Traditional Chinese medicine Pien-Tze-Huang ameliorates LPS-induced sepsis through bile acid-mediated activation of TGR5-STAT3-A20 signalling.

Pien Tze Huang (PZH), a class I nationally protected traditional Chinese medicine (TCM), has been used to treat liver diseases such as hepatitis; however, the effect of PZH on the progression of sepsis is unknown. Here, we reported that PZH attenuated lipopolysaccharide (LPS)-induced sepsis in mice and reduced LPS-induced production of proinflammatory cytokines in macrophages by inhibiting the activation of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signalling. Mechanistically, PZH stimulated signal transducer and activator of transcription 3 (STAT3) phosphorylation to induce the expression of A20, which could inhibit the activation of NF-κB and MAPK signalling. Knockdown of the bile acid (BA) receptor G protein-coupled bile acid receptor 1 (TGR5) in macrophages abolished the effects of PZH on STAT3 phosphorylation and A20 induction, as well as the LPS-induced inflammatory response, suggesting that BAs in PZH may mediate its anti-inflammatory effects by activating TGR5. Consistently, deprivation of BAs in PZH by cholestyramine resin reduced the effects of PZH on the expression of phosphorylated-STAT3 and A20, the activation of NF-κB and MAPK signalling, and the production of proinflammatory cytokines, whereas the addition of BAs to cholestyramine resin-treated PZH partially restored the inhibitory effects on the production of proinflammatory cytokines. Overall, our study identifies BAs as the effective components in PZH that activate TGR5-STAT3-A20 signalling to ameliorate LPS-induced sepsis.

Tumor-suppressive miR-4732-3p is sorted into fucosylated exosome by hnRNPK to avoid the inhibition of lung cancer progression.

BACKGROUND: Aberrant fucosylation observed in cancer cells contributes to an augmented release of fucosylated exosomes into the bloodstream, where miRNAs including miR-4732-3p hold promise as potential tumor biomarkers in our pilot study. However, the mechanisms underlying the sorting of miR-4732-3p into fucosylated exosomes during lung cancer progression remain poorly understood. METHODS: A fucose-captured strategy based on lentil lectin-magnetic beads was utilized to isolate fucosylated exosomes and evaluate the efficiency for capturing tumor-derived exosomes using nanoparticle tracking analysis (NTA). Fluorescence in situ hybridization (FISH) and qRT-PCR were performed to determine the levels of miR-4732-3p in non-small cell lung cancer (NSCLC) tissue samples. A co-culture system was established to assess the release of miRNA via exosomes from NSCLC cells. RNA immunoprecipitation (RIP) and miRNA pull-down were applied to validate the interaction between miR-4732-3p and heterogeneous nuclear ribonucleoprotein K (hnRNPK) protein. Cell functional assays, cell derived xenograft, dual-luciferase reporter experiments, and western blot were applied to examine the effects of miR-4732-3p on MFSD12 and its downstream signaling pathways, and the impact of hnRNPK in NSCLC. RESULTS: We enriched exosomes derived from NSCLC cells using the fucose-captured strategy and detected a significant upregulation of miR-4732-3p in fucosylated exosomes present in the serum, while its expression declined in NSCLC tissues. miR-4732-3p functioned as a tumor suppressor in NSCLC by targeting 3'UTR of MFSD12, thereby inhibiting AKT/p21 signaling pathway to induce cell cycle arrest in G2/M phase. NSCLC cells preferentially released miR-4732-3p via exosomes instead of retaining them intracellularly, which was facilitated by the interaction of miR-4732-3p with hnRNPK protein for selective sorting into fucosylated exosomes. Moreover, knockdown of hnRNPK suppressed NSCLC cell proliferation, with the elevated levels of miR-4732-3p in NSCLC tissues but the decreased expression in serum fucosylated exosomes. CONCLUSIONS: NSCLC cells escape suppressive effects of miR-4732-3p through hnRNPK-mediated sorting of them into fucosylated exosomes, thus supporting cell malignant properties and promoting NSCLC progression. Our study provides a promising biomarker for NSCLC and opens a novel avenue for NSCLC therapy by targeting hnRNPK to prevent the "exosome escape" of tumor-suppressive miR-4732-3p from NSCLC cells.

