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Bacterial pathogens can subvert host responses by producing effector proteins that directly target the nucleus of eukaryotic cells in animals and plants. Nuclear‐targeting proteins are categorised as either: "nucleomodulins," which have epigenetic‐modulating activities; or "cyclomodulins," which specifically interfere with the host cell cycle. Bacteria can deliver these effector proteins to eukaryotic cells via a range of strategies. Despite an increasing number of reports describing the effects of bacterial effector proteins on nuclear processes in host cells, the intracellular pathways used by these proteins to traffic to the nucleus have yet to be fully elucidated. This review will describe current knowledge about how nucleomodulins and cyclomodulins enter eukaryotic cells, exploit endocytic pathways and translocate to the nucleus. We will also discuss the secretion of nuclear‐targeting proteins or their release in bacterial membrane vesicles and the trafficking pathways employed by each of these forms. Besides their importance for bacterial pathogenesis, some nuclear‐targeting proteins have been implicated in the development of chronic diseases and even cancer. A greater understanding of nuclear‐targeting proteins and their actions will provide new insights into the pathogenesis of infectious diseases, as well as contribute to advances in the development of novel therapies against bacterial infections and possibly cancer. [ABSTRACT FROM AUTHOR]

Tumor-associated carbohydrate antigens (TACAs) provide a special class of tumor-specific antigens that show promising applications in cancer immunotherapy. However, the weak immunogenicity and structural complexity of TACAs are obstacles to their clinical application. Here, based on a fast and low-cost purification strategy for oligosaccharide synthesis, the synthesis of tumour-associated carbohydrate antigens Globo H and mannobiose which resembles repeat unit of mannan was achieved. To enhance the immunogenicity and multivalent effect, Globo H and mannobiose were covalently attached to degradable polymer backbones. 2D spindle-like lamellar micelle and globular micelle were obtained from glycopolymer through a solvent-exchange method of self-assembly. The glyconanoparticle showed good biocompatibility and degradability. Immunological functions of these glyconanoparticles such as stimulation of BMDC to cause upregulation of inflammatory factors were preliminarily explored. [ABSTRACT FROM AUTHOR]

Interferon epsilon (IFNε) is a unique type I interferon (IFN) that shows distinct constitutive expression in reproductive tract epithelium. Understanding how IFNε expression is regulated is critical for the mechanism of action in protecting the mucosa from infection. Combined computational and experimental investigation of the promoter of IFNε predicted transcription factor binding sites for the ETS family of transcription factors. We demonstrate here that Ifnε is regulated by Elf3, an epithelial restricted member of the ETS family. It is co-expressed with IFNε at the epithelium of uterus, lung and intestine, and we focused on regulation of IFNε expression in the uterus. Promoter reporter studies demonstrated that Elf3 was a strong driver of Ifnε expression; knockdown of Elf3 reduced expression levels of IFNε; Elf3 regulated Ifnε expression and chromatin immunoprecipitation (ChIP) confirmed the direct binding of Elf3 to the IFNε promoter. These data show that Elf3 is important in regulating protective mucosal immunity by driving constitutive expression of IFNε to protect mucosal tissues from infection in at least three organ systems. [ABSTRACT FROM AUTHOR]

Epigallocatechin-3-gallate ( EGCG) is a type of catechin. It exhibits excellent antioxidant effects and anti-tumour activities for cancer chemoprevention. The mechanism of anti-tumour effects of EGCG on different cancers has been studied for the past few decades, but remains controversial. To investigate the potential role that EGCG may play in the epigenetic regulation of colorectal cancer ( CRC) cell line, we integrated bioinformatics analysis with experimental validation. We found that levels of the enhancer of zeste homologue 2 ( EZH2) were significantly higher in CRC tissues compared to normal adjacent tissues, based on the Genomic Data Commons ( GDC) data portal. Different human CRC cell lines exhibited differing expression of levels of the EZH2 protein. In RKO cells, EGCG and the EZH2 inhibitor GSK343 exhibited similar inhibitory efficacy on the proliferation, invasion and migration abilities of the cells, and suppressed protein expression of trimethylated lysine 27 on histone H3 (H3K27me3), which may be caused by the loss of the enzymatic function of EZH2. EGCG and GSK343 were found to have a synergistic effect on the growth of RKO cells in lower concentrations. EZH2-correlated genes were enriched in the cell cycle pathway, the top-ranking up-regulated pathway in tumour tissues, based on pathway analyses using the Kyoto Encyclopedia of Genes and Genomes ( KEGG) and Gene Set Enrichment Analysis ( GSEA). In accord with this, we confirmed that EGCG and GSK343 could both significantly arrest the G0/G1 phase in RKO cell cycle, suggesting EGCG and EZH2 inhibitor share a common mechanism of action in RKO cells. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease ( NAFLD) and associated advanced liver diseases have become prevalent conditions in many countries and are associated with increased mortality. Gene expression profiles in NAFLD have been examined recently but changes in expression elicited by chemical compound treatments have not been investigated. Since (-)-Epigallocatechin-3-gallate ( EGCG) and atorvastatin ( ATST) exhibit similar efficacy in NAFLD models, we reasoned that some common key genes might alter after treatment of EGCG and ATST. Accordingly, we applied integrated bioinformatics analyses of RNA microarray data from EGCG and ATST treatment groups compared to controls in a NAFLD phenotypic mouse model. Using differential expression ( DE) analysis, Kyoto Encyclopaedia of Genes and Genomes ( KEGG) pathway analysis, Gene Set Enrichment Analysis ( GSEA) and Clue GO enrichment, shared EGCG and ATST down-regulated pathways were identified which included extracellular matrix ( ECM)-receptor interaction and protein processing in endoplasmic reticulum ( ER). To refine key genes associated with liver fibrosis, a human NAFLD signature derived from patients of different fibrosis stages was analyzed. The results showed that fibrosis-related genes Col1a1, Col1a2, Col3a1 and Col6a3 were significantly down-regulated. These four genes were further validated as down-regulated in an independent mouse NAFLD dataset. We conclude that EGCG and ATST treatment results in the significant down-regulation of genes related to liver fibrosis. [ABSTRACT FROM AUTHOR]

[Display omitted] • NLRP3 inflammasome related inflammatory signaling pathway plays an promoting role in HCC. • Classical pyroptosis mediated by NLRP3 inflammasome plays an inhibitory role in HCC. • The role of the substance targeting NLRP3 inflammasome in HCC depends on the emphasis of the substance on these two mechanisms. In recent years, the study of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome has become a hot topic, especially its role in various tumors. The incidence of hepatocellular carcinoma is ranked in the top five in China. Hepatocellular carcinoma (HCC) is the predominant and typical form of primary liver cancer. Due to the close relationship between NLRP3 inflammasome and cancers, many studies have investigated its role in HCC. The results suggest that NLRP3 inflammasome participates in both tumor growth inhibition and tumor growth promotion in HCC. Therefore, this review elaborates on the relationship between NLRP3 and HCC and explains its role in HCC. In addition, the potential of NLRP3 as a therapeutic target for cancer therapy is explored, summarizing and classifying impacts of and processes underlying different NLRP3 inflammasome-targeting drugs on HCC. [ABSTRACT FROM AUTHOR]

