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Purpose: To investigate the risk factors for corneal endothelial cell density (ECD) loss of two types of iris-fixated phakic intraocular lenses (pIOL) and indicate the cutoff values for preventing irreversible ECD loss after explantation., Design: The retrospective, comparative, clinical cohort study METHODS: Total 114 eyes of 61 patients were included in this study. Fifty-five eyes with Artisan pIOL and 59 eyes with Artiflex pIOL had undergone explantation of pIOLs due to continuous ECD loss. Correlation analysis was performed to assess the ocular parameters associated with ECD loss. Receiver operating characteristic (ROC) curve was performed to set cutoff values of ocular parameters to prevent ECD loss after explantation., Result: The mean ECD before explantation was 1637 cells/mm 2 in Artisan group and 1769 cells/mm 2 in Artiflex group. The distance of cornea endothelium to IOL center and edges were all significantly higher in Artisan group (p <0.05). The risk factor of decreased ECD in Artisan group were small anterior chamber angle (ACA), and distance of nasal edge of IOL to endothelium and iris fixation to nasal limbus distance, and differences of fixation length. In Artiflex group, ACA, distance of nasal edge of IOL to endothelium, both limbus to IOL fixation length, fixation length, iris pigmentation grading were the risk factors. At 1 year after the pIOL removal, the population demonstrating ΔECD >10% were significantly higher in Artisan group than Artiflex group (p <0.05). In ROC curve analysis, the cutoff value of preoperative ECD to prevent significant post-explantation ECD loss was 1683.5 cells/mm 2 in Artisan group and 1648 cells/mm 2 in Artiflex group., Conclusion: This study examined the existing explantation guidelines for these lenses. In analyzing the longterm prognosis of cornea ECD with Iris-fixated phakic intraocular lens, it is important to identify the relevant anatomical factors. Small ACA, and short distances from IOL to endothelium and from limbus to iris fixation especially in the nasaSSSl region were significant risk factors to continuous ECD loss in both lenses. To minimize irreversible ECD loss after explantation, it is important to determine the optimal period of explantation by observing both ECD and structural changes., Competing Interests: Conflicts of Interest The authors have no potential conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Deep learning-based super-resolution ultrasound (DL-SRU) framework has been successful in improving spatial resolution and measuring the velocity field information of a blood flows by localizing and tracking speckle signals of red blood cells (RBCs) without using any contrast agents. However, DL-SRU can localize only a small part of the speckle signals of blood flow owing to ambiguity problems encountered in the classification of blood flow signals from ultrasound B-mode images and the building up of suitable datasets required for training artificial neural networks, as well as the structural limitations of the neural network itself. An artificial intelligence-based speckle featurization and localization (AI-SFL) framework is proposed in this study. It includes a machine learning-based algorithm for classifying blood flow signals from ultrasound B-mode images, dimensionality reduction for featurizing speckle patterns of the classified blood flow signals by approximating them with quantitative values. A novel and robust neural network (ResSU-net) is trained using the online data generation (ODG) method and the extracted speckle features. The super-resolution performance of the proposed AI-SFL and ODG method is evaluated and compared with the results of previous U-net and conventional data augmentation methods under in silico conditions. The predicted locations of RBCs by the AI-SFL and DL-SRU for speckle patterns of blood flow are applied to a PTV algorithm to measure quantitative velocity fields of the flow. Finally, the feasibility of the proposed AI-SFL framework for measuring real blood flows is verified under in vivo conditions., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sang Joon Lee reports financial support was provided by The Defense Acquisition Program Administration of Korean government. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chronic stress is a pervasive and complex issue that contributes significantly to various mental and physical health disorders. Using the previously established chronic unpredictable stress (CUS) model, which simulates human stress situations, it has been shown that chronic stress induces major depressive disorder (MDD) and memory deficiency. However, this established model is associated with several drawbacks, such as limited research reproducibility and the inability to sustain stress response. To resolve these issues, we developed a new CUS model (CUS+C) that included exogenous corticosterone exposure to induce continuous stress response. Thereafter, we evaluated the effect of this new model on brain health. Thus, we observed that the use of the CUS+C model decreased body and brain weight gain and induced an uncontrolled coat state as well as depressive-like behavior in adult mice. It also impaired learning memory function and cognitive abilities, reduced adult hippocampal neurogenesis as well as the number of hippocampal astrocytes, and downregulated glial fibrillary acidic protein expression in the brains of adult mice. These findings can promote the utilization and validity of the animal stress model and provide new information for the treatment of chronic stress-induced depressive and memory disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