The multifaceted therapeutic value of targeting steroid receptor coactivator-1 in tumorigenesis.

Steroid receptor coactivator-1 (SRC-1, also known as NCOA1) frequently functions as a transcriptional coactivator by directly binding to transcription factors and recruiting to the target gene promoters to promote gene transcription by increasing chromatin accessibility and promoting the formation of transcriptional complexes. In recent decades, various biological and pathological functions of SRC-1 have been reported, especially in the context of tumorigenesis. SRC-1 is a facilitator of the progression of multiple cancers, including breast cancer, prostate cancer, gastrointestinal cancer, neurological cancer, and female genital system cancer. The emerging multiorgan oncogenic role of SRC-1 is still being studied and may not be limited to only steroid hormone-producing tissues. Growing evidence suggests that SRC-1 promotes target gene expression by directly binding to transcription factors, which may constitute a novel coactivation pattern independent of AR or ER. In addition, the antitumour effect of pharmacological inhibition of SRC-1 with agents including various small molecules or naturally active compounds has been reported, but their practical application in clinical cancer therapy is very limited. For this review, we gathered typical evidence on the oncogenic role of SRC-1, highlighted its major collaborators and regulatory genes, and mapped the potential mechanisms by which SRC-1 promotes primary tumour progression.

High diffraction efficiency varied-line-space concave gratings for the Lyman ultraviolet explorer.

In this paper we present the design and fabrication of the reflection varied-line-space concave grating (VLSCG) for the project of CAFE (the Census of warm-hot intergalactic medium, Accretion, and Feedback Explorer), which aims to detect and map the warm-hot circumgalactic medium via OVI emission at 103.2 nm and 103.8 nm, using two off-Rowland-circle spectrograph channels. High diffraction efficiency at LUV is supposed for the VLSCG and an aperture ratio as small as $F/3.6$ is desired for a compact design. The gratings are fabricated by holographic lithography and ion beam etching techniques. We introduce an additional lens into the normal holographic exposing system to generate the varied-line-space grating patterns. Grooves with triangle profiles are obtained to increase the diffraction efficiency by oblique ion beam bombardment during the etching process. Finally, several VLSCGs with a central line density of 3300 lines/mm have been fabricated successfully. The measured results show that the groove efficiency reaches 51% at 106.4 nm and 31% at 127.4 nm. We imitated the working optical path of the spectrometer and used the ${-}{1}$ order of the VLSCG to measure the image near the exit slit. The results showed that the image of the point source has a vertical extent of 0.68 mm, and the aberrations have been corrected.

JMJD2D stabilises and cooperates with HBx protein to promote HBV transcription and replication.

Background & Aims: HBV infection is a global health burden. Covalently closed circular DNA (cccDNA) transcriptional regulation is a major cause of poor cure rates of chronic hepatitis B (CHB) infection. Herein, we evaluated whether targeting host factors to achieve functional silencing of cccDNA may represent a novel strategy for the treatment of HBV infection. Methods: To evaluate the effects of Jumonji C domain-containing (JMJD2) protein subfamily JMJD2A-2D proteins on HBV replication, we used lentivirus-based RNA interference to suppress the expression of isoforms JMJD2A-2D in HBV-infected cells. JMJD2D-knockout mice were generated to obtain an HBV-injected model for in vivo experiments. Co-immunoprecipitation and ubiquitylation assays were used to detect JMJD2D-HBx interactions and HBx stability modulated by JMJD2D. Chromatin immunoprecipitation assays were performed to investigate JMJD2D-cccDNA and HBx-cccDNA interactions. Results: Among the JMJD2 family members, JMJD2D was significantly upregulated in mouse livers and human hepatoma cells. Downregulation of JMJD2D inhibited cccDNA transcription and HBV replication. Molecularly, JMJD2D sustained HBx stability by suppressing the TRIM14-mediated ubiquitin-proteasome degradation pathway and acted as a key co-activator of HBx to augment HBV replication. The JMJD2D-targeting inhibitor, 5C-8-HQ, suppressed cccDNA transcription and HBV replication. Conclusion: Our study clarified the mechanism by which JMJD2D regulates HBV transcription and replication and identified JMJD2D as a potential diagnostic biomarker and promising drug target against CHB, and HBV-associated hepatocarcinoma. Impact and implications: HBV cccDNA is central to persistent infection and is a major obstacle to healing CHB. In this study, using cellular and animal HBV models, JMJD2D was found to stabilise and cooperate with HBx to augment HBV transcription and replication. This study reveals a potential novel translational target for intervention in the treatment of chronic hepatitis B infection.

