Anti-rheumatic property and physiological safety of KMU-11342 in in vitro and in vivo models.

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder characterized by joint destruction due to synovial hypertrophy and the infiltration of inflammatory cells. Despite substantial progress in RA treatment, challenges persist, including suboptimal treatment responses and adverse effects associated with current therapies. This study investigates the anti-rheumatic capabilities of the newly identified multi-protein kinase inhibitor, KMU-11342, aiming to develop innovative agents targeting RA. In this study, we synthesized the novel multi-protein kinase inhibitor KMU-11342, based on indolin-2-one. We assessed its cardiac electrophysiological safety using the Langendorff system in rat hearts and evaluated its toxicity in zebrafish in vivo. Additionally, we examined the anti-rheumatic effects of KMU-11342 on human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), THP-1 cells, and osteoclastogenesis in RAW264.7 cells. KMU-11342 demonstrated the ability to inhibit LPS-induced chemokine inhibition and the upregulation of pro-inflammatory cytokines, cyclooxygenase-2, inducible nitric oxide synthase, p-IKKα/ß, p-NF-κB p65, and the nuclear translocation of NF-κB p65 in RA-FLS. It effectively suppressed the upregulation of NLR family pyrin domain containing 3 (NLRP3) and caspase-1 cleavage. Furthermore, KMU-11342 hindered the activation of osteoclast differentiation factors such as RANKL-induced TRAP, cathepsin K, NFATc-1, and c-Fos in RAW264.7 cells. KMU-11342 mitigates LPS-mediated inflammatory responses in THP-1 cells by inhibiting the activation of NLRP3 inflammasome. Notably, KMU-11342 exhibited minimal cytotoxicity in vivo and electrophysiological cardiotoxicity ex vivo. Consequently, KMU-11342 holds promise for development as a therapeutic agent in RA treatment.

Radiosurgery vs. microsurgery for newly diagnosed, small petroclival meningiomas with trigeminal neuralgia.

Trigeminal neuralgia (TN) is an excruciating pain that can occur with petroclival meningiomas (PCMs). Gamma knife radiosurgery (GKRS) is an appealing option for small PCMs, but the role of microsurgery (MS) compared to GKRS is not well defined for small PCMs with regard to TN relief. From January 2009 to September 2019, 70 consecutive patients were treated by GKRS or MS for newly diagnosed, small (< 3.5 cm) PCMs with TN. GKRS or MS were performed for 35 patients each. The surgical outcome and TN control according to Barrow Neurological Institute (BNI) score were retrospectively analyzed and compared between GKRS and MS. The predominant origin of PCMs was upper clival (49%) with trigeminal nerve compression at the medial dorsal root entry zone. Tumor control rates were equally 94% with GKRS or MS for a mean tumor size and volume of 2.3 cm and 5.3 cm3, respectively. The preoperative BNI scores were mostly II (40%) and IV (37%) with GKRS and MS, respectively. TN relief without medications (BNI scores I and II) was achieved in 13 of 35 patients (37%) with GKRS and 32 of 35 patients (91%) with MS during a mean follow-up of 50.5 months. The most common complications after GKRS and MS were dysesthesia (23%) and diplopia (9%), respectively. MS could be more effective than GKRS in providing prompt, medication-free pain relief from TN for small PCMs. The risks of MS have to be considered carefully in experienced hands, especially for small PCMs.

Period-chirped gratings fabricated by laser interference lithography with a concave Lloyd's mirror.

We developed a laser interference lithography (LIL) system for fabrication of period-chirped gratings, which would be useful for sophisticated optical components. Despite its simplicity, the developed LIL system, based on a Lloyd's mirror interferometer with a cylindrically concave mirror, can generate chirped gratings, yet over a large area at high throughput owing to the nature of LIL. We have derived exact theoretical equations needed for system design, built the LIL system, and subsequently realized period-chirped gratings. A fabricated sample whose center period is Λ≈600 nm exhibits a continuous period variation of ΔΛ=92 nm across 17 mm width.

Macular inner plexiform and retinal nerve fiber layer thickness in glaucoma.

