Feasibility of Treatment Agents in Radioactive Iodine Separation from Waste Liquids.

ABSTRACT: To discharge waste liquid containing radioactive iodine into sewage systems, long-term storage or dilution with a large amount of water may be required until the radioactivity concentration reduces below the standard value. Processing the waste liquid could be easier if radioactive iodine could be separated from the water. This study verified the effectiveness of superabsorbent polymer and α-cyclodextrin as treatment agents to separate radioactive iodine from waste liquids. Sodium iodide (Na125I) was added to purified water and artificial urine to prepare simulated waste liquids containing iodine equivalent to the urine of patients treated with radioactive iodine. The as-prepared simulated waste liquid was poured into a container with superabsorbent polymer and left for 90 d. The residual iodine rate in the simulated waste liquid was estimated by measuring 125I radioactivity. When the water was sufficiently dried, residual iodine rates on day 15 were 0.102 and 0.884 in the simulated waste liquids comprising purified water and artificial urine, respectively. The simulated waste liquid comprising purified water with 5% α-cyclodextrin absorbed by 1 g of superabsorbent polymer had a residual rate of 0.980. Moreover, the residual rate of simulated waste liquid comprising artificial urine with 2% α-cyclodextrin absorbed by 1 g of SAP was 0.949. Superabsorbent polymer combined with α-cyclodextrin was an effective treatment agent for separating radioactive iodine from waste liquids.

Characterization, Preparation, and Promotion of Plant Growth of 1,3-Diphenylurea/ß-Cyclodextrin Derivatives Inclusion Complexes.

The study aimed to prepare inclusion complexes of 1,3-diphenylurea (DPU) with ß-cyclodextrin (ßCD) and 2-hydroxypropyl-ß-cyclodextrin (HP-ßCD) using a three-dimensional ground mixture (3DGM). Their physicochemical properties, intermolecular interactions, solubilities, and plant growth-promoting activities were investigated on broccoli sprouts. Phase-solubility diagrams indicated the stability constant (Ks) and complexation efficiency (CE) of ßCD/DPU were found to be K1/1 = 250 M-1, CE = 2.48× 10-3. The Ks and CEs of HP-ßCD/DPU were found to be K1/1 = 427 M-1, CE = 3.93 × 10-3 and K2/1 = 196 M-1, CE = 1.93 × 10-3 respectively. The powder X-ray diffraction results of 3DGM (ßCD/DPU = 2/1, HP-ßCD/DPU = 2/1) showed that the diffraction peaks originating from the DPU and ßCD disappeared, indicating a halo pattern. Differential scanning calorimetry results showed an endothermic peak at 244 °C derived from the melting point of DPU, but the endothermic peak disappeared in the 3DGM (ßCD/DPU = 2/1, HP-ßCD/DPU = 2/1). Near-infrared absorption spectra showed peak shifts in 3DGM (ßCD/DPU and HP-ßCD/DPU) at the -CH and -NH groups of DPU and the -OH groups of ßCDs and free water. In the dissolution test (after 5 min), the concentration of intact DPU was 0.083 µg/mL. However, the dissolution concentrations of DPU in the 3DGM (ßCD/DPU = 1/1), 3DGM (ßCD/DPU = 2/1), 3DGM (HP-ßCD/DPU = 1/1), and 3DGM (HP-ßCD/DPU = 2/1) were 3.27, 3.64, 5.70, and 7.03 µg/mL, respectively, indicating higher solubility than that of the intact DPU. Further, 1H-1H NOESY NMR spectroscopic measurements showed cross-peaks between H-A (7.32 ppm) and H-B (7.12 ppm) of DPU and H-6 (3.79 ppm) in the ßCD cavity of the 3DGM (ßCD/DPU = 2/1). A cross-peak was also observed among DPU H-A (7.32 ppm), H-B (7.11 ppm), and H-6 (3.78 ppm) in the ßCD cavity. The results of the broccoli sprout cultivation experiment showed that 3DGM (ßCD/DPU = 1/1), 3DGM (ßCD/DPU = 2/1), 3DGM (HP-ßCD/DPU = 1/1), and 3DGM (HP-ßCD/DPU = 2/1) increased the stem thickness compared with that of the control group (DPU). These results indicated that the ßCD/DPU and HP-ßCD/DPU inclusion complexes were formed by the three-dimensional mixing and milling method, which enhanced the solubility and plant growth-promoting effects.