Can One Series of Self-Organized Nanoripples Guide Another Series of Self-Organized Nanoripples during Ion Bombardment: From the Perspective of Power Spectral Density Entropy?

Ion bombardment (IB) is a promising nanofabrication tool for self-organized nanostructures. When ions bombard a nominally flat solid surface, self-organized nanoripples can be induced on the irradiated target surface, which are called intrinsic nanoripples of the target material. The degree of ordering of nanoripples is an outstanding issue to be overcome, similar to other self-organization methods. In this study, the IB-induced nanoripples on bilayer systems with enhanced quality are revisited from the perspective of guided self-organization. First, power spectral density (PSD) entropy is introduced to evaluate the degree of ordering of the irradiated nanoripples, which is calculated based on the PSD curve of an atomic force microscopy image (i.e., the Fourier transform of the surface height. The PSD entropy can characterize the degree of ordering of nanoripples). The lower the PSD entropy of the nanoripples is, the higher the degree of ordering of the nanoripples. Second, to deepen the understanding of the enhanced quality of nanoripples on bilayer systems, the temporal evolution of the nanoripples on the photoresist (PR)/antireflection coating (ARC) and Au/ARC bilayer systems are compared with those of single PR and ARC layers. Finally, we demonstrate that a series of intrinsic IB-induced nanoripples on the top layer may act as a kind of self-organized template to guide the development of another series of latent IB-induced nanoripples on the underlying layer, aiming at improving the ripple ordering. The template with a self-organized nanostructure may alleviate the critical requirement for periodic templates with a small period of ~100 nm. The work may also provide inspiration for guided self-organization in other fields.

Traditional Chinese Medicine Pien-Tze-Huang Inhibits Colorectal Cancer Growth and Immune Evasion by Reducing ß-catenin Transcriptional Activity and PD-L1 Expression.

Pien Tze Huang (PZH) is a valuable traditional Chinese medicine, which has a variety of biological activities such as clearing heat-toxin, resolving blood stasis, detoxifying, relieving pain, and anti-inflammation. PZH has a partial role in suppressing the progression of CRC, while the underlying mechanism is a pending mystery; especially whether PZH mediates the immune escape of CRC remains unclear. Our study reported that PZH suppressed the proliferative activity of CRC by inhibiting Wnt/ß-catenin signaling to down-regulate the expression of PCNA and Cyclin D1. In addition, PZH suppressed the immune escape of CRC and elevated the infiltration of CD8+ T cells in tumor tissues, which depends on the suppression of PD-L1 levels via inhibiting IFNGR1-JAK1-STAT3-IRF1 signaling. More importantly, PZH pharmacologically elevated the antitumor efficacy of anti-PD-1/PD-L1 immunotherapy as demonstrated by slower tumor growth, higher infiltration and function of CD8+ T cells in the combination of PZH and PD-1/PD-L1 antibody compared with monotherapy with either agent. These results demonstrate that PZH has the potential role in inhibiting CRC proliferation and immune evasion, especially the synergistic enhancement effect of PZH on immunotherapy.

Demethylase JMJD2D induces PD-L1 expression to promote colorectal cancer immune escape by enhancing IFNGR1-STAT3-IRF1 signaling.

