Time-sequential fibroblast-to-myofibroblast transition in elastin-variable 3D hydrogel environments by collagen networks.

BACKGROUND: Fibrosis plays an important role in both normal physiological and pathological phenomena as fibroblasts differentiate to myofibroblasts. The activation of fibroblasts is determined through interactions with the surrounding extracellular matrix (ECM). However, how this fibroblast-to-myofibroblast transition (FMT) is regulated and affected by elastin concentration in a three-dimensional (3D) microenvironment has not been investigated. METHODS: We developed an insoluble elastin-gradient 3D hydrogel system for long-lasting cell culture and studied the molecular mechanisms of the FMT in embedded cells by nanoflow LC-MS/MS analysis along with validation through real-time PCR and immunofluorescence staining. RESULTS: By optimizing pH and temperature, four 3D hydrogels containing fibroblasts were successfully fabricated having elastin concentrations of 0, 20, 50, and 80% in collagen. At the low elastin level (20%), fibroblast proliferation was significantly increased compared to others, and in particular, the FMT was clearly observed in this condition. Moreover, through mass spectrometry of the hydrogel environment, it was confirmed that differentiation proceeded in two stages. In the early stage, calcium-dependent proteins including calmodulin and S100A4 were highly associated. On the other hand, in the late stage after several passages of cells, distinct markers of myofibroblasts were presented such as morphological changes, increased production of ECM, and increased α-SMA expression. We also demonstrated that the low level of elastin concentration induced some cancer-associated fibroblast (CAF) markers, including PDGFR-ß, and fibrosis-related disease markers, including THY-1. CONCLUSION: Using our developed 3D elastin-gradient hydrogel system, we evaluated the effect of different elastin concentrations on the FMT. The FMT was induced even at a low concentration of elastin with increasing CAF level via calcium signaling. With this system, we were able to analyze varying protein expressions in the overall FMT process over several cellular passages. Our results suggest that the elastin-gradient system employing nonlinear optics imaging provides a good platform to study activated fibroblasts interacting with the microenvironment, where the ECM plays a pivotal role.

The congruency sequence effect of the Simon task in a cross-modality context.

One of the prime measures of cognitive control is the congruency sequence effect (CSE), which refers to a reduced congruency effect following incongruent trials compared to congruent trials. Some researchers have argued that the conflict resolution process exerts its effect at the level of whole task-set, whereas others have argued that the control process applies to parts of a task-set. The present study examined whether the sequential modulation of the congruency effect transfers across two tasks even when they are highly distinguished by different stimulus sensory modalities. Participants performed auditory horizontal and visual vertical Simon tasks by using unimanual aimed movements. The cross-task CSE was obtained between the auditory and visual Simon tasks when the target modality was easily predicted in Experiment 1 and when the auditory and visual tasks were further distinguished by different task-relevant stimulus dimensions in Experiment 2. The results were replicated in a task-switching context in Experiment 3. These results indicate that cognitive control exerts its effect at a level of a specific component of a task-set instead of the level of a whole task-set itself. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Computational integration and meta-analysis of abandoned cardio-(vascular/renal/metabolic) therapeutics discontinued during clinical trials from 2011 to 2022.

Cardiovascular/renal/metabolic (CVRM) diseases collectively comprise the leading cause of death worldwide and disproportionally affect older demographics and historically underrepresented minority populations. Despite these critical unmet needs, pharmaceutical research and development (R&D) efforts have historically struggled with high drug failure rates, low approval rates, and other challenges. Drug repurposing is one approach to recovering R&D costs and meeting unmet demands in therapeutic markets. While there are multiple approaches to conducting drug repurposing, we recognize the importance of bringing together and consolidating discontinued drug information to help identify prospective repurposing candidates. In this study, we have harmonized and integrated information on all relevant CVRM drug assets from U.S. Securities and Exchange Commission (SEC) filings, clinical trial records, PharmGKB, Open Targets, and other platforms. A list of existing therapeutics discontinued or shelved by pharmaceutical/biotechnology companies in 2011-2022 were manually curated and interpreted for insights using information on each drug's genetic target, mechanism of action (MOA), clinical indication, and R&D information including highest phase of clinical development, year of discontinuation, previous repurposing attempts (if any), and other actionable metadata. This study also summarizes the profiles of CVRM drugs discontinued within the past decade and identifies the limitations of publicly available information on discontinued drug assets. The constructed database could serve as a tool for identifying candidates for drug repurposing and developing query methods for collecting R&D information.

Targeting the cytoskeleton and extracellular matrix in cardiovascular disease drug discovery.

