Single-Cell Oral Delivery Platform for Enhanced Acid Resistance and Intestinal Adhesion.

Oral delivery of cells, such as probiotics and vaccines, has proved to be inefficient since cells are generally damaged in an acidic stomach prior to arrival at the intestine to exert their health benefits. In addition, short retention in the intestine is another obstacle which affects inefficiency. To overcome these obstacles, a cell-in-shell structure was designed with pH-responsive and mucoadhesive properties. The pH-responsive shell consisting of three cationic layers of chitosan and three anionic layers of trans-cinnamic acid (t-CA) was made via layer-by-layer (LbL) assembly. t-CA layers are hydrophobic and impermeable to protons in acid, thus enhancing cell gastric resistance in the stomach, while chitosan layers endow strong interaction between the cell surface and the mucosal wall which facilitates cell mucoadhesion in the intestine. Two model cells, probiotic L. rhamnosus GG and dead Streptococcus iniae, which serve as inactivated whole-cell vaccine were chosen to test the design. Increased survival and retention during oral administration were observed for coated cells as compared with naked cells. Partial removal of the coating (20-60% removal) after acid treatment indicates that the coated vaccine can expose its surface immunogenic protein after passage through the stomach, thus facilitating vaccine immune stimulation in the intestine. As a smart oral delivery platform, this design can be extended to various macromolecules, thus providing a promising strategy to formulate oral macromolecules in the prevention and treatment of diseases at a cellular level.

Role of HMGB1 in Vitiligo: Current Perceptions and Future Perspectives.

Vitiligo is a chronic depigmenting disorder of the skin and mucosa caused by the destruction of epidermal melanocytes. Although the exact mechanism has not been elucidated, studies have shown that oxidative stress plays an important role in the pathogenesis of vitiligo. High mobility group box protein B1 (HMGB1) is a major nonhistone protein and an extracellular proinflammatory or chemotactic molecule that is actively secreted or passively released by necrotic cells. Recent data showed that HMGB1 is overexpressed in both blood and lesional specimens from vitiligo patients. Moreover, oxidative stress triggers the release of HMGB1 from keratinocytes and melanocytes, indicating that HMGB1 may participate in the pathological process of vitiligo. Overall, this review mainly focuses on the role of HMGB1 in the potential mechanisms underlying vitiligo depigmentation under oxidative stress. In this review, we hope to provide new insights into vitiligo pathogenesis and treatment strategies.

Damage-associated molecular patterns in vitiligo: igniter fuse from oxidative stress to melanocyte loss.

OBJECTIVES: The pathogenesis of vitiligo remains unclear. In this review, we comprehensively describe the role of damage associated molecular patterns (DAMPs) during vitiligo pathogenesis. METHODS: Published papers on vitiligo, oxidative stress and DAMPs were collected and reviewed via database searching on PubMed, MEDLINE and Embase, etc. RESULTS: Oxidative stress may be an important inducer of vitiligo. At high oxidative stress levels, damage-associated molecular patterns (DAMPs) are released from keratinocytes or melanocytes in the skin and induce downstream immune responses during vitiligo. Treatment regimens targeting DAMPs can effectively improve disease severity. DISCUSSION: DAMPs play key roles in initiating host defenses against danger signals, deteriorating the condition of vitiligo. DAMP levels in serum and skin may be used as biomarkers to indicate vitiligo activity and prognosis. Targeted therapies, incorporating HMGB1, Hsp70, and IL-15 could significantly improve disease etiology. Thus, novel strategies could be identified for vitiligo treatment by targeting DAMPs.

CircMMP9 accelerates the progression of hepatocellular carcinoma through the miR-149/CCND2 axis.