Toll-like receptor 4 (TLR4) plays an important role as a key signal-receiving transmembrane protein molecule in the liver, and substances that target the liver exert therapeutic effects via TLR4-related signaling pathways. This article provides a comprehensive review of targeting the TLR4 signaling axis to play an important role in the liver based on endogenous substances. Articles were divided into 5 major types of liver disease, acute liver injury, viral hepatitis, alcoholic and non-alcoholic liver disease, cirrhosis, and liver cancer, to elucidate how various endogenous substances affect the liver via the TLR4 pathway and the important role of the pathway itself in liver-related diseases to discover the potential therapeutic implications of the TLR4-related pathway in the liver. The results indicate that activation of the TLR4-related signaling axis primarily plays a role in promoting disease progression in liver-related diseases, and the TLR4/MyD88/NF-κB axis plays the most dominant role. Therefore, exploring the full effects of drugs targeting the TLR4-related signaling axis in the liver and the new use of old drugs may be a new research direction. [ABSTRACT FROM AUTHOR]

A FRET-based sensor is anchored on the cell surface through streptavidin–biotin interactions. Due to the excellent properties of the pH-sensitive i-motif structure, the sensor can detect extracellular pH with high sensitivity and excellent reversibility. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme 2 (ACE2) has been shown to prevent atherosclerotic lesions and renal inflammation. However, little was elucidated upon the effects and mechanisms of ACE2 in atherosclerotic kidney fibrosis progression. Here, we examined regulatory roles of ACE2 in renal fibrosis in the apolipoprotein E (ApoE) knockout (KO) mice. The ApoEKO mice were randomized to daily deliver either angiotensin (Ang) II (1.5 mg/kg) and/or human recombinant ACE2 (rhACE2; 2 mg/kg) for 2 weeks. Downregulation of ACE2 and upregulation of phosphorylated Akt, mTOR and ERK1/2 levels were observed in ApoEKO kidneys. Ang II infusion led to increased tubulointerstitial fibrosis in the ApoEKO mice with greater activation of the mTOR/ERK1/2 signaling. The Ang II-mediated renal fibrosis and structural injury were strikingly rescued by rhACE2 supplementation, associated with reduced mRNA expression of TGF-β1 and collagen I and elevated renal Ang-(1–7) levels. In cultured mouse kidney fibroblasts, exposure with Ang II (100 nmol L −1 ) resulted in obvious elevations in superoxide generation, phosphorylated levels of mTOR and ERK1/2 as well as mRNA levels of TGF-β1, collagen I and fibronectin 1, which were dramatically prevented by rhACE2 (1 mg mL −1 ) or mTOR inhibitor rapamycin (10 μmol L −1 ). These protective effects of rhACE2 were eradicated by the Ang-(1–7)/Mas receptor antagonist A779 (1 μmol L −1 ). Our results demonstrate the importance of ACE2 in amelioration of kidney fibrosis and renal injury in the ApoE-mutant mice via modulation of the mTOR/ERK signaling and renal Ang-(1–7)/Ang II balance, thus indicating potential therapeutic strategies by enhancing ACE2 action for preventing atherosclerosis and fibrosis-associated kidney disorders. [ABSTRACT FROM AUTHOR]

Based on the orthogonalities among the spherical vector wave functions, the expressions of scattering fields are developed as the particle being irradiated by the zeroth-order field and the first-order fields of x, y, and z. A general relation between the expansion coefficients of scattering field and incident field is presented. With the example of the elliptical beam, the scattering property of a particle in beam is investigated. Upon analyzing of the effects of the beam waist, irradiating distance, etc., on scattering property, the validity of the algorithm used is demonstrated. The results show that the beam waist may improve the particle's identification property and the particle has a strong scattering property in both forward and backward directions. The method used is simple and provides a new way for investigating the scattering fields from particles in electromagnetic beams. [ABSTRACT FROM PUBLISHER]

The backscatter properties of millimeter wave radar in sand and dust storms have been addressed. An expression for signal attenuation of millimeter wave radar is derived in terms of visibility and frequency. The results show that the values calculated by the proposed model are in good agreement with those obtained by Goldhirsh’s model and Alhaider’s formula. The general formulas of the backscatter power and equivalent scattering cross-section through sandstorms, suitable for any particle size distribution, are developed in terms of radar range, visibility, and wave attenuation. The results of the calculation show that the equivalent scattering cross-section increases with the increase of radar range less than 35 km, whereas the echo power decreases with the increase of radar range. It is confirmed that the equivalent scattering cross-section and echo power decrease rapidly as the radar range increases for the lower visibility, and decrease slowly with the increase of radar range for the bigger visibility. It is found that the particle size distribution is one major factor which will affect the backscattering properties of millimeter wave radar in sand and dust storms. [ABSTRACT FROM PUBLISHER]

Based on the analysis of the factors that affect retweet behavior, this paper proposed a predict SVM algorithm with five features: user influence, user activity, interest similarity, the importance of micro-blog content and users closeness. Furthermore, it proposed the predict algorithm of retweet scale on the basis of SVM, also, gave a method to evaluate the predict accuracy. The experiment with Sina micro-blog data shows a good result that the predict accuracy is up to 86.63%. [ABSTRACT FROM AUTHOR]

The analytical expressions of the external and internal electric fields for an anisotropic particle in electromagnetic (EM) beams are presented by transforming anisotropic dielectric particle into the isotropic one based on the scales transformation of EM theory. The theoretical expressions are in good agreement with that in literatures. Taking the case of elliptical Gaussian beam, simulations of influence induced by dielectric tensor and the waists, etc., on the fields are demonstrated. The numerical simulations show that the electric field increases with the augment of beam and the higher order electric field is much smaller than the lower field. [ABSTRACT FROM PUBLISHER]

The general formulas of the wave propagation constant through sand and dust storms are developed in this paper, which is based on the forward scattering amplitude of particle under the Rayleigh approximation. Expressions for attenuation and phase shift coefficients for a medium with sand and dust particles are derived in terms of visibility and frequency. Computations show that the predicted values from the given mathematical expressions are an excellent agreement with the values by Goldhirsh's formula. Expressions for the differential attenuation and differential phase shift are also derived for both vertical and horizontal polarizations. Obtained results of the attenuation of horizontal and vertical polarization wave are compared with those obtained by Wenyan 's formula and Ghobriel 's formula, respectively. It is found that the attenuation obtained by our proposed formula and Ghobrial 's formula show close agreement. The cross-polar discrimination is calculated and discussed. [ABSTRACT FROM PUBLISHER]

Analytical expressions of electric fields inside and outside an anisotropic dielectric sphere are presented by transforming an anisotropic medium into an isotropic one based on the multi-scale transformation of electromagnetic theory. The theoretical expressions are consistent with those in the literature. The inside electric field, the outside electric field and the angle between their directions are derived in detail. Numerical simulations show that the direction of the outside field influences the magnitude of the inside field, while the dielectric constant tensor greatly affects its direction. [ABSTRACT FROM AUTHOR]

