes-a gender-based study.

Purpose: This study aimed to understand the gender-specific alcohol-induced biochemical changes and TBARS association with the endocrine system.

Methods: Human male and female subjects ranging from 35 ± 10 years old with an 8-10-year drinking history were included in the study.

Results: The results demonstrated that testosterone levels were lower in male alcoholics and higher in female alcoholics, as well as higher estrogen and cortisol levels in both genders.

The Response of the Replication Apparatus to Leading Template Strand Blocks.

Duplication of the genome requires the replication apparatus to overcome a variety of impediments, including covalent DNA adducts, the most challenging of which is on the leading template strand. Replisomes consist of two functional units, a helicase to unwind DNA and polymerases to synthesize it. The helicase is a multi-protein complex that encircles the leading template strand and makes the first contact with a leading strand adduct.

Imaging the cellular response to an antigen tagged interstrand crosslinking agent.

Immunofluorescence imaging is a standard experimental tool for monitoring the response of cellular factors to DNA damage. Visualizing the recruitment of DNA Damage Response (DDR) components requires high affinity antibodies, which are generally available. In contrast, reagents for the display of the lesions that induce the response are far more limited.

Eco-Friendly Preparation of Silver Nanoparticles and Their Antiproliferative and Apoptosis-Inducing Ability against Lung Cancer.

In the present study, the anti-proliferative and apoptotic potential of in lung cancer was assessed. Silver nanoparticles (AgNPs) of were synthesized using an ethanolic extract and characterized by adopting various parameters. Herein, the eco-friendly, cost-effective, and green synthesis of AgNPs was evaluated using an ethanolic extract of .

Development and Validation for Quantification of Cephapirin and Ceftiofur by Ultraperformance Liquid Chromatography with Triple Quadrupole Mass Spectrometry.

Cross contamination of β-lactams is one of the highest risks for patients using pharmaceutical products. Penicillin and some non-penicillin β-lactams may cause potentially life-threatening allergic reactions. The trace detection of β-lactam antibiotics in cleaning rinse solutions of common reactors and manufacturing aids in pharmaceutical facilities is very crucial.

Acid-Catalyzed Synthesis of Isatoic Anhydride-8-Secondary Amides Enables IASA Transformations for Medicinal Chemistry.

Quinazolin-dione--3-alklyl derivatives are the core scaffolds for several categories of bioactive small molecules, but current synthetic methods are costly, involve environmental hazards, and are not uniformly scalable. Here, we report an inexpensive, flexible, and scalable method for the one-pot synthesis of substituted quinazolin-dione--3-alkyls (isomers of isatoic-8-secondary amides (IASAs)) from isatin that take advantage of capture of imidic acid under acidic conditions. We further show that this method can be used for the synthesis of a wide variety of derivatives with medicinal uses.

Visualizing replication fork encounters with DNA interstrand crosslinks.

Replication forks encounter numerous challenges as they move through eu- and hetero-chromatin during S phase in mammalian cells. These include a variety of impediments to the unwinding of DNA by the replicative helicase such as alternate DNA structures, transcription complexes and R-loops, DNA-protein complexes, and DNA chemical adducts. Much of our knowledge of these events is based on analysis of markers of the replication stress and DNA Damage Response that follow stalling of replisomes.

Structural Insights of Three 2,4-Disubstituted Dihydropyrimidine-5-carbonitriles as Potential Dihydrofolate Reductase Inhibitors.

In this report, we describe the structural characterization of three 2,4-disubstituted-dihydropyrimidine-5-carbonitrile derivatives, namely 2-{[(4-nitrophenyl)methyl]sulfanyl}-6-oxo-4-propyl-1,6-dihydropyrimidine-5-carbonitrile , 4-(2-methylpropyl)-2-{[(4-nitrophenyl)methyl]sulfanyl}-6-oxo-1,6-dihydropyrimidine-5-carbonitrile , and 2-[(2-ethoxyethyl)sulfanyl]-6-oxo-4-phenyl-1,6-dihydropyrimidine-5-carbonitrile monohydrate . An X-ray diffraction analysis revealed that these compounds were crystallized in the centrosymmetric space groups and adopt an L-shaped conformation. One of the compounds () crystallized with a water molecule.

Analysis of maslinic acid and gallic acid compounds as xanthine oxidase inhibitors in isoprenaline administered myocardial necrotic rats.

Objective: This research designed to analyze the and ameliorative action of maslinic acid (MA) and gallic acid (GA) on reactive oxygen species generating enzyme xanthine oxidase (XO) in isoprenaline or isoproterenol (ISO) induced myocardial infarcted rats.

Methods: Albino Wistar rats were categorized into four groups with eight rats in each group. A dose of 15 mg/kg of MA and GA were pretreated to each MA and GA groups for seven days.

Characterization of SPK 98, a Torin2 analog, as ATR and mTOR dual kinase inhibitor.

A series of Torin2, a second-generation ATP-competitive inhibitor, analogues were biologically characterized to identify their potential for ATR and mTOR kinase inhibition. Compound SPK 98 was observed to inhibit ATR/mTOR kinase selectively over ATM kinase in HCT 116 cell line. In addition to that, SPK 98 on 30 min incubation with human, mice and rat liver microsomes showed improved properties with an increased half-life (a maximum T ½ of 157 min) and internal clearance in mouse as compared to Torin2.

Recombinant Tumor Suppressor TSC1 Differentially Interacts with DnaK and Human HSP70.

