Effects of Aloe vera Flower Extract and Its Active Constituent Isoorientin on Skin Moisturization via Regulating Involucrin Expression: In Vitro and Molecular Docking Studies.

Skin moisturization is very crucial for maintaining the flexibility, viscoelasticity, and differentiation of the epidermis and its deprivation causes several diseases from dry skin to dermatitis. Aloe vera, a miracle plant having diverse medicinal properties including skin moisturization effects. This study investigated for the first time the molecular mechanism targeting skin moisturization effects of the Aloe vera flower and its major active constituent. By treating human epidermal keratinocytes (HaCaT cells) with Aloe vera flower water extract (AFWE), we found that AFWE upregulated epidermal involucrin by activating the expression of protein kinase C, p38, and ERK 1/2. Additionally, it modulated filaggrin, increased aquaporin expression, and hyaluronan synthesis via a balanced regulation of HAS1 and HYAL1 protein. Similarly, it was able to protect UVB-induced photodamage. Western blot analysis, ELISA, and qRT- PCR were performed to evaluate various epidermal differentiation markers and moisturization-related factors on human epidermal keratinocytes (HaCaT cells). TLC and HPLC were used to detect and analyze the chemical constituents. Among them, we found that an active component of Aloe vera flower, isoorientin (IO) has a high binding affinity to all of its targeted proteins such as involucrin, PKC, P38, etc. through molecular docking assay. This study indicated that the Aloe vera flower and its active constituent, IO can be used as a prominent ingredient to enhance skin barrier function and improve its related pathologies.

Distinct hypoxic regulation of preadipocyte factor-1 (Pref-1) in preadipocytes and mature adipocytes.

Preadipocyte factor-1 (Pref-1) is a secretory soluble protein, which exerts pleiotropic effects on maintenance of cancer stem cell characteristics and commitment of mesenchymal stem cell lineages by inhibiting adipogenesis. Observations that obesity renders the microenvironment of adipose tissues hypoxic and that hypoxia inhibits adipogenesis lead us to investigate whether hypoxia increases the expression of anti-adipogenic Pref-1 in preadipocytes, mature adipocytes, and adipose tissues from obese mouse. In 3T3-L1 preadipocytes, hypoxia induces Pref-1 by a hypoxia-inducible factor 1 (HIF-1)-dependent mechanism accompanied by increase in the levels of the active histone mark, acetylated H3K9/14 (H3K9/14Ac). Adipogenesis increased the levels of the heterochromatin histone mark, trimethylated H3K27 (H3K27me3), whereas it decreased the levels of H3K4me3 and H3K9/14Ac euchromatin marks of the mouse Pref-1 promoter. However, differently from preadipocytes, in mature adipocytes hypoxia failed to reverse the repressive epigenetic changes of Pref-1 promoter and to increase its expression. Short term (8weeks) high fat diet (HFD) increased HIF-1α protein in subcutaneous and epididymal adipose tissues, but did not increase Pref-1 expression. Unlike in 3T3-L1 preadipocytes, HIF-1α did not increase Pref-1 expression in adipose tissues in which mature adipocytes constitute the main population. Interestingly, long term (35weeks) HFD increased Pref-1 in serum but not in obese adipose tissues. This study suggests that Pref-1 is an endocrine factor which is synergistically increased by obesity and age.

Digital cameras with designs inspired by the arthropod eye.

In arthropods, evolution has created a remarkably sophisticated class of imaging systems, with a wide-angle field of view, low aberrations, high acuity to motion and an infinite depth of field. A challenge in building digital cameras with the hemispherical, compound apposition layouts of arthropod eyes is that essential design requirements cannot be met with existing planar sensor technologies or conventional optics. Here we present materials, mechanics and integration schemes that afford scalable pathways to working, arthropod-inspired cameras with nearly full hemispherical shapes (about 160 degrees). Their surfaces are densely populated by imaging elements (artificial ommatidia), which are comparable in number (180) to those of the eyes of fire ants (Solenopsis fugax) and bark beetles (Hylastes nigrinus). The devices combine elastomeric compound optical elements with deformable arrays of thin silicon photodetectors into integrated sheets that can be elastically transformed from the planar geometries in which they are fabricated to hemispherical shapes for integration into apposition cameras. Our imaging results and quantitative ray-tracing-based simulations illustrate key features of operation. These general strategies seem to be applicable to other compound eye devices, such as those inspired by moths and lacewings (refracting superposition eyes), lobster and shrimp (reflecting superposition eyes), and houseflies (neural superposition eyes).

