Potent human glutaminyl cyclase inhibitors as potential anti-Alzheimer's agents: Structure-activity relationship study of Arg-mimetic region.

Pyroglutamate-modified amyloid ß peptides (pGlu-Aß) are highly neurotoxic and promote the formation of amyloid plaques. The pGlu-Aß peptides are generated by glutaminyl cyclase (QC), and recent clinical studies indicate that QC represents an alternative therapeutic target to treat Alzheimer's disease (AD). We have previously developed a series of QC inhibitors with an extended pharmacophoric scaffold, termed the Arg-mimetic D-region. In the present study, we focused on the structure activity relationship (SAR) of analogues with modifications in the D-region and evaluated their biological activity. Most compounds in this series exhibited potent activity in vitro, and our SAR analysis and the molecular docking studies identified compound 202 as a potential candidate because it forms an additional hydrophobic interaction in the hQC active site. Overall, our study provides valuable insights into the Arg-mimetic pharmacophore that will guide the design of novel QC inhibitors as potential treatments for AD.

Structure-activity relationship investigation of Phe-Arg mimetic region of human glutaminyl cyclase inhibitors.

Glutamyl cyclase (QC) is a promising therapeutic target because of its involvement in the pathogenesis of Alzheimer's disease. In this study, we developed novel QC inhibitors that contain 3-aminoalkyloxy-4-methoxyphenyl and 4-aminoalkyloxyphenyl groups to replace the previously developed pharmacophore. Several potent inhibitors were identified, showing IC50 values in a low nanomolar range, and were further studied for in vitro toxicity and in vivo activity. Among these, inhibitors 51 and 53 displayed the most potent AßN3pE-40-lowering effects in in vivo acute model with reasonable BBB penetration, without showing cytotoxicity and hERG inhibition. The molecular modeling analysis of 53 indicated that the salt bridge interaction and the hydrogen bonding in the active site provided a high potency. Given the potent activity and favorable BBB penetration with low cytotoxicity, we believe that compound 53 may serve as a potential candidate for anti-Alzheimer's agents.

The Accuracy of Ultrasonography on the Location of Lipomas in the Forehead.

BACKGROUND: Preoperative recognition of tumor plane is important to avoid surgical complications in surgeries involving the scalp. Ultrasonography is a useful diagnostic tool to detect the depth of tumor noninvasively. However, some findings are not always in accordance with the actual locations of lipomas, especially in the forehead. OBJECTS: To evaluate the accuracy of preoperative ultrasonographic findings for the location of lipomas in the forehead. MATERIALS AND METHODS: The study included 14 patients with lipomas in the forehead who all underwent preoperative ultrasonography and surgical excision of the lesions. The authors compared the diagnostic location of tumors by ultrasonography with the actual location in the surgical field. RESULTS: On ultrasonography, 10 of 14 cases were diagnosed as frontalis-associated lipomas. However, 13 cases were confirmed as frontalis-associated lipomas intraoperatively, and only 1 case as superficial lipoma, which did not correspond with the ultrasonographic finding. The ultrasonographic findings were accurate in 9 of 14 cases (64.3%). CONCLUSION: The accuracy of ultrasonography on the location of lipomas in the forehead is not as high as expected. Therefore, the surgeon must consider the possibility of deep lipoma even if a forehead lipoma is superficial in location on ultrasonography.

6-Phenoxy-2-phenylbenzoxazoles, novel inhibitors of receptor for advanced glycation end products (RAGE).

Receptor for advanced glycation end products (RAGE) is known to be involved in the transportation of amyloid ß (Aß) peptides and causes the accumulation of Aß in the brain. Moreover, recent studies suggest that the interactions between RAGE and Aß peptides may be the culprit behind Alzheimer's disease (AD). Inhibitors of the RAGE-Aß interactions would not only prevent the accumulation of toxic Aß in the brain, and but also block the progress of AD, therefore, have the potential to provide a 'disease-modifying therapy'. In this study, we have developed a series of 6-phenoxy-2-phenylbenzoxazole analogs as novel inhibitors of RAGE. Among these derivatives, we found several effective inhibitors that block the RAGE-Aß interactions without causing significant cellular toxicity. Further testing showed that compound 48 suppressed Aß induced toxicity in mouse hippocampal neuronal cells and reduced Aß levels in the brains of a transgenic mouse model of AD after oral administration.

Correlation between platinum nanoparticle surface rearrangement induced by heat treatment and activity for an oxygen reduction reaction.

Heat treatment of nanoparticles could induce the surface rearrangement for more stable facet exposure induced by thermodynamics. By changing the heat treatment environment, we confirmed the correlation between the oxygen reduction activity and the effect of surface oxide and the degree of surface rearrangement of Pt nanoparticles. Native surface oxide was not a critical factor for oxygen reduction activity. However, the degree of surface rearrangement could affect the activity, which was confirmed by the surface sensitive techniques such as CO(ad) oxidation and potential of zero total charge. Analysis indicated that the driving force for nanoparticle surface rearrangement was affected by the heat treatment environment such as gas, in our case.