A Case of Autism Spectrum Disorder with Perforated Keratomalacia due to Vitamin A Deficiency.

We report a case of a patient with autism spectrum disorder (ASD) and perforated keratomalacia secondary to vitamin A deficiency. A 6-year-old boy complained of difficulty in opening the eyelids. The ocular conjunctiva was hyperemic and keratinized with purulent ocular (eye) discharge. Both corneas showed epithelial defects with hypopyon. The serum vitamin A level was ≤5 IU/dL (normal 97-316), leading to a diagnosis of xerophthalmia and keratomalacia due to vitamin A deficiency. Intramuscular injection of vitamin A (50,000 IU/day), as well as oral administration of multivitamin (containing 2,500 IU of vitamin A) and zinc supplement at 50 mg/day, allowed him to open both eyes and show interest in tablet devices 14 days after the diagnosis. During the course of the treatment, corneal perforation was observed, but it was closed without contact lens wear or amniotic patch and managed with vitamin A replacement therapy and antimicrobial eye drops. The epithelium extended to the area of the right cornea that had been melted, and although scarring corneal opacity remained, there were no obvious signs of infection. Early diagnosis is difficult because children with ASD do not express complaints, and vitamin A deficiency should be considered in patients with a severely unbalanced diet and complaints of difficulty opening the eyelids.

Soy Extract, Rich in Hydroxylated Isoflavones, Exhibits Antidiabetic Properties In Vitro and in Drosophila melanogaster In Vivo.

In the context of the growing prevalence of type 2 diabetes (T2DM), control of postprandial hyperglycemia is crucial for its prevention. Blood glucose levels are determined by various factors including carbohydrate hydrolyzing enzymes, the incretin system and glucose transporters. Furthermore, inflammatory markers are recognized predictors of diabetes outcome. Although there is some evidence that isoflavones may exhibit anti-diabetic properties, little is known about to what extent their corresponding hydroxylated metabolites may affect glucose metabolism. We evaluated the ability of a soy extract before (pre-) and after (post-) fermentation to counteract hyperglycemia in vitro and in Drosophila melanogaster in vivo. Fermentation with Aspergillus sp. JCM22299 led to an enrichment of hydroxy-isoflavones (HI), including 8-hydroxygenistein, 8-hydroxyglycitein and 8-hydroxydaidzein, accompanied by an enhanced free radical scavenging activity. This HI-rich extract demonstrated inhibitory activity towards α-glucosidase and a reduction of dipeptidyl peptidase-4 enzyme activity. Both the pre- and post-fermented extracts significantly inhibited the glucose transport via sodium-dependent glucose transporter 1. Furthermore, the soy extracts reduced c-reactive protein mRNA and secreted protein levels in interleukin-stimulated Hep B3 cells. Finally, supplementation of a high-starch D. melanogaster diet with post-fermented HI-rich extract decreased the triacylglyceride content of female fruit flies, confirming its anti-diabetic properties in an in vivo model.

A Case of Cat Scratch Disease with Neuroretinitis in a 16-Month-Old Boy.

Purpose: We report a case of neuroretinitis associated with cat scratch disease (CSD) in young children. Method: Case report. Results: A 16-month-old boy was admitted for a detailed examination and treatment of a fever of unknown origin. Blood tests revealed no significant findings other than a white blood cell count of 16,100/mm3 and C-reactive protein level of 9.89 mg/dL. Computed tomography revealed no relevant findings to determine the causative disease. Antibiotic therapy with cefotaxime was initiated; however, the fever did not resolve. The patient was referred to our department for further examination to detect the cause of the fever. Fundoscopy revealed neuroretinitis in the right eye. His mother reported a history of breeding cats. Cat scratch disease (CSD) was suspected based on the clinical course and fundus findings. Cefotaxime was discontinued, and azithromycin, rifampicin, and prednisolone were administered, following which the fever disappeared and fundus findings improved. Immunoglobulin G (IgG) and IgM antibodies against Bartonella henselae was positive, leading to a definitive diagnosis of CSD. Conclusion: Infants cannot complain of decreased visual acuity; therefore, these findings may be overlooked unless a fundus examination is performed. As in this case, the early detection of neuroretinitis by an ophthalmologist may help in the diagnosis of CSD. It is extremely difficult to capture a photograph of the fundus of an infant, and recording with a smartphone is relatively simple and useful for monitoring continuous changes. Summary. We describe a case of neuroretinitis associated with cat scratch disease (CSD) that was diagnosed on the basis of fundus findings. The findings suggest the importance of an aggressive ophthalmologic examination when CSD is suspected in young children who are unable to describe their symptoms.

