Selective ALDH3A1 Inhibition by Benzimidazole Analogues Increase Mafosfamide Sensitivity in Cancer Cells

Aldehyde dehydrogenase enzymes irreversibly oxidize aldehydes generated from metabolism of amino acids, fatty acids, food, smoke, additives, and xenobiotic drugs. Cyclophosphamide is one such xenobiotic used in cancer therapies. Upon activation, cyclophosphamide forms an intermediate, aldophosphamide, which can be detoxified to carboxyphosphamide by aldehyde dehydrogenases (ALDH), especially ALDH1A1 and ALDH3A1. Consequently, selective inhibition of ALDH3A1 could increase chemosensitivity toward cyclophosphamide in ALDH3A1 expressing tumors. Here, we report detailed kinetics and structural characterization of a highly selective submicromolar inhibitor of ALDH3A1, 1-[(4-fluorophenyl)sulfonyl]-2-methyl-1H-benzimidazole (CB7, IC50 of 0.2 μM). CB7 does not inhibit ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, or ALDH2 activity. Structural, kinetics, and mutagenesis studies show that CB7 binds to the aldehyde binding pocket of ALDH3A1. ALDH3A1-expressing lung adenocarcinoma and glioblastoma cell lines are sensitized toward mafosfamide (MF) treatment in the presence analogues of CB7, whereas primary lung fibroblasts lacking ALDH3A1 expression, are not

Mechanisms and dynamics of the metastable decay in Ar-2(+)

A detailed experimental as well as theoretical investigation of the properties of the metastable dissociation Ar-2(+)--\u3eAr++Ar is presented. The mass-analyzed ion kinetic energy (MIKE) scan technique has been performed using a three sector field mass spectrometer. The possible mechanisms of the metastability of Ar-2(+) have been examined and the observed decay process is assigned to the II(1/2)(u)--\u3eI(1/2)(g) bound to continuum radiative transition, in agreement with earlier work. The calculation of the theoretical shape of the kinetic energy release distribution of fragment ions allowed us to construct the theoretical MIKE peak and compare it with the raw experimental data. The accuracy of various sets of potential energy curves for Ar-2(+) is discussed, as well as the way of production of the metastable Ar-2(+)[II(1/2)(u)] electronic state by electron impact. Excellent agreement between the experimental data and theoretical model has been observed. (C) 2004 American Institute of Physics

N,N-diethylaminobenzaldehyde (DEAB) as a substrate and mechanism-based inhibitor for human ALDH isoenzymes

N,N-diethylaminobenzaldehyde (DEAB) is a commonly used "selective" inhibitor of aldehyde dehydrogenase isoenzymes in cancer stem cell biology due to its inclusion as a negative control compound in the widely utilized Aldefluor assay. Recent evidence has accumulated that DEAB is not a selective inhibitory agent when assayed in vitro versus ALDH1, ALDH2 and ALDH3 family members. We sought to determine the selectivity of DEAB toward ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, ALDH1L1, ALDH2, ALDH3A1, ALDH4A1 and ALDH5A1 isoenzymes and determine the mechanism by which DEAB exerts its inhibitory action. We found that DEAB is an excellent substrate for ALDH3A1, exhibiting a Vmax/KM that exceeds that of its commonly used substrate, benzaldehyde. DEAB is also a substrate for ALDH1A1, albeit an exceptionally slow one (turnover rate ∼0.03 min(-1)). In contrast, little if any turnover of DEAB was observed when incubated with ALDH1A2, ALDH1A3, ALDH1B1, ALDH2 or ALDH5A1. DEAB was neither a substrate nor an inhibitor for ALDH1L1 or ALDH4A1. Analysis by enzyme kinetics and QTOF mass spectrometry demonstrates that DEAB is an irreversible inhibitor of ALDH1A2 and ALDH2 with apparent bimolecular rate constants of 2900 and 86,000 M(-1) s(-1), respectively. The mechanism of inactivation is consistent with the formation of quinoid-like resonance state following hydride transfer that is stabilized by local structural features that exist in several of the ALDH isoenzymes

