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Oligomeric bile acid-mediated oral delivery of low molecular weight heparin
Al-Hilal, T.A.,Park, J.,Alam, F.,Chung, S.W.,Park, J.W.,Kim, K.,Kwon, I.C.,Kim, I.S.,Kim, S.Y.,Byun, Y. Elsevier Science Publishers 2014 Journal of controlled release Vol.175 No.-
Intestinal transporters are limited to the transport of small molecular substrates. Here, we describe the development of apical sodium-dependent bile acid transporter (ASBT)-targeted high-affinity oligomeric bile acid substrates that mediate the transmembrane transport of low molecular weight heparin (LMWH). Several oligomers of deoxycholic acid (oligoDOCA) were synthesized to investigate the substrate specificity of ASBT. To see the binding of oligoDOCA on the substrate-binding pocket of ASBT, molecular docking was used and the dissociation rate constants (K<SUB>D</SUB>) were measured using surface plasmon resonance. The K<SUB>D</SUB> for tetrameric DOCA (tetraDOCA) was 50-fold lower than that for monomeric DOCA, because tetraDOCA interacted with several hydrophobic grooves in the substrate-binding pocket of ASBT. The synthesized oligoDOCA compounds were subsequently chemically conjugated to macromolecular LMWH. In vitro, tetraDOCA-conjugated LMWH (LHe-tetraD) had highest selectivity for ASBT during its transport. Orally administered LHe-tetraD showed remarkable systemic anticoagulation activity and high oral bioavailability of 33.5+/-3.2% and 19.9+/-2.5% in rats and monkeys, respectively. Notably, LHe-tetraD successfully prevented thrombosis in a rat model of deep vein thrombosis. These results represent a major advancement in ASBT-mediated LMWH delivery and may facilitate administration of many important therapeutic macromolecules through a non-invasive oral route.
Improvement of COP with Heat Recovery Scheme for Solar Adsorption Cooling System
K. M. Ariful Kabir,Rifat A. Rouf,M. M. A. Sarker,K. C. Amanul Alam,Bidyut B. Saha 대한설비공학회 2018 International Journal Of Air-Conditioning and Refr Vol.26 No.2
Heat recovery ensures optimum usage of the collected energy, and thus, minimizes heat loss for a solar adsorption chiller. Two-bed adsorption chiller with conventional single stage, run by direct solar coupling with heat recovery, has been studied mathematically. In a heat recovery adsorption refrigeration system, to facilitate heat transfer, heat transfer fluid is distributed between two adsorbers maintaining the same mass flow rate. There is no mass transfer between system components during this phase. It is a semi-continuous system performed between two adsorption beds. After completion of desorption/condensation mode, heat transfer fluid is allowed to circulate between the heated desorber and the cooled adsorber. This process distributes some heat of the desorption bed to the adsorber preparing it for the next preheating mode where heat transfer between them is done adiabatically. Consequently, the performance has been checked and a satisfactory increase in the Coefficient of Performance (COP) (approximately 15%) has been detected in the calculated results for the heat recovery operation. It is also observed that the heat recovery process enhances the working hour and overall performances of the solar heat driven adsorption chiller.
Prevention effect of orally active heparin conjugate on cancer-associated thrombosis
Al-Hilal, T.A.,Alam, F.,Park, J.W.,Kim, K.,Kwon, I.C.,Ryu, G.H.,Byun, Y. Elsevier Science Publishers 2014 Journal of controlled release Vol.195 No.-
Thrombogenesis is a major cause of morbidity and mortality in cancer patients. Prophylaxis with low-molecular-weight heparin (LMWH) is recommended for cancer patients, but requires non-parenteral delivery methods for long-term treatments. In this study, we sought to generate a new oligomeric-bile acid conjugate of LMWH that can be used for oral delivery. We first synthesized a tetramer of deoxycholic acid (tetraDOCA), which was site-specifically conjugated at the end saccharide of LMWH. When LMWH-tetraDOCA conjugate (LHe-tetraD) was orally administered at a dose of 5mg/kg in ICR mice, the maximum anti-factor Xa level was increased up to 0.62+/-0.05IU/mL without any evidence of liver toxicity, gastrointestinal damage, or thrombocytopenia. The cancer-associated thrombosis was induced in tumor-bearing mice by local heat application, and the fibrin deposition in tumors was evaluated. The oral administration of LHe-tetraD (either a single dose or multiple daily doses for up to 10days) in mice substantially abolished the coagulation-dependent tropism of fibrinogen in the heated tumors and significantly decreased hemorrhage, compared to the mice treated with saline or subcutaneous injection of LMWH. Thus, the anticoagulation effect of oral LHe-tetraD invokes the benefits of oral delivery and promises to provide an effective and convenient treatment for cancer patients at risk of thrombosis.