The EEN (extra eleven nineteen) gene is one of the fusion partners of mixed-lineage leukemia, located on chromosome 19p13. Here we cloned two een genes (designated as eena and eenb) in zebrafish, which are assigned to linkage groups 8 and 2, respectively. Whole-mount in situ hybridization assay showed that eena and eenb have overlapping but distinct expression patterns during embryogenesis. Ubiquitous or targeted overexpression of eena, but not eenb, into wild-type or transgenic embryos (green fluorescent protein-labeled myeloid progenitors) induced a significant proliferation and ectopic distribution of myeloid progenitors in the yolk sac. Using a morpholino anti-sense gene knockdown approach, we showed that the number of myeloid progenitors and their downstream mature myelomonocytic cells was significantly decreased in the eena- deficient embryos. Mechanistically, overexpression of eena selectively stimulated ERK phosphorylation and increased the level of transcription factor c-Fos in vitro and in vivo, whereas eena lacking the Src homology 3 domain completely abolished these effects. Furthermore, a MAPK/ERK kinase (MEK) inhibitor, PD98059, blocked the eena-induced cell proliferation and activation of ERK signaling. The results suggest that eena plays an important role in the development of the myeloid cell through activation of the ERK pathway and may provide a valuable reference for future studies of the role of EEN in leukemogenesis. [ABSTRACT FROM AUTHOR]

Current studies aiming at identifying single immune markers with prognostic value have limitations in the context of complex antitumor immunity and cancer immune evasion. Here, we show how the integration of several immune markers influences the predictions of prognosis of gastric cancer (GC) patients. We analyzed Tissue Microarray (TMA) by multiplex immunohistochemistry and measured the expression of immune checkpoint molecule PD-L1 together with antitumor CD8 T cells and immune suppressive FOXP3 Treg cells in a cohort of GC patients. Unsupervised hierarchical clustering analysis of these markers was used to define correlations between CD8 T, FOXP3 Treg and PD-L1 cell densities. We found that FOXP3 and PD-L1 densities were elevated while CD8 T cells were decreased in tumor tissues compared to their adjacent normal tissues. However, patient stratification based on each one of these markers individually did not show significant prognostic value on patient survival. Conversely, combination of the ratios of CD8/FOXP3 and CD8/PD-L1 enabled the identification of patient subgroups with different survival outcomes. As such, high densities of PD-L1 in patients with high CD8/FOXP3 and low CD8/PD-L1 ratios correlated with increased survival. Collectively, this work demonstrates the need for the integration of several immune markers to obtain more meaningful survival prognosis and patient stratification. In addition, our work provides insights into the complex tumor immune evasion and immune regulation by the tumor-infiltrating effector and suppressor cells, informing on the best use of immunotherapy options for treating patients. [ABSTRACT FROM AUTHOR]

A 2-D Cd(II) coordination polymer (CP), {[Cd2(L)2(4,4′-bipy)2(H2O)∙7H2O]n (1), has been synthesized using 5-aminoisophthalic acid (H2L) as ligand and 4,4′-bipyridine as co-ligand. A single-crystal X-ray diffraction study shows that 1 is an infinite 2-D layer. CP 1 behaves as a highly selective and sensitive fluorescence chemosensor for detection of Hg2+ and 2,4,6-trinitrotoluene (TNT). Furthermore, possible emission quenching in 1 in the presence of nitroaromatics has been addressed with the aid of theoretical calculations. The calculations indicated that there are both electron and energy transfer processes, in addition to electrostatic interaction between 1 and nitroaromatics which contributes to the selective fluorescence quenching. [ABSTRACT FROM AUTHOR]

Based on the orthogonalities of the vector wave functions, the expressions of scattering fields are developed as the particle in the zero order field and in the first order fields of x, y, and z, respectively. A general relation between the expansion coefficients of scattering field and incident field is presented. Taking the elliptical beam for example, the scattering property of a particle in beam is investigated. After analyzing the effects of the beam waist, irradiating distance, etc. on scattering property, the validity of the proposed algorithm is demonstrated. Results show that the beam waist may improve the particle identification property and the particle has a strong scattering both in the forward direction and in the backward direction. The method proposed is simple and is a new way of researching the scattering from particles in electromagnetic beams. [ABSTRACT FROM AUTHOR]

Three new polycyclic phenol derivatives, 2-acetyl-4-hydroxy-6H-furo [2,3-g]chromen-6-one (1), 2-(1′,2′-dihydroxypropan-2′-yl)-4-hydroxy-6H-furo [2,3-g][1]benzopyran-6-one (2) and 3,8,10-trihydroxy-4,9-dimethoxy-6H-benzo[c]chromen-6-one (8), along with seven known ones (3–7, 9 and 10) were isolated for the first time from the leaves of Spermacoce latifolia. Their structures were determined by spectroscopic analysis and comparison with literature-reported data. These compounds were tested for their in vitro antibacterial activity against four Gram-(+) bacteria: Staphyloccocus aureus (SA), methicillin-resistant Staphylococcus aureus (MRSA), Bacillus cereus (BC), Bacillus subtilis (BS), and the Gram-(−) bacterium Escherichia coli. Compounds 1, 2, 5 and 8 showed antibacterial activity toward SA, BC and BS with MIC values ranging from 7.8 to 62.5 µg/mL, but they were inactive to MRSA. Compound 4 not only showed the best antibacterial activity against SA, BC and BS, but it further displayed significant antibacterial activity against MRSA (MIC 1.95 µg/mL) even stronger than vancomycin (MIC 3.9 µg/mL). No compounds showed inhibitory activity toward E. coli. Further bioassay indicated that compounds 1, 4, 5, 6, 8 and 9 showed in vitro α-glucosidase inhibitory activity, among which compound 9 displayed the best α-glucosidase inhibitory activity with IC50 value (0.026 mM) about 15-fold stronger than the reference compound acarbose (IC50 0.408 mM). These results suggested that compounds 4, 8 and 9 were potentially highly valuable compounds worthy of consideration to be further developed as an effective anti-MRSA agent or effective α-glucosidase inhibitors, respectively. In addition, the obtained data also supported that S. latifolia was rich in structurally diverse bioactive compounds worthy of further investigation, at least in searching for potential antibiotics and α-glucosidase inhibitors. [ABSTRACT FROM AUTHOR]

Angiotensin converting enzyme 2 (ACE2) has recently been identified as the functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent response for novel coronavirus disease 2019 (COVID-19). This study aimed to explore the roles of ACE2, apelin and sodium-glucose cotransporter 2 (SGLT2) in SARS-CoV-2-mediated cardiorenal damage. The published RNA-sequencing datasets of cardiomyocytes infected with SARS-CoV-2 and COVID-19 patients were used. String, UMAP plots and single cell RNA sequencing data were analyzed to show the close relationship and distinct cardiorenal distribution patterns of ACE2, apelin and SGLT2. Intriguingly, there were decreases in ACE2 and apelin expression as well as marked increases in SGLT2 and endothelin-1 levels in SARS-CoV-2-infected cardiomyocytes, animal models with diabetes, acute kidney injury, heart failure and COVID-19 patients. These changes were linked with downregulated levels of interleukin (IL)-10, superoxide dismutase 2 and catalase as well as upregulated expression of profibrotic genes and pro-inflammatory cytokines/chemokines. Genetic ACE2 deletion resulted in upregulation of pro-inflammatory cytokines containing IL-1β, IL-6, IL-17 and tumor necrosis factor α. More importantly, dapagliflozin strikingly alleviated cardiorenal fibrosis in diabetic db / db mice by suppressing SGLT2 levels and potentiating the apelin-ACE2 signaling. Downregulation of apelin and ACE2 and upregulation of SGLT2, endothelin-1 and pro-inflammatory cytokines contribute to SARS-CoV-2-mediated cardiorenal injury, indicating that the apelin-ACE2 signaling and SGLT2 inhibitors are potential therapeutic targets for COVID-19 patients. [Display omitted] • Infection of SARS-CoV-2 leads to reduction of ACE2 and promotion of inflammation in cardiomyocytes and COVID-19 patients. • There are marked decreases in apelin and ACE2 and increase in SGLT2 in post-MI heart failure rats, AKI and diabetic mice. • Dapagliflozin alleviates myocardial and renal fibrosis in the diabetic db / db mice by activating the apelin-ACE2 signaling. • The apelin-ACE2 signaling and SGLT2 inhibitors are potential therapeutic targets for COVID-19 patients. [ABSTRACT FROM AUTHOR]