Tuberous sclerosis complex (TSC) is a neurological syndrome manifested by non-cancerous tumors in several organs. Mutations in either or tumor suppressor gene cause the disease. In the cell, TSC1 is known to form a heterodimer with TSC2 because of which an active complex is formed that negatively regulates the mTORC1 activity during cellular stress.

Structural and strategic landscape of PIKK protein family and their inhibitors: an overview.

Phosphatidylinositol-3 kinase-related kinases (PIKKs) is a class of six unique serine/threonine kinases that are characterized as high molecular mass colossal proteins present in multicellular organisms. They predominantly regulate the innumerable eukaryotic cellular processes, for instance, cell-signaling cascades related to DNA damage and repair, cell growth and proliferation, cell cycle arrest, genome surveillance, gene expression and many other important yet diverse functions. A characteristic PIKK member comprises of an N-terminal HEAT domain, followed by FAT domain, a highly conserved kinase catalytic domain, and a C-terminal FATC domain.

Evolution of PIKK family kinase inhibitors: A new age cancer therapeutics.

Phosphatidylinositol-3 kinase-related kinases (PIKKs) belong to a family of atypical serine/threonine kinases in humans. They actively participate in a diverse set of cellular functions such as meiotic, V(D)J recombination, chromosome maintenance, DNA damage sensing and repair, cell cycle progression and arrest. ATR, ATM, DNA-PKcs, mTOR and hSMG are the members of the PIKK family that play an important role in in cancer cell proliferation, autophagy, and cell survival to radio and chemotherapy.

Combined cardio-protective ability of syringic acid and resveratrol against isoproterenol induced cardio-toxicity in rats via attenuating NF-kB and TNF-α pathways.

The study was conducted to evaluate the cardio-protective activity of combination (COMB) of syringic acid (SA) and resveratrol (RV) against isoproterenol (ISO) induced cardio-toxicity in rats. Rats were pre-treated orally with SA (50 mg/kg), RV (50 mg/kg) and combination of SA (25 mg/kg) and RV (25 mg/kg) along with positive control gallic acid (50 mg/kg) for 30 days. The effects of ISO on cardiac markers, lipid profile and lipid peroxidation marker, anti-oxidant enzymes and m-RNA expression of nuclear factor-kappa B (NF-kB) and tumor necrosis factor-α (TNF-α) were observed along with histopathological observations of simple and transmission electron microscopes (TEM).

One- and Two-Component Organogels Containing Cyanostilbene without any Auxiliary Substituents.

Pyridyl acrylonitrile without traditional auxiliary groups form stable organogels in ethanol. The addition of a second non-gelating cyanostilbene component results in a more stable two-component gel. Single crystal X-ray data reveal the influence of C-H⋅ ⋅ ⋅N, C-H⋅ ⋅ ⋅π, and π-π interactions in the formation of organogels.

Protective effects of syringic acid, resveratrol and their combination against isoprenaline administered cardiotoxicity in wistar rats.

Objective: To evaluate the cardio-protection of syringic acid (SA) in combination with resveratrol (RV) in isoproterenol (ISO) induced myocardial infarcted (MI) rats.

Methods: Groups of all rats were subjected oral pre-treatment at the beginning of the study with SA (50 mg/kg), RV (50 mg/kg) and combination (COMB) of SA (25 mg/kg) and RV (25 mg/kg) along with gallic acid (GA) (50 mg/kg) for 30 days. After sacrification, homogenate of heart tissue along with serum were utilized for further biochemical investigations.

Inhibitors of inosine 5'-monophosphate dehydrogenase as emerging new generation antimicrobial agents.

Inosine 5'-monophosphate dehydrogenase (IMPDH) is a vital enzyme involved in the synthesis of guanine nucleotides. IMPDH catalyzes a crucial step of converting IMP into XMP that is further converted into GMP. Microbial infections rely on the rapid proliferation of bacteria, and this requires the rate-limiting enzyme IMPDH to expand the guanine nucleotide pool and hence, IMPDH has recently received lots of attention as a potential target for treating infections.

Novel Pyrazolo[4, 3-c]Quinolin-3-One Derivatives as PDE5A Inhibitors.

Background: PDE5A is a phosphodiesterase which specifically hydrolyzes the cGMP to GMP. It takes part in several physiological and pathological pathways and is considered an important drug target. Currently, PDE5 inhibitors (ex; Sildenafil, Tadalafil) available in the market are not only being used for the treatment of erectile dysfunction but at the same time, they are also in clinical trials being investigated as anticancer agents.

Identification of selective inhibitors of Helicobacter pylori IMPDH as a targeted therapy for the infection.

Helicobacter pylori (H. pylori), the major cause of several gastric disorders has been recognied as a type I carcinogen. By virtue of resistance developed by H.

Evaluation of Maltose Binding Protein-Tagged hATR Kinase Domain Catalytic Activity with p53 Ser-15 Phosphorylation.

DNA damage response (DDR) pathways form an integral part of the body's repair machinery, and ATR (ataxia-telangiectasia and Rad3-related kinase) protein is one of the key mediators in the DDR pathway that helps in maintaining genomic integrity. A growing body of evidence suggests that inhibition of ATR can help sensitize tumor cells to combinatorial treatment. However, specific ATR kinase inhibitors have largely remained elusive until now.

Exploring a solvated dimer of Gefitinib: a quantitative analysis.

Gefitinib or Iressa is an orally administered anilinoquinazoline used in cancer chemotherapy for the treatment of lung and breast cancer. It is reported to exist in two polymorphic forms, a stable form I and a metastable form II. Both of the forms belong to the triclinic P-1 space group.