PURPOSE: To compare the parameters of the macular ganglion cell-inner plexiform layer (mGCIPL) thickness measured by Cirrus high-definition optical coherence tomography in normal-tension glaucoma (NTG) and primary open-angle glaucoma (POAG). METHODS: Eighty patients with NTG, 80 patients with POAG, and 100 normal control subjects were enrolled. The mGCIPL and peripapillary retinal nerve fiber layer (pRNFL) thicknesses measured by Cirrus high-definition optical coherence tomography were compared in patients with glaucoma. The areas under the receiver operating characteristic curve (AROCs) were calculated to compare the diagnostic power of the mGCIPL thickness with that of the pRNFL thickness. Pearson correlation coefficients were determined to investigate the correlation between the mGCIPL or pRNFL thickness parameters and the mean deviation (MD) values of visual field tests. RESULTS: All parameters of the mGCIPL thickness were significantly different between normal control subjects and patients with glaucoma. The superior, superotemporal, and superonasal thickness of mGCIPL and the superior thickness of pRNFL showed significant reductions and significantly higher AROCs for distinguishing between normal eyes and eyes with glaucoma in POAG compared with those in NTG. In NTG or POAG groups, the mGCIPL and pRNFL parameters with the highest AROC were the minimum and average thickness, respectively. The average, minimum, inferior, inferotemporal, and inferonasal thickness of mGCIPL and the average and inferior thickness of pRNFL were correlated with MD in NTG (p < 0.05 for all parameters), whereas all parameters of the mGCIPL thickness except the inferonasal thickness and all parameters of the pRNFL thickness except the temporal thickness were correlated with MD in POAG (p < 0.05 for all parameters). CONCLUSIONS: The diagnostic ability of the mGCIPL thickness was comparable to that of the pRNFL thickness in patients with NTG or POAG. The mGCIPL loss in NTG was localized and mainly concentrated on the inferior portion compared with diffuse mGCIPL loss in POAG.

Identification and Kinetic Characterization of Serum- and Glucocorticoid-Regulated Kinase Inhibitors Using a Fluorescence Polarization-Based Assay.

The serum- and glucocorticoid-regulated kinase (SGK) family consists of three isoforms (SGK1, SGK2, and SGK3) that have been implicated in the regulation of tumor growth, metastasis, autophagy, and epithelial ion transport. SGK1 and SGK3 play essential roles in protein kinase B (AKT or PKB)-independent phosphoinositide 3-kinases (PI3K)-mediated tumorigenesis, as evidenced by the significantly elevated expression levels of SGK1 and SGK3 in many cancers, including prostate cancer, colorectal carcinoma, estrogen-dependent breast cancer, and glioblastoma. Therefore, SGK is a potential target for anticancer therapy. A small kinase-focused library comprising 160 compounds was screened against SGK1 using a fluorescence polarization-based kinase assay that yielded a Z'-factor of 0.82. Among the 39 compounds obtained as initial hits in a primary screen, 12 compounds contained the thiazolidine-2,4-dione scaffold. The inhibitory mechanisms of the most potent hit, KMU010402, were further investigated using kinetic analyses, followed by determination of the inhibition constants for SGK1, SGK2, and SGK3. Molecular modeling was used to propose a potential binding mode of KMU010402 to SGK1.

The behavior of residual tumors following incomplete surgical resection for vestibular schwannomas.

The management of vestibular schwannoma (VS) with residual tumor following incomplete resection remains controversial and little is known regarding postoperative tumor volume changes. The behavior of residual tumors was analyzed for 111 patients who underwent surgery for newly diagnosed VS between September 2006 and July 2017. The postoperative tumor volume changes were assessed during a mean follow-up of 69 months (range 36-147 months). Fifty-three patients underwent imaging surveillance following incomplete resection. There was no residual tumor growth in 44 patients (83%). A significant regression of residual tumor volume was noted in the no growth group at postoperative 1 year (p = 0.028), 2 years (p = 0.012), but not from 3 years onwards. Significant predictors of regrowth were immediate postoperative tumor volume ≥ 0.7 cm3 (HR 10.5, p = 0.020) and residual tumor location other than the internal auditory canal (IAC) (HR 6.2, p = 0.026). The mean time to regrowth was 33 months (range 5-127 months). The 2-, 5-, and 10-year regrowth-free survival rates were 90.6%, 86.8%, and 83%, respectively. In conclusion, significant residual tumor regression could occur within 2 years for a VS with an immediate postoperative tumor volume less than 0.7 cm3 or residual tumor in IAC.