As plastic production has been increasing steadily, environmental pollution resulting from microplastics (MPs) continues to draw considerable attention of the researchers. Several studies have reported that MPs are risk factors for various cellular and systemic dysfunctions. However, the effects of chronic MP exposure from the embryonic stage to adulthood on mouse brain remain unclear. Accordingly, determining the impacts of maternal exposure to MPs on mouse offspring was the main goal of this study. To this end, single cells of primary cortical neurons were isolated from mouse embryos. Subsequently, the cells were exposed to 2 µm polystyrene microplastics (PS-MPs), which resulted in a notable reduction in dendritic length, and PS-MPs cannot pass through the cellular membrane of neurons. Moreover, exposure to PS-MPs caused the proliferation increase and apoptosis in primary cortical neuronal cells. We then evaluated the neurotoxicity associated with chronic PS-MP exposure from the embryonic stage to adulthood in C57BL/6 J mouse offspring. PS-MPs were found to accumulate in the digestive and excretory organs of the offspring but not in the brain tissue. However, offspring exposed to PS-MPs exhibited no differences in the levels of expression of genes related to brain cell markers or synaptic organization. Nevertheless, PS-MP-exposed mice exhibited impaired social novelty preferences; however, no changes were observed in the emotional, compulsive, or cognitive behaviors. Taken together, these results demonstrate the potential neurotoxic effects of chronic exposure to PS-MPs in mouse offspring., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Tumor necrosis factor-α (TNF-α) is an inflammatory cytokine involved in cell survival, apoptosis, and homeostasis. However, the regulatory effect of TNF-α on mesenchymal stem cell (MSC) redox regulation remains unknown. The process of delaying the senescence of MSCs and maintaining antioxidation mechanism is important in transplantation therapy to treat inflammatory diseases that result from restricted immunomodulatory effects of senescent MSCs. Thus, we examined the role of TNF-α-mediated signaling and its regulatory mechanisms on the senescence of umbilical cord blood-derived MSCs (UCB-MSCs) and identified its therapeutic efficacy in a collagen-induced arthritis (CIA) mouse model. We found that TNF-α increased fatty acid synthesis and lipid droplet (LD) formation through NF-κB/SREBP1-mediated FASN, SCD1, and DGAT2 expression, which protects UCB-MSCs from oxidative stress against accumulated toxic lipids. Additionally, DGAT2-mediated LD formation was regulated by TNF-α-activated TNF receptor (TNFR)1 signaling. We also found that storage of unsaturated FAs in LDs is regulated by SIRT5-dependent β-oxidation of FAs, which reduces mitochondrial ROS (mtROS) accumulation. Particularly, mtROS homeostasis was maintained by superoxide dismutase 2 (SOD2) upregulation through TNFR2-mediated SIRT5/Nrf2 signaling. In a CIA mouse model, UCB-MSCs transfected with SIRT5 siRNA exhibited reduced therapeutic effects compared with UCB-MSCs transfected with NT siRNA. Overall, the results indicated that SIRT5 plays a central role in protecting TNF-α-induced UCB-MSC senescence through FA β-oxidation and SOD2-mediated antioxidation., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To compare the accuracy of the Barrett toric calculator with and without posterior corneal astigmatism and the Kane toric calculator., Design: Retrospective cross-sectional study., Methods: The study included a total of 79 eyes of 79 patients who underwent toric intraocular lens (IOL) insertion during uncomplicated cataract surgery by a single surgeon. Using vector analysis, the mean absolute prediction error, the standard deviation of the prediction error, and the percentage of eyes with a prediction error within ±0.50 diopter (D), ± 0.75 D, and ± 1.00 D were calculated. The IOL Master 700 (Carl Zeiss Meditec AG, Jena, Germany) was used for measuring biometry including posterior corneal astigmatism. The main analysis was designed to provide the clinical outcomes with each formula using the postoperative keratometry values and the measured postoperative IOL axis. Real-world analysis was performed using the preoperative keratometry values and the intended IOL axis., Results: There was no significant difference in mean absolute prediction errors calculated with 2 versions of the Barrett toric formula (predicted posterior corneal astigmatism and measured posterior corneal astigmatism) and the Kane toric formula (P > .05). The Barrett toric calculator with predicted and measured posterior corneal astigmatism yielded the best results, with 60.8% <0.50 D prediction error in the main analysis. In the real-world analysis, the Barrett toric calculator with predicted posterior corneal astigmatism showed the best result, with 53.2% <0.50 D prediction error., Conclusion: The Barrett toric formula with and without posterior corneal astigmatism measurements using the IOL Master 700 and the Kane toric formula yielded accurate and comparable outcomes in this single-surgeon analysis. Am J Ophthalmol 2021;221:•••-•••. © 2021 Elsevier Inc. All rights reserved., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Amyloid β (Aβ) aggregation inhibitor activity cliff involving a curcumin structure was predicted using the SAR Matrix method on the basis of 697 known Aβ inhibitors from ChEMBL (data set 2487). Among the compounds predicted, compound B was found to possess approximately 100 times higher inhibitory activity toward Aβ aggregation than curcumin. TEM images indicate that compound B induced the shortening of Aβ fibrils and increased the generation of Aβ oligomers in a concentration dependent manner. Furthermore, compound K, in which the methyl ester of compound B was replaced by the tert-butyl ester, possessed low cytotoxicity on N2A cells and attenuated Aβ-induced cytotoxicity, indicating that compound K would have an ability for preventing neurotoxicity caused by Aβ aggregation., (Copyright © 2021. Published by Elsevier Ltd.)

Although osteoarthritis (OA) is the most prevalent degenerative joint disease, there is no effective disease-modifying therapy. We report an empty self-assembled hyaluronic acid nanoparticle (HA-NP) as a potential therapeutic agent for OA treatment. In mouse primary articular chondrocytes, HA-NPs blocked the receptor-mediated cellular uptake of free low-molecular-weight HA, and the cellular uptake of HA-NPs increased by ectopic expression of CD44, using an adenoviral delivery system (Ad-Cd44). HA-NP showed in vitro resistance to digestion with hyaluronidase and in vivo long-term retention ability in knee joint, compared with free high-molecular-weight (HMW) HA. CD44 expression increased in the damaged articular cartilage of patients and mice with OA. Ad-Cd44 infection and IL-1β treatment induced in vitro phenotypes of OA by enhancing catabolic gene expression in primary articular chondrocytes, and these effects were attenuated by HA-NP, but not HMW HA. Both Cd44 deficiency and intra-articular injection of HA-NP protected joint cartilage against OA development in the OA mouse model. NF-κB was found to mediate CD44-induced catabolic factor expression and HA-NP inhibited CD44-induced NF-κB activation in chondrocytes. Our results identify an empty HA-NP as a potential therapeutic agent targeting CD44 for OA treatment, and the CD44-NF-κB-catabolic gene axis as an underlying mechanism of destructive cartilage disorders., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: With emerging basic research evidence suggesting that fibroblast growth factor (FGF) 21 is a catabolic molecule on muscle metabolism, we aimed to analyze the serum FGF21 level in relation to sarcopenia in older adults., Methods: Blood samples were collected from 125 participants who underwent evaluation for muscle mass and function in an outpatient geriatric clinic of a teaching hospital. Sarcopenia and related components were determined using cutoff values for the Asian population. The serum FGF21 level was measured using enzyme linked immunosorbent assay., Results: After controlling for age, sex, and body mass index (BMI), participants with sarcopenia, low muscle mass, and weak muscle strength had 2.3-, 2.0-, and 1.5-fold higher serum FGF21 levels than controls, respectively (p = .033 to <0.001). The serum FGF21 level was positively correlated with sarcopenia phenotype score and inversely correlated with skeletal muscle mass index and grip strength by both crude and multivariate analysis adjusting potential confounders (p = .017 to <0.001). Consistently, higher serum FGF21 level was significantly associated with increased odds for sarcopenia, low muscle mass, and low muscle strength after adjusting for age, sex, and BMI (odds ratio, 1.53-2.61; p = .048 to <0.001)., Conclusions: Higher circulating FGF21 was associated with the likelihood of sarcopenia, lower muscle mass, and worse grip strength in older adults, supporting a potential catabolic role of FGF21 on human muscle health., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new strain of coronavirus not previously identified in humans. Globally, the number of confirmed cases and mortality rates of coronavirus disease 2019 (COVID-19) have risen dramatically. Currently, there are no FDA-approved antiviral drugs and there is an urgency to develop treatment strategies that can effectively suppress SARS-CoV-2-mediated cytokine storms, acute respiratory distress syndrome (ARDS), and sepsis. As symptoms progress in patients with SARS-CoV-2 sepsis, elevated amounts of cell-free DNA (cfDNA) are produced, which in turn induce multiple organ failure in these patients. Furthermore, plasma levels of DNase-1 are markedly reduced in SARS-CoV-2 sepsis patients. In this study, we generated recombinant DNase-1-coated polydopamine-poly(ethylene glycol) nanoparticulates (named long-acting DNase-1), and hypothesized that exogenous administration of long-acting DNase-1 may suppress SARS-CoV-2-mediated neutrophil activities and the cytokine storm. Our findings suggest that exogenously administered long-acting nanoparticulate DNase-1 can effectively reduce cfDNA levels and neutrophil activities and may be used as a potential therapeutic intervention for life-threatening SARS-CoV-2-mediated illnesses., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Docetaxel, a chemotherapeutic agent used to treat breast cancer, produces a robust painful neuropathy that is aggravated by mechanical and thermal stimuli. This study was undertaken to investigate the analgesic effects of electrical stimulation on docetaxel-induced neuropathic pain in mice and to identify associated changes in ultrasound vocalizations. Peripheral neuropathy was induced with intraperitoneally injected docetaxel (5 mg/kg) on 3 times every 2 days in male ICR mice. Electrical wrist stimulation was administered and pain behavior signs were evaluated by von Frey filaments and thermal stimulation on the hind paw. Ultrasound vocalizations were measured using ultrasound microphones, after electrical stimulation. After mice developed docetaxel-induced neuropathic pain behavior, an electrical stimulation temporarily attenuated mechanical allodynia and thermal hyperalgesia. In formalin and NMDA test, pain-induced mice showed increases in 10-30 kHz ultrasound vocalizations, but not in 30-50 and 50-80 kHz vocalizations. Treatment with docetaxel selectively increased 10-30 kHz ultrasound vocalizations, whereas electrical stimulation caused a meaningful decrease. Moreover, electrical stimulation suppressed the docetaxel-enhanced phosphorylation of the NMDA receptor NR2B subunit in the spinal dorsal horn. These results of the analgesic effect of electrical stimulation in chemotherapy-induced neuropathy could potentially provide a new method to treat and manage peripheral neuropathy in patients with cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Inc.)