Retinoic acid-inducible gene I (RIG-I) is up-regulated during granulocytic differentiation of acute promyelocytic leukemia (APL) cells induced by all-trans retinoic acid (ATRA). It has been reported that RIG-I recognizes virus-specific 5'-ppp-double-stranded RNA (dsRNA) and activates the type I interferons signaling pathways in innate immunity. However, the functions of RIG-I in hematopoiesis remain unclear, especially regarding its possible interaction with endogenous RNAs and the associated pathways that could contribute to the cellular differentiation and maturation. Herein, we identified a number of RIG-I-binding endogenous RNAs in APL cells following ATRA treatment, including the tripartite motif-containing protein 25 (TRIM2S) messenger RNA (mRNA). TRIM25 encodes the protein known as an E3 ligase for ubiquitin/interferon (IFN)-induced 15-kDa protein (ISG15) that is involved in RIG-I-mediated antiviral signaling. We show that RIG-I could bind TRIM2S mRNA via its helicase domain and C-terminal regulatory domain, enhancing the stability of TRIM2S transcripts. RIG-I could increase the transcriptional expression of TRIM2S by caspase recruitment domain (CARD) domain through an IFN-stimulated response element. In addition, RIG-I activated other key genes in the ISGylation pathway by activating signal transducer and activator of transcription 1 (STAT1), including the modifier ISG15 and several enzymes responsible for the conjugation of ISG15 to protein substrates. RIG-I cooperated with STAT1/2 and interferon regulatory factor 1 (IRF1) to promote the activation of the ISGylation pathway. The integrity of ISGylation in ATRA or RIG-I-induced cell differentiation was essential given that knockdown of TRIM25 or ISG15 resulted in significant inhibition of this process. Our results provide insight into the role of the RIG-I-TRIM25-ISGylation axis in myeloid differentiation. [ABSTRACT FROM AUTHOR]

Objectives: To facilitate disease prognosis and improve precise immunotherapy of gastric cancer (GC) patients, a comprehensive study integrating immune cellular and molecular analyses on tumor tissues and peripheral blood was performed. Methods: The association of GC patients' outcomes and the immune context of their tumors was explored using multiplex immunohistochemistry (mIHC) and transcriptome profiling. Potential immune dysfunction mechanism/s in the tumors on the systemic level was further examined using mass cytometry (CyTOF) in complementary peripheral blood from selected patients. GC cohorts with mIHC and gene expression profiling data were also used as validation cohorts. Results: Increased CD4+FOXP3+ T‐cell density in the GC tumor correlated with prolonged survival. Interestingly, CD4+FOXP3+ T cells had a close interaction with CD8+ T cells rather than tumor cells. High densities of CD4+FOXP3+ T cells and CD8+ T cells (High‐High) independently predicted prolonged patient survival. Furthermore, the interferon‐gamma (IFN‐γ) gene signature and PDL1 expression were up‐regulated in this group. Importantly, a subgroup of genomically stable (GS) tumors and tumors with chromosomal instability (CIN) within this High‐High group also had excellent survival. The High‐High GS/CIN tumors were coupled with increased frequencies of Tbet+CD4+ T cells and central memory CD4+ T cells in the peripheral blood. Conclusion: These novel findings identify the combination of CD8+ T cells and FOXP3+CD4+ T cells as a significant prognostic marker for GC patients, which also could potentially be targeted and applied in the combination therapy with immune checkpoint blockades in precision medicine. [ABSTRACT FROM AUTHOR]

Krüppel-like factor (KLF) 15 has emerged as a critical regulator of fibrosis in cardiovascular diseases. However, the precise role that KLF15 and its functional domain played in adventitial inflammation and fibrosis remains unclear. This study aims to investigate the role of the transactivation domain (TAD) of KLF15 in angiotensin II (Ang II)-induced adventitial pathologic changes. KLF15 expression was decreased in the vascular adventitia of Ang II-infused mice (1000 ng/kg/min, 14 d) and in adventitial fibroblasts (AFs) stimulated by Ang II (10-7 M). Adenovirus-mediated KLF15 overexpression normalized Ang II-induced vascular hypertrophy, increased collagen deposition, macrophage infiltration, and CCL2 and VCAM-1 expression. Interestingly, KLF15-ΔTAD (KLF15 with deletion of TAD at amino acids 132-152) overexpression showed no effect on the above pathologic changes. Similarly, perivascularly overexpression of KLF15 but not KLF15-ΔTAD in carotid arteries also attenuated Ang II-induced vascular inflammation and fibrosis. Furthermore, KLF15 overexpression after Ang II infusion rescued Ang II-induced vascular remodeling. CCL2 or VCAM-1-mediated monocyte and macrophage migration or adhesion to AFs in response to Ang II was negatively regulated by KLF15 through TAD. Ang II-enhanced Smad2/3 activation and adventitial migration, proliferation, and differentiation of AFs were suppressed by KLF15 but not KLF15-ΔTAD overexpression. Conversely, small interfering RNA knockdown of KLF15 aggravated Ang II-induced Smad2/3 activation and dysfunction of AFs. Luciferase, coimmunoprecipitation, and chromatin immunoprecipitation assay were used to demonstrate that interaction of KLF15 with Smad2/3 suppressed CCL2 expression through TAD. Mechanistically, activation of Ang II type 1 receptor/phospholipase Cγ 1/ERK1/2 signaling resulted in a decrease of KLF15 expression. In conclusion, these results demonstrate that KLF15 negatively regulates activation of AFs through TAD, which plays an important role in Ang II-induced adventitial inflammation and fibrosis. [ABSTRACT FROM AUTHOR]

