The Molecular Mechanisms of Neuroinflammation in Alzheimer's Disease, the Consequence of Neural Cell Death.

Alzheimer's disease (AD) is accompanied by neural cell loss and memory deficit. Neural cell death, occurring via apoptosis and autophagy, is widely observed in the AD brain in addition to neuroinflammation mediated by necroptosis and the NLRP3 inflammasome. Neurotoxicity induced by amyloid-beta (Aß) and tau aggregates leads to excessive neural cell death and neuroinflammation in the AD brain. During AD progression, uncontrolled neural cell death results in the dysregulation of cellular activity and synaptic function. Apoptosis mediated by pro-apoptotic caspases, autophagy regulated by autophagy-related proteins, and necroptosis controlled by the RIPK/MLKL axis are representative of neural cell death occurred during AD. Necroptosis causes the release of cellular components, contributing to the pro-inflammatory environment in the AD brain. Inordinately high levels of neural cell death and pro-inflammatory events lead to the production of pro-inflammatory cytokines and feed-forward hyper neuroinflammation. Thus, neural cell death and neuroinflammation cause synaptic dysfunction and memory deficits in the AD brain. In this review, we briefly introduce the mechanisms of neural cell death and neuroinflammation observed in the AD brain. Combined with a typical strategy for targeting Aß and tau, regulation of neural cell death and neuroinflammation may be effective for the amelioration of AD pathologies.

Evaluation of the Antiviral Activity of Tabamide A and Its Structural Derivatives against Influenza Virus.

Influenza viruses cause severe endemic respiratory infections in both humans and animals worldwide. The emergence of drug-resistant viral strains requires the development of new influenza therapeutics. Tabamide A (TA0), a phenolic compound isolated from tobacco leaves, is known to have antiviral activity. We investigated whether synthetic TA0 and its derivatives exhibit anti-influenza virus activity. Analysis of structure-activity relationship revealed that two hydroxyl groups and a double bond between C7 and C8 in TA0 are crucial for maintaining its antiviral action. Among its derivatives, TA25 showed seven-fold higher activity than TA0. Administration of TA0 or TA25 effectively increased survival rate and reduced weight loss of virus-infected mice. TA25 appears to act early in the viral infection cycle by inhibiting viral mRNA synthesis on the template-negative strand. Thus, the anti-influenza virus activity of TA0 can be expanded by application of its synthetic derivatives, which may aid in the development of novel antiviral therapeutics.

A randomized split-face comparative study of long-pulsed alexandrite plus low-fluence Nd:YAG laser versus pulsed-dye laser in the treatment of rosacea.

OBJECTIVES: To compare the effectiveness of long-pulsed alexandrite laser (LPAL) with that of pulsed-dye laser (PDL) for rosacea. METHODS: This was a single-blind randomized controlled trial on 27 patients who were clinically diagnosed with rosacea. Randomly assigned split face in each patient received four times monthly treatment of LPAL plus low-fluence Nd:YAG with the contralateral side serving as the control treated with PDL. At every visit, the erythema index (EI) was measured with skin analysis systems, and two independent dermatologists evaluated digital photographs for five-point global aesthetic improvement scale (GAIS). RESULTS: The EI significantly decreased on both treated sides (LPAL 366.5 ± 101.0 vs. 295.8 ± 90.2, p < 0.001, PDL 369.0 ± 124.3 vs. 302.7 ± 92.1, p < 0.001) 1 month after fourth treatment (visit 5). Also 3 months after the fourth treatment (visit 6), the reduction in the EI was well maintained on both sides (LPAL 360.3 ± 96.8 vs. 282.0 ± 89.2, p < 0.001, PDL 364.3 ± 121.6 vs. 281.6 ± 97.8, p < 0.001). When comparing the improvement in the EI between the two groups, the percentage reduction in the EI on the LPAL-treated side was not inferior to the PDL-treated side (visit 5: LPAL 18.7 ± 15.7% vs. PDL 16.4 ± 12.9%, p = 0.501 and visit 6: LPAL 21.7 ± 13.9% vs. PDL 21.9 ± 15.2%, p = 0.943). The GAIS and patient satisfaction were comparable between the LPAL and PDL sides and did not show any significant difference. No serious adverse events occurred on either of the treated sides. CONCLUSION: This study showed that the decrease in EI in the treatment of rosacea was comparable between PDL and LPAL. Therefore, LPAL could be a promising alternative treatment option with good merits for rosacea, considering no consumables are required for device maintenance.