Background: Primary yolk sac tumor (YST) of the vulva is extremely rare and only introduced in case reports [1]. For those, routine inguinal lymph node dissection (LND) in absence of palpable inguinal lymph node is questionable. To avoid complications of inguinal LND, such as lymphedema, inguinal sentinel lymph node biopsy (SLNB) can be considered [2,3]. Since recent studies reported feasibility of robot-assisted inguinal lymphadenectomy [4], we showed the surgical procedures of robot-assisted inguinal SLNB., Video: A 33-year-old woman with vulvar YST was referred. Two 2 cm sized masses were founded in right vulvar area, and lymph node enlargement was detected in only right external iliac area on imaging studies. Thus, we planned robot-assisted surgical treatment including inguinal SLNB using the fluorescent dye indocyanine green (ICG) during surgery for the vulvar YST. First, we performed intradermal and peri-tumoral injection of 1 ml solution including 1.25 mg of ICG at each 2, 5, 7, and 10 o'clock position for the two tumors. Fifteen minutes later, three-arm robotic surgical system was installed on right thigh. Dissecting the subcutaneous space under the Scarpa's fascia towards the inguinal ligament, one fluorescent inguinal sentinel lymph node was identified and excised, which showed no tumor on pathologic examination (Fig. 1)., Results: The procedure time was 70 minutes, and she underwent subsequent robot-assisted pelvic and para-aortic lymphadenectomy and wide local excision of the vulva., Conclusion: Robot-assisted inguinal SLNB is feasible. It may be an alternative to inguinal LND for avoiding relevant complications in patients with vulvar malignancy., (Copyright © 2018. Published by Elsevier Ltd.)