Cr3+ substitution effect on Co-Cu and Cu-Co nano ferrites on structural and morphological properties

The Cr3+ substituted Co-Cu (Co0.7Cu0.3Fe2-xCrxO4) and Cu-Co (Cu0.7Co0.3Fe2-xCrxO4) where x = 0.0, 0.05, 0.1, 0.15, 0.2 and 0.25 nano ferrite composite were prepared with the sol-gel approach. Their structural, dc electrical resistivity, and magnetic properties were analyzed. XRD shows the single-phase spinel ferrite. Adding Cr3+ ions decreases the lattice volume and the size of the crystallite respectively. FESEM images show non-spherical particles on a largely uniform surface shape with decreasing grain size on doping Cr3+. The FTIR pattern supports the XRD patterns for spinel ferrite

Discovery of Novel Regulators of Aldehyde Dehydrogenase Isoenzymes

Over the past three years we have been involved in high-throughput screening in an effort to discover novel small molecular modulators of aldehyde dehydrogenase (ALDH) activity. In particular, we have been interested in both the activation and inhibition of the three commonly studied isoenzymes, ALDH1A1, ALDH2 and ALDH3A1, as their distinct, yet overlapping substrate specificities, present a particularly difficult challenge for inhibitor discovery and design. Activation of ALDH2 has been shown to benefit cardiovascular outcome following periods of ischemia and renewed interest in specific inhibition of ALDH2 has application for alcohol aversion therapy, and more recently, in cocaine addiction. In contrast, inhibition of either ALDH1A1 or ALDH3A1 has application in cancer treatments where the isoenzymes are commonly over-expressed and serve as markers for cancer stem cells. We are taking two distinct approaches for these screens: in vitro enzyme activity screens using chemical libraries and virtual computational screens using the structures of the target enzymes as filters for identifying potential inhibitors, followed by in vitro testing of their ability to inhibit their intended targets. We have identified selective inhibitors of each of these three isoenzymes with inhibition constants in the high nanomolar to low micromolar range from these screening procedures. Together, these inhibitors provide proof for concept that selective inhibition of these broad specificity general detoxication enzymes through small molecule discovery and design is possible

Distribution of Dental Diseases and Treatment Delivered amongst Patients Visiting Dental Outpatient Department at Gandaki Medical College, Nepal

Introduction: A study of dental diseases amongst patients attending dental outpatient department (OPD) helps us plan a preventive, and/or a definitive dental treatment. Objectives: To find out the distribution of dental diseases amongst patients visiting dental OPD at College of Dental Surgery, Gandaki Medical College (GMC), Pokhara, Nepal. Methods: The present study was a hospital based cross sectional descriptive study carried out during a period of one year extending from 1st February 2016 to 31st January 2017. A total of 3052 patients attending the dental OPD were included in the study. The distribution of dental diseases according to sex, age and diagnosis were collected and analyzed. Additionally, frequency distribution of treatments provided to the patients was observed. Results: Dental caries was the most prevalent dental disease (64.41%) followed by gingivitis (13.04%). The prevalence of dental caries was significantly higher in females (Females 56.91% vs. males 43.08%, P <0.05). Conversely, the prevalence of maxillofacial injuries (85.06%), dental impactions (72%), and malocclusion (53.88%) were significantly more common in male patients (P <0.05). The age group <19 years comprised 23.98 % of patients who visited the dental OPD, and the dental caries was most prevalent (27.10%) in the age group. The order of more frequent dental treatments was root canal treatment (18.84%), tooth extraction (18.44%), dental restoration (10.48%), and scaling (9.20%). Conclusions: The most prevalent dental disease was dental caries and it was more prevalent in females than in males. The most common age group reporting to Dental OPD was <19 years.  J-GMC-N | Volume 11 | Issue 01 | January-June 2018, Page: 29-3

Development of selective inhibitors for human aldehyde dehydrogenase 3A1 (ALDH3A1) for the enhancement of cyclophosphamide cytotoxicity