Positivity of Rapid Antigen Testing for SARS-CoV-2 With Serial Followed-up Nasopharyngeal Swabs in Hospitalized Patients due to COVID-19.

Despite the accuracy of nucleic acid amplification tests (NAATs), rapid antigen tests (RATs) for severe acute respiratory syndrome coronavirus-2 are widely used as point-of-care tests. A total of 282 pairs of reverse transcription-polymerase chain reaction and Standard Q COVID-19 Ag tests were serially conducted for 68 patients every 3-4 days until their discharge. Through a field evaluation of RATs using direct nasopharyngeal swabs, the sensitivities were 84.6% and 87.3% for E and RNA-dependent RNA polymerase (RdRp) genes, respectively, for specimens with cycle thresholds (Cts) < 25. The Ct values of E and RdRp genes for 95% detection rates by RATs were 16.9 and 18.1, respectively. The sensitivity of RAT was 48.4% after the onset of symptoms, which was not sufficient. RAT positivity gradually decreased with increased time after symptom onset and had continuously lower sensitivity than NAATs.

NXP031 Improves Cognitive Impairment in a Chronic Cerebral Hypoperfusion-Induced Vascular Dementia Rat Model through Nrf2 Signaling.

Vascular dementia (VaD) is a progressive cognitive impairment caused by a reduced blood supply to the brain. Chronic cerebral hypoperfusion (CCH) is one cause of VaD; it induces oxidative stress, neuroinflammation, and blood-brain barrier (BBB) disruption, damaging several brain regions. Vitamin C plays a vital role in preventing oxidative stress-related diseases induced by reactive oxygen species, but it is easily oxidized and loses its antioxidant activity. To overcome this weakness, we have developed a vitamin C/DNA aptamer complex (NXP031) that increases vitamin C's antioxidant efficacy. Aptamers are short single-stranded nucleic acid polymers (DNA or RNA) that can interact with their corresponding target with high affinity. We established an animal model of VaD by permanent bilateral common carotid artery occlusion (BCCAO) in 12 week old Wistar rats. Twelve weeks after BCCAO, we injected NXP031 into the rats intraperitoneally for two weeks at moderate (200 mg/4 mg/kg) and high concentrations (200 mg/20 mg/kg). NXP031 administration alleviates cognitive impairment, microglial activity, and oxidative stress after CCH. NXP031 increased the expression of basal lamina (laminin), endothelial cell (RECA-1, PECAM-1), and pericyte (PDGFRß); these markers maintain the BBB integrity. We found that NXP031 administration activated the Nrf2-ARE pathway and increased the expression of SOD-1 and GSTO1/2. These results suggest that this new aptamer complex, NXP031, could be a therapeutic intervention in CCH-induced VaD.

Natural Products Targeting Amyloid Beta in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by severe brain damage and dementia. There are currently few therapeutics to treat this disease, and they can only temporarily alleviate some of the symptoms. The pathogenesis of AD is mainly preceded by accumulation of abnormal amyloid beta (Aß) aggregates, which are toxic to neurons. Therefore, modulation of the formation of these abnormal aggregates is strongly suggested as the most effective approach to treat AD. In particular, numerous studies on natural products associated with AD, aiming to downregulate Aß peptides and suppress the formation of abnormal Aß aggregates, thus reducing neural cell death, are being conducted. Generation of Aß peptides can be prevented by targeting the secretases involved in Aß-peptide formation (secretase-dependent). Additionally, blocking the intra- and intermolecular interactions of Aß peptides can induce conformational changes in abnormal Aß aggregates, whereby the toxicity can be ameliorated (structure-dependent). In this review, AD-associated natural products which can reduce the accumulation of Aß peptides via secretase- or structure-dependent pathways, and the current clinical trial states of these products are discussed.

Long-term clinical course and outcome of interstitial pneumonia with autoimmune features.