Background: This study aimed to verify the hypothesis that circular RNA MMP9 (circMMP9) promotes hepatocellular carcinoma (HCC) progression through targeting miR-149 and regulating cyclin D2 (CCND2) expression. Methods: Expression of circMMP9, miR-149 and CCND2 was detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR) or protein blotting. Cell Counting Kit-8 (CCK-8) was used to evaluate cell proliferation. The HCC cell migration and invasion were evaluated using wound healing and transwell assays. The interaction among circMMP9, miR-149, and CCND2 was evaluated using luciferase, RNA-pull down, and RNA immunoprecipitation (RIP) assays, respectively. Cell apoptosis and cycle were examined by flow cytometry. A subcutaneous HCC xenograft mouse model was established for analyzing the role of circMMP9 in regulating the progression of HCC in vivo. Results: The expression of circMMP9 was elevated in HCC tissues and its high expression correlated with poor prognosis (P<0.05). Knockdown of circMMP9 restrained the proliferation, migration, and invasion of HCC cells and led to arrested cell cycle and increased apoptosis (all P<0.05). Furthermore, knockdown of circMMP9 attenuated HCC growth in vivo (P<0.05). Mechanically, circMMP9 acted as a sponge for miR-149 and enhanced CCND2 expression in HCC cells (P<0.05). Inhibition of miR-149 or overexpression of CCND2 abrogated knockdown of circMMP9-mediated alleviation of the malignant phenotypes of HCC (P<0.05). Conclusions: For the first time, we demonstrated that circMMP9 exacerbated HCC progression through the miR-149/CCND2 axis, which suggested that circMMP9 could be potentially targeted for HCC treatment.

A CASE REPORT of Lichen Nitidus on the Penis: Tiny but Annoying Eruptions.

Most patients are anxious about the skin lesions on the penis. This study reports a case of lichen nitidus on the penis and reviews related literature. A 40-year-old male has presented with small papules with skin color on the penis for one year. The patient was diagnosed with lichen nitidus, and tacrolimus cream and humectant were topically administered after diagnosis. The symptoms were alleviated after treatment. We first report a series of the cases with lichen nitidus on the penis, knowing the clinical and pathological manifestations of this disease can reduce misdiagnosis and unnecessary treatment.

The Sex Features of Patients With Solid Pseudopapillary Neoplasms of the Pancreas: A Retrospective Study.

BACKGROUND: Solid pseudopapillary neoplasms of the pancreas (SPNs) in male patients are more frequently reported. The aim of the study was to evaluate the sex features of SPN and the risk factors that predict tumor recurrence. METHODS: From 2013 to 2019, patients who were pathologically confirmed to have SPNs were retrospectively reviewed. The baseline study parameters were compared between males and females. A logistic regression model was established to identify the independent risk factors for tumor recurrence. RESULTS: In total, 221 patients were included in this study. Of them, 53 patients (24.0%) were males. Male patients were older than female patients (39.1 vs 31.6 years, P=0.001), and the tumor size in male patients was smaller than that in female patients (50.38 vs 39.65 mm, P=0.038). The preoperative imaging diagnostic accuracy was significantly higher in females than in males (70.5% vs 54%, P=0.02). SPNs in male patients tended to be misdiagnosed with other malignant tumors (37.7% vs 10.7%, P<0.0001), with a more solid component observed in images (66.8% vs 24.7%, P<0.0001). For immunohistochemical staining, the expression of beta catenin was significantly lower in male patients (P=0.002), and the expression of vimentin was the opposite (P=0.01). The overall survival rate and disease-free survival were not different. Based on multivariate analysis, older age [hazard ratio (HR)= 1.094, 95% confidence interval (CI): 1.005-1.190] and KI 67 index grade III (HR=12.029, 95% CI: 2.399-60.311) were independent risk factors for tumor recurrence. CONCLUSION: The clinical and imaging features of SPN in males were not in full accord with those in females; however, the differences did not influence prognosis.

The effect of solvent quality on pathway-dependent solution-state self-assembly of an amphiphilic diblock copolymer.

The cholesterol-functionalized polycarbonate-based diblock copolymer, PEG113-b-P(MTC-Chol)30, forms pathway-dependent nanostructures via dialysis-based solvent exchange. The initial organic solvent that dissolves or disperses the polymer dictates a self-assembly pathway. Depending upon the initial solvent, nanostructures of disk-like micelles, exhibiting asymmetric growth and hierarchical features, are accessible from a single amphiphilic precursor. Dioxane and tetrahydrofuran (THF) molecularly dissolve the block copolymer, but THF yields disks, while dioxane yields stacked disks after dialysis against water. Dimethylformamide and methanol display dispersed disks and then form stacked disk structures after dialysis. The path-dependent morphology was correlated to solubility parameters, an understanding of which offers routes to tailor self-assemblies with limited sets of building blocks.