Highlights • Exogenous EGCG alleviates multiple abiotic stress, e.g. cold, heat, salt and drought. • EGCG-induced enhanced stress tolerance is attributed to the improved ROS scavenging. • EGCG preferentially triggered apoplastic H2O2 production via NADPH oxidase activation. • Silencing of RBOH1 compromised EGCG-induced reduction of ROS under abiotic stress. • RBOH1 -dependent apoplastic H2O2 is critical for EGCG-induced abiotic stress tolerance. Abstract Responses of plants to abiotic stimuli are mediated by a plethora of bioactive compounds. Flavonoids are a large group of plant secondary metabolites, playing diverse roles in plant growth, development and responses to stress. Despite the recent report on epigallocatechin-3-gallate (EGCG, a bioactive flavonoids)-induced enhanced tolerance to salt stress, the underlying molecular mechanisms of stress tolerance remain unclear. Moreover, whether such stress protective role of EGCG is common for other environmental stressors also remains elusive. In the current study, we showed that EGCG functions as a broad spectrum stress protectant that alleviates a variety of abiotic stresses such as cold, heat, salinity and drought in tomato plants. While those abiotic stresses inhibited leaf photosynthetic activity by enhancing reactive oxygen species (ROS) production and membrane damage, exogenous EGCG protected photosynthetic apparatus by reducing ROS accumulation. Furthermore, EGCG-induced attenuation of ROS accumulation was largely attributed to the enhanced activity of antioxidant enzymes such as superoxide dismutase (SOD), peroxidase (POD), catalase (CAT) and ascorbate peroxidase (APX). Analysis of sub-cellular localization of ROS revealed that EGCG preferentially induced apoplastic H 2 O 2 production by activation of RESPIRATORY BURST OXIDASE HOMOLOG1 (RBOH1)-encoded NADPH oxidase. Further investigation using virus-induced gene silencing showed that suppression of RBOH1 expression aggravated abiotic stress-induced ROS accumulation and compromised EGCG-induced ROS scavenging, implying that RBOH1 -dependent H 2 O 2 production is critical for the EGCG-induced tolerance to abiotic stress. This study advances our current understanding of stress protective role of flavonoids and unveils a critical mechanism of EGCG-induced abiotic stress tolerance in tomato plants. [ABSTRACT FROM AUTHOR]

A series of geminal diethynylethene (gem-DEE) bridged diferrocenyl compounds with varying pendant substituents at the side chain, including xanthene, thioxanthene, dibenzo[a,d]cycloheptene, and fluorene, is reported with the aim of exploring electronic interactions in the cross-conjugated system. The compounds 9-[bis(ferrocenylethynyl)methylene]-9H-xanthene (1), 9-[bis(ferrocenylethynyl)methylene]-9H-thioxanthene (2), 5-[bis(ferrocenylethynyl)methylene]-5H-dibenzo[a,d]cycloheptene (3), and 9-[bis(ferrocenylethynyl)methylene]-9H-fluorene (4) were synthesized and characterized by using spectroscopic methods and single-crystal X-ray diffraction analyses. Electrochemical measurements using the weakly coordinating electrolyte Na[B{C6H3(3,5-CF3)2}4] reveal the moderate electronic coupling between the ferrocenyl (Fc) termini. Hush analysis of the intervalence charge-transfer (IVCT) bands for the monocation species is suggestive of the weakly coupled Robin-Day class II mixed-valence compounds. DFT and TDDFT calculations suggest that the low-energy transitions of these compounds mainly involve a metal to ligand charge transfer (MLCT) transition from the iron center of ferrocenyl termini to the pendant substituent. [ABSTRACT FROM AUTHOR]

Background: Understanding immune phenotypes and human gastric disease in situ requires an approach that leverages multiplexed immunohistochemistry (mIHC) with multispectral imaging to facilitate precise image analyses.Methods: We developed a novel 4-color mIHC assay based on tyramide signal amplification that allowed us to reliably interrogate immunologic checkpoints, including programmed death-ligand 1 (PD-L1), cytotoxic T cells (CD8+T) and regulatory T cells (Foxp3), in formalin-fixed, paraffin-embedded tissues of various human gastric diseases. By observing cell phenotypes within the disease tissue microenvironment, we were able to determine specific co-localized staining combinations and various measures of cell density.Results: We found that PD-L1 was expressed in gastric ulcer and in tumor cells (TCs), as well as in tumor-infiltrating immune cells (TIICs), but not in normal gastric mucosa or other gastric intraepithelial neoplastic tissues. Furthermore, we found no significant reduction in CD8+T cells, whereas the ratio of CD8+T:Foxp3 cells and CD8+T:PD-L1 cells was suppressed in tumor tissues and elevated in adjacent normal tissues. An unsupervised hierarchical analysis also identified correlations between CD8+T and Foxp3+ tumor-infiltrating lymphocyte (TIL) densities and average PD-L1 levels. Three main groups were identified based on the results of CD8+T:PD-L1 ratios in gastric tumor tissues. Furthermore, integrating CD8+T:Foxp3 ratios, which increased the complexity for immune phenotype status, revealed 6-7 clusters that enabled the separation of gastric cancer patients at the same clinical stage into different risk-group subsets.Conclusions: Characterizing immune phenotypes in human gastric disease tissues via multiplexed immunohistochemistry may help guide PD-L1 clinical therapy. Observing unique disease tissue microenvironments can improve our understanding of immune phenotypes and cell interactions within these microenvironments, providing the ability to predict safe responses to immunotherapies. [ABSTRACT FROM AUTHOR]

Apelin has been proved to be a critical mediator of vascular function and homeostasis. Here, we investigated roles of Apelin in aortic remodeling and fibrosis in rats with transverse aortic constriction (TAC). Male Sprague-Dawley rats were subjected to TAC and then randomized to daily deliver Apelin-13 (50 μg/kg) or angiotensin type 1 receptor (AT1) blocker Irbesartan (50 mg/kg) for 4 weeks. Pressure overload resulted in myocardial hypertrophy, systolic dysfunction, aortic remodeling and adventitial fibrosis with reduced levels of Apelin in ascending aortas of rat after TAC compared with sham-operated group. These changes were associated with marked increases in levels of miRNA-122, TGFβ1, CTGF, NFAT5, LGR4, and β-catenin. More importantly, Apelin and Irbesartan treatment strikingly prevented TAC-mediated aortic remodeling and adventitial fibrosis in pressure overloaded rats by blocking AT1 receptor and miRNA-122 levels and repressing activation of the CTGF-NFAT5 and LGR4-β-catenin signaling. In cultured primary rat adventitial fibroblasts, exposure to angiotensin II (100 nmol L −1 ) led to significant increases in cellular migration and levels of TGFβ1, CTGF, NFAT5, LGR4 and β-catenin, which were effectively reversed by pre-treatment with Apelin (100 nmol L −1 ) and miRNA-122 inhibitor (50 nmol L −1 ). In conclusion, Apelin counterregulated against TAC-mediated ascending aortic remodeling and angiotensin II-induced promotion of cellular migration by blocking AT1 receptor and miRNA-122 levels and preventing activation of the TGFβ1-CTGF-NFAT5 and LGR4-β-catenin signaling, ultimately contributing to attenuation of aortic adventitial fibrosis. Our data point to Apelin as an important regulator of aortic remodeling and adventitial fibrosis and a promising target for vasoprotective therapies. [ABSTRACT FROM AUTHOR]

Due to its low cytotoxicity, high resistance to enzymatic degradation, and cellular permeability, a DNA tetrahedron-based molecular beacon (DTMB) is designed for tumor-related TK1 mRNA detection in living cells, where the target sequence can induce the tetrahedron from contraction to extension, resulting in fluorescence restoration. [ABSTRACT FROM AUTHOR]

We report a supersandwich fluorescence in situ hybridization (SFISH) strategy for highly sensitive and selective in situ visualization of mRNA expression patterns at the single-cell level. This strategy uses two fluorophore-labeled signal probes to generate a supersandwich product, which in turn generates numerous signal probes located at the target mRNA position, resulting in the in situ fluorescence signal amplification. [ABSTRACT FROM AUTHOR]