BACKGROUND AND OBJECTIVE: Idiopathic interstitial pneumonia (IIP) with autoimmune features that does not fulfil connective tissue disease (CTD) criteria has been recently defined as interstitial pneumonia with autoimmune features (IPAF). However, its long-term clinical course and outcome are poorly understood. METHODS: We included consecutive patients diagnosed with IIP (n = 586) or CTD-related interstitial lung disease (CTD-ILD, n = 149). Some patients with IIP were reclassified as IPAF based on recent guidelines. RESULTS: The median follow-up period was 45 months. Among the IIP patients, 109 (18.6%) were reclassified as IPAF. Compared to the non-IPAF-IIP group, the IPAF group had slower diffusing capacity of the lung for carbon monoxide (DLCO ) and total lung capacity declines, and more frequent CTD development during follow-up periods. The prognosis of the IPAF was better than that of the non-IPAF-IIP and similar to that of the CTD-ILD. IPAF was associated with better prognosis in the IIP cohort on univariate but not on multivariate analysis. Usual interstitial pneumonia (UIP) pattern, old age and low DLCO independently predicted mortality in the IPAF group. CONCLUSION: Compared to the non-IPAF-IIP group, the IPAF group had slower lung function declines and more frequent CTD development during follow-up. Although the prognosis of IPAF group was better than that of non-IPAF-IIP group and similar to that of CTD-ILD group, it showed poor prognosis in patients with old age, UIP pattern, and low DLCO .

Chemerin Treatment Inhibits the Growth and Bone Invasion of Breast Cancer Cells.

Chemerin is secreted as prochemerin from various cell types and then cleaved into the bioactive isoform by specific proteases. In various cancer types, chemerin exhibits pro- or antitumor effects. In the present study, chemerin treatment significantly inhibited the viability and invasion of breast cancer cells in the absence or presence of transforming growth factor (TGF)-ß and insulin-like growth factor (IGF)-1. The expression levels of E-cadherin and vimentin were reduced in chemerin-treated breast cancer cells. However, chemerin treatment recovered the reduced E-cadherin expression level in breast cancer cells treated with TGF-ß or IGF-1. Chemerin treatment inhibited nuclear ß-catenin levels in breast cancer cells stimulated with or without TGF-ß or IGF-1. In addition, chemerin treatment blocked the increase in the receptor activator of nuclear factor kappa-Β ligand (RANKL)/osteoprotegerin (OPG) ratio in osteoblastic cells exposed to metastatic breast cancer cell-derived conditioned medium. Chemerin treatment inhibited RANKL-induced osteoclast formation and bone resorption by reducing the secretion of matrix metalloproteinase (MMP)-2, MMP-9, and cathepsin K. Intraperitoneal administration of chemerin inhibited tumor growth in MCF-7 breast cancer cell-injected mice and reduced the development of osteolytic lesions resulting from intratibial inoculation of MDA-MB-231 cells. Taken together, chemerin inhibits the growth and invasion of breast cancer cells and prevents bone loss resulting from breast cancer cells by inhibiting finally osteoclast formation and activity.

Wear resistance of 3D-printed denture tooth resin opposing zirconia and metal antagonists.

STATEMENT OF PROBLEM: Additive manufacturing technology can be used for denture bases and also denture teeth. Therefore, the mechanical properties of 3D-printed resin denture teeth should be evaluated. PURPOSE: The purpose of this in vitro study was to compare the wear resistance of 3D-printed denture tooth resin with that of conventionally prefabricated denture teeth. MATERIAL AND METHODS: Eighty substrate specimens were prepared with 5 kinds of resin denture teeth: 3D-printed denture tooth resin (DENTCA denture tooth resin; DENTCA, Inc), Artic 6 (Kulzer GmbH), Preference (Candulor AG), Premium 6 (Kulzer GmbH), and Surpass (GC Corp). The 3D-printed denture tooth specimens were made of methacrylate-based photopolymerized resin by stereolithography 3D printing. Antagonistic surfaces were made from zirconia by milling and from cobalt-chromium (Co-Cr) alloy by 3D printing and casting. The specimens were loaded at 49 N for 30 000 cycles under thermocycling conditions in a mastication simulator. Wear resistance was measured by calculating the volume of substance lost. Wear surface characteristics were observed by using a scanning electron microscope (SEM). Two-way ANOVA was used to analyze the data (α=.05). RESULTS: The influence of the resin denture teeth and the type of antagonist were both statistically significant. The wear volume loss of the 3D-printed denture tooth resin was higher than that of Artic 6 and Preference when opposing the zirconia and the metal antagonists (P<.05). The 3D-printed denture tooth resin did not show a significant difference from Premium 6 with the zirconia and the metal antagonists or Surpass with the zirconia antagonist. From the SEM images, the specimens of the 3D-printed denture tooth resin showed a relatively smooth surface with the zirconia antagonist and exhibited cracks when opposed by the metal antagonist. CONCLUSIONS: The results suggest that 3D-printing by using resin materials provides adequate wear resistance for denture tooth use.