Background: We investigated whether an increase in the value of red cell distribution width (RDW) was associated with thromboembolic outcomes in patients with atrial fibrillation (AF)., Methods: We performed a retrospective analysis of 5082 consecutive patients with non-valvular AF. Thromboembolic events (N=723, 14.2%) were recorded and analysed according to RDW value., Results: The peak RDW value during follow-up was higher in patients with thromboembolic events than in those without thromboembolic events (15.1% vs. 14.2%, p<0.001). The RDW value showed similar power in predicting thromboembolic outcomes compared with the factor of age. The risk of thromboembolic events was higher in patients with a peak RDW≥13.9% than in patients with a peak RDW<13.9% (hazard ratio 1.63, p<0.001), and increased with each quartile increase of RDW. In a subgroup of 739 patients with congestive heart failure (CHF), there were 112 (15.2%) thromboembolic events. The peak RDW value of patients with CHF with thromboembolic events was also significantly higher (16.4% vs. 15.6%, p=0.019) compared to that of those without thromboembolic events., Conclusion: An increased RDW value during follow-up could be associated with thromboembolic events in patients with non-valvular AF. The suggested cut-off values for RDW used to predict an increased thromboembolic risk in were ≥13.9% in patients with AF in general, ≥15% in patients with co-existing AF and CHF., (Copyright © 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Recurrent cervical cancer with the pelvic side wall invasion has a deleterious effect on prognosis if there is no alternative method to achieve local tumor control [1, 2]. For the surgical treatment, super-radical hysterectomy has been introduced by Ryukichi Mibayashi in 1941 [3, 4]. However, its feasibility and safety is still on debate because of a lack of reproducibility and high level of surgical techniques. Thus, we showed the surgical procedure of super-radical hysterectomy for recurrent cervical cancer., Video: A 40 year-old woman visited after diagnosis of the pelvic recurrence, who received concurrent chemoradiation before 13 months due to stage IIB cervical cancer. Preoperative examination showed tumor invasion to upper third of the vagina, the right distal ureter and urethra, the posterior bladder wall and the right pelvic wall. Thus, we performed anterior pelvic exenteration with super-radical hysterectomy for removing the right pelvic side wall tumors. First, we ligated the right superior gluteal vessels, and then ligated the right internal iliac vessels. Second, we ligated the right inferior gluteal vessels, and subsequently the right internal pudendal vessels. Third, we resected her genitourinary tract with the right internal iliac vessels around the pelvic floor completely., Results: The procedure time was 160 minutes, and she underwent subsequent procedures including ileal conduit and omental J flap. She was discharged after 2 weeks without complications., Conclusion: Super-radical hysterectomy can be considered to be feasible and safe through the step-wise ligation of the internal iliac vessels for recurrent cervical cancer with the pelvic side wall invasion., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Pendred syndrome is the most common form of syndromic deafness. It is associated with a mutation in the SLC26A4 gene that encodes pendrin, which is thought to maintain the ion concentration of endolymph in the inner ear most likely by acting as a chloride/bicarbonate transporter. Mutations in the SLC26A4 gene are responsible for sensorineural hearing loss. In this study, we established a stable HEK293 cell line expressing P123S mutant pendrin and developed screening methods for compounds that show pharmacological chaperone activity by image analysis using CellInsight™. Morphological analysis of stained cells in each well of 96-well plates yielded six compounds in the compound library. Furthermore, fluorescence intensity analysis of the intracellular localization of P123S mutant pendrin in HEK293 cells using FLUOVIEW™ and cytotoxicity experiments revealed that (2-aminophenyl)methanol 8 is the most promising molecular chaperone to rescue P123S mutant pendrin: the plasma membrane (M)/cytoplasm (C) ratios are 1.5 and 0.9 at the concentrations of 0.3 and 0.1mM, respectively, and a sustained effect was observed 12h after removal of the compound from the cell medium. Because the M/C ratio of salicylate, which was previously discovered as a molecular chaperone of P123S mutant pendrin, was approximately 1 at 10mM concentration and a sustained effect was not observed even at 6h, (2-aminophenyl)methanol 8 was 100 times more potent and exhibited a longer sustained effect than salicylate. These findings suggest that (2-aminophenyl)methanol 8 is an attractive candidate for therapeutic agent for Pendred syndrome patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Oncogene-targeted nucleic acid therapy has been spotlighted as a new paradigm for cancer therapeutics. However, in vivo delivery issues and uncertainty of therapeutic antisense drug reactions remain critical hurdles for a successful targeted cancer therapy. In this study, we developed a fluorescence-switchable theranostic nanoplatform using hyaluronic acid (HA)-conjugated graphene oxide (GO), which is capable of both sensing oncogenic miR-21 and inhibiting its tumorigenicity simultaneously. Cy3-labeled antisense miR-21 peptide nucleic acid (PNA) probes loaded onto HA-GO (HGP21) specifically targeted CD44-positive MBA-MB231 cells and showed fluorescence recovery by interacting with endogenous miR-21 in the cytoplasm of the MBA-MB231 cells. Knockdown of endogenous miR-21 by HGP21 led to decreased proliferation and reduced migration of cancer cells, as well as the induction of apoptosis, with enhanced PTEN levels. Interestingly, in vivo fluorescence signals markedly recovered 3 h after the intravenous delivery of HGP21 and displayed signals more than 5-fold higher than those observed in the HGPscr-treated group of tumor-bearing mice. These findings demonstrate the possibility of using the HGP nanoplatform as a cancer theranostic tool in miRNA-targeted therapy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In vitro metabolism of a new synthetic cannabinoid, EAM-2201, has been investigated with human liver microsomes and major cDNA-expressed cytochrome P450 (CYP) isozymes using liquid chromatography-high resolution mass spectrometry (LC-HRMS). Incubation of EAM-2201 with human liver microsomes in the presence of NADPH resulted in the formation of 37 metabolites, including nine hydroxy-EAM-2201 (M1-M9), five dihydroxy-EAM-2201 (M10-M14), dihydrodiol-EAM-2201 (M15), oxidative defluorinated EAM-2201 (M16), two hydroxy-M16 (M17 and M18), three dihydroxy-M16 (M19-M21), N-dealkyl-EAM-2201 (M22), two hydroxy-M22 (M23 and M24), dihydroxy-M22 (M25), EAM-2201 N-pentanoic acid (M26), hydroxy-M26 (M27), dehydro-EAM-2201 (M28), hydroxy-M28 (M29), seven dihydroxy-M28 (M30-M36), and oxidative defluorinated hydroxy-M28 (M37). Multiple CYPs, including CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2J2, 3A4, and 3A5, were involved in the metabolism of EAM-2201. In conclusion, EAM-2201 is extensively metabolized by CYPs and its metabolites can be used as an indicator of EAM-2201 abuse., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Silencing target genes such as inducible nitric oxide synthase (iNOS) using small interfering double-stranded RNA (siRNA) in islet cells has been attempted to enhance the survival of transplanted islets. However, the efficient and safe delivery of siRNA into intact islets is challenging. Here, we prepared R3V6 peptides containing a three-arginine stretch and a six-valine stretch, which form micelles with hydrophobic valine cores and cationic arginine surfaces in aqueous solution, to co-deliver siRNA and cytoprotective hydrophobic drugs to islet cells. The cationic surfaces bound to the negatively charged iNOS siRNA, and the hydrophobic core was loaded with 17β-estradiol (E2), which exerts anti-apoptotic effects on the islet cells. The E2-loaded R3V6 peptide micelles delivered siRNA-5'-FITC to mouse islets more efficiently than did Lipofectamine 2000, and without cytotoxicity. The micelle complexes containing siRNA-iNOS knocked down the expression of iNOS mRNA by >60% in islets and reduced cytokine-induced apoptotic cell death in vitro significantly. The delivery of siRNA-iNOS and E2 simultaneously using E2-loaded R3V6 peptide micelles improved the diabetes reversal rate of marginal mass islet transplantation into the renal subcapsular space of diabetic syngeneic mice significantly compared with the siRNA-iNOS and E2 alone treatment control groups. Our results demonstrated that the co-delivery of siRNA and a cytoprotective drug within a single non-toxic carrier, R3V6 peptide micelles, provides a novel rational strategy for combined ex vivo islet therapy to improve the outcome of islet transplantation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Our group reported a significant association between hexokinase II overexpression and chemoresistance in ovarian cancer, suggesting that aerobic glycolysis in the so-called Warburg effect might contribute to cancer progression. However, a growing body of evidence indicates contradictory findings with regard to the Warburg effect, such as high mitochondrial activity in highly invasive tumors and low ATP contribution of glycolysis in ovarian cancer. As a solution for the dilemma of the Warburg effect, the "reverse Warburg effect" was proposed in which aerobic glycolysis might occur in the stromal compartment of the tumor rather than in the cancer cells, indicating that the glycolytic tumor stroma feed the cancer cells through a type of symbiotic relationship. The reverse Warburg effect acting on the relationship between cancer cells and cancer-associated fibroblasts has evolved into dynamic interplay between cancer cells and multiple tumor stromal compartments, including cancer-associated fibroblasts, the extracellular matrix, endothelial cells, mesenchymal stem cells, adipocytes, and tumor-associated macrophages. Peritoneal cavities including ascites and the omentum also form a unique environment that is highly receptive for carcinomatosis in the advanced stages of ovarian cancer. The complicated but ingeniously orchestrated stroma-mediated cancer metabolism in ovarian cancer provides great heterogeneity in tumors with chemoresistance, which makes the disease thus far difficult to cure by single stromal-targeting agents. This review will discuss the experimental and clinical evidence of the cross-talk between cancer cells and various components of tumor stroma in terms of heterogeneous chemoresistance with focal points for therapeutic intervention in ovarian cancer., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Hypoxia is a condition found in various intractable diseases. Here, we report self-assembled nanoparticles which can selectively release the hydrophobic agents under hypoxic conditions. For the preparation of hypoxia-responsive nanoparticles (HR-NPs), a hydrophobically modified 2-nitroimidazole derivative was conjugated to the backbone of the carboxymethyl dextran (CM-Dex). Doxorubicin (DOX), a model drug, was effectively encapsulated into the HR-NPs. The HR-NPs released DOX in a sustained manner under the normoxic condition (physiological condition), whereas the drug release rate remarkably increased under the hypoxic condition. From in vitro cytotoxicity tests, it was found the DOX-loaded HR-NPs showed higher toxicity to hypoxic cells than to normoxic cells. Microscopic observation showed that the HR-NPs could effectively deliver DOX into SCC7 cells under hypoxic conditions. In vivo biodistribution study demonstrated that HR-NPs were selectively accumulated at the hypoxic tumor tissues. As consequence, drug-loaded HR-NPs exhibited high anti-tumor activity in vivo. Overall, the HR-NPs might have a potential as nanocarriers for drug delivery to treat hypoxia-associated diseases., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: To determine the efficacy of 1 intravitreal bevacizumab injection followed by pro re nata (1 + PRN) injection in cases of subfoveal myopic choroidal neovascularization (CNV) and to identify CNV-recurrence-related prognostic factors., Design: Retrospective observational case series., Methods: In total, 103 eyes of 89 consecutive naive patients who had subfoveal myopic CNV and had been followed-up for at least 2 years were included. Of those eyes, 24 had recurrences. The remaining eyes were stable after the initial treatment., Results: The average patient age was 51.1 ± 15.2 years. The average follow-up duration was 44.1 ± 12.7 months. At baseline and at the 1-year, 2-year, and final visits, the average best corrected visual acuities (BCVAs) were 0.57 ± 0.45, 0.38 ± 0.51, 0.40 ± 0.52, and 0.41 ± 0.41 logMAR, respectively. The recurrence rate during follow-up was 23.3%. The BCVA improved by 0.2 logMAR after 2.7 injections in the eyes without recurrence but by only 0.08 logMAR after 6.9 injections in the eyes with recurrence. In univariate analysis, recurrence was associated with older age, more myopic refraction, thinner choroid, larger CNV lesions, and subfoveal hemorrhage at baseline. In multivariate analysis, only baseline CNV lesion size associated significantly with CNV recurrence (P = 0.002). Recurrence, baseline BCVA, choroidal thickness, and CNV size associated significantly with final BCVA (P = 0.026, <0.0001, 0.007, and 0.002, respectively). Baseline choroidal thickness, CNV size, age, and presence of lacquer cracks associated significantly with injection number (P < 0.0001, <0.0001, 0.026, and 0.035, respectively)., Conclusions: 1 + PRN intravitreal bevacizumab monotherapy effectively stabilized subfoveal myopic CNV. The CNV size, the baseline BCVA, and the choroidal thickness were the main prognostic factors of subfoveal myopic CNV after 1 + PRN injection of bevacizumab., (Copyright © 2013 Elsevier Inc. All rights reserved.)