Aldehyde dehydrogenase 3A1 (ALDH3A1) plays an important role in many cellular oxidative processes, including cancer chemoresistance, by metabolizing activated forms of oxazaphosphorine drugs such as cyclophosphamide (CP) and its analogues, such as mafosfamide (MF), ifosfamide (IFM), and 4-hydroperoxycyclophosphamide (4-HPCP). Compounds that can selectively target ALDH3A1 could permit delineation of its roles in these processes and could restore chemosensitivity in cancer cells that express this isoenzyme. Here we report the detailed kinetic and structural characterization of an ALDH3A1-selective inhibitor, CB29, previously identified in a high-throughput screen. Kinetic and crystallographic studies demonstrate that CB29 binds within the aldehyde substrate-binding site of ALDH3A1. Cellular proliferation of ALDH3A1-expressing lung adenocarcinoma (A549) and glioblastoma (SF767) cell lines, as well as ALDH3A1 non-expressing lung fibroblast (CCD-13Lu) cells, is unaffected by treatment with CB29 and its analogues alone. However, sensitivity toward the anti-proliferative effects of mafosfamide is enhanced by treatment with CB29 and its analogue in the tumor cells. In contrast, the sensitivity of CCD-13Lu cells toward mafosfamide was unaffected by the addition of these same compounds. CB29 is chemically distinct from the previously reported small-molecule inhibitors of ALDH isoenzymes and does not inhibit ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, or ALDH2 isoenzymes at concentrations up to 250 μM. Thus, CB29 is a novel small molecule inhibitor of ALDH3A1, which might be useful as a chemical tool to delineate the role of ALDH3A1 in numerous metabolic pathways, including sensitizing ALDH3A1-positive cancer cells to oxazaphosphorines

Control of crystal size tailors the electrochemical performance of alpha-V2O5 as a Mg2+ intercalation host

α-V2O5 has been extensively explored as a Mg2+ intercalation host with potential as a battery cathode, offering high theoretical capacities and potentials vs. Mg2+/Mg. However, large voltage hysteresis is observed with Mg insertion and extraction, introducing significant and unacceptable round-trip energy losses with cycling. Conventional interpretations suggest that bulk ion transport of Mg2+ within the cathode particles is the major source of this hysteresis. Herein, we demonstrate that nanosizing α-V2O5 gives a measurable reduction to voltage hysteresis on the first cycle that substantially raises energy efficiency, indicating that mechanical formatting of the α-V2O5 particles contributes to hysteresis. However, no measurable improvement in hysteresis is found in the nanosized α-V2O5 in latter cycles despite the much shorter diffusion lengths, suggesting that other factors aside from Mg transport, such as Mg transfer between the electrolyte and electrode, contribute to this hysteresis. This observation is in sharp contrast to the conventional interpretation of Mg electrochemistry. Therefore, this study uncovers critical fundamental underpinning limiting factors in Mg battery electrochemistry, and constitutes a pivotal step towards a high-voltage, high-capacity electrode material suitable for Mg batteries with high energy density

Sol-gel synthesis, characterization of ZnO thin films on different substrates, and bandgap calculation by the Tauc plot method

The sol-gel spin coating method was used for the preparation of the Zinc Oxide which was coated over polymer, transparent, and glass translucent substrates and characterized with the help of a UV-Vis Spectroscope. The wavelength bandgap of those samples was found to be 296nm, 310.5nm, and 330nm respectively. The actual band gap of ZnO is 388nm. Similarly, their optical bandgap energy calculated by the Tauc Plot method were 3.641eV, 3.385eV, and 3.495 eV respectively. The transparent polymer slide has the lowest wavelength bandgap and the translucent glass slide has the highest. Further, the bandgap’s value differs from its actual value to the difference in the absorption process due to the presence of the substrate. These results suggest that the choice of substrate can significantly impact the optical properties and performance of the zinc oxide thin film. This result can be applied in developing and optimizing zinc oxide thin films for various purposes, such as in solar cells, sensors, and optoelectronics. By carefully selecting the substrate, it may be possible to tailor the bandgap energy and other optical properties of the thin film to better suit the specific application