A Case of Fabry Disease with Central Retinal Artery Occlusion.

We report a case of Fabry disease diagnosed after recurrent cerebral infarction in a patient with central retinal artery occlusion (CRAO). A 23-year-old man presented with vision loss in his right eye (20/2000), showing CRAO. There was no identified cause for the loss of vision; however, corneal verticillata was detected in both eyes on the recurrence of the cerebral infarction. The α-galactosidase activity in leukocytes was significantly reduced to <0.3 nmol/mg of protein/hour, leading to a definitive diagnosis of Fabry disease. Enzyme replacement therapy was commenced concomitant to rehabilitation. It is necessary to identify Fabry disease as a cause of CRAO in young individuals, and the detection of cornea verticillata, used frequently as an ocular finding, is helpful.

Additive-manufactured single-piece thin multi-layer tungsten heater for an electrothermal thruster.

In this study, a novel single-piece thin multi-layer tungsten resistive heater was successfully fabricated using additive manufacturing and tested as an electrothermal thruster. The heater has 12 resistive layers, with each layer having a thickness and height of 0.15 and 81 mm, respectively, and can provide high heating efficiency. A single-piece or monolithic heater was manufactured via additive manufacturing technique, which drastically improved its reliability and decreased its manufacturing cost. In the heating and thrust measurement tests that used nitrogen gas as a propellant, the heater reached a gas temperature of ∼2000 K at a 140-A heater current without experiencing any failure. The tungsten-heater resistance linearly increased with an increase in temperature due to the temperature dependence of tungsten's resistivity. The specific impulse and thrust increased with the heater temperature in accordance with the theoretical prediction. Even including a voltage drop due to a contact resistance, the achieved heater efficiency reached 63% at a 100-A heater current even without a thermal insulation around the thruster. The heater efficiency decreased with an increase in the heater temperature due to heat loss to the surroundings. The heat-loss analysis indicated that both thermal conduction and radiation heat losses were crucial for improving the heater performance at a high-temperature operation of over 2000 K.

Preparation and Characterization of a Hybrid Complex of Cyclodextrin-Based Metal-Organic Frameworks-1 and Ascorbic Acid Derivatives.

Cyclodextrin-based metal-organic frameworks-1 (CD-MOF-1) prepared using potassium hydroxide, ethanol, and γ-cyclodextrin (γ-CD) has been reported as a new type of MOF for the development of pharmaceutical formulations. The present study aimed to investigate the physicochemical properties of ascorbic acid derivatives (L-ascorbyl 6-palmitate (ASCP); L-ascorbyl 2,6-palmitate (ASCDP)) complexed with CD-MOF-1 by a solvent evaporation method. Powder X-ray diffraction revealed that the crystal diffraction pattern of CD-MOF-1 changed from α-type to ß-type when prepared by a solvent evaporation method. For ASCP/CD-MOF-1 = 1/2 and ASCDP/CD-MOF-1 = 1/4 evaporated samples, the crystal diffraction peaks derived from ASCP and ASCDP disappeared, indicating a ß-like behavior. Differential scanning calorimetry results revealed that the endothermic peaks of evaporated samples (ASCP/CD-MOF-1 = 1/2 and ASCDP/CD-MOF-1 = 1/4) were not detected due to melting. Furthermore, intermolecular interactions were observed in the hydrogen bonds between the CH groups of the side chains of ASCP and ASCDP and the OH group of CD-MOF-1 in (ASCP/CD-MOF-1 = 1/2) and EVP (ASCDP/CD-MOF-1 = 1/4), based on the near-infrared absorption spectroscopy analysis. CD-MOF-1 did not form inclusion complexes with the lactone rings of ASCP and ASCDP, but with the lipophilic side chains. These results suggested that CD-MOF-1 may be useful in preparing novel drug carriers for ASCP and ASCDP.