Multi-dimensional histone methylations for coordinated regulation of gene expression under hypoxia.

Hypoxia increases both active and repressive histone methylation levels via decreased activity of histone demethylases. However, how such increases coordinately regulate induction or repression of hypoxia-responsive genes is largely unknown. Here, we profiled active and repressive histone tri-methylations (H3K4me3, H3K9me3, and H3K27me3) and analyzed gene expression profiles in human adipocyte-derived stem cells under hypoxia. We identified differentially expressed genes (DEGs) and differentially methylated genes (DMGs) by hypoxia and clustered the DEGs and DMGs into four major groups. We found that each group of DEGs was predominantly associated with alterations in only one type among the three histone tri-methylations. Moreover, the four groups of DEGs were associated with different TFs and localization patterns of their predominant types of H3K4me3, H3K9me3 and H3K27me3. Our results suggest that the association of altered gene expression with prominent single-type histone tri-methylations characterized by different localization patterns and with different sets of TFs contributes to regulation of particular sets of genes, which can serve as a model for coordinated epigenetic regulation of gene expression under hypoxia.

The association between Helicobacter pylori infection and the risk of advanced colorectal neoplasia may differ according to age and cigarette smoking.

BACKGROUND: The association between Helicobacter pylori infection and advanced colorectal neoplasia (ACN) remains controversial. This study aimed to clarify the association between H. pylori infection and ACN according to age groups. METHODS: We retrospectively analyzed the association between H. pylori infection and ACN in patients aged <50 and ≥50 years receiving a health checkup that included colonoscopy. Helicobacter pylori positivity was determined by the results of serum anti-H. pylori immunoglobulin G or rapid urease test, if the anti-H. pylori immunoglobulin G was in the borderline range. RESULTS: Among the 19 337 patients who were included, 56.2% and 3.4% were positive for H. pylori and ACN, respectively. Helicobacter pylori infection independently increased the risk of ACN in patients aged <50 years (odds ratio [OR], 1.602; 95% confidence intervals [CI], 1.194-2.150) but not in patients aged ≥50 years (OR, 1.046; 95% CI, 0.863-1.268). The positive association between H. pylori infection and ACN was affected by smoking history. When stratified by age and smoking history, H. pylori infection conferred an increased risk of ACN in patients aged <50 years with a history of smoking (OR, 1.926; 95% CI, 1.336-2.775) but not in the other 3 groups (3-way interaction test P = .023). Among patients aged <50 years with ACN, ACN in the left colon was found more frequently in patients with H. pylori infection and a history of smoking than in those without (69.3% vs 54.4%, respectively; P = .031). CONCLUSIONS: Helicobacter pylori infection confers an increased risk of ACN, but the association may differ according to age and smoking history.

Maintenance of the fistulous tract after recanalization via magnetic compression anastomosis in completely obstructed benign biliary stricture.

OBJECTIVE: This study compared the efficacy of a percutaneous transhepatic cholangioscopy (PTCS) catheter and a fully covered self-expandable metal stent (FCSEMS) for maintaining biliary tract patency after magnetic compression anastomosis (MCA). METHODS: This study included patients with completely obstructed benign biliary stricture (BBS), which was resolved by MCA and subsequent insertion of a PTCS catheter or FCSEMS. We compared the restenosis-free time after removal of the PTCS catheter or FCSEMS, and the rate of complications. RESULTS: A total of 49 patients were analyzed. The mean ages of the patients in these groups were 50.1 and 49.6 years, respectively. The predisposing conditions causing complete BBS were liver transplantation (n = 38), abdominal surgery (n = 10) and trauma (n = 1). The mean indwelling durations were 176 and 128 days in the PTCS catheter and FCSEMS groups, respectively. The mean follow-up duration after removal of the PTCS catheter and FCSEMS were 2259 and 680.5 days, respectively. Three patients in the PTCS group and three patients in the FCSEMS group experienced stricture relapse. The mean duration between recurrence and stent removal were 924 and 265 days, respectively, and the numbers of stricture-free days did not differ significantly between the two groups. The adverse event rate did not differ significantly between the PTCS and FCSEMS groups (50% vs. 24.2%, respectively). CONCLUSIONS: FCSEMSs have an efficacy and safety similar to those of PTCS catheters for maintaining biliary tract patency after MCA, but are more convenient for patients.