Arsenic is highly effective for treating acute promyelocytic leukemia (APL) and has shown significant promise against many other tumors. However, although its mechanistic effects in APL are established, its broader anticancer mode of action is not understood. In this study, using a human proteome microarray, we identified 360 proteins that specifically bind arsenic. Among the most highly enriched proteins in this set are those in the glycolysis pathway, including the rate-limiting enzyme in glycolysis, hexokinase-1. Detailed biochemical and metabolomics analyses of the highly homologous hexokinase-2 (HK2), which is overexpressed in many cancers, revealed significant inhibition by arsenic. Furthermore, overexpression of HK2 rescued cells from arsenic-induced apoptosis. Our results thus strongly implicate glycolysis, and HK2 in particular, as a key target of arsenic. Moreover, the arsenic-binding proteins identified in this work are expected to serve as a valuable resource for the development of synergistic antitumor therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: The renin-angiotensin system (RAS) has been implicated in atherosclerotic lesions and progression to chronic kidney diseases. We examined regulatory roles of angiotensin-converting enzyme 2 (ACE2) in the apolipoprotein E (ApoE) knockout (KO) kidneys. Methods: The 3-month-old wild-type, ApoEKO, ACE2KO and ApoE/ACE2 double-KO (DKO) mice in a C57BL/6 background were used. The ApoEKO mice were randomized to daily deliver either Ang II (1.5 mg/kg) and/or human recombinant ACE2 (rhACE2; 2 mg/kg) for 2 weeks. We examined changes in pro-inflammatory cytokines, renal ultrastructure, and pathological signaling in mouse kidneys. Results: Downregulation of ACE2 and nephrin levels was observed in ApoEKO kidneys. Genetic ACE2 deletion resulted in modest elevations in systolic blood pressure levels and Ang II type 1 receptor expression and reduced nephrin expression in kidneys of the ApoE/ACE2 DKO mice with a decrease in renal Ang-(1-7) levels. These changes were linked with marked increases in renal superoxide generation, NADPH oxidase (NOX) 4 and proinflammatory factors levels, including interleukin (IL)-1beta, IL-6, IL-17A, RANTES, ICAM-1, Tumor necrosis factor-alpha (TNF-alpha) and TNFRSF1A. Renal dysfunction and ultrastructure injury were aggravated in the ApoE/ACE2 DKO mice and Ang IIinfused ApoEKO mice with increased plasma levels of creatinine, blood urea nitrogen and enhanced levels of Ang II in plasma and kidneys. The Ang II-mediated reductions of renal ACE2 and nephrin levels in ApoEKO mice were remarkably rescued by rhACE2 supplementation, along with augmentation of renal Ang-(1-7) levels. More importantly, rhACE2 treatment significantly reversed Ang II-induced renal inflammation, superoxide generation, kidney dysfunction and adverse renal injury in ApoEKO mice with suppression of the NOX4 and TNF-alpha-TNFRSF1A signaling. However, rhACE2 had no effect on renal NOX2 and TNFRSF1B expression and circulating lipid levels. Conclusions: ACE2 deficiency exacerbates kidney inflammation, oxidative stress and adverse renal injury in the ApoE-mutant mice through modulation of the nephrin, NOX4 and TNF-alpha-TNFRSF1A signaling. While rhACE2 supplementation alleviates inflammation, renal dysfunction and glomerulus injury in the ApoE-mutant mice associated with upregulations of Ang-(1-7) levels and nephrin expression and suppression of the TNF-alpha-TNFRSF1A signaling. Strategies aimed at enhancing the ACE2/Ang-(1-7) actions may have important therapeutic potential for atherosclerotic renal injury and kidney diseases. [ABSTRACT FROM AUTHOR]

Herein we introduce an enzyme-free and amplified colorimetric detection strategy, which is based on gold nanoparticle (AuNP) aggregation through target-catalytic DNA circuits (HCR and CHA). [ABSTRACT FROM AUTHOR]

Background: Angiotensin-converting enzyme 2 (ACE2), a monocarboxypeptidase which metabolizes angiotensin II (Ang II) to generate Ang-(1-7), has been shown to prevent cardiac hypertrophy and injury but the mechanism remains elusive. Irbesartan has the dual actions of angiotensin receptor blockade and peroxisome proliferatoractivated receptor-γ (PPARγ) activation. We hypothesized that irbesartan would exert its protective effects on ACE2 deficiency-mediated myocardial fibrosis and cardiac injury via the PPARγ signaling. Methods: 10-week-old ACE2 knockout (ACE2KO; Ace2-/y) mice received daily with irbesartan (50 mg/kg) or saline for 2 weeks. The wild-type mice (Ace2+/y) were used to the normal controls. We examined changes in myocardial ultrastructure, fibrosis-related genes and pathological signaling by real-time PCR gene array, Western blotting, Masson trichrome staining and transmission electron microscope analyses, respectively. Results: Compared with the Ace2+/y mice, cardiac expression of PPARα and PPARγ were reduced in Ace2-/y mice and the myocardial collagen volume fraction (CVF) and expression of fibrosis-related genes were increased, including transforming growth factor-β1 (TGFβ1), connective tissue growth factor (CTGF), collagen I and collagen III. Moreover, ACE2 deficiency triggered cardiac hypertrophy, increased myocardial fibrosis and adverse ultrastructure injury in ACE2KO hearts with higher levels of atrial natriuretic factor (ANF) and phosphorylated extracellular signalregulated kinase 1/2 (ERK1/2), without affecting cardiac systolic function. Intriguingly, treatment with irbesartan significantly reversed ACE2 deficiency-mediated pathological hypertrophy and myocardial fibrosis in Ace2-/y mice linked with enhancement of plasma Ang-(1-7) level and downregulation of AT1 receptor in heart. Consistent with attenuation of myocardial fibrosis and ultrastructure injury, the myocardial CVF and levels of ANF, TGFβ1, CTGF, collagen I, collagen III and phosphorylated ERK1/2 were lower, and expression of PPARγ was higher in ACE2KO mice in response to irbesartan treatment, without affecting cardiac expression of PPARα, PPARδ, β-myosin heavy chain, TGFβ2 and fibronectin. Conclusions: We conclude that irbesartan prevents ACE2 deficiency-mediated pathological hypertrophy and myocardial fibrosis in ACE2 mutant mice via activation of the PPARγ signaling and suppression of the TGFβ-CTGF -ERK signaling, resulting in attenuation of myocardial injury. Drugs targeting ACE2 and PPARγ represent potential candidates to prevent and treat myocardial injury and related cardiac disorders. [ABSTRACT FROM AUTHOR]

Abstract: In bioelectrochemically reductive dechlorination of chlorinated organic compounds (COCs), the electrons transfer from enzyme in the electrode to COCs was the key step, which determined the average current efficiency (CE) and was influenced by the pH and temperature of the systems. In this work, the effect of temperature (288–318K) and pH (2–11) of the electrolyte on decholrination of trichloroacetic acid (TCA) was investigated in the sodium alginate/hemoglobin-multiwalled carbon nanotubes-graphite composite electrode (Hb/SA–MWCNT–GE). The results showed that the most favourable degradation conditions for TCA by Hb/SA–MWCNT–GE were found to be pH 3 and 310K. By varying the pH of the systems, it was found that a proton accompanied with an electron transfer between the electrode and heme Fe(III)/Fe(II) of Hb during the reaction. Additionally, the activation energy of 26.2kJmol−1 was also calculated by the Arrhenius equation for the reaction. The total mass balance of the reactant and the products was in the range of 97–105% during the bioelectrochemically reductive reaction. The CE only decreased from 87% to 83% when the Hb/SA–MWCNT–GE was used 5 times. Based on the intermediates detected, a pathway was proposed for TCA degradation in which it underwent dechlorination process. The main degradation mechanism described by a parallel reaction rather than by a sequential reaction for dechlorination of TCA in Hb/SA–MWCNT–GE system was proposed. These data provided relevant information about the applicability of bioelectrocatalytic systems for treatment of wastewater contaminated by COCs. [Copyright &y& Elsevier]