Programmed death-ligand 1 (PD-L1) is an important immunosuppressive molecule highly expressed on the surface of cancer cells. IFNγ triggered cancer cell immunosuppression against CD8+ T cell surveillance via up-regulation of PD-L1. Histone demethylase JMJD2D promotes colorectal cancer (CRC) progression; however, the role of JMJD2D in cancer immune escape is unknown. Here, we report that both PD-L1 and JMJD2D are frequently overexpressed in human CRC specimens with a significant positive correlation. Genetic ablation of JMJD2D in CRC cells attenuated the expression of PD-L1 and stalled tumor growth in mice, accompanied by the elevated number and effector function of tumor infiltrating CD8+ T cells. Mechanistically, JMJD2D coactivated SP-1 to promote the expression of IFNGR1, which elevated STAT3-IRF1 signaling and promoted PD-L1 expression. Again, JMJD2D is a major coactivator for STAT3-IRF1 axis to enhance PD-L1 transcription in a demethylation activity dependent manner. Furthermore, pharmacological inhibition of JMJD2D conduced to improve the anti-tumor efficacy of PD-L1 antibody as demonstrated by slower tumor growth and higher infiltration and function of CD8+ T cells in the combination of JMJD2D inhibitor 5-c-8HQ and PD-L1 antibody group compared with monotherapy with either agent. These results demonstrate that JMJD2D promotes CRC immune escape by enhancing PD-L1 expression to inhibit the activation and tumor infiltration of CD8+ T cells; targeting JMJD2D has the potential role in promoting the efficacy of anti-PD-1/PD-L1 immunotherapy.

High-efficiency broadband polarization-independent binary fused silica gratings for large astronomical telescopes.

The binary fused silica gratings (BFSGs) with high diffraction efficiency are presented for large astronomical ground-based telescopes. Calculations demonstrate that the BFSGs could obtain high diffraction efficiency in a wider wavelength range and angle of incident (AOI) range compared with volume phase holographic gratings. Several gratings with a size of 60mm×60mm have been fabricated by holographic lithography and reactive ion-beam etching technology. The measured peak diffraction efficiency reaches 94%, and results show that there are 130 nm wavelength bandwidth and 12° AOI bandwidth in which diffraction efficiency is higher than 70%. The stray light causes the diffraction efficiency to decrease by about 0.48%. All measurements have indicated good consistency with the simulation results.

Enhancing the quality of self-organized nanoripples by Ar-ion bombardment of a bilayer system.

Ion bombardment (IB) is a promising nanofabrication technique for producing nanoripples. A critical issue that restricts the application of IB is the limited quality of IB-induced nanoripples. Photoresist (PR) and antireflection coating (ARC) are of technological relevance for lithographic exposure processes. Moreover, to improve the quality of IB-induced self-organized nanoripples, in this study, a PR/ARC bilayer was bombarded at an incidence angle of 50°. The surface normalized defect density and power spectral density, obtained via scanning atomic force microscopy, indicate the superiority of the PR/ARC bilayer nanoripples over those of single PR or ARC layers. The growth mechanism of the improved nanoripples, deciphered via the temporal evolution of the morphology, involves the following processes: (i) formation of a well-grown IB-induced nanoripple prepattern on the PR, (ii) transfer of nanoripples from the PR to the ARC, forming an initial ARC nanoripple morphology for subsequent IB, and (iii) conversion of the initial nonuniform ARC nanoripples into uniform nanoripples. In this unique method, the angle of ion-incidence should be chosen so that ripples form on both PR and ARC films. Overall, this method facilitates nanoripple improvement, including prepattern fabrication for guiding nanoripple growth and sustainable nanoripple development via a single IB. Thus, the unique method presented in this study can aid in advancing academic research and also has potential applications in the field of IB-induced nanoripples.

Optical anisotropy of self-organized gold quasi-blazed nanostructures based on a broad ion beam.

To circumvent elaborate conventional lithographic methods for realizing metallic nanostructures, it is necessary to develop self-organized nanofabrication methods for suitable template structures and their optical characterization. We demonstrate the potential of ion bombardment with impurity co-deposition to fabricate terraced or quasi-blazed nanostructure templates. Self-organized terraced nanostructures on fused silica were fabricated using Ar+ ion bombardment with iron impurity co-deposition and subsequent Au shadow deposition. The aspect ratios are enhanced threefold, and the range of nanostructure period variation is significantly increased with respect to that of conventional nanostructures realized by pure ion bombardment. We reveal the key features of the method via atomic force microscopy and optical characterization. Variable-profile quasiperiodic nanostructures with periods of 100-450 nm, heights of 25-180 nm, and blaze angles of 10°-25° were fabricated over an area of 20×40mm2, and these exhibited tunable and broadening optical anisotropy across the nanostructured area. Thus, the proposed method is a viable technique for rapid, cost-effective, and deterministic fabrication of variable nanostructure templates for potential optical applications.