Gene expression alterations of human liver cancer cells following borax exposure.

Borax is a boron compound that is becoming widely recognized for its biological effects, including lipid peroxidation, cytotoxicity, genotoxicity, antioxidant activity and potential therapeutic benefits. However, it remains unknown whether exposure of human liver cancer (HepG2) cells to borax affects the gene expression of these cells. HepG2 cells were treated with 4 mM borax for either 2 or 24 h. Gene expression analysis was performed using Affymetrix GeneChip Human Gene 2.0 ST Arrays, which was followed by gene ontology analysis and pathway analysis. The clustering result was validated using reverse transcription­quantitative polymerase chain reaction. A cell proliferation assay was performed using Celigo Image Cytometer Instrumentation. Following this, 2­ or 24­h exposure to borax significantly altered the expression level of a number of genes in HepG2 cells, specifically 530 genes (384 upregulated and 146 downregulated) or 1,763 genes (1,044 upregulated and 719 downregulated) compared with the control group, respectively (≥2­fold; P<0.05). Twenty downregulated genes were abundantly expressed in HepG2 cells under normal conditions. Furthermore, the growth of HepG2 cells was inhibited through the downregulation of PRUNE1, NBPF1, PPcaspase­1, UPF2 and MBTPS1 (≥1.5­fold, P<0.05). The dysregulated genes potentially serve important roles in various biological processes, including the inflammation response, stress response, cellular growth, proliferation, apoptosis and tumorigenesis/oncolysis.

Effect of temperature on the structure and dynamics of triblock polyelectrolyte gels.

Triblock polyelectrolyte gels were characterized by small-angle neutron scattering (SANS) and dynamic light scattering (DLS). The oppositely charged end blocks self-assemble into polyelectrolyte complex cores, while the neutral poly(ethylene oxide) middle block bridges adjacent cores. The size of the polyelectrolyte complex core does not change with temperature. However, the neutral middle block displays a temperature-dependent conformation. The liquid-like order of the complex core within the gel phase leads to stretched bridging chains that approach their unperturbed dimensions with increasing concentration. A stretch ratio for bridging chains was defined as the ratio between stretched and unperturbed dimensions. A further reduction in the chain stretching occurs with increasing temperature due to solvent quality. DLS observes multiple modes consistent with a collective diffusion (fast mode) and diffusion of clusters (slow mode). The dynamics of these clusters are at length scales associated with the SANS excess scattering, but with relaxation time near the crossover frequency observed by mechanical spectroscopy.

[Effects of Epihopin on Proliferation and Apoptosis of KG-1a cells and Its Related Mechanism].

OBJECTIVE: To explore the possible mechanism underlaying interference of epihopin on the proliferation of AML KG-1a cells by inhibiting the Wnt/ß-catenin signaling pathway, so as to prvide the experimental basis for development of drug to treat the AML. METHODS: A total of 50 c57BL/6 mice were randomy divided into 5 group:blank control, model control, high, medium and low dose of epihopin. Except the blank control group, the KG-1a cells were injected in abdominal cavity of 4 groups for the establishment of model. The mice in high, middle and low dose groups were injected intramuscularly with 80, 40 and 20 mg/kg of epihopin respectively, while the mice in blank control and model control group were injected intramuscularly with saline. The Western blot was used to detect the expression of S phase kinase-related protein 2(SKP-2), ß-catenin, E-cadherin and poly-(ADP ribose) polymerase (PARP); the spectrophotometry was used to detect the activity of caspase 3 and procaspase-3, the flow cytometry was used to detect the cell cycle distribution and the apoptotic rate of KG-1a cells treated with epihopin. RESULTS: The epihopin could enhance the activity of caspase 3, decrease the level of procaspase 3; also could up-regulate the expression of E-acadherin and down-regulate the expression of SKP-2 and ß-catenin; and could increase the expression of PARP in dose-dependent manner. After KG-1a cels were treated with epihopin, the apoptosis rate of cells significantly increased, the KG-1a cells were arrested in G0/G1 phase, therefore the growth of KG-1a cells was significantly inhibited. CONCLUSION: The epihopin can dose-dependently split PARP to induce the apoptosis of KG-1a cells, its mechanism may relate with inhibition of Wnt/ß-catenin signaling pathway and its down-stream-related gene expression.