This study was to investigate the effect of nicotine on insulin sensitivity and explore the underlying mechanisms. Treatment of Sprague-Dawley rats with nicotine (3 mg/kg/day) for 6 weeks reduced 43% body weight gain and 65% blood insulin level, but had no effect on blood glucose level. Both insulin tolerance test and glucose tolerance test demonstrated that nicotine treatment enhanced insulin sensitivity. Pretreatment of rats with hexamethonium (20 mg/kg/day) to antagonize peripheral nicotinic receptors except for α7 nicotinic acetylcholine receptor (α7-nAChR) had no effect on the insulin sensitizing effect of nicotine. However, the insulin sensitizing effect but not the bodyweight reducing effect of nicotine was abrogated in α7-nAChR knockout mice. Further, chronic treatment with PNU-282987 (0.53 mg/kg/day), a selective α7- nAChR agonist, significantly enhanced insulin sensitivity without apparently modifying bodyweight not only in normal mice but also in AMP-activated kinase-α2 knockout mice, an animal model of insulin resistance with no sign of inflammation. Moreover, PNU-282987 treatment enhanced phosphorylation of signal transducer and activator of transcription 3 (STAT3) in skeletal muscle, adipose tissue and liver in normal mice. PNU-282987 treatment also increased glucose uptake by 25% in C2C12 myotubes and this effect was total abrogated by STAT3 inhibitor, S3I-201. All together, these findings demonstrated that nicotine enhanced insulin sensitivity in animals with or without insulin resistance, at least in part via stimulating α7- nAChR-STAT3 pathway independent of inflammation. Our results contribute not only to the understanding of the pharmacological effects of nicotine, but also to the identifying of new therapeutic targets against insulin resistance. [ABSTRACT FROM AUTHOR]

Glycosylation is one of the most abundant protein posttranslational modifications. Protein glycosylation plays important roles not only in eukaryotes but also in prokaryotes. To further understand the roles of protein glycosylation in prokaryotes, we developed a lectin binding assay to screen glycoproteins on an Escherichia coli proteome microarray containing 4,256 affinity-purified E.coli proteins. Twenty-three E.coli proteins that bound Wheat-Germ Agglutinin (WGA) were identified. PANTHER protein classification analysis showed that these glycoprotein candidates were highly enriched in metabolic process and catalytic activity classes. One sub-network centered on deoxyribonuclease I (sbcB) was identified. Bioinformatics analysis suggests that prokaryotic protein glycosylation may play roles in nucleotide and nucleic acid metabolism. Fifteen of the 23 glycoprotein candidates were validated by lectin (WGA) staining, thereby increasing the number of validated E. coli glycoproteins from 3 to 18. By cataloguing glycoproteins in E.coli, our study greatly extends our understanding of protein glycosylation in prokaryotes. [ABSTRACT FROM AUTHOR]

Abstract: To develop early diagnostic reagents, effective vaccines, and even drugs against SARS-associated coronavirus (SARS-CoV), the human single fold single-chain antibody fragments, (scFv) libraries I+J (Tomlinson I+J) were used to identify novel scFvs, which can specifically bind to SARS-CoV. Interestingly, two scFvs (B5 and B9) exhibited higher binding specificity to SARS-CoV with the OD450 value 0.608 and 0.545, respectively, and their coding sequences shared the identical sequence composed of VH gene (351bp) and VL gene (327bp), so the two scFvs were uniformly named as SA59B and chosen for further analysis. SA59B scFv was expressed in soluble form in Escherichia coli HB2151 and purified by immobilized metal affinity chromatography. The soluble 30kDa SA59B scFv-antibody was verified in SDS–PAGE and Western-blot. The purified SA59B scFv-antibody was labeled with HRP by the glutaraldehyde method, and the concentration of HRP and SA59B scFv-antibody in the SA59B-HRP solution reached 2.4 and 2.28mg/ml, respectively. Then, the binding ability of SA59B-HRP to SARS-CoV was evaluated by ELISA with S/N of 11.6, indicating higher binding specificity between them. Finally, both the SA59B sequence specificity and its application for diagnosis, prophylaxis or therapy of SARS were discussed. [Copyright &y& Elsevier]

Hypertensive renal injury is accompanied by tubular interstitial fibrosis leading to increased risk for renal failure. This study aimed to explore the influences of miR-122–5p in hypertension-mediated renal fibrosis and damage. 14-week-old male SHR and WKY rats were randomly assigned to treat with rAAV-miR-122–5p or rAAV-GFP for 8 weeks. There were marked increases in miR-122–5p and Kim-1 levels and decreases in FOXO3 and SIRT6 levels in hypertensive rats. Transfection with rAAV-miR-122–5p triggered exacerbation of renal fibrosis, apoptosis and inflammatory injury in SHR, associated with downregulated levels of FOXO3, SIRT6, ATG5 and BNIP3 as well as upregulated expression of Kim-1, NOX4, CTGF, and TGF-β1. In cultured primary mouse renal tubular interstitial fibroblasts, exposure to angiotensin II resulted in obvious downregulation of FOXO3, SIRT6, ATG5, BNIP3 and nitric oxide levels as well as augmented cellular migration, oxidative stress, and inflammation, which were exacerbated by miR-122–5p mimic while rescued by miR-122–5p inhibitor and rhFOXO3, respectively. Notably, knockdown of FOXO3 strikingly blunted cellular protective effects of miR-122–5p inhibitor. In summary, miR-122–5p augments renal fibrosis, inflammatory and oxidant injury in hypertensive rats by suppressing the expression of FOXO3. Pharmacological inhibition of miR-122–5p has potential therapeutic significance for hypertensive renal injury and fibrosis-related kidney diseases. • MiR-122–5p leads to loss of FOXO3 and promotion of tubular interstitial fibrosis in kidneys of hypertensive rats. • There are increases in renal apoptosis, inflammation and superoxide generation in rAAV-miR-122-5p-treated hypertensive rats. • Inhibition of miR-122–5p alleviates inflammatory injury in mouse renal tubular interstitial fibroblasts by activating FOXO3. • FOXO3 and miR-122–5p inhibitors are potential therapeutic targets for patients with hypertensive renal fibrosis. [ABSTRACT FROM AUTHOR]