Salidroside ameliorates liver metabonomics in relation to modified gut-liver FXR signaling in furan-induced mice.

The study aimed to investigate the ameliorative effect of salidroside (SAL) on the crosstalk among liver metabonomics, gut barrier function and bile acids in furan-induced mice. Forty male mice were randomly divided into the following five groups: CON, FUR 8 (8 mg/kg/day furan), SAL 10 (8 mg/kg/day furan+10 mg/kg/day SAL), SAL 20 (8 mg/kg/day furan+20 mg/kg/day SAL), and SAL 40 (8 mg/kg/day+40 mg/kg/day SAL). Mice were administered with furan for 30 days and SAL was administered for 15 days from day 16. Principal components analysis (PCA) and heatmap were employed to probe metabonomics profile alterations in liver tissues and select thirty-eight potential biomarkers. Pathway analysis revealed primary bile acids were largely changed in the biosynthesis pathway. Moreover, SAL regulated the activation of farnesoid X receptor (FXR), downregulating hepatic heterodimer partner (SHP), upregulating cholesterol 7a-hydroxylase (CYP7A1) as well as decreasing the expression of portal fibroblast growth factor 15 (FGF15), compared to the furan-treated group. Importantly, SAL dramatically increased the level of tight junction proteins, as immunohistochemistry results show. In conclusion, the ameliorative effects of SAL on liver damage induced by furan might be due to altered gut barrier function, while FXR signaling acted a significant role in the function of SAL.

Soft X-ray varied-line-spacing gratings fabricated by near-field holography using an electron beam lithography-written phase mask.

A fabrication method comprising near-field holography (NFH) with an electron beam lithography (EBL)-written phase mask was developed to fabricate soft X-ray varied-line-spacing gratings (VLSGs). An EBL-written phase mask with an area of 52 mm × 30 mm and a central line density greater than 3000 lines mm-1 was used. The introduction of the EBL-written phase mask substantially simplified the NFH optics for pattern transfer. The characterization of the groove density distribution and diffraction efficiency of the fabricated VLSGs indicates that the EBL-NFH method is feasible and promising for achieving high-accuracy groove density distributions with corresponding image properties. Vertical stray light is suppressed in the soft X-ray spectral range.

Allicin alleviates acrylamide-induced oxidative stress in BRL-3A cells.

AIM: Acrylamide (AA) is a common heat-generated toxicant in some food. Inhibiting its formation with natural antioxidants is of great significance. The current study aims to investigate the alleviative effect and the underlying mechanism of allicin against AA-induced oxidative stress in BRL-3A cells. MAIN METHODS: BRL-3A cells were pretreated with allicin at different concentrations for 2 h, followed by AA treatment. Cell viability was determined by Cell Counting kit-8 (CCK-8). Intracellular reactive oxygen species (ROS) status was measured using the 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) method. Levels of oxidative stress markers were determined by measuring total superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and 8-hydroxy-desoxyguanosine (8-OHdG) using commercial kits. Expression of the mitogen-activated protein kinase (MAPK) pathway-related proteins was determined by Western blotting. KEY FINDINGS: Allicin markedly mitigated oxidative and DNA damage by increasing the activities of SOD and GSH-Px and decreasing the levels of ROS and 8-OHdG. Concomitant with these biochemical parameters, pretreatment with allicin reversed the impact of AA on the expression of p-JNK, p-ERK1/2 and p-p38. Allicin combined with SP600125 (JNK inhibitor) and SB202190 (p38 inhibitor) enhanced cell viability in the presence of AA, as opposed to SCH772984 (ERK inhibitor). Notably, allicin ameliorated the expression of KGF, Gadd45a, c-Fos, Dusp5 and Phospholipase A2, which were related to liver injury. SIGNIFICANCE: Collectively, these findings demonstrate that allicin exerts protective effects against AA-induced oxidative stress by modulating the MAPK signaling pathway in BRL-3A cells.

Ameliorative effect of salidroside from Rhodiola Rosea L. on the gut microbiota subject to furan-induced liver injury in a mouse model.