Chemical tuning of electrochemical properties of Pt-skin surfaces for highly active oxygen reduction reactions.

Pt-skin surfaces were successfully fabricated by the chemical deposition of additional Pt on corrugated Pt-Ni nanoparticles with Pt-skeleton surfaces. Compared to the Pt-skin formed by heat annealing, the chemically-tuned Pt-skin had a higher Pt coordination number and surface crystallinity, which resulted in superior ORR activity and durability.

Discovery of Nonpungent Transient Receptor Potential Vanilloid 1 (TRPV1) Agonist as Strong Topical Analgesic.

Paradoxically, some TRPV1 agonists are, at the organismal level, both nonpungent and clinically useful as topical analgesics. Here, we describe the scaled-up synthesis and characterization in mouse models of a novel, nonpungent vanilloid. Potent analgesic activity was observed in models of neuropathic pain, and the compound blocked capsaicin induced allodynia, showing dermal accumulation with little transdermal absorption. Finally, it displayed much weaker systemic toxicity compared to capsaicin and was negative in assays of genotoxicity.

Suicide and the standardized mortality ratio among Republic of Korea Armed Forces personnel, 2011-2016.

PURPOSE: This study examined the number of suicides in the Republic of Korea (ROK) Armed Forces and compared the relative suicide risk of military personnel with that in the general population. METHODS: Age-, sex-, and calendar year-adjusted standardized mortality ratios (SMRs) and 95% confidence intervals were calculated to compare the number of suicides between the ROK Armed Forces and the general population. RESULTS: Between 2011 and 2016, there were 405 suicides by ROK Armed Forces Personnel. The ROK Armed Forces had significantly fewer suicides than expected compared with the general population (SMR = 0.46, 95% confidence interval 0.41~0.50, based on 405 deaths). This was evident for both rank groups (soldiers and officers). In addition, a significant decrease was observed in the soldier group when comparing the SMR in 2016 with the previous 5-year average. CONCLUSIONS: Overall, during the period 2011-2016, the ROK Armed Forces had fewer suicides than expected when compared with the general population.

Discovery of Conformationally Restricted Human Glutaminyl Cyclase Inhibitors as Potent Anti-Alzheimer's Agents by Structure-Based Design.

Alzheimer's disease (AD) is an incurable, progressive neurodegenerative disease whose pathogenesis cannot be defined by one single element but consists of various factors; thus, there is a call for alternative approaches to tackle the multifaceted aspects of AD. Among the potential alternative targets, we aim to focus on glutaminyl cyclase (QC), which reduces the toxic pyroform of ß-amyloid in the brains of AD patients. On the basis of a putative active conformation of the prototype inhibitor 1, a series of N-substituted thiourea, urea, and α-substituted amide derivatives were developed. The structure-activity relationship analyses indicated that conformationally restrained inhibitors demonstrated much improved QC inhibition in vitro compared to nonrestricted analogues, and several selected compounds demonstrated desirable therapeutic activity in an AD mouse model. The conformational analysis of a representative inhibitor indicated that the inhibitor appeared to maintain the Z-E conformation at the active site, as it is critical for its potent activity.

Parry-Romberg Syndrome Augmented by Hyaluronic Acid Filler.

Parry Romberg Syndrome (PRS), also known as idiopathic progressive hemifacial atrophy, is a rare neurocutaneous disorder characterized by loss of skin and subcutaneous fat of face, muscles, and bones causing unilateral atrophy. Most patients require only soft tissue augmentation although syndrome has varying grades of severity. In the majority of reported cases, it has been treated with surgical flap or autologous fat transplantation. However, these treatments need complicated surgical skills which take a lot of time and cost. Herein we report the first case of PRS augmented by hyaluronic acid (HA) filler in a 42-year-old female patient to suggest that HA filler could be a safe, simple, and even rational economic alternative to surgical treatment.

Discovery of an Orally Bioavailable Benzofuran Analogue That Serves as a ß-Amyloid Aggregation Inhibitor for the Potential Treatment of Alzheimer's Disease.

We developed an orally active and blood-brain-barrier-permeable benzofuran analogue (8, MDR-1339) with potent antiaggregation activity. Compound 8 restored cellular viability from Aß-induced cytotoxicity but also improved the learning and memory function of AD model mice by reducing the Aß aggregates in the brains. Given the high bioavailability and brain permeability demonstrated in our pharmacokinetic studies, 8 will provide a novel scaffold for an Aß-aggregation inhibitor that may offer an alternative treatment for AD.