Anti-tumor efficacy of a novel CLK inhibitor via targeting RNA splicing and MYC-dependent vulnerability.

The modulation of pre-mRNA splicing is proposed as an attractive anti-neoplastic strategy, especially for the cancers that exhibit aberrant pre-mRNA splicing. Here, we discovered that T-025 functions as an orally available and potent inhibitor of Cdc2-like kinases (CLKs), evolutionally conserved kinases that facilitate exon recognition in the splicing machinery. Treatment with T-025 reduced CLK-dependent phosphorylation, resulting in the induction of skipped exons, cell death, and growth suppression in vitro and in vivo Further, through growth inhibitory characterization, we identified high CLK2 expression or MYC amplification as a sensitive-associated biomarker of T-025. Mechanistically, the level of CLK2 expression correlated with the magnitude of global skipped exons in response to T-025 treatment. MYC activation, which altered pre-mRNA splicing without the transcriptional regulation of CLKs, rendered cancer cells vulnerable to CLK inhibitors with synergistic cell death. Finally, we demonstrated in vivo anti-tumor efficacy of T-025 in an allograft model of spontaneous, MYC-driven breast cancer, at well-tolerated dosage. Collectively, our results suggest that the novel CLK inhibitor could have therapeutic benefits, especially for MYC-driven cancer patients.

CDK8/19 inhibition induces premature G1/S transition and ATR-dependent cell death in prostate cancer cells.

The CDK8/19 kinase module comprises a subcomplex that interacts with the Mediator complex and regulates gene expression through phosphorylation of transcription factors and Mediator subunits. Mediator complex subunits have been increasingly implicated in cancer and other diseases. Although high expression of CDK8/19 has been demonstrated in prostate cancer, its function has not been thoroughly examined. Here we report that CDK8/19 modulates the gene expression of cell cycle regulators and thereby maintains the proper G1/S transition in prostate cancer cells. We show that highly selective CDK8/19 inhibitors exerted anti-proliferative activity in prostate cancer cells both in vitro and in vivo. In CDK8/19 inhibitor-sensitive prostate cancer cells, the compounds reduced the population of G1 phase cells and elevated that of S phase cells through the modulation of G1/S transition regulators at the level of mRNA expression. Furthermore, the premature G1/S transition induced a DNA damage response that was followed by ATR-dependent and caspase-independent cell death. These findings suggest a novel role of CDK8/19 in transcription-mediated cell cycle control, albeit with possible contribution of other proteins inhibited by the compounds. Our data provide a rationale for further investigation of CDK8/19 inhibitors as a new therapeutic approach to prostate cancer.

Studying anti-oxidative properties of inclusion complexes of α-lipoic acid with γ-cyclodextrin in single living fission yeast by confocal Raman microspectroscopy.

α-lipoic acid (ALA) is an essential cofactor for many enzyme complexes in aerobic metabolism, especially in mitochondria of eukaryotic cells where respiration takes place. It also has excellent anti-oxidative properties. The acid has two stereo-isomers, R- and S- lipoic acid (R-LA and S-LA), but only the R-LA has biological significance and is exclusively produced in our body. A mutant strain of fission yeast, Δdps1, cannot synthesize coenzyme Q10, which is essential during yeast respiration, leading to oxidative stress. Therefore, it shows growth delay in the minimal medium. We studied anti-oxidant properties of ALA in its free form and their inclusion complexes with γ-cyclodextrin using this mutant yeast model. Both free forms R- and S-LA as well as 1:1 inclusion complexes with γ-cyclodextrin recovered growth of Δdps1 depending on the concentration and form. However, it has no effect on the growth of wild type fission yeast strain at all. Raman microspectroscopy was employed to understand the anti-oxidant property at the molecular level. A sensitive Raman band at 1602cm-1 was monitored with and without addition of ALAs. It was found that 0.5mM and 1.0mM concentrations of ALAs had similar effect in both free and inclusion forms. At 2.5mM ALAs, free forms inhibited the growth while inclusion complexes helped in recovered. 5.0mM ALA showed inhibitory effect irrespective of form. Our results suggest that the Raman band at 1602cm-1 is a good measure of oxidative stress in fission yeast.