INTRODUCTION: Currently, cardiovascular disease (CVD) drug discovery has focused primarily on addressing the inflammation and immunopathology aspects inherent to various CVD phenotypes such as cardiac fibrosis and coronary artery disease. However, recent findings suggest new biological pathways for cytoskeletal and extracellular matrix (ECM) regulation across diverse CVDs, such as the roles of matricellular proteins (e.g. tenascin-C) in regulating the cellular microenvironment. The success of anti-inflammatory drugs like colchicine, which targets microtubule polymerization, further suggests that the cardiac cytoskeleton and ECM provide prospective therapeutic opportunities. AREAS COVERED: Potential therapeutic targets include proteins such as gelsolin and calponin 2, which play pivotal roles in plaque development. This review focuses on the dynamic role that the cytoskeleton and ECM play in CVD pathophysiology, highlighting how novel target discovery in cytoskeletal and ECM-related genes may enable therapeutics development to alter the regulation of cellular architecture in plaque formation and rupture, cardiac contractility, and other molecular mechanisms. EXPERT OPINION: Further research into the cardiac cytoskeleton and its associated ECM proteins is an area ripe for novel target discovery. Furthermore, the structural connection between the cytoskeleton and the ECM provides an opportunity to evaluate both entities as sources of potential therapeutic targets for CVDs.

Lomens-P0 (mixed extracts of Hordeum vulgare and Chrysanthemum zawadskii) regulate the expression of factors affecting premenstrual syndrome symptoms.

BACKGROUND/OBJECTIVES: Premenstrual syndrome (PMS) is a disorder characterized by repeated emotional, behavioral, and physical symptoms before menstruation, and the exact cause and mechanism are uncertain. Hyperprolactinemia interferes with the normal production of estrogen and progesterone, leading to PMS symptoms. Thus, we judged that the inhibition of prolactin hypersecretion could mitigate PMS symptoms. MATERIALS/METHODS: Hordeum vulgare L. extract (HVE), Chrysanthemum zawadskii var. latilobum extract (CZE), and Lomens-P0 the mixture of these extracts were tested in subsequent experiments. The effect of extracts on prolactin secretion at the in vitro level was measured in GH3 cells. Nitric oxide and pro-inflammatory mediator expression were measured in RAW 264.7 cells to confirm the anti-inflammatory effect. Also, the hyperprolactinemic Institute for Cancer Research (ICR) mice model was used to measure extract effects on prolactin and hormone secretion and uterine inflammation. RESULTS: Anti-inflammatory effects of and prolactin secretion suppress by HVE and CZE were confirmed through in vitro experiments (P < 0.05). Treatment with Lomens-P0 inhibited prolactin secretion (P < 0.05) and restored normal sex hormone secretion in the hyperprolactinemia mice model. In addition, extracts significantly inhibited the expression of pro-inflammatory biomarkers, including interleukin-1ß, and -6, tumor necrosis factor-α, inducible nitric oxide synthase, and cyclooxygenase-2 (P < 0.01). We used high-performance liquid chromatography analyses to identify tricin and chlorogenic acid as the respective components of HVE and CZE that inhibit prolactin secretion. The Lomens-P0, which includes tricin and chlorogenic acid, is expected to be effective in improving PMS symptoms in the human body. CONCLUSIONS: The Lomens-P0 suppressed the prolactin secretion in hyperprolactinemia mice, normalized the sex hormone imbalance, and significantly suppressed the expression of inflammatory markers in uterine tissue. This study suggests that Lomens-P0 may have the potential to prevent or remedy materials to PMS symptoms.

Evaluation of genetic toxicity, acute and sub-chronic oral toxicity and systemic safety of Agrimonia pilosa and Rhus gall 50% ethanolic extract mixture (APRG64) in vitro and in vivo (rodent and non-rodent animal models).

Agrimonia pilosa (AP) and Rhus gall (RG) are traditional medicinal plants. The bioflavonoid composition standardized by HPLC analysis was named APRG64. Despite many studies reported to beneficial bioactivities of AP and RG, very limited range of toxicity tests have documented. So, we did experiment diversely on the toxicity tests of the substance APRG64. Genotoxicity (mammalian chromosomal aberration test, micronoucleus test) against APRG64, acute and sub-chronic toxicity test from rodent/non-rodent, and systemic safety pharmacology test were conducted. As a result of the test, genotoxicity against APRG64 was not observed. The NOAEL of rodents was confirmed as 2000 mg/kg/day and non-rodents was confirmed as 500 mg/kg/day. In addition, systemic safety pharmacological toxicity (effects on respiratory system, central nervous system, cardiovascular system) following administration of APRG64 was not observed. Finally, we accomplished ten potential toxicity tests and evaluated extensive safety of APRG64. Consequently, APRG64 may be a promising material for nutraceuticals and natural medicines.