The role of upfront autologous stem cell transplantation in high-risk younger patients with primary central nervous system lymphoma.

Upfront autologous stem cell transplantation (ASCT) has shown favourable outcome in patients with primary central nervous system lymphoma (PCNSL), but the role of risk-adapted upfront ASCT consolidation has not been evaluated in PCNSL. As PCNSL patients with the International Extranodal Lymphoma Study Group (IELSG) prognostic score ≥2 or those who did not achieve complete response after two courses of induction chemotherapy (non-CR1) have shown inferior outcomes, we retrospectively analysed the role of upfront ASCT in 66 high-risk (IELSG ≥2 and/or non-CR1) younger (age <65 years) immunocompetent PCNSL patients who achieved at least partial response after initial high-dose methotrexate-based chemotherapy. Nineteen patients who received upfront ASCT exhibited significantly better overall survival (OS, P = 0·021) and progression-free survival (PFS, P = 0·005) compared to 47 patients who did not. In univariate and multivariate analyses, upfront ASCT was associated with better OS (P = 0·037 and P = 0·025, respectively) and PFS (P = 0·009 and P = 0·007, respectively). In a propensity score-matched cohort (n = 36), patients who received upfront ASCT also showed better outcome (P = 0·037 for OS, P = 0·001 for PFS). Our results suggest that upfront ASCT consolidation might be especially beneficial for high-risk PCNSL patients.

The action of HIF-3α variants on HIF-2α-HIF-1ß heterodimer formation is directly probed in live cells.

Hypoxia-inducible factors (HIFs), consisting of α and ß subunits, activate various genes to adapt to low oxygen environments through their heterodimeric complex formation in the nucleus. While most of the studies have been extensively focused on the HIF-1α isoform, the effect of HIF-α isoforms on the complex formation between HIF-2α and HIF-1ß in live cells has not been reported in detail. To probe these interactions in a physiological condition, we established a fluorescence resonance energy transfer (FRET) assay by introducing fluorescent reporter proteins onto the N-termini of HIF-2α and HIF-1ß in live PC3 cells. After thorough validations of our FRET assay system, we showed that both HIF-1α and HIF-3α variants likely function as negative regulators on the heterodimer formation of HIF-2α with HIF-1ß in cells. We also characterized the localization and stabilization of HIF-3α variants and measured the interaction between HIF-3α variants and other HIF isoforms in live cells. In contrast to the previous results showing HIF-3α-mediated blockage of HIF-1α translocation, the presence of HIF-3α did not affect the localization of HIF-2α, suggesting distinct roles of HIF-3α in regulation of two HIF-α isoforms.

Elliptical silicon nanowire photodetectors for polarization-resolved imaging.

Polarization-resolved imaging offers many advantages over conventional imaging because it provides additional information on materials and scenes. In this study, we present an image sensor pixel for polarization-resolved imaging based on an all-silicon nanowire device. As the structure has an intrinsically polarization-dependent response, it is not necessary to employ a polarizer. We fabricate pixels consisting of etched vertical silicon nanowires with elliptical cross-sections that incorporate vertical p-i-n junctions. Our photocurrent measurement reveals that the spectral responsivities are dependent on the polarization state of incident light. Polarization-resolved imaging is performed with fabricated devices. This approach is different from conventional approaches using polarization filters because absorbed light in the elliptical nanowire is converted to photocurrent while light absorbed by a polarization filter is discarded.

Rotationally reconfigurable metamaterials based on moiré phenomenon.

Exploiting moiré interference, we make a new type of reconfigurable metamaterials and study their transmission tunability for incident electromagnetic waves. The moiré pattern is formed by overlapping two transparent layers, each of which has a periodic metallic pattern, and the cluster size of the resulting moiré pattern can be varied by changing the relative superposition angle of the two layers. In our reconfigurable metamaterials, both the size and structural shape of the unit cell can be varied simultaneously through moiré interference. We show that the transmission of electromagnetic waves can be controlled from 90% to 10% at 11 GHz by experiments and numerical simulation. The reconfigurable metamaterial proposed here can be applied in bandpass filters and tunable modulation devices.