A fast, sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the detection and quantitation of propofol glucuronide in human hair has been developed and validated. Propofol glucuronide was extracted from 10mg of hair using a simple methanol extraction method, with recovery greater than 91% at 3 quality control samples (15, 100, 4000 pg/mg). A reversed phase column (C8) was used to analyze and the mobile phase was composed of ammonium formate and acetonitrile gradient at a flow rate of 0.2 mL/min. The lower limit of quantitation (LLOQ) was 5 pg/mg and the assay was linear to 5000 pg/mg. The intra- and inter-day precision (% CV, coefficient of variation) ranged from 1.26 to 4.50% while the accuracy (% RE, relative error) were -4.24 to 4.4%. The matrix effects were monitored at 3 different concentrations and the %CV of the results for these concentrations was less than 10.6%. Propofol glucuronide was stable during processing and analysis in human hair. The procedure was validated and applied to the analysis of hair samples in human subjects previously administered in propofol., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the ocular biometric parameters associated with intraocular pressure (IOP) reduction after phacoemulsification., Design: Prospective, observational case series., Methods: The study included 999 patients who had undergone uncomplicated phacoemulsification. IOP and ocular biometric parameters were checked preoperatively and 3 months postoperatively using anterior segment optical coherence tomography, optical biometry, and ultrasonic biomicroscopy. The relationship between IOP change and the parameters, including preoperative IOP, anterior chamber depth, axial length, angle opening distance at 500 μm, anterior chamber area, corneal thickness, lens thickness, and iris thickness at 750 μm, was evaluated., Results: The mean patient age was 67.1 ± 4.3 years. The average change in IOP was -1.6 mm Hg (-11.8%). In univariate analysis, axial length, corneal thickness, and iris thickness were not significantly associated with IOP reduction. However, preoperative IOP, anterior chamber depth, angle opening distance, anterior chamber area, and lens thickness were significantly associated with IOP change (P < .05). Furthermore, changes in anterior chamber depth (standardized coefficient beta [B] = -0.082), angle opening distance (B = -0.095), and anterior chamber area (B = -0.380) were more strongly correlated with IOP change than were preoperative factors (B = -0.078, B = -0.071, and B = -0.067, respectively). In multivariate analysis, preoperative IOP, lens thickness, angle opening distance change, and anterior chamber area change were significantly associated with IOP change (P < .005)., Conclusion: In addition to preoperative IOP and lens thickness, parameters such as changes in anterior chamber area and angle opening distance were significantly associated positively with reduced IOP after phacoemulsification., (Copyright © 2013 Elsevier Inc. All rights reserved.)

G-quadruplexes, formed of four stranded guanine bases stabilized by monovalent cations, serve important role in cancer cell growth and control gene expression in telomere. Since there are various types of quadruplex structures, rapid and simple screening methods with high selectivity, sensitivity and nontoxicity are required for understanding about the biological roles of quadruplex DNA as well as in designing therapeutics. Herein, we report a pyrene-imidazolium derivative, JY-1, which can with high selectivity recognize G-quadruplex using fluorescence and NMR spectroscopy. This is the first example based on the imidazolium derivative, which can detect the G-quadruplex directly to utilize the excimer/monomer emission change in pyrene fluorophore. The selectivity of strong binding to a specific sequence can allow for quadruplex sensing and the detection method presented here is very simple, using fluorescence and NMR study. Also, the groove binding characteristic of JY-1 to the G-quadruplex has a relatively low nonspecific toxicity and the structure-specific differences in fluorescent character between DNA duplex and G-quadruplex may offer more discovery and application in biological study., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