In our study, the ameliorative effect of salidroside (SAL) from Rhodiola Rosea L. on the intestinal microflora subject to furan-induced liver injury in a mouse model was investigated by 16 S rDNA, oxidative indexes, LPS and cytokine levels. The results demonstrated that SAL alleviated hepatic oxidative injury by inhibiting the activities of AST, ALT and the content of MDA, and promoting the activities of SOD, GSH and GST, compared to the furan-treated group. SAL significantly modified the intestinal microbial diversity and downregulated the circulating levels of serum LPS, IL-6, and TNF-α, as well as enhanced the content of IL-10. Importantly, SAL dramatically increased LPS-suppressing bacteria genera Akkermansia, and decreased LPS-producing bacteria phyla Proteobacteria. Our results indicate that SAL supplement restrains intestinal microbial dysbiosis and systemic low-grade inflammation induced by furan. Hopefully, SAL is a potential therapeutical and prophylactic compound in medicament for hepatic diseases.

Reducing Rowland ghosts in diffraction gratings by dynamic exposure near-field holography.

Near-field holography (NFH) combined with electron beam lithography (EBL)-written phase masks is a promising method for the rapid realization of diffraction gratings with high resolution and high accuracy in line density distribution. We demonstrate a dynamic exposure method in which the grating substrate is shifted during pattern transfer. This reduces the effects of stitching errors, resulting in the decreased intensity of the optical stray light (i.e., Rowland ghosts). We demonstrate the intensity suppression of ghosts by 60%. This illustrates the potential for dynamic NFH to suppress undesirable periodic patterns from phase masks and alleviate the stitching errors induced by EBL.

Structure dependence of lasing action in organic polymer films on DFB gratings for dinitrotoluene vapor detection.

Structure effects of distributed feedback (DFB) gratings on lasing action have been investigated for detecting explosive vapors. For the first time, we have established the optimized profiles of the DFB grating, and given the theoretical path to design its structure for amplified spontaneous emission (ASE) of organic polymer films based on Bragg conditions. A poly(p-phenylene ethynylene) (PPE) film can realize detection of dinitrotoluene (DNT) vapors in 2 min with a reduced excitation threshold of 26 mJ cm(-2) by using a simple and common 405 nm laser.

Design of multi-area grating for soft x-ray flat-field spectrograph.

A soft x-ray flat-field grating with a nominal groove density of 2400 grooves/mm is typically used in wavelengths of 1-6 nm or 1-7 nm for plasma diagnostics. However, measurement of wavelengths even down to 0.6 nm simultaneously is expected in practice. Unfortunately, a grating has a poor spectral image at wavelengths below 1.3 nm. In order to improve the spectral image at lower wavelengths, multi-area gratings (divided perpendicular to the direction of grating grooves) are devised. To reduce the contribution of certain areas with poor spectral image to the final spectral image, the profile parameters of groove on the area are optimized by suppressing spectral efficiency. Theoretical analysis demonstrates that, using multi-area gratings, the spectral image at lower wavelengths could be obviously improved; thus, the spectral resolving power at a wavelength of 0.7 nm is increased from 94 to 398.

Alignment method for fabricating a parallel flat-field grating used in soft x-ray region.

Parallel flat-field gratings consist of two flat-field gratings lying on one substrate, one for 5-20 nm and the other for 2-5 nm spectral regions, and thus can be widely used in various fields to record broader spectra in the soft x-ray region. The alignment of two subgratings directly determines the resolving power of parallel flat-field gratings. The theoretical resolving power is evaluated by means of the ray-tracing method and the maximal allowable alignment error is 0.366°. Alignment is based on diffraction patterns and moiré fringes and the total alignment error in our experiment is within 0.234°. The results demonstrate that this alignment method is an effective way for fabricating parallel flat-field gratings.

Alignment method combining interference lithography with anisotropic wet etch technique for fabrication of high aspect ratio silicon gratings.

A method was developed for aligning interference fringes generated in interference lithography to the vertical {111} planes of <110> oriented silicon wafers. The alignment error is 0.036°. This high precision method makes it possible to combine interference lithography with anisotropic wet etch technique for the fabrication of high aspect ratio silicon gratings with extremely smooth sidewalls over a large sample area. With this alignment method, 320 nm and 2 µm period silicon gratings have been successfully fabricated. The highest aspect ratio is up to 100. The sample area is about 50 mm × 60 mm. The roughness (root mean square) of the sidewall is about 0.267 nm.