Filter-free image sensor pixels comprising silicon nanowires with selective color absorption.

The organic dye filters of conventional color image sensors achieve the red/green/blue response needed for color imaging, but have disadvantages related to durability, low absorption coefficient, and fabrication complexity. Here, we report a new paradigm for color imaging based on all-silicon nanowire devices and no filters. We fabricate pixels consisting of vertical silicon nanowires with integrated photodetectors, demonstrate that their spectral sensitivities are governed by nanowire radius, and perform color imaging. Our approach is conceptually different from filter-based methods, as absorbed light is converted to photocurrent, ultimately presenting the opportunity for very high photon efficiency.

Beta-lapachone inhibits pathological retinal neovascularization in oxygen-induced retinopathy via regulation of HIF-1α.

Retinal neovascularization in retinopathy of prematurity (ROP) is the most common cause of blindness for children. Despite evidence that hypoxia inducible factor (HIF)-1α -VEGF axis is associated with the pathogenesis of ROP, the inhibitors of HIF-1α have not been established as a therapeutic target in the control of ROP pathophysiology. We investigated the hypothesis that degradation of HIF-1α as a master regulator of angiogenesis in hypoxic condition, using ß-lapachone, would confer protection against hypoxia-induced retinopathy without affecting physiological vascular development in mice with oxygen-induced retinopathy (OIR), an animal model of ROP. The effects of ß-lapachone were examined after intraocular injection in mice with OIR. Intraocular administration of ß-lapachone resulted in significant reduction in hypoxia-induced retinal neovascularization without retinal toxicity or perturbation of developmental retinal angiogenesis. Our results demonstrate that HIF-1α-mediated VEGF expression in OIR is associated with pathological neovascularization, not physiological angiogenesis. Thus, strategies blocking HIF-1α in the developing eye in the pathological hypoxia could serve as a novel therapeutic target for ROP.

Hypoxia-inducible factor-2α-dependent hypoxic induction of Wnt10b expression in adipogenic cells.

Adipocyte hyperplasia and hypertrophy in obesity can lead to many changes in adipose tissue, such as hypoxia, metabolic dysregulation, and enhanced secretion of cytokines. In this study, hypoxia increased the expression of Wnt10b in both human and mouse adipogenic cells, but not in hypoxia-inducible factor (HIF)-2α-deficient adipogenic cells. Chromatin immunoprecipitation analysis revealed that HIF-2α, but not HIF-1α, bound to the Wnt10b enhancer region as well as upstream of the Wnt1 gene, which is encoded by an antisense strand of the Wnt10b gene. Hypoxia-conditioned medium (H-CM) induced phosphorylation of lipoprotein-receptor-related protein 6 as well as ß-catenin-dependent gene expression in normoxic cells, which suggests that H-CM contains canonical Wnt signals. Furthermore, adipogenesis of both human mesenchymal stem cells and mouse preadipocytes was inhibited by H-CM even under normoxic conditions. These results suggest that O2 concentration gradients influence the formation of Wnt ligand gradients, which are involved in the regulation of pluripotency, cell proliferation, and cell differentiation.

Hypoxia enhances the expression of prostate-specific antigen by modifying the quantity and catalytic activity of Jumonji C domain-containing histone demethylases.

Oxygen concentration in prostate cancer tissue is significantly low, i.e. ~0.3% O2. This study showed that pathological hypoxia (<0.5% O2) increased the expression of androgen receptor (AR) target genes such as prostate-specific antigen (PSA) and kallikrein-related peptidase 2 in LNCaP human prostate cancer cells by modifying the quantity and activity of related Jumonji C domain-containing histone demethylases (JMJDs). Under pathological hypoxia, the catalytic activities of JMJD2A, JMJD2C and Jumonji/ARID domain-containing protein 1B (JARID1B) were blocked due to the lack of their substrate, i.e. oxygen. Chromatin immunoprecipitation analyses showed that hypoxia increased the appearance of H3K9me3 and H3K4me3, substrates of JMJD2s and JARID1B, respectively, in the PSA enhancer. In contrast, JMJD1A, which demethylates both H3K9me2 and H3K9me1, maintained its catalytic activity even under severe hypoxia. Furthermore, hypoxia increased the expression of JMJD1A. Hypoxia and androgen additively increased the recruitment of JMJD1A and p300 on the enhancer region of PSA through interaction with the hypoxia-inducible factor-1α and AR, both of which bind the PSA enhancer. Thus, hypoxia enhanced the demethylation of H3K9me2 and H3K9me1, leading to provide unmethylated H3K9 residues that are substrates for histone acetyltransferase, p300. Consequently, hypoxia increased the acetylation of histones of the PSA enhancer, which facilitates its transcription.