Potential applications of graphene-based nanomaterials as adsorbent for removal of volatile organic compounds.

In recent years, graphene-based materials (GBMs) have been regarded as the core technology in diverse research fields. Consequently, the demand for large-scale synthesis of GBMs has been increasing continuously for various fields of industry. These materials have become a competitive adsorbent for the removal of environmental pollutants with improved adsorption capacity and cost effectiveness through hybridization or fabrication of various functionalities on their large surface. In particular, their applicability opens up new avenues for the adsorptive removal of volatile organic compounds (VOCs) (e.g., through the build-up of efficient air purification systems). This review explored the basic knowledge and synthesis approaches for GBMs and their performances as adsorbent for VOC removal. Moreover, the mechanisms associated with the VOC removal were explained in detail. The performance of GBMs has also been evaluated along with their present limitations and future perspectives.

Utilization of activated carbon as an effective replacement for a commercialized three-bed sorbent (Carbopack) to quantitate aromatic hydrocarbons in ambient air.

The potential use of activated carbon (AC) as an inexpensive and effective alternative sorbent material in thermal desorption is presented and validated for the analysis of aromatic volatile organic compounds (VOCs) such as benzene, toluene, m-xylene, and styrene (BTXS) in air. The optimum desorption conditions of an AC sampling tube (2 mg AC bed) were determined and compared with a commercial three-bed (Carbopack; C + B + X) tube sampler as a reference. The AC sampler exhibited good linearity (R2 > 0.99) and reproducibility (RSE of 2.38 ±â€¯0.21%) for BTXS analysis. The AC tube sampler showed good storability (up to 3 d) and excellent recyclability (up to 50 cycles). An analysis of BTXS in ambient air showed excellent agreement between AC and CBX (bias < 5%). The 1% breakthrough volume values for 2 mg AC, when tested at 100 ppb of benzene as a sole component or in a BTXS mixture, were 10,000 or 5000 L g-1, respectively. The results of this study support the performance of AC as a suitable medium for sampling VOCs as reliable as high-cost commercial sorbent products.

Organometallic Iridium(III) Complex Sensitized Ternary Hybrid Photocatalyst for CO2 to CO Conversion.

A series of heteroleptic iridium(III) complexes functionalized with two phosphonic acid (-PO3 H2 ) groups (dfppy IrP, ppy IrP, btp IrP, and piq IrP) were prepared and anchored onto rhenium(I) catalyst (ReP)-loaded TiO2 particles (TiO2 /ReP) to build up a new IrP-sensitized TiO2 photocatalyst system (IrP/TiO2 /ReP). The photosensitizing behavior of the IrP series was examined within the IrP/TiO2 /ReP platform for the photocatalytic conversion of CO2 into CO. The four IrP-based ternary hybrids showed increased conversion activity and durability than that of the corresponding homo- (IrP+ReP) and heterogeneous (IrP+TiO2 /ReP) mixed systems. Among the four IrP/TiO2 /ReP photocatalysts, the low-energy-light (>500 nm) activated piq IrP immobilized ternary system (piq IrP/TiO2 /ReP) exhibited the most durable conversion activity, giving a turnover number of ≥730 for 170 h. A similar kinetic feature observed through time-resolved photoluminescence measurements of both btp IrP/TiO2 and TiO2 -free btp IrP films suggests that the net electron flow in the ternary hybrid proceeds dominantly through a reductive quenching mechanism, unlike the oxidative quenching route of typical dye/TiO2 -based photolysis.

Roseomonas radiodurans sp. nov., a gamma-radiation-resistant bacterium isolated from gamma ray-irradiated soil.

A bacterial strain, designated 17Sr1-1T, was isolated from gamma ray-irradiated soil. Cells of this strain were Gram-stain-negative, strictly aerobic, motile and non-spore-forming rods. Growth occurred at 18-42 ˚C and pH 6.0-8.0, but no growth occurred at 2 % NaCl concentration. The major fatty acids of strain 17Sr1-1T were summed feature 8 (C18 : 1ω7c and/or C18 : 1ω6c), iso-C17 : 1ω5c and C16 : 0. The polar lipid profile contained diphosphatidylglycerol, glycolipid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol and four unidentified lipids. The G+C content of the genomic DNA of 17Sr1-1T was 71.9 mol%. The 16S rRNA gene sequence analysis showed that strain 17Sr1-1T was phylogenetically related to Roseomonas pecuniae N75T and Roseomonas rosea 173-96T (96.6 and 96.3 % sequence similarity, respectively). The genotypic and phenotypic data showed that strain 17Sr1-1T could be distinguished from its phylogenetically related species, and that this strain represented a novel species within the genus Roseomonas, for which the name Roseomonas radiodurans sp. nov. (type strain 17Sr1-1T=KCTC 52899T=NBRC 112872T) is proposed as the first reported gamma ray-resistant Roseomonas species.