This randomized trial enrolled 442 infants in the Republic of Korea to assess the immunogenicity and safety of a combined diphtheria, tetanus, acellular pertussis, and inactivated poliovirus vaccine (DTaP-IPV; Tetraxim™) for primary vaccination at 2, 4 and 6 months of age compared with DTaP and IPV vaccines given separately. Immunogenicity was high in both groups; seroprotection and seroconversion rates of the combined vaccine (Group A) were non-inferior to the control vaccines (Group B). All subjects were seroprotected against poliovirus types 1, 2 and 3 (≥ 81/dil) and anti-diphtheria (≥ 0.01 IU/mL); 99.0% were seroprotected against tetanus (≥ 0.1 IU/mL). At least 93.6% had anti-diphtheria antibody titers ≥ 0.1 IU/mL. Anti-pertussis toxoid (PT) and anti-filamentous haemagglutinin (FHA) seroconversion (≥ 4-fold increase in antibody titer) rates were 96.6% and 94.4% for Group A, 92.2% and 78.4% for Group B. Most solicited reactions occurred within 4 days of vaccination, resolved within 3 days and were mild. Severe solicited reactions occurred after ≤ 0.5% of doses in Group A and ≤ 0.9% in Group B. No withdrawals occurred because of adverse events. The DTaP-IPV combined vaccine given at 2, 4, and 6 months of age was well tolerated; immunogenicity was similar to the control vaccines., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Human papillomavirus (HPV) infection is considered to be the necessary cause of cervical cancer. E6 and E7 oncoproteins of HPV have been known to play major roles in malignant transformation of cervical cells, inhibiting the tumor suppressors p53 and Rb. However, the role of E5 oncoprotein has been relatively less defined. HPV 16 E5 is a hydrophobic membrane-bound protein which associates with the Golgi apparatus, endoplasmic reticulum and perinuclear membrane. Accumulating evidences have suggested that E5 oncoprotein may also contribute to cervical carcinogenesis through modulating cellular signaling pathways in addition to augmenting the immortalization potential of E6 and E7. Multiple mechanisms, including activation of EGFR or inflammatory cell signaling pathway, have been implicated in malignant transformation by HPV 16 E5. Therefore, targeting E5 may be a rational approach for chemoprevention and treatment of cervical cancer, and understanding its oncogenic processes may help us to design novel therapeutic strategies. In this review, we discussed the roles of HPV 16 E5 in cervical carcinogenesis, altering several cellular signaling pathways involved in cell proliferation, angiogenesis and apoptosis., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Pituitary gonadotropins (GTHs), follicle stimulating hormone beta (FSH-beta), and luteinizing hormone beta (LH-beta) are the key hormones in the hypothalamus-pituitary-gonad (HPG) axis, and form the heterodimers between a common alpha subunit (gonadotropin-alpha) and FSH-beta and/or LH-beta. To obtain a better understanding on the modulation of gonadotropin subunit genes expression upon bisphenol A (BPA) exposure in hermaphroditic fish, we studied differential regulation of gonadotropin subunit genes from Kryptolebias marmoratus after the exposure of several EDCs. Expression profiles of these three genes when using quantitative real-time RT-PCR revealed that brain/pituitary tissues were highly expressed in these genes compared to other tissues. At different developmental stages, expression of those genes dramatically increased over the course of development but showed a decrease in expression at the secondary male (showing atresia) stage. When adult fish were exposed to BPA (600 microg/L for 96 h), a significant upregulation of these three genes was observed in the brain/pituitary. A time course study also revealed the increased expression of gonadotropin subunit genes over 12 h with a more pronounced effect on the expression of FSH-beta and LH-beta genes, indicating that both genes were associated with the BPA exposure on the transcriptional regulation. This is the first report of gonadotropin subunit genes from K. marmoratus, with particular emphasis on the modulation of their expressions by EDCs. In addition, these findings suggest that EDCs modulate the expression of gonadotropin subunit genes and would act as potential biomarkers upon EDCs exposure., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Growing resistance of prevalent antitubercular (antiTB) agents in clinical isolates of Mycobacterium tuberculosis (MTB) provoked an urgent need to discover novel antiTB agents. Enoyl acyl carrier protein (ACP) reductase (InhA) from Mtb is a well known and thoroughly studied as antitubucular therapy target. Here we have reported the discovery of potent antiTB agents through ligand and structure based approaches using computational tools. Initially compounds with more than 0.500 Tanimoto similarity coefficient index using functional class fingerprints (FCFP&#95;4) to the reference chemotype were mined from the chemdiv database. Further, the molecular docking was performed to select the compounds on the basis of their binding energies, binding modes, and tendencies to form reasonable interactions with InhA (PDB ID=2NSD) protein. Eighty compounds were evaluated for antitubercular activity against H37RV M. tuberculosis strain, out of which one compound showed MIC of 5.70 microM and another showed MIC of 13.85 microM. We believe that these two new scaffolds might be the good starting point from hit to lead optimization for new antitubercular agents., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

A method based on a capillary electrophoresis with laser induced fluorescence detection was developed and validated for simultaneous separation of doxorubicin (DOX) and liposomal encapsulated DOX. The separation was accomplished using a fused silica capillary (60cm in total length, 75microm I.D.) and potassium phosphate buffer [12.5mM, pH 7.4] as the running buffer. The effect of sample preparation conditions on maintaining liposomal integrity was also investigated. The limit of detection for DOX was 0.1microg/ml and the precision and accuracy of CE/LIF method was within the ranges of FDA guidelines. The validated method was successfully used to quantify DOX in human plasma using a direct injection of a 4-fold dilution of spiked liposomal DOX in human plasma., (Copyright 2009. Published by Elsevier B.V.)

Closo-dodecaborate lipid liposomes were developed as new vehicles for boron delivery system (BDS) of neutron capture therapy. The current approach is unique because the liposome shell itself possesses cytocidal potential in combination with neutron irradiation. The liposomes composed of closo-dodecaborate lipids DSBL and DPBL displayed high cytotoxicity with thermal neutron irradiation. The closo-dodecaborate lipid liposomes were taken up into the cytoplasm by endocytosis without degradation of the liposomes. Boron concentration of 22.7 ppm in tumor was achieved by injection with DSBL-25% PEG liposomes at 20mg B/kg. Promising BNCT effects were observed in the mice injected with DSBL-25% PEG liposomes: the tumor growth was significantly suppressed after thermal neutron irradiation (1.8 x 10(12)neutrons/cm(2))., ((c) 2010 Elsevier Ltd. All rights reserved.)