Menadione and ethacrynic acid inhibit the hypoxia-inducible factor (HIF) pathway by disrupting HIF-1α interaction with p300.

Hypoxia is a general characteristic of most solid malignancies and intimately related to neoplastic diseases and cancer progression. Homeostatic response to hypoxia is primarily mediated by hypoxia inducible factor (HIF)-1α that elicits transcriptional activity through recruitment of the CREB binding protein (CBP)/p300 coactivator. Targeted blockade of HIF-1α binding to CBP/p300 would thus constitute a novel approach for cancer treatment by suppressing tumor angiogenesis and metastasis. Here, we identified inhibitors against the interaction between HIF-1α and p300 by a fluorescence polarization-based assay employing a fluorescently-labeled peptide containing the C-terminal activation domain of HIF-1α. Two small molecule inhibitors, menadione (MD) and ethacrynic acid (EA), were found to decrease expression of luciferase under the control of hypoxia-responsive elements in hypoxic cells as well as to efficiently block the interaction between the full-length HIF-1α and p300. While these compounds did not alter the expression level of HIF-1α, they down-regulated expression of a HIF-1α target vascular endothelial growth factor (VEGF) gene. Considering hypoxia-induced VEGF expression leading to highly aggressive tumor growth, MD and EA may provide new scaffolds for development of tumor therapeutic reagents as well as tools for a better understanding of HIF-1α-mediated hypoxic regulation.

The role of Acidithiobacillus ferrooxidans and Acidithiobacillus thiooxidans in arsenic bioleaching from soil.

Bioleaching of As from the soil in an abandoned Ag-Au mine was carried out using Acidithiobacillus ferrooxidans and Acidithiobacillus thiooxidans. A. ferrooxidans is an iron oxidizer and A. thiooxidans is a sulfur oxidizer. These two microbes are acidophilic and chemoautotrophic microbes. Soil samples were collected from the Myoungbong and Songcheon mines. The main contaminant of the soil was As, with an average concentration of 4,624 mg/kg at Myoungbong and 5,590 mg/kg at Songcheon. A. ferrooxidans and A. thiooxidans generated lower pH conditions during their metabolism process. The bioleaching of As from soil has a higher removal efficiency than chemical leaching. A. ferrooxidans could remove 70 % of the As from the Myoungbong and Songcheon soils; however, A. thiooxidans extracted only 40 % of the As from the Myoungbong soil. This study shows that bioleaching is an effective process for As removal from soil.

Effects of clioquinol analogues on the hypoxia-inducible factor pathway and intracelullar mobilization of metal ions.

We previously found that clioquinol (CQ) increases functional hypoxia-inducible factor-1α (HIF-1α) with enhanced transcription of its target genes. Here we report that compounds derived from 8-hydroxyquinoline including CQ, broxyquinoline (BQ), iodoquinol (IQ) and chloroacetoxyquinoline (CAQ) promote neovascularization effectively based on chick chorioallantoic membrane assays. The CQ analogues induce stabilization of HIF-1α as well as enhance HIF-1-mediated vascular endothelial growth factor transcription. These analogues also exert inhibitory effects on the activity of prolyl and asparaginyl hydroxylations of HIF-1α in vitro. Despite metal ion-dependent restoration of the inhibited HIF-1α hydroxylase activity, the cellular HIF-1α-inducing effects of the CQ analogues are reversed to varying degrees by Zn(2+) and Fe(2+). While CQ and BQ are completely reversed by Zn(2+), co-administration of Zn(2+) and IQ has only a partial reversing effect. On the other hand, CAQ-mediated stabilization of HIF-1α is reversed by Fe(2+) but not by Zn(2+). These phenomena are found to coincide with elevation of the intracellular Zn(2+) and Fe(2+) levels by the CQ analogues, suggesting that metal ion effects on HIF-1α in cells likely reflect the differential transporting capability of the analogues.