Enthalpy-driven micellization of oligocarbonate-fluorene end-functionalized Poly(ethylene glycol)☆.

A fluorescent pyrene probe method was applied to measure the critical micelle concentration (CMC) of oligocarbonate-fluorene end-functionalized poly(ethylene glycol) (FmE445Fm) triblock copolymers in water. The CMC decreases with lower temperature and higher values of the hydrophobic block length, m. When analyzed by a closed-assembly micelle model, the estimated energetic parameters find a negative ΔH°mic and small positive ΔS°mic suggestive of enthalpy-driven micellization, which differs from entropy-driven oxyethylene/oxybutylene triblock copolymers and octaethylene glycol-n-alkyl ethers. The enthalpy-driven micellization of FmE445Fm may result from the limited hydration of individual hydrophobic F blocks that leads to few hydrogen-bonded waters released during F block association. The π-π stacking oligocarbonate-fluorene system also observed enthalpy-entropy compensation when compared to a series of published data on diblock and triblock copolymer systems. An anomalously low partition equilibrium constant for m = 15.3 implies a tightly-packed core that excludes pyrene intercalation into the fluorene core. This is discussed along with the possible limited applicability to estimate the CMC and potential model drug molecule insertions into the intercalated micelle core.

Spatial Distribution of Hydrophobic Drugs in Model Nanogel-Core Star Polymers.

Star polymers with a cross-linked nanogel core are promising carriers of cargo for therapeutic applications due to the synthetic control of amphiphilicity of arms and stability at infinite dilution. Three nanogel-core star polymers were investigated to understand how the arm-block chemical structure controls loading efficiency of a model drug, ibuprofen, and its spatial distribution. The spatial distribution profiles of hydrophobic core, hydrophilic corona, and encapsulated drug were determined by small-angle neutron scattering (SANS). SANS provides the nanometer-scale sensitivity to determine how the arm-block chemistry enhances the sequestering of ibuprofen. Validated molecular dynamics simulations capture the trends in drug profile and polymer segment distribution with further details on drug orientation distribution. This work provides a basis to study structure-function relationships in macromolecular-based carriers of cargo and represents a path toward validated and predictive simulation.

Synthesis, Characterization and Performance of P3HT-Azide-PCBM Microgel.

Spherical Poly(3-hexylthiophene)-azide-[6,61-phenyl-C61-butyric acid methyl ester (P3HT-azide-PCBM) microgel was synthesized by introducing an azide cross-linkable group into the conjugated polymer. Its UV-vis spectrum shifts blue as a result of the systematic disruption of planarity along the P3HT backbone and a reduction in long range conjugation. And the corresponding fluorescence spectrum also indicates that a strong intra-molecular photo-induced electron transfer is originated from the covalent linkage of PCBM moiety to the P3HT backbone via the hexyl bridge upon photoexcitation. Combined Gel Permeation Chromatography (GPC), dynamic and static light scattering (DLS and SLS) measurements prove that the resultant P3HT-azide-PCBM copolymer is a uniform spherical microgel with a hydrodynamic radius of 130 nm at room temperature. The spherical P3HT-azide-PCBM microgel can be used as electron donor or compatibilizer in bulk-heterojunction (BHJ) devices, but its introduction reduces the photovoltaic performance compared with the blend of P3HT/PCBM, because the hole mobility in the crosslinked polythiophene backbones is largely decreased.

Effects of particle softness on shear thickening of microgel suspensions.

A series of microgel particles composed of a polystyrene (PS) core and a thermo-sensitive poly(N-isopropylacrylamide) (PNIPAM) shell with different shell thicknesses were investigated to elucidate the effect of microgel softness on its shear thickening behavior. Since the softness of the microgels increases with decreasing temperature through the volume phase transition effect of PNIPAM shell, the measured softness parameter, n, which is derived from the Zwanzig-Mountain equation, was used to measure and describe the combined influences of temperature and shell thickness. Confocal microscopy is used to investigate the interaction potential between microgel particles with different softness parameters. According to the obtained results, the softness parameter can provide an estimate for the shear thickening behavior of microgel suspensions, at least semi-quantitatively.