Evaluation of pharmacokinetics/pharmacodynamics and efficacy of one-month depots of TAK-448 and TAK-683, investigational kisspeptin analogs, in male rats and an androgen-dependent prostate cancer model.

TAK-448 and TAK-683 are kisspeptin agonist analogs with improved in vivo stability and activity. Previous studies showed that continuous subcutaneous administration of TAK-448 or TAK-683 caused rapid and profound reductions in plasma testosterone levels in various species, including male healthy volunteers, suggesting their therapeutic potential as anti-prostate cancer agents. For clinical drug development, one-month sustained-release depots of TAK-448 and TAK-683, TAK-448-SR(1M) and TAK-683-SR(1M), were designed to improve usability in clinical practice. In this study, the pharmacokinetics/pharmacodynamics (PK/PD) profiles of TAK-448-SR(1M) and TAK-683-SR(1M) were initially tested in male rats to ensure their eligibility as one-month depots. The therapeutic advantages of TAK-448-SR(1M) and TAK-683-SR(1M) over TAP-144-SR(1M) were then investigated in a JDCaP xenograft rat model. TAK-448-SR(1M) and TAK-683-SR(1M) maintained certain levels of plasma TAK-448 free form (TAK-448F) and plasma TAK-683 free form (TAK-683F) for at least 4 weeks, before clearance from the circulation. Accompanying their desirable PK profiles, TAK-448-SR(1M) and TAK-683-SR(1M) showed favorable PD responses as one-month depots and demonstrated better testosterone control than TAP-144-SR(1M). Both depots exerted rapid and profound suppression of plasma testosterone levels in male rats. These profound suppressive effects were maintained in dose-dependent manners, before recovery toward normal levels. In the JDCaP xenograft model, TAK-448-SR(1M) and TAK-683-SR(1M) both showed better prostate-specific antigen (PSA) control than TAP-144-SR(1M), although all treatment groups eventually experienced PSA recurrence and tumor regrowth. In conclusion, this study demonstrates that both TAK-448-SR(1M) and TAK-683-SR(1M) have desirable and better PK/PD profiles than TAP-144-SR(1M) in rats, which could potentially provide better clinical outcomes in androgen-dependent prostate cancer.

Discovery of Novel 5-(Piperazine-1-carbonyl)pyridin-2(1H)-one Derivatives as Orally eIF4A3-Selective Inhibitors.

Starting from our previous eIF4A3-selective inhibitor 1a, a novel series of (piperazine-1-carbonyl)pyridin-2(1H)-one derivatives was designed, synthesized, and evaluated for identification of orally bioavailable probe molecules. Compounds 1o and 1q showed improved physicochemical and ADMET profiles, while maintaining potent and subtype-selective eIF4A3 inhibitory potency. In accord with their promising PK profiles and results from initial in vivo PD studies, compounds 1o and 1q showed antitumor efficacy with T/C values of 54% and 29%, respectively, without severe body weight loss. Thus, our novel series of compounds represents promising probe molecules for the in vivo pharmacological study of selective eIF4A3 inhibition.

Glycogen synthase kinase-3 inhibitors suppress the AR-V7-mediated transcription and selectively inhibit cell growth in AR-V7-positive prostate cancer cells.

BACKGROUND: Recent evidence suggests that androgen receptor (AR) splice variants, including AR-V7, play a pivotal role in resistance to androgen blockade in prostate cancer treatment. The development of new therapeutic agents that can suppress the transcriptional activities of AR splice variants has been anticipated as the next generation treatment of castration-resistant prostate cancer. METHODS: High-throughput screening of AR-V7 signaling inhibitors was performed using an AR-V7 reporter system. The effects of a glycogen synthase kinase-3 (GSK3) inhibitor, LY-2090314, on endogenous AR-V7 signaling were evaluated in an AR-V7-positive cell line, JDCaP-hr, by quantitative reverse transcription polymerase chain reaction. The relationship between AR-V7 signaling and ß-catenin signaling was assessed using RNA interference. The effect of LY-2090314 on cell growth in various prostate cancer cell lines was also evaluated. RESULTS: We identified GSK3 inhibitors as transcriptional suppressors of AR-V7 using a high-throughput screen with an AR-V7 reporter system. LY-2090314 suppressed the reporter activity and endogenous AR-V7 activity in JDCaP-hr cells. Because silencing of ß-catenin partly rescued the suppression, it was evident that the suppression was mediated, at least partially, via the activation of ß-catenin signaling. AR-V7 signaling and ß-catenin signaling reciprocally regulate each other in JDCaP-hr cells, and therefore, GSK3 inhibition can repress AR-V7 transcriptional activity by accumulating intracellular ß-catenin. Notably, LY-2090314 selectively inhibited the growth of AR-V7-positive prostate cancer cells in vitro. CONCLUSIONS: Our findings demonstrate the potential of GSK3 inhibitors in treating advanced prostate cancer driven by AR splice variants. In vivo evaluation of AR splice variant-positive prostate cancer models will help illustrate the overall significance of GSK3 inhibitors in treating prostate cancer.