A large intrauterine vascular lesion developing after the successful treatment of a cesarean scar pregnancy with methotrexate injection.

A cesarean scar pregnancy is a rare type of ectopic pregnancy. Induced abortion by local methotrexate (MTX) injection is an effective management approach. We describe a case in which a large intrauterine vascular lesion appeared after the sonographic-guided local injection of MTX, which successfully induced the abortion of the cesarean scar pregnancy. Although a cesarean scar pregnancy may be safely treated with a local MTX injection, close follow-up, including serum ß-human chorionic gonadotropin level measurement and Doppler sonography, is needed because an intrauterine vascular lesion could develop even after a successfully induced abortion. © 2017 Wiley Periodicals, Inc. J Clin Ultrasound 46:222-226, 2018.

TSG-6 secreted by mesenchymal stem cells suppresses immune reactions influenced by BMP-2 through p38 and MEK mitogen-activated protein kinase pathway.

Bone morphogenetic protein 2 (BMP-2) has a critical function in bone and cartilage development and in repairing damaged organs and tissue. However, clinical use of BMP-2 at doses of 0.5-1 mg/ml for orthopedics has been associated with severe postoperative swelling requiring emergency surgical intervention. We determined whether a high concentration of BMP-2 induces inflammatory responses in macrophages and the suppression of osteogenesis in hMSCs. We obtained human periodontal ligament stem cells and bone marrow stem cells from the maxilla, i.e., human mesenchymal stem cells (hMSCs), from the periodontal ligament of extracted third molar teeth and from the bone marrow of the maxilla, respectively. Osteogenic differentiation was measured by alkaline phosphatase activity and alizarin red S staining. Proteins were assessed by flow cytometry, enzyme-linked immunosorbent assay, Western blot and immunocytochemistry. Changes of gene expression were measured by reverse transcription plus the polymerase chain reaction (RT-PCR) and real-time PCR. A high BMP-2 concentration inhibited the early stages of osteogenesis in hMSCs. Co-culturing THP-1 cells (human monocytic cells) with hMSCs reduced the late stages of osteogenesis compared with those seen in hMSCs alone. In addition, high-dose BMP-2 induced the expression of inflammatory cytokines in THP-1 cells and the expression of the anti-inflammatory cytokine tumor-necrosis-factor-α-inducible gene 6 protein (TSG-6) in hMSCs. Consistent with the anti-inflammatory effects of hMSCs when co-cultured with THP-1 cells, interleukin-1ß expression was downregulated by TSG-6 treatment of THP-1 cells. Our findings suggest that a high BMP-2 concentration triggers inflammation that causes inflammatory cytokine release from THP-1 cells, leading to the suppression of osteogenesis, whereas TSG-6 secreted by hMSCs suppresses inflammatory reactions through p38 and ERK in the mitogen-activated protein kinase pathway.

Early Development in the Peritoneal Cavity of CD49dhigh Th1 Memory Phenotype CD4+ T Cells with Enhanced B Cell Helper Activity.