3'-Sialyllactose prebiotics prevents skin inflammation via regulatory T cell differentiation in atopic dermatitis mouse models.

3'-Sialyllactose (3'-SL), a natural prebiotic, maintains immune homeostasis and exerts anti-inflammatory and anti-arthritic effects. Although regulatory T cells (Tregs) prevent excessive inflammation and maintain immune tolerance, the effect of 3'-SL on Treg regulation is unclear. This study aimed to investigate the effect of 3'-SL on Treg responses in atopic dermatitis (AD) pathogenesis. Oral administration of 3'-SL reduced AD-like symptoms such as ear, epidermal, and dermal thickness in repeated topical application of house dust mites (HDM) and 2,4-dinitrochlorobenzene (DNCB). 3'-SL inhibited IgE, IL-1ß, IL-6, and TNF-α secretion and markedly downregulated AD-related cytokines including IL-4, IL-5, IL-6, IL-13, IL-17, IFN-γ, TNF-α, and Tslp through regulation of NF-κB in ear tissue. Additionally, in vitro assessment of Treg differentiation revealed that 3'-SL directly induced TGF-ß-mediated Treg differentiation. Furthermore, 3'-SL administration also ameliorated sensitization and elicitation of AD pathogenesis by suppressing mast cell infiltration and production of IgE and pro-inflammatory cytokines in mouse serum by mediating the Treg response. Furthermore, Bifidobacterium population was also increased by 3'-SL administration as prebiotics. Our data collectively show that 3'-SL has therapeutic effects against AD progression by inducing Treg differentiation, downregulating AD-related cytokines, and increasing the Bifidobacterium population.

Structural analysis and mode of action of BMAP-27, a cathelicidin-derived antimicrobial peptide.

BMAP-27, a member of cathelicidin family, plays an important role against microorganisms, including bacteria and fungi. BMAP-27 may exert antimicrobial effects through membrane integrity disruption, but the exact molecular mechanism remains unclear. To identify the structural features important for antimicrobial activity and propose a mechanism underlying antibacterial effects, we determined the nuclear magnetic resonance structure of BMAP-27 in a membrane-mimetic environment and investigated its interactions with lipid membranes. BMAP-27 exhibited a long N-terminal α-helix with faces patterned into aromatic and cationic regions, central kink, and short hydrophobic C-terminal helix. While the N-terminal 18-residue peptide (BMAP-18) exerted only antibacterial activity, BMAP-27 showed potent activity against bacteria and cancer cells. Both peptides inhibited bacterial growth, but BMAP-18 showed delayed bactericidal activity and BMAP-27 completely killed bacteria within 20 min. The differences in antimicrobial activities and microbicidal kinetics may be associated with membrane permeabilisation; BMAP-27 rapidly and largely disrupted membrane integrity, whereas BMAP-18 showed low membrane disruption activity. Thus, the N-terminal helix is sufficient to inhibit bacterial growth and the C-terminal helix is involved in membrane permeabilisation for rapid bactericidal and efficient anticancer activities. The structural and functional characterisation of BMAP-27 may encourage the development of novel antimicrobial/anticancer agents.

Tunable colloidal quantum dot distributed feedback lasers integrated on a continuously chirped surface grating.

We report a colloidal quantum dot (CQD) distributed feedback (DFB) laser structure containing a chirped grating. The device exhibits single-mode DFB lasing, of which the wavelength is spatially dispersed in a single chip. A period-chirped surface grating is fabricated using a modified Lloyd-type laser interference lithography setup, where a flat Lloyd's mirror is replaced with a concave one. A dense red-emitting CdSe/CdS/ZnS CQD film is prepared on a temporary substrate by spin-coating, which is subsequently released and wet-transferred onto a period-chirped quartz surface grating. Upon optical excitation, the fabricated DFB laser device lases in a single mode at a laser threshold of ∼400 µJ cm-2, with its lasing wavelength shifted linearly (in proportion to the grating pitch) along the chirp direction from 613.4 nm to 623.2 nm over a distance of ∼5.6 mm.