A series of 4-anilinoquinazolines with C-C multiple bond substitutions at the 6-position were synthesized and investigated for their potential to inhibit epidermal growth factor receptor (EGFR) tyrosine kinase activity. Among the compounds synthesized, alkyne 6d and allenes 7d and 7f significantly inhibited EGFR tyrosine kinase activity. These compounds inhibited EGF-mediated phosphorylation of EGFR in A431 cells, resulting in cell-cycle arrest and apoptosis induction. The C-C multiple bonds substituted at the C-6 position of the anilinoquinazoline framework were essential for the significant inhibitory activity. Compounds with long carbon chains (n=3-6), such as 6c-f, 7c-f, 11, and 12, displayed prolonged inhibitory activity., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Choriogenins (Chgs) are precursors of inner layer of egg envelope that are synthesized in fish liver in response to estrogens. Therefore, study of their expression serves as biomarker of exposure to endocrine disrupting chemicals (EDCs). The self-fertilizing fish, Kryptolebias marmoratus has been established as a model species for testing the action of EDCs. To use this fish as a model for assessing estrogenic activity of EDCs on Chg expression, two K. marmoratus choreogenin genes, Km-ChgH and Km-ChgL were cloned and their expression was analyzed in different tissues and in developmental stages by real-time RT-PCR. Expression levels of liver mRNA were compared between hermaphrodites and secondary males after exposure to EDCs. Km-ChgH and Km-ChgL genes that were predominantly expressed in liver contained zona pellucida (ZP) domains. During embryonic development, low expression of mRNA was observed at stage 1 (2 dpf) that reached highest level at stage 4 (12 dpf) or stage 5 (5 h post hatching). The expression of Km-Chg mRNAs was highly increased in liver exposed to natural estrogen, 17alpha-estradiol (E2) as well as EDCs such as bisphenol A and 4-n-nonylphenol in both the gender types. Another EDC, 4-tert-octylphenol, showed modulatory effect only on Km-ChgH in hermaphrodites. Tamoxifen, an antagonist of the estrogen receptor showed no effect on expression of Chg genes in either of the gender types of K. marmoratus. These findings indicate that Km-Chg genes would be associated with estrogen and measurement of their expression would serve as a surrogate biomarker of exposure to environmental EDCs.

A fast and specific liquid chromatography-mass spectrometry method for the determination of (R,R)-fenoterol ((R,R)-Fen) in rat plasma has been developed and validated. (R,R)-Fen was extracted from 125 microl of plasma using solid phase extraction and analyzed on Atlantis HILIC Silica 3 microm column. The mobile phase was composed of acetonitrile:ammonium acetate (pH 4.1; 20mM) (85:15, v/v), at a flow rate of 0.2 ml/min. The lower limit of detection (LLOD) was 2 ng/ml . The procedure was validated and applied to the analysis of plasma samples from rats previously administered (R,R)-Fen in an intravenous bolus.

In this work, amorphous atorvastatin calcium nanoparticles were successfully prepared using the supercritical antisolvent (SAS) process. The effect of process variables on particle size and distribution of atorvastatin calcium during particle formation was investigated. Solid state characterization, solubility, intrinsic dissolution, powder dissolution studies and pharmacokinetic study in rats were performed. Spherical particles with mean particle size ranging between 152 and 863 nm were obtained by varying process parameters such as precipitation vessel pressure and temperature, drug solution concentration and feed rate ratio of CO2/drug solution. XRD, TGA, FT-IR, FT-Raman, NMR and HPLC analysis indicated that atorvastatin calcium existed as anhydrous amorphous form and no degradation occurred after SAS process. When compared with crystalline form (unprocessed drug), amorphous atorvastatin calcium nanoparticles were of better performance in solubility and intrinsic dissolution rate, resulting in higher solubility and faster dissolution rate. In addition, intrinsic dissolution rate showed a good correlation with the solubility. The dissolution rates of amorphous atorvastatin calcium nanoparticles were highly increased in comparison with unprocessed drug by the enhancement of intrinsic dissolution rate and the reduction of particle size resulting in an increased specific surface area. The absorption of atorvastatin calcium after oral administration of amorphous atorvastatin calcium nanoparticles to rats was markedly increased.

Recent reports have shown that cytokines inhibit fluid absorption by suppressing Na(+) channel activity in various epithelia. In this study, we investigated the role of epithelial sodium channel (ENaC) in fluid absorption in normal human middle ear epithelial (NHMEE) cells, as well as the effects of Interleukin (IL)-1beta on ENaC expression and fluid absorption in NHMEE cells. We confirmed that ENaC alpha, beta and gamma were predominantly expressed on the apical surface of the NHMEE cells by immunocytochemistry. Addition of amiloride, a potent ENaC blocker, to apical membranes of NHMEE cells decreased the fluid absorption rate in a dose-dependent manner. Treatment with 10 ng/ml IL-1beta for 24 h suppressed ENaC beta expression, the ENaC-dependent short-circuit current (Isc), and ENaC-dependent fluid absorption. When the NHMEE cells were pretreated with a phospholipase C (PLC)inhibitor (U73122, 10 microM), a protein kinase C (PKC) inhibitor (Calphostin C, 0.1 microM), or extracellular signal regulated kinase (ERK) 1/2 inhibitor (PD98059, 10 microM), the amiloride-sensitive currents in IL-1beta-treated cells were reversed to control levels; an effect not seen with SB202190 (an inhibitor of p38 mitogen-activated protein (MAP) kinase) or SP600125 (a reversible inhibitor of c-Jun N-terminal kinase). In this study we showed that ENaC is essential for fluid absorption in NHMEE cells and that IL-1beta suppresses the ENaC-dependent current via the PLC-PKC-ERK1/2 pathway. These results suggest that IL-1beta may contribute to fluid retention in otitis media with effusion by changing electrolyte transport and reducing middle ear epithelial fluid absorption.

The purpose of this study was to compare the osseointegration of 4 different kinds of bioactive ceramic-coated screws with uncoated screws by biomechanical and histomorphometric analysis. Calcium pyrophosphate (CPP), apatite-wollastonite 1:3 glass ceramic (W3G), apatite-wollastonite 1:1 glass ceramic (WAG) and bioactive CaO-SiO2-B2O3 glass ceramic (CSG) coatings were prepared and coated by the dipping method. Coated and uncoated titanium screws were inserted into the tibia of 18 adult mongrel male dogs for 2, 4, and 8 weeks. The insertion torques, radiographs, undecalcified histology, histomorphometric analysis, and extraction torques were evaluated. No difference of insertion torque was found among the five screw types. At 2 and 4 weeks after implantation, the extraction torque of ceramic-coated screws was significantly higher than that of uncoated screws (p < or = 0.0001). At 8 weeks, the extraction torques of CPP-, W3G-, and WAG-coated screws were significantly higher than those of CSG-coated and uncoated screws (p<0.0001). At 2, 4, and 8 weeks, the extraction torques of 4 different ceramic-coated screws were significantly higher than the corresponding insertion torque. Strong fixation was observed even at 2 weeks in the CPP-, W3G- and WAG-coated screws. The bone-screw contacts of the 4 different coated screws at 2 and 4 weeks were statistically higher than that of the uncoated screws, and the bone-screw contacts of the CPP-, W3G- and WAG-coated screws at 8 weeks were also statistically higher than that of the uncoated screws. The fixation strength was increased by the presence of osteoconductive coating materials, such as CPP, W3G, and WAG, which enabled to achieve higher fixation strength even as early as 2-8 weeks after the insertion.

