Structural and Binding Properties of Two Paralogous Fatty Acid Binding Proteins of Taenia Solium Metacestode.

Structural and Binding Properties of Two Paralogous Fatty Acid Binding Proteins of Taenia solium Metacestode.

Filed under: Drug and Alcohol Rehabilitation

PLoS Negl Trop Dis. 2012 Oct; 6(10): e1868
Kim SH, Bae YA, Yang HJ, Shin JH, Diaz-Camacho SP, Nawa Y, Kang I, Kong Y

BACKGROUND: Fatty acid (FA) binding proteins (FABPs) of helminths are implicated in acquisition and utilization of host-derived hydrophobic substances, as well as in signaling and cellular interactions. We previously demonstrated that secretory hydrophobic ligand binding proteins (HLBPs) of Taenia solium metacestode (TsM), a causative agent of neurocysticercosis (NC), shuttle FAs in the surrounding host tissues and inwardly transport the FAs across the parasite syncytial membrane. However, the protein molecules responsible for the intracellular trafficking and assimilation of FAs have remained elusive. METHODOLOGY/PRINCIPAL FINDINGS: We isolated two novel TsMFABP genes (TsMFABP1 and TsMFABP2), which encoded 133- and 136-amino acid polypeptides with predicted molecular masses of 14.3 and 14.8 kDa, respectively. They shared 45% sequence identity with each other and 15-95% with other related-members. Homology modeling demonstrated a characteristic ?-barrel composed of 10 anti-parallel ?-strands and two ?-helices. TsMFABP2 harbored two additional loops between ?-strands two and three, and ?-strands six and seven, respectively. TsMFABP1 was secreted into cyst fluid and surrounding environments, whereas TsMFABP2 was intracellularly confined. Partially purified native proteins migrated to 15 kDa with different isoelectric points of 9.2 (TsMFABP1) and 8.4 (TsMFABP2). Both native and recombinant proteins bound to 11-([5-dimethylaminonaphthalene-1-sulfonyl]amino)undecannoic acid, dansyl-DL-?-amino-caprylic acid, cis-parinaric acid and retinol, which were competitively inhibited by oleic acid. TsMFABP1 exhibited high affinity toward FA analogs. TsMFABPs showed weak binding activity to retinol, but TsMFABP2 showed relatively high affinity. Isolation of two distinct genes from an individual genome strongly suggested their paralogous nature. Abundant expression of TsMFABP1 and TsMFABP2 in the canal region of worm matched well with the histological distributions of lipids and retinol. CONCLUSIONS/SIGNIFICANCE: The divergent biochemical properties, physiological roles and cellular distributions of the TsMFABPs might be one of the critical mechanisms compensating for inadequate de novo FA synthesis. These proteins might exert harmonized or independent roles on lipid assimilation and intracellular signaling. The specialized distribution of retinol in the canal region further implies that cells in this region might differentiate into diverse cell types during metamorphosis into an adult worm. Identification of bioactive systems pertinent to parasitic homeostasis may provide a valuable target for function-related drug design.
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In Vivo Study on the Pharmacological Interactions between a Chinese Herbal Formula ELP and Antiresorptive Drugs to Counteract Osteoporosis.

Filed under: Drug and Alcohol Rehabilitation

Evid Based Complement Alternat Med. 2012; 2012: 203732
Ko CH, Siu WS, Wong HL, Gao S, Shum WT, Lau CP, Cheng SW, Tam JC, Hung LK, Fung KP, Lau CB, Han QB, Leung PC

Antiresorptive drugs, alendronate and raloxifene, are effective in lowering bone mineral density (BMD) loss in postmenopausal women. However, long-term treatment may be associated with serious side effects. Our research group has recently discovered that a Chinese herbal formula, ELP, could significantly reduce BMD loss in animal and human studies. Therefore, the present study aimed to investigate the potential synergistic bone-protective effects of different herb-drug combinations using ovariectomized rats. To assess the efficacy of different combinations, the total BMD was monitored biweekly in the 8-week course of daily oral treatment. Bone microarchitecture, bone strength, and deoxypyridinoline level were also determined after 8 weeks. From our results, coadministration of ELP and raloxifene increased the total tibial BMD by 5.26% (2.5?mg/kg/day of raloxifene; P = 0.014) and 5.94% (0.25?mg/kg/day of raloxifene; P = 0.026) when compared with the respective dosage groups with raloxifene alone. Similar synergistic effects were also observed in BMD increase at distal femur (0.25?mg/kg/day; P = 0.001) and reduction in urinary deoxypyridinoline crosslink excretion (2.5 and 0.25?mg/kg/day; both P = 0.02). However, such interactions could not be observed in all alendronate-treated groups. Our data provide first evidence that ELP could synergistically enhance the therapeutic effects of raloxifene, so that the clinical dosage of raloxifene could be reduced.
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Roles Played by Chemolipiodolization and Embolization in Chemoembolization for Hepatocellular Carcinoma: Single-Blind, Randomized Trial.

Filed under: Drug and Alcohol Rehabilitation

J Natl Cancer Inst. 2012 Nov 12;
Shi M, Lu LG, Fang WQ, Guo RP, Chen MS, Li Y, Luo J, Xu L, Zou RH, Lin XJ, Zhang YQ

BackgroundThe aim of our study was to compare the efficacy and safety of: 1) transarterial chemolipiodolization with gelatin sponge embolization vs chemolipiodolization without embolization, and 2) chemolipiodolization with triple chemotherapeutic agents vs epirubicin alone.MethodsA single-blind, three parallel arm, randomized trial was conducted at three clinical centers with patients with biopsy-confirmed unresectable hepatocellular carcinoma. Arm 1 received triple-drug chemolipiodolization and sponge embolization, whereas Arm 2 received triple-drug chemolipiodolization only. Patients in arm 3 were treated with single-drug chemolipiodolization and sponge embolization. We compared overall survival and time to progression. Event-time distributions were estimated by the Kaplan-Meier method. All statistical tests were two-sided.ResultsFrom July 2007 to November 2009, 365 patients (Arm 1: n = 122; Arm 2: n = 121; Arm 3: n = 122) were recruited. The median tumor size was 10.9cm (range = 7-22cm), and 34.5% had macrovascular invasion. The median survivals and time to progression in Arm 1, Arm 2, and Arm 3 were 10.5 and 3.6 months, 10.1 and 3.1 months, and 5.9 and 3.1 months, respectively. Survival was statistically significantly better in Arm 1 than in Arm 3 (P < .001), whereas there was no statistically significant difference between Arm 1 and Arm 2 (P = .20). Objective response rates were 45.9%, 29.7%, and 18.9% for Arm 1, Arm 2, and Arm 3, respectively.ConclusionsChemolipiodolization played an important role in transarterial chemoembolization, and the choice of chemotherapy regimen may largely affect survival outcomes. However, the removal of embolization from chemoembolization might not statistically significantly decrease survival. HubMed – drug


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