The RNA helicase DDX39B and its paralog DDX39A regulate androgen receptor splice variant AR-V7 generation.

Mounting evidence suggests that constitutively active androgen receptor (AR) splice variants, typified by AR-V7, are associated with poor prognosis and resistance to androgen deprivation therapy in prostate cancer patients. However, mechanisms governing the generation of AR splice variants are not fully understood. In this study, we aimed to investigate the dynamics of AR splice variant generation using the JDCaP prostate cancer model that expresses AR splice variants under androgen depletion. Microarray analysis of JDCaP xenografts before and after expression of AR splice variants suggested that dysregulation of RNA processing pathways is likely involved in AR splice variant generation. To explore factors contributing to generation of AR-V7 mRNA, we conducted a focused RNA interference screen in AR-V7-positive JDCaP-hr cells using an shRNA library targeting spliceosome-related genes. This screen identified DDX39B as a regulator of AR-V7 mRNA expression. Simultaneous knockdown of DDX39B and its paralog DDX39A drastically and selectively downregulated AR-V7 mRNA expression in multiple AR-V7-positive prostate cancer cell lines. DDX39B was upregulated in relapsed JDCaP xenografts expressing AR splice variants, suggesting its role in expression of AR splice variants. Taken together, our findings offer insight into the mechanisms of AR splice variant generation and identify DDX39 as a potential drug target for the treatment of AR splice variant-positive prostate cancer.

Growth Inhibition by Testosterone in an Androgen Receptor Splice Variant-Driven Prostate Cancer Model.

BACKGROUND: Castration resistance creates a significant problem in the treatment of prostate cancer. Constitutively active splice variants of androgen receptor (AR) have emerged as drivers for resistance to androgen deprivation therapy, including the next-generation androgen-AR axis inhibitors abiraterone and enzalutamide. In this study, we describe the characteristics of a novel castration-resistant prostate cancer (CRPC) model, designated JDCaP-hr (hormone refractory). METHODS: JDCaP-hr was established from an androgen-dependent JDCaP xenograft model after surgical castration. The expression of AR and its splice variants in JDCaP-hr was evaluated by immunoblotting and quantitative reverse transcription-polymerase chain reaction. The effects of AR antagonists and testosterone on JDCaP-hr were evaluated in vivo and in vitro. The roles of full-length AR (AR-FL) and AR-V7 in JDCaP-hr cell growth were evaluated using RNA interference. RESULTS: JDCaP-hr acquired a C-terminally truncated AR protein during progression from the parental JDCaP. The expression of AR-FL and AR-V7 mRNA was upregulated by 10-fold in JDCaP-hr compared with that in JDCaP, indicating that the JDCaP and JDCaP-hr models simulate castration resistance with some clinical features, such as overexpression of AR and its splice variants. The AR antagonist bicalutamide did not affect JDCaP-hr xenograft growth, and importantly, testosterone induced tumor regression. In vitro analysis demonstrated that androgen-independent prostate-specific antigen secretion and cell proliferation of JDCaP-hr were predominantly mediated by AR-V7. JDCaP-hr cell growth displayed a bell-shaped dependence on testosterone, and it was suppressed by physiological concentrations of testosterone. Testosterone induced rapid downregulation of both AR-FL and AR-V7 expression at physiological concentrations and suppressed expression of the AR target gene KLK3. CONCLUSIONS: Our findings support the clinical value of testosterone therapy, including bipolar androgen therapy, in the treatment of AR-overexpressed CRPC driven by AR splice variants that are not clinically actionable at present. Prostate 76:1536-1545, 2016. © 2016 Wiley Periodicals, Inc.