In cultures of the murine macrophage cell line RAW 264.7, effects of four 2'-hydroxychalcone derivatives, 2'-hydroxy-4'-methoxychalcone (compound 1), 2',4-dihydroxy-4'-methoxychalcone (compound 2), 2',4-dihydroxy-6'-methoxychalcone (compound 3) and 2'-hydroxy-4,4'-dimethoxychalcone (compound 4), on lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and tumor necrosis factor (TNF)-alpha were examined. Compounds 1, 2 and 3 at 3-30microM inhibited the production with almost the same potency. Compound 4 showed no inhibitory activity. Compounds 1, 2 and 3 at 3-30microM inhibited the LPS-induced expression of inducible nitric oxide synthase (iNOS) and TNF-alpha mRNA. To clarify the mechanism involved, effects of compounds 1, 2 and 3 on the activation of nuclear factor (NF)-kappaB and activator protein-1 (AP-1) were examined. Both the LPS-induced activation of NF-kappaB and AP-1 were blocked by compounds 1, 2 and 3 at 3-30microM. Moreover, the three compounds at such concentrations inhibited the LPS-induced IkappaB degradation and the phosphorylation of c-jun N-terminal kinase (JNK) and c-jun. These findings suggest that the inhibition of the LPS-induced production of NO and TNF-alpha by the 2'-hydroxychalcone derivatives is due to the inhibition of NF-kappaB and AP-1 activations.

The sintering behavior, mechanical properties and biocompatibility of magnesia (MgO)-doped HA/TCP biphasic ceramics were studied. Pure HA/TCP ceramics showed poor sinterability due to the phase transformation of beta- to alpha-TCP. MgO-doped HA/TCP ceramics showed high density without any phase transformation of beta-TCP up to 1300 degrees C, for MgO dopants incorporated into the beta-TCP preferably and increased thermal stability of beta-TCP. However, the addition of MgO higher than a critical content, suppressed grain growth of HA/TCP ceramics and lowered sinterability. The optimum amount of MgO doping was 1 wt%, which lead 99% relative density and higher mechanical properties than HA or beta-TCP ceramics. From in vitro test and in vivo test, 1 wt% MgO-doped HA/TCP ceramics showed a good biocompatibility without cytotoxicity. After implantation under the muscle of rabbits, beta-TCP phase was dissolved from the surface and a biological apatite covered the surface. These results proved that MgO addition increased drastically the sintering and mechanical properties of HA/beta-TCP ceramics without altering the biological safety and biocompatibility of the original composite.

Galactose moiety as the hepatocyte anchorage was covalently coupled with chitosan for the development of synthetic extracellular matrix. Hepatocytes adhesion to galactosylated chitosan (GC)-coated polystyrene (PS) dish became as high as 94.7% after 2 h incubation whereas the hepatocytes adhesion to chitosan-coated PS dish was 69.1%, indication of galactose-specific recognition between GC molecules and asialoglycoprotein receptors of hepatocytes. The DNA synthesis of the hepatocytes adhered to GC-coated dish was increased in the presence of epidermal growth factor (EGF) at low concentration of GC (0.05 microg/ml) whereas the DNA synthesis of the hepatocytes adhered to GC-coated dish was decreased in the presence of EGF at high concentration of GC (5 microg/ml). The spreading shapes of the hepatocytes adhered to the surface in the presence of EGF at low concentration of GC (0.05 microg/ml) were enhanced than in the absence of EGF. The hepatocytes adhered to the surface at high concentration of GC (5 microg/ml) showed round shapes and exhibited many spheroid formation after 24 h in the presence of EGF.

Five lignans, l-sesamin, savinin, helioxanthin, taiwanin C, and cis-dibenzylbutyrolactone, were isolated from the root of Acanthopanax chiisanensis (Araliaceae), a Korean medicinal plant, and their inhibitory effects on the production of prostaglandin (PG) E(2) stimulated by 12-O-tetradecanoylphorbol 13-acetate (TPA) in rat peritoneal macrophages were examined. Among the five lignans, taiwanin C was the most potent (IC(50)=0.12 microM), followed by helioxanthin, cis-dibenzylbutyrolactone, and savinin. l-Sesamin had no effect. Taiwanin C showed no inhibitory effect on the TPA-induced release of radioactivity from [3H]arachidonic acid-labeled macrophages, nor did it inhibit the expression of cyclooxygenase (COX)-2 protein induced by TPA. However, the activities of isolated COX-1 and COX-2 were inhibited by taiwanin C (IC(50)=1.06 and 9.31 microM, respectively), reflecting the inhibition of both COX-1- and COX-2-dependent PGE(2) production in the cell culture system. These findings suggest that the mechanism of action of taiwanin C in the inhibition of PGE(2) production is the direct inhibition of COX enzymatic activity.

The sintering behavior of calcium pyrophosphate (CPP, Ca2P2O7)-doped beta-tricalcium phosphate [TCP, Ca3(PO4)2], prepared by solid state reaction, was investigated in-situ, using dilatometry. Pure beta-TCP undergoes phase transition to alpha-TCP at about 1200 degrees C; hence pure beta-TCP ceramics should be sintered bclow 1200 degrees C. Pure beta-TCP sintered body can achieve a relative density of only 86% when sintered at 1150 degrees C. However, the addition of CPP in the range of 0.5-3 wt% delays phasc transition of beta-TCP and enables sintering of beta-TCP at 1200 degrees C without a phase transformation to alpha-TCP. Due to this effect of CPP added to TCP, CPP-doped beta-TCP ceramics with relative density over 95% could be obtained when sintered at 1200 degrees C for 2 h.

OBJECTIVE: We hypothesize that ECG-gated positron emission tomography (PET) using Fluorodeoxyglucose F-18 (FDG) alone can determine myocardial viability by identifying dysfunctional myocardium with preserved glucose metabolism. We compared the contraction-metabolism pattern of gated FDG PET with the perfusion-metabolism pattern of conventional PET using N-13 ammonia (NH(3)) as a perfusion agent and FDG as a glucose metabolism agent in 21 consecutive patients with chronic coronary artery disease with left ventricular dysfunction (mean ejection fraction 23.6 +/- 7.7%).METHODS: The left ventricle was divided into 17 segments. Uptakes of NH(3) and FDG were scored from absent (0) to normal (4), and wall motion was scored from dyskinesia (-1) to normal (3). Scores were determined by the visual interpretation of the majority of 3 blinded expert readers. Viable myocardium was defined by normal or mildly reduced uptakes of both NH(3) and FDG, perfusion-metabolism mismatch on NH(3)-FDG PET, or normal to mildly reduced uptake of FDG with regional dysfunction on gated FDG PET.RESULTS: Gated FDG PET identified 184 segments as viable, all of which were determined as viable by NH(3)-FDG PET. Among 125 segments identified as nonviable by NH(3)-FDG PET, 76 segments were determined as nonviable by NH(3)-FDG PET. The results provided a positive and negative predictive value of gated FDG PET for the determination of myocardial viability to be 100% and 60.8%, respectively.CONCLUSIONS: Gated FDG PET has a high positive predictive value (100%) for the identification of viable myocardium.