Gold and silver plasmonic nanoprobes trace the positions of histone codes.

We visualized the distribution of heterochromatin in a single nucleus using plasmonic nanoparticle-conjugated H3K9me3 and H3K27me3 antibodies. Due to distance-dependent plasmonic coupling effects between nanoprobes, their scattering spectra shift to longer wavelengths as the distance between heterochromatin histone markers reduced during oncogene-induced senescence (OIS). These observations were supported by simulating scattering profiles based on considerations of particle numbers, interparticle distances, and the spatial arrangements of plasmonic nanoprobes. Using this plasmon-based colourimetric imaging, we estimated changes in distances between H3K9me3 and H3K27me3 during the formation of senescence-associated heterochromatin foci in OIS cells. We anticipate that the devised analytical technique combined with high-spatial imaging and spectral simulation will eventually lead to a new means of diagnosing and monitoring disease progression and cellular senescence. [BMB Reports 2022; 55(3): 111-112].

YAP-dependent Wnt5a induction in hypertrophic adipocytes restrains adiposity.

Wnt5a, a prototypic non-canonical Wnt, is an inflammatory factor elevated in the sera of obese humans and mice. In the present study, fat-specific knockout of Wnt5a (Wnt5a-FKO) prevented HFD-induced increases in serum Wnt5a levels in male C57BL/6 J mice, which suggested adipocytes are primarily responsible for obesity-induced increases in Wnt5a levels. Mouse subcutaneous white adipose tissues (WATs) more sensitively responded to HFD, in terms of cell size increases and Wnt5a levels than epididymal WATs. Furthermore, adipocyte sizes were positively correlated with Wnt5a levels in vitro and in vivo. In hypertrophic adipocytes, enlarged lipid droplets increased cell stiffness and rearranged the f-actin stress fibers from the cytoplasm to the cortical region. The activities of YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) increased in response to these mechanical changes in hypertrophic adipocytes, and inhibition or knock-down of YAP and TAZ reduced Wnt5a expression. ChIP (chromatin immunoprecipitation) analyses revealed that YAP was recruited by Wnt5a-1 gene promoter and increased Wnt5a expression. These results suggested that YAP responds to mechanical stress in hypertrophic adipocytes to induce the expression Wnt5a. When 8-week-old Wnt5a-FKO mice were fed an HFD for 20 weeks, the fat mass increased, especially in subcutaneous WATs, as compared with that observed in floxed mice, without significant changes in food intake or activity. Furthermore, Wnt5a-FKO mice showed impaired glucose tolerance regardless of diet type. Our findings show that hypertrophy/YAP/Wnt5a signaling constitutes a negative-feedback loop that retrains adipose tissue hypertrophy.

Clioquinol as an inhibitor of JmjC-histone demethylase exhibits common and unique histone methylome and transcriptome between clioquinol and hypoxia.

Clioquinol (CQ) is a hypoxic mimicker to activate hypoxia-inducible factor-1α (HIF-1α) by inhibiting HIF-1α specific asparaginyl hypoxylase (FIH-1). The structural similarity of the Jumonji C (JmjC) domain between FIH-1 and JmjC domain-containing histone lysine demethylases (JmjC-KDMs) led us to investigate whether CQ could inhibit the catalytic activities of JmjC-KDMs. Herein, we showed that CQ inhibits KDM4A/C, KDM5A/B, and KDM6B and affects H3K4me3, H3K9me3, and H3K27me3 marks, respectively. An integrative analysis of the histone methylome and transcriptome data revealed that CQ-mediated JmjC-KDM inhibition altered the transcription of target genes through differential combinations of KDMs and transcription factors. Notably, functional enrichment of target genes showed that CQ and hypoxia commonly affected the response to hypoxia, VEGF signaling, and glycolysis, whereas CQ uniquely altered apoptosis/autophagy and cytoskeleton/extracellular matrix organization. Our results suggest that CQ can be used as a JmjC-KDM inhibitor, HIF-α activator, and an alternative therapeutic agent in hypoxia-based diseases.