Zeb, A.,Park, C.,Son, M.,Rampogu, S.,Alam, S. I.,Park, S. J.,Lee, K. W. Imperial College Press 2018 JOURNAL OF BIOINFORMATICS AND COMPUTATIONAL BIOLOG Vol.16 No.3
<P>Proteins deacetylation by Histone deacetylase 6 (HDAC6) has been shown in various human chronic diseases like neurodegenerative diseases and cancer, and hence is an important therapeutic target. Since, the existing inhibitors have hydroxamate group, and are not HDAC6-selective, therefore, this study has designed to investigate non-hydroxamate HDAC6 inhibitors. Ligand-based pharmacophore was generated from 26 training set compounds of HDAC6 inhibitors. The statistical parameters of pharmacophore (Hypo1) included lowest total cost of 115.63, highest cost difference of 135.00, lowest RMSD of 0.70 and the highest correlation of 0.98. The pharmacophore was validated by Fischer's Randomization and Test Set validation, and used as screening tool for chemical databases. The screened compounds were filtered by fit value (> 10.00), estimated Inhibitory Concentration (IC50) (<0.459), Lipinski's Rule of Five and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) Descriptors to identify drug-like compounds. Furthermore, the drug-like compounds were docked into the active site of HDAC6. The best docked compounds were selected having gold fitness score > 66.46 and chemscore < -28.31, and hydrogen bond interaction with catalytic active residues. Finally, three inhibitors having sulfamoyl group were selected by Molecular Dynamic (MD) simulation, which showed stable root mean square deviation (RMSD) (1.6-1.9 angstrom), lowest potential energy (< -6.3 x 10(5) kJ/mol), and hydrogen bonding with catalytic active residues of HDAC6.</P>
Pankaj Kumar Jha,Md. Golam Shahi Alam,Md. Abdullah Al Mansur,Mohammad Rafiqul Islam Talukder,Nazmun Naher,A. K. M. Anisur Rahman,David C. Hall,Farida Yeasmin Bari 한국동물생명공학회(구 한국동물번식학회) 2020 Journal of Animal Reproduction and Biotechnology Vol.35 No.2
The effects of the number of frozen-thawed ram sperm per single and double intra-cervical artificial insemination (AI) on fertility in ewes were studied. A total of 89 non-pregnant ewes were synchronized for oestrus with two doses of 100 μg PGF2α (Cloprostenol) 9 days apart. The ewes were randomly assigned to one of four groups; D200 (n = 23; double AI with 200 × 106 sperm), S200 (n = 24; single AI with 200 × 106 sperm), D100 (n = 24; double AI with 100 × 106 sperm) and S100 (n = 18; single AI with 100 × 106 sperm). Ewes were inseminated within 12 to 18 h for single AI and, within 10 to 12 h and 16 to 18 h for double AI after the onset of oestrus. The onset of oestrus ranged from 28 to 76 h (54.33 ± 1.28 h). The high percentage (29.2%) of ewes showed oestrus between 51 to 60 h. The non-return rates were highest in group D200 (56.5%) and differed significantly (p < 0.05) from group S100 (11.1%). No ewes were pregnant in group S100, and the pregnancy rates among the remaining groups did not differ. The mean gestation period was 152.8 ± 0.5 days and no difference was observed among the groups. The lambing and multiple birth rates were 100% in group D200. The single and twin lambing was highest in group D100 (33.3%) and group D200 (83.3%), respectively. Only one triplet lambing and the highest lambing size (2.2 ± 0.2) was recorded in group D200. In conclusion, double AI with 200 × 106 sperm showed comparatively most practical for achieving high pregnancy rates and lambing performances in Bangladeshi ewes under field conditions.