Erdheim-Chester Disease Involving Lymph Nodes and Liver Clinically Mimicking Lymphoma: A Case Report.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis and multisystem disease. First described in 1930, there are no more than 750 cases reported. The etiology remains unknown, but a majority of cases of ECD and Langerhans cell histiocytosis were found to have clonal mutations involving genes of the mitogen-activated protein kinase pathway. We recently encountered a 53-year-old male patient with extensive ECD involving the systemic lymph nodes, pleura, liver, and long bones clinically mimicking malignant lymphoma. Biopsies were performed at multiple sites, including a pleural mass, an external iliac lymph node, bone marrow, and the liver. Based on histopathological and immunohistochemical findings of positivity for CD68 and negativity for CD1a and S-100, the patient was diagnosed with ECD. Interferon-α was administered as the first-line treatment, but the patient rapidly progressed to hepatic failure after 2 months of treatment. We report this rare case of ECD clinically mimicking malignant lymphoma and diagnosed by careful pathological review.

Clinical effects of pre-transplant serum 25-hydroxyvitamin D level on post-transplant immunologic and non-immunologic outcomes in kidney transplant recipients.

BACKGROUND: The aim of this study was to investigate the effects of pre-transplant serum 25-hydroxyvitamin D (25(OH)D) level on non-immunologic and immunologic aspects of post-transplant clinical outcomes in kidney transplant recipients (KTRs). METHODS: We investigated 174 KTRs with low immunologic risk at baseline. We divided the patients into three groups according to baseline serum 25(OH)D level and compared the post-transplant clinical outcomes of acute rejection, infectious complications, and osteoporosis among the groups. RESULT: Thirty cases of biopsy-proven acute rejection (BPAR) were detected during the first year after KT. In the highest tertile, the rate of acute rejection (8.6%) was significantly lower than that in the lowest tertile (25.4%) (p=0.016), and a high 25(OH)D level was independently associated with a low incidence of BPAR in multivariate analysis. In contrast, serum 25(OH)D level did not show a significant association with overall or any specific type of infectious complication. Lipid profile, intact parathyroid hormone (PTH) level, and hemoglobin level were similar among the three tertile groups. The incidence of osteoporosis and bone mineral density (BMD) score were also similar across all three groups. CONCLUSIONS: Pre-transplant serum 25(OH)D level is a significant predictor of acute rejection, but it does not predict infection or metabolic complications.

A bi-ligand co-functionalized gold nanoparticles-based calcium ion probe and its application to the detection of calcium ions in serum.

In this study, the use of bi-ligand co-functionalized gold nanoparticles in a highly selective and sensitive colorimetric probe for Ca(2+) ions is demonstrated and this probe also determined the concentrations of Ca(2+) ions in serum samples.

XPD Polymorphisms and Risk of Squamous Cell Carcinoma of the Head and Neck in a Korean Sample.

OBJECTIVES: XPD is a major player in nucleotide excision repair, which is one of the basic pathways of DNA repair. The objective of this study was to investigate the association of XPD single nucleotide polymorphisms (SNPs) and the risk of squamous cell carcinoma of the head and neck (SCCHN) in Koreans. METHODS: We performed XPD +23591G>A and +35931A>C genotyping in 290 SCCHN patients and 358 controls. RESULTS: The frequencies of the XPD +23591G>A (GG/GA/AA) genotypes were 89.0%/11.0%/0% in the patients and 90.3%/8.8%/0.9% in the controls, respectively. The odds ratio (OR) of the XPD +23591 GA genotype was 1.94 (0.92 to 4.08) in reference to the GG genotype. The frequencies of the XPD +35931A>C (AA/AC/CC) genotypes were 86.9%/12.0%/1.1% in the patients and 85.6%/13.8%/0.6% in the controls, respectively. The OR of the XPD +35931 AC and CC genotypes were 0.98 (0.51 to 1.88) and 2.68 (0.71 to 10.1), respectively, in reference to the AA genotype. On the subgroup analyses according to the smoking and drinking statuses, the SNPs and haplotypes of XPD showed no statistically significant association with the risk of SCCHN. CONCLUSION: The results of this study suggest that the XPD +23591G>A and +35931A>C SNPs are not associated with the risk of SCCHN in Koreans; however, a further study with a larger number of subjects is necessary to verify this conclusion.