A colloidal quantum dot photonic crystal phosphor: nanostructural engineering of the phosphor for enhanced color conversion.

Phosphors, long-known color-converting photonic agents, are gaining increasing attention owing to the interest in white LEDs and related applications. Conventional material-based approaches to phosphors focus on obtaining the desired absorption/emission wavelengths and/or improving quantum efficiency. Here, we report a novel approach for enhancing the performance of phosphors: structural modification of phosphors. We incorporated inorganic colloidal quantum dots (CQDs) into a lateral one-dimensional (1D) photonic crystal (PhC) thin-film structure, with its photonic band-edge (PBE) modes matching the energy of 'excitation photons' (rather than 'emitted photons', as in most other PBE application devices). At resonance, we observed an approximately 4-fold enhancement of fluorescence over the reference bulk phosphor, which reflects an improved absorption of the excitation photons. This nano-structural engineering approach is a paradigm shift in the phosphor research area and may help to develop next-generation higher efficiency phosphors with novel characteristics.

Expression, purification and transduction of PEP-1-botulinum neurotoxin type A (PEP-1-BoNT/A) into skin.

Botulinum neurotoxin A (BoNT/A) has been used therapeutically to treat muscular hypercontractions and sudomotor hyperactivity and it has been reported that BoNT/A might have analgesic properties in headache. PEP-1 peptide is a known carrier peptide that delivers full-length native proteins in vitro and in vivo. In this study, a BoNT/A gene were fused with PEP-1 peptide in a bacterial expression vector to produce a genetic in-frame PEP-1-BoNT/A fusion protein. The expressed and purified PEP-1-BoNT/A fusion proteins were efficiently transduced into cells in a time- and dose-dependent manner when added exogenously in a culture medium. In addition, immunohistochemical analysis revealed that PEP-1-BoNT/A fusion protein efficiently penetrated into the epidermis as well as the dermis of the subcutaneous layer, when sprayed on mice skin. These results suggest that PEP-1-BoNT/A fusion protein provide an efficient strategy for therapeutic delivery in various human diseases related to this protein.

Validity of the temporal-to-nasal macular ganglion cell-inner plexiform layer thickness ratio as a diagnostic parameter in early glaucoma.

PURPOSE: To evaluate the diagnostic validity of temporal-to-nasal macular ganglion cell-inner plexiform layer thickness (TNM) ratio using Cirrus high definition-optical coherence tomography (HD-OCT) in patients with early glaucomatous damage. METHODS: Enrolled participants included 130 normal controls, 50 patients with preperimetric glaucoma and 106 patients with early glaucoma. The patients with early glaucoma were classified into two subgroups according to the pattern of the visual field (VF) defects: the paracentral scotoma (PCS, n = 54) and the peripheral scotoma (PPS, n = 52). The thickness of the macular ganglion cell-inner plexiform layer (mGCIPL) and circumpapillary retinal nerve fibre layer (cpRNFL) was measured by Cirrus HD-OCT, and the average, superior and inferior TNM ratio was calculated. The average TNM ratio is a sum of superotemporal and inferotemporal mGCIPL thicknesses divided by the sum of superonasal and inferonasal mGCIPL thicknesses. Area under the receiver operating characteristic curve (AROC) of each parameter was compared between the groups. RESULTS: The parameter with the best AROC was the average TNM ratio and inferotemporal mGCIPL thickness in the PCS group and average cpRNFL thickness in the PPS group. The AROCs of the average, superior and inferior TNM ratio (p < 0.001, p = 0.007 and p < 0.001, respectively), minimum, average, inferotemporal and inferior mGCIPL thickness (p = 0.004, p = 0.003, p = 0.002 and p = 0.001, respectively) of the PCS were significantly higher than those of the PPS. However, the AROCs of the all cpRNFL thickness parameters did not show statistically significant differences between two subgroups. CONCLUSION: Asymmetry of temporal-to-nasal mGCIPL thickness could be an important parameter in the diagnosis of early glaucoma with paracentral VF defects.