Isomeric effects of anti-diabetic α-lipoic acid with γ-cyclodextrin.

AIMS: Previous studies reported the anti-diabetic effects of α-lipoic acid (αLA) isomers: racemic-αLA, R-αLA, or S-αLA. Previously, we examined the anti-diabetic effects of αLA administered as a food additive, but were unable to demonstrate the differences among different isomers. In this study, αLAs were complexed with γ-cyclodextrin (γCD) for the stability.We then investigated the anti-diabetic effects of racemic-, R-, and S-αLA/γCDs in KKAy mice. MAIN METHODS: Male type 2 diabetic KKAy mice were divided into 5 groups, and fed either a high-fat-diet (HFD),HFD supplemented with γCD, or HFD supplemented with racemic-αLA/γCD, R-αLA/γCD, or S-αLA/γCD for 4 weeks. At the end of the feeding period, HbA1c and adiponectin levels were measured, PPARγ2mRNA expression levels were assessed in adipose tissues using real-time PCR, and AMP-activated protein kinase (AMPK) phosphorylation levels were evaluated in the liver by Western blotting. KEY FINDINGS: The anti-diabetic effects of αLA; the isomeric compounds racemic-, R-, and S-αLA/γCD were investigated using amale type 2 diabetic KKAy mousemodel. Significant differences were observed in HbA1c and plasma adiponectin levels between R-αLA/γCD-treated mice and control mice. PPARγ2 mRNA expression levels were slightly higher in racemic- and R-αLA/γCD-treated mice. Moreover, AMPK phosphorylation levels were elevated in racemic-αLA/γCD- and R-αLA/γCD-treated mice, but remained unchanged in S-αLA/γCD-treated mice. SIGNIFICANCE: These results suggested that the stereoisomerism mediates a difference in the anti-diabetic effects of racemic-, R-, and S-αLA/γCDs. Furthermore, the anti-diabetic mechanism of αLA/γCD action may be attributed to the activation of AMPK in the liver.

Antidiabetic effect of the α-lipoic acid γ-cyclodextrin complex.

In recent years, the number of patients suffering from diabetes mellitus has been increasing worldwide. In particular, type 2 diabetes mellitus, a lifestyle-related disease, is recognized as a serious disease with various complications. Many types of pharmaceutics or specific health foods have been used for the management of diabetes mellitus. At the same time, the relationship between diabetes mellitus and α-lipoic acid has been recognized for many years. In this study, we found that the α-lipoic acid γ-cyclodextrin complex exhibited an HbA1c lowering effect for treating type 2 diabetes mellitus in animal models. Moreover, in this study, we investigated the activation of phosphorylation of AMP-activated protein kinase, which plays a role in cellular energy homeostasis, in the liver of KKA(y) mice by using α-lipoic acid and the α-lipoic acid γ-cyclodextrin complex. Our results show that the α-lipoic acid γ-cyclodextrin complex strongly induced the phosphorylation of AMP-activated protein kinase. Thus, we concluded that intake of the α-lipoic acid γ-cyclodextrin complex exerted an antidiabetic effect by suppressing the elevation of postprandial hyperglycemia as well as doing exercise.

Increased N-glycosylation of Asn88 in serum pancreatic ribonuclease 1 is a novel diagnostic marker for pancreatic cancer.

Alterations of carbohydrate structures in cancer cells are the most promising targets for developing clinical diagnostic reagents. Pancreatic cancer is one of the most difficult cancers to diagnose because it lacks definitive symptoms. Two antibodies were raised against human pancreatic ribonuclease 1 that bind to the enzyme containing unglycosylated Asn(88), but not when its Asn(88) is N-glycosylated. Differential studies using these antibodies in immunoassays and Western blot analyses showed a significant increase in the serum levels of pancreatic ribonuclease 1 containing N-glycosylated Asn(88) in pancreatic cancer patients compared with normal human subjects. Focusing on the increase in an N-glycosylated Asn residue of serum pancreatic ribonuclease 1, specifically Asn(88), affords a new diagnostic marker for pancreatic cancer. This is the first report of a diagnostic cancer marker that takes advantage of the presence or absence of N-glycosylation at a specific Asn residue of a glycoprotein.