Phenolics are the main bioactive components in tea and greatly contribute to human health. Three phenolic‐enriched extracts, the ethyl acetate fraction (TEF), n‐butanol fraction (TBF), and water fraction (TWF), were obtained from Tieguanyin oolong tea, which is considered a typical type of semi‐fermented tea. The chemicals in the extracts and their antioxidant activity and cytotoxicity against 4T1 breast cancer cells were investigated in the present work. TEF was found to have the highest contents of phenolics, flavonoids, procyanidins, sugars, and catechin monomers. Meanwhile, TEF exhibited the strongest antioxidant capacity, which may be due to its abundant bioactive compounds, as validated by Pearson correlation and hierarchical clustering analysis. Furthermore, TEF showed greater inhibition of the growth of 4T1 murine breast cancer cells than TBF and TWF. Practical applications: Fermentation during the processing of oolong tea causes many alterations in polyphenols, leading to different bioactivities. In the present work, three phenolic‐enriched extracts, the ethyl acetate fraction (TEF), n‐butanol fraction (TBF), and water fraction (TWF), were obtained from Tieguanyin oolong tea. Further tests showed that TEF and TBF from Tieguanyin oolong tea possessed remarkable antioxidant activity and inhibitory potential inhibition of the growth of 4T1 murine breast cancer cells in vitro due to their main bioactive compounds, including phenolics and flavonoids. Thus, the phenolic‐enriched extracts from Tieguanyin tea are expected to have a potential application in the food and pharmaceutical industries after further study. [ABSTRACT FROM AUTHOR]

Background: The renin-angiotensin system (RAS) has been implicated in atherosclerotic lesions and progression to chronic kidney diseases. We examined regulatory roles of angiotensin-converting enzyme 2 (ACE2) in the apolipoprotein E (ApoE) knockout (KO) kidneys.Methods: The 3-month-old wild-type, ApoEKO, ACE2KO and ApoE/ACE2 double-KO (DKO) mice in a C57BL/6 background were used. The ApoEKO mice were randomized to daily deliver either Ang II (1.5 mg/kg) and/or human recombinant ACE2 (rhACE2; 2 mg/kg) for 2 weeks. We examined changes in pro-inflammatory cytokines, renal ultrastructure, and pathological signaling in mouse kidneys.Results: Downregulation of ACE2 and nephrin levels was observed in ApoEKO kidneys. Genetic ACE2 deletion resulted in modest elevations in systolic blood pressure levels and Ang II type 1 receptor expression and reduced nephrin expression in kidneys of the ApoE/ACE2 DKO mice with a decrease in renal Ang-(1-7) levels. These changes were linked with marked increases in renal superoxide generation, NADPH oxidase (NOX) 4 and proinflammatory factors levels, including interleukin (IL)-1beta, IL-6, IL-17A, RANTES, ICAM-1, Tumor necrosis factor-alpha (TNF-alpha) and TNFRSF1A. Renal dysfunction and ultrastructure injury were aggravated in the ApoE/ACE2 DKO mice and Ang II-infused ApoEKO mice with increased plasma levels of creatinine, blood urea nitrogen and enhanced levels of Ang II in plasma and kidneys. The Ang II-mediated reductions of renal ACE2 and nephrin levels in ApoEKO mice were remarkably rescued by rhACE2 supplementation, along with augmentation of renal Ang-(1-7) levels. More importantly, rhACE2 treatment significantly reversed Ang II-induced renal inflammation, superoxide generation, kidney dysfunction and adverse renal injury in ApoEKO mice with suppression of the NOX4 and TNF-alpha-TNFRSF1A signaling. However, rhACE2 had no effect on renal NOX2 and TNFRSF1B expression and circulating lipid levels.Conclusions: ACE2 deficiency exacerbates kidney inflammation, oxidative stress and adverse renal injury in the ApoE-mutant mice through modulation of the nephrin, NOX4 and TNF-alpha-TNFRSF1A signaling. While rhACE2 supplementation alleviates inflammation, renal dysfunction and glomerulus injury in the ApoE-mutant mice associated with upregulations of Ang-(1-7) levels and nephrin expression and suppression of the TNF-alpha-TNFRSF1A signaling. Strategies aimed at enhancing the ACE2/Ang-(1-7) actions may have important therapeutic potential for atherosclerotic renal injury and kidney diseases. [ABSTRACT FROM AUTHOR]

Based on laser radar equations, a Doppler shift model of a laser pulse beam scattered by a rotating arbitrary convex target is reported in this paper. The boundary relations between an incident pulse beam and the detected area elements are analyzed by geometric methods. The Doppler shift characteristics of the rotating cone and cylinder are discussed and the difference between the laser pulse beam and the plane wave scattered from the same rotating target is compared accordingly. Numerical simulations show that the Doppler shift is tightly relevant to their dimensions, speeds, and so on. In the same incidence conditions, the pulse beam and plane wave have difference peak values and the same Doppler shift bandwidth. If the waist radius of the pulse beam is larger, the peak value is higher, and the Doppler shifts are proportional to the speed of the rotating target. By virtue of our theoretical model, we probe into the scattered characteristics of the Doppler shifts of a laser pulse beam, which would benefit target identification in national defense. [ABSTRACT FROM AUTHOR]

Background: Angiotensin-converting enzyme 2 (ACE2), a monocarboxypeptidase which metabolizes angiotensin II (Ang II) to generate Ang-(1-7), has been shown to prevent cardiac hypertrophy and injury but the mechanism remains elusive. Irbesartan has the dual actions of angiotensin receptor blockade and peroxisome proliferator-activated receptor-γ (PPARγ) activation. We hypothesized that irbesartan would exert its protective effects on ACE2 deficiency-mediated myocardial fibrosis and cardiac injury via the PPARγ signaling.Methods: 10-week-old ACE2 knockout (ACE2KO; Ace2(-/y)) mice received daily with irbesartan (50 mg/kg) or saline for 2 weeks. The wild-type mice (Ace2(+/y)) were used to the normal controls. We examined changes in myocardial ultrastructure, fibrosis-related genes and pathological signaling by real-time PCR gene array, Western blotting, Masson trichrome staining and transmission electron microscope analyses, respectively.Results: Compared with the Ace2(+/y) mice, cardiac expression of PPARα and PPARγ were reduced in Ace2(-/y) mice and the myocardial collagen volume fraction (CVF) and expression of fibrosis-related genes were increased, including transforming growth factor-β1 (TGFβ1), connective tissue growth factor (CTGF), collagen I and collagen III. Moreover, ACE2 deficiency triggered cardiac hypertrophy, increased myocardial fibrosis and adverse ultrastructure injury in ACE2KO hearts with higher levels of atrial natriuretic factor (ANF) and phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), without affecting cardiac systolic function. Intriguingly, treatment with irbesartan significantly reversed ACE2 deficiency-mediated pathological hypertrophy and myocardial fibrosis in Ace2(-/y) mice linked with enhancement of plasma Ang-(1-7) level and downregulation of AT1 receptor in heart. Consistent with attenuation of myocardial fibrosis and ultrastructure injury, the myocardial CVF and levels of ANF, TGFβ1, CTGF, collagen I, collagen III and phosphorylated ERK1/2 were lower, and expression of PPARγ was higher in ACE2KO mice in response to irbesartan treatment, without affecting cardiac expression of PPARα, PPARδ, β-myosin heavy chain, TGFβ2 and fibronectin.Conclusions: We conclude that irbesartan prevents ACE2 deficiency-mediated pathological hypertrophy and myocardial fibrosis in ACE2 mutant mice via activation of the PPARγ signaling and suppression of the TGFβ-CTGF-ERK signaling, resulting in attenuation of myocardial injury. Drugs targeting ACE2 and PPARγ represent potential candidates to prevent and treat myocardial injury and related cardiac disorders. [ABSTRACT FROM AUTHOR]