The Th cells that regulate peritoneal B-1 cell functions have not yet been well characterized. To address this question, we investigated peritoneal CD4(+) T cells, observed a high frequency of the conjugates of B-CD4(+) T cells in the peritoneal cavity, and identified a population of CD49d(high)CD4(+) T cells that constituted about half of all CD4(+) T cells in the peritoneal cavity, but were rarely found in other compartments. Peritoneal CD49d(high)CD4(+) T cells were CD44(high)CD62L(low); expressed integrin α4ß1 and CXCR3; and rapidly secreted IFN-γ, TNF-α, and IL-2, showing features of proinflammatory Th1 cells. Peritoneal CD49d(high)CD4(+) T cells developed spontaneously, were detected at the age of 12 d, and showed stem cell-like properties. Their development was observed in mice deficient for signaling lymphocytic activation molecule-associated protein, but not in athymic nude mice and mice lacking in expression of MHC class II on thymic epithelial cells. Peritoneal CD49d(high)CD4(+) T cells were more resistant to irradiation and more sensitive to NAD-induced cell death than CD49d(low)CD4(+) T cells. Notably, peritoneal CD49d(high)CD4(+) T cells also showed some characteristics of follicular Th cells, such as the expression of programmed cell death 1, ICOS, IL-21, and CXCR5. Moreover, peritoneal CD49d(high)CD4(+) T cells enhanced the secretion of IgM Abs by B-1a cells and IgG Abs by splenic B cells. These data suggest that peritoneal CD49d(high)CD4(+) T cells may be innate-like CD4(+) T cells, which develop early and have a dual capacity to support both humoral and cellular immunity.

The efficacy of 308-nm excimer laser/light (EL) and topical agent combination therapy versus EL monotherapy for vitiligo: A systematic review and meta-analysis of randomized controlled trials (RCTs).

BACKGROUND: Combination therapies of excimer laser/light (EL) and various topical agents are widely used in the treatment of vitiligo. OBJECTIVE: We sought to compare the efficacy of EL and topical agent combination therapy versus EL monotherapy for vitiligo. METHODS: Manual searches of reference lists and computerized searches of the MEDLINE, EMBASE, and Cochrane library (from inception through December 15, 2014) were conducted to identify randomized controlled trials that assessed the efficacy of EL alone or in combination with topical agents for vitiligo. The primary outcome was treatment success (≥75% repigmentation), and the secondary outcome was treatment failure (<25% repigmentation); meta-analyses were performed when possible. RESULTS: We analyzed 8 randomized controlled trials comprising a total of 425 patches/patients. The combination of EL and topical calcineurin inhibitors (4 studies: relative risk 1.93, 95% confidence interval 1.28-2.91; number needed to treat 4.5, 95% confidence interval 2.9-10) was superior to EL monotherapy for vitiligo. There was insufficient evidence to support beneficial effects of topical vitamin-D3 analogs (3 studies) and corticosteroids (1 study). LIMITATIONS: These findings are based on small numbers of randomized controlled trials and heterogeneities among included studies are another limitation. CONCLUSION: Topical calcineurin inhibitors in conjunction with EL are more effective compared with EL monotherapy.

Metastatic melanomas of unknown primary show better prognosis than those of known primary: a systematic review and meta-analysis of observational studies.

BACKGROUND: Melanoma of unknown primary (MUP) is a condition of metastatic melanoma without a primary lesion. OBJECTIVE: We sought to identify the prognosis of MUP compared with melanoma of known primary (MKP). METHODS: We searched for observational studies containing at least 10 patients with MUP from MEDLINE and EMBASE from inception to December 22, 2012. The outcomes of interest were overall and disease-free survival; meta-analyses of hazard ratio stratified by stage using a random effects model were performed. In addition, second systematic review identified risk factors influencing the survival of patients with MUP. RESULTS: Eighteen studies including 2084 patients with MUP and 5894 with MKP were included. MUP had a better overall survival compared with MKP in stage III (15 studies; hazard ratio 0.83, 95% confidence interval 0.73-0.96, P = .010) and stage IV (6 studies; hazard ratio 0.85, 95% confidence interval 0.75-0.96, P = .008). Secondly, 22 studies including 3312 patients with MUP were reviewed, and increased stage and old age were the risk factors in patients with MUP. LIMITATIONS: Diverse observational studies were reviewed, and selection and reporting biases are possible. CONCLUSIONS: The current meta-analyses suggest better survival outcomes in patients with MUP than those in patients with MKP with the same corresponding tumor stage.

A comparative study on hulled adlay and unhulled adlay through evaluation of their LPS-induced anti-inflammatory effects, and isolation of pure compounds.