Cutaneous Plasmacytoma: Metastasis of Multiple Myeloma at the Fracture Site.

Multiple myeloma (MM) can be defined as a malignancy with monoclonal plasma cell proliferation. A 66-year-old man presented with pruritic erythematous to purplish plaque grouped nodule with black pigmentations and purpura on the right forearm. The patient was diagnosed with MM about five years prior to the visit at our hospital. Erythematous plaque on his right arm grew rapidly in size over one month and appeared about seven months after the fracture surgery. Skin biopsy showed multiple plasma cell infiltration with monoclonality for lambda light chain, which was consistent with cutaneous plasmacytoma. The patient refused to be treated and died two months later. We herein report an interesting case of cutaneous plasmacytoma at the surgical site of fracture repair.

Self-Assembled Dendritic Pt Nanostructure with High-Index Facets as Highly Active and Durable Electrocatalyst for Oxygen Reduction.

The durability issues of Pt catalyst should be resolved for the commercialization of proton exchange membrane fuel cells. Nanocrystal structures with high-index facets have been recently explored to solve the critical durability problem of fuel cell catalysts as Pt catalysts with high-index facets can preserve the ordered surfaces without change of the original structures. However, it is very difficult to develop effective and practical synthetic methods for Pt-based nanostructures with high-index facets. The current study describes a simple one-pot synthesis of self-assembled dendritic Pt nanostructures with electrochemically active and stable high-index facets. Pt nanodendrites exhibited 2 times higher ORR activity and superior durability (only 3.0 % activity loss after 10 000 potential cycles) than a commercial Pt/C. The enhanced catalytic performance was elucidated by the formation of well-organized dendritic structures with plenty of reactive interfaces among 5 nm-sized Pt particles and the coexistence of low- and high-index facets on the particles.

Eccrine Squamous Syringometaplasia Associated with Pelubiprofen Therapy.

Eccrine squamous syringometaplasia (ESS) is a histologically distinctive skin eruption occurring predominantly in acral or intertriginous areas presenting as erythematous macules, papules or patches. The etiology of ESS remains unclear, but it is usually reported in patients receiving chemotherapy for various malignant neoplasms. To date, only two cases of ESS associated with non-steroidal anti-inflammatory drugs (NSAIDs), which has distinctive clinical features and pathogenesis, have been reported in the literature. Herein, we report a rare and interesting case of ESS associated with pelubiprofen, a recently developed NSAID, which appeared after pelubiprofen therapy and resolved spontaneously after discontinuing the medication.

Discovery of Potent Human Glutaminyl Cyclase Inhibitors as Anti-Alzheimer's Agents Based on Rational Design.

Glutaminyl cyclase (QC) has been implicated in the formation of toxic amyloid plaques by generating the N-terminal pyroglutamate of ß-amyloid peptides (pGlu-Aß) and thus may participate in the pathogenesis of Alzheimer's disease (AD). We designed a library of glutamyl cyclase (QC) inhibitors based on the proposed binding mode of the preferred substrate, Aß3E-42. An in vitro structure-activity relationship study identified several excellent QC inhibitors demonstrating 5- to 40-fold increases in potency compared to a known QC inhibitor. When tested in mouse models of AD, compound 212 significantly reduced the brain concentrations of pyroform Aß and total Aß and restored cognitive functions. This potent Aß-lowering effect was achieved by incorporating an additional binding region into our previously established pharmacophoric model, resulting in strong interactions with the carboxylate group of Glu327 in the QC binding site. Our study offers useful insights in designing novel QC inhibitors as a potential treatment option for AD.

Hidden Pictures of Kaposi's Sarcoma in Psoriatic Lesions: A Diagnostic Challenge.

Kaposi's sarcoma is a multifocal proliferative vascular tumor involving the skin and other organ and psoriasis is a chronic cutaneous disease with papules and plaques with white scale. Development of Kaposi's sarcoma in psoriasis patients has been reported rarely. A 71-year-old man presented with multiple brownish to violaceous plaques on both feet and arms which were found 4 months ago. The biopsy confirmed Kaposi's sarcoma. The patient was diagnosed with psoriasis vulgaris 10 years ago and Kaposi's sarcoma lesions developed between psoriatic plaques. We herein report a rare case of simultaneous occurrence of Kaposi's sarcoma and psoriasis vulgaris which need quite different treatment.

A simple synthesis of urchin-like Pt-Ni bimetallic nanostructures as enhanced electrocatalysts for the oxygen reduction reaction.

The synthesis of urchin-like Pt-Ni bimetallic nanostructures is achieved by a controlled one-pot synthesis. Pt-Ni nanostructures have superior oxygen reduction reaction activities in both with and without specific anion adsorption electrolytes due to the geometric and alloying effects.