Coicis semen (=the hulled seed of Coix lacryma-jobi L. var. ma-yuen (Rom.Caill.) Stapf; Gramineae), commonly known as adlay and Job's tears, is widely used in traditional medicine and as a nutritious food. Bioassay-guided fractionation of the AcOEt fraction of unhulled adlays, using measurement of nitric oxide (NO) production on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells, led to the isolation and identification of two new stereoisomers, (+)-(7'S,8'R,7″S,8″R)-guaiacylglycerol ß-O-4'-dihydrodisinapyl ether (1) and (+)-(7'S,8'R,7″R,8″R)-guaiacylglycerol ß-O-4'-dihydrodisinapyl ether (2), together with six known compounds, 3-8. Compounds 3 and 4 exhibited inhibitory activities on LPS-induced NO production with IC50 values of 1.4 and 3.7 µM, respectively, and suppressed inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expressions in RAW 264.7 macrophage cells. Simple high-performance liquid chromatography with ultraviolet detection (HPLC/UV) was used to compare the AcOEt fraction of unhulled adlays responsible for the anti-inflammatory activity in RAW 264.7 cells and the inactive AcOEt fraction of hulled adlays.

The efficacy of intradermal hyaluronic acid filler as a skin quality booster: A prospective, single-center, single-arm pilot study.

BACKGROUND: The use of "skin boosters" comprised of hyaluronic acid (HA)-based fillers to improve skin quality has gained popularity recently, especially in individuals interested in skin rejuvenation. AIM: This study aimed to evaluate the efficacy and safety of intradermal micropuncture injections of HA-based gel filler combined with lidocaine (BYRYZN® SKINBOOSTER HA, ACROSS Co., Ltd., Gangwon-do, Korea). PATIENTS/METHODS: A prospective, single-arm, open-label pilot study was conducted with study subjects who were aged between 30 and 60 years old and exhibited evidence of skin aging, such as wrinkles and loss of elasticity. They received three injections at 2-week intervals and were followed up for a total of 12 weeks. RESULTS: Twenty subjects with a mean age of 54.1 years were included. The mean Lemperle wrinkle scale demonstrated a 40% decrease from 2.60 ± 0.60 at baseline to 1.55 ± 0.51 at week 8. The improvement rate was maintained at about 33% until week 12. The average maximum height of the wrinkle (Rz, µm), average skin roughness (Ra, µm), skin elasticity (R2, AU), facial curved length (mm), skin pore size (mm2 ), skin hydration (AU), TEWL (g/hm2 ), and skin glossiness (gloss value, AU) exhibited statistically significant improvements over time compared with the baseline measurements. No serious adverse effects or persistent adverse effects were reported, except for a transient subcutaneous nodule in one subject. CONCLUSIONS: This study demonstrates that multiple microinjections of HA-based gel filler for facial skin aging are safe and effective in improving facial skin quality.

Direct and indirect contribution of human embryonic stem cell-derived hepatocyte-like cells to liver repair in mice.

BACKGROUND & AIMS: Many studies of embryonic stem cells have investigated direct cell replacement of damaged tissues, but little is known about how donor cell-derived signals affect host tissue regeneration. We investigated the direct and indirect roles of human embryonic stem cell-derived cells in liver repair in mice. METHODS: To promote the initial differentiation of human embryonic stem cells into mesendoderm, we activated the ß-catenin signaling pathway with lithium; cells were then further differentiated into hepatocyte-like cells. The differentiated cells were purified by indocyanine green staining and laser microdissection and characterized by immunostaining, polymerase chain reaction, biochemical function, electron microscopy, and transplantation analyses. To investigate indirect effects of these cells, secreted proteins (secretomes) were analyzed by a label-free quantitative mass spectrometry. Carbon tetrachloride was used to induce acute liver injury in mice; cells or secreted proteins were administered by intrasplenic or intraperitoneal injection, respectively. RESULTS: The differentiated hepatocyte-like cells had multiple features of normal hepatocytes, engrafted efficiently into mice, and continued to have hepatic features; they promoted proliferation of host hepatocytes and revascularization of injured host liver tissues. Proteomic analysis identified proteins secreted from these cells that might promote host tissue repair. Injection of the secreted proteins into injured livers of mice promoted significant amounts of tissue regeneration without cell grafts. CONCLUSIONS: Hepatocyte-like cells derived from human embryonic stem cells contribute to recovery of injured liver tissues in mice, not only by cell replacement but also by delivering trophic factors that support endogenous liver regeneration.