Arctigenin Attenuates Ischemia/Reperfusion Induced Ventricular Arrhythmias by Decreasing Oxidative Stress in Rats.

BACKGROUND/AIMS: Arctigenin (ATG) has been shown to possess anti-inflammatory, immunemodulatory, anti-viral, anti-microbial, anti-carcinogenic, vasodilatory and anti-platelet aggregation properties. However, the protective role of ATG in prevention of arrhythmias induced by myocardial ischemia/reperfusion is unknown. The aim of this study was to investigate the anti-arrhythmia effect of ATG in an ischemia/reperfusion injured rat heart model and explore the related mechanisms. METHODS: Rats were randomly exposed to sham operation, myocardial ischemia/ reperfusion (MI/R) alone, ATG+ MI/R, pretreated with ATG in low (12.5 mg/kg/day), medium (50 mg/kg/day) and high dose (200 mg/kg/day), respectively. Ventricular arrhythmias were assessed. The activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and the level of malondialdehyde (MDA) in myocardial tissue were determined by chemical analysis. RESULTS: Compared to MI/R, rats pretreated with ATG in doses of 50 mg/kg/day and 200 mg/kg/day showed significantly reduced incidence and duration of ventricular fibrillation, ventricular tachycardia and ventricular ectopic beat (VEB), and decreased the arrhythmia score during the 30-min ischemia. Incidence and duration of ventricular tachycardia, infarction size and arrhythmia scores in these groups were significantly decreased during the 120-min reperfusion. No ventricular fibrillation occurred during the period of reperfusion. Rats pretreated with ATG in doses of 50 mg/kg/day and 200 mg/kg/ day markedly enhanced the activities of antioxidant enzymes SOD and GSH-Px, reduced the level of MDA. No differences were observed between the group pretreated with a low dose of ATG and the sham group. Administration of ATG significantly increased the expression of antioxidant stress protein Nrf2, Trx1 and Nox1. CONCLUSION: Our data suggested that ATG plays anti-arrhythmia role in ischemia/reperfusion injury, which is probably associated with attenuating oxidative stress by Nrf2 signaling pathway.

Amine-Functionalized Silica Nanoparticles with Drug and Gene Co-Delivery for Anti-Angiogenesis Therapy of Breast Cancer.

In our study, we report on the design and characterization of a combined angiogenesis therapy for breast cancer based on well-formed amine-functionalized silica nanoparticles (SLNs). The aminefunctionalized SLNs was employed to simultaneously deliver angiostatin (ANG) plasmid and candesartan (CD) to the same cancer cell. The well-formed ANG/CD/SLNs exhibited small particle size, reasonable positive charges, excellent loading of drug and gene in vitro. Moreover, aminefunctionalized SLNs were almost no cytotoxicity. ANG/CD/SLNs resulted in enhanced gene transfection compared to naked plasmid. More importantly, ANG/CD/SLNs as a co-delivery system achieved a stronger inhibitory effect on angiogenesis in vitro, possibly resulting from significant downregulation of vascular endothelial growth factor (VEGF) expression via different pathways. In particular, in vivo investigation on nude mice bearing MCF-7 xenografts confirmed that ANG/CD/SLNs codelivery system exerted strong anti-tumor efficacy by synergistic antiangiogenic mechanism.

Staphylococcus Aureus Induces Osteoclastogenesis via the NF-κB Signaling Pathway.

BACKGROUND Osteomyelitis is one of the refractory diseases encountered in orthopedics, while Staphylococcus aureus (S. aureus) is the most common causative organism in osteomyelitis. However, the precise mechanisms underlying the bone loss caused by S. aureus infection have not been well defined. Here, we investigated the effect of S. aureus on osteoclast differentiation and the probable molecular mechanism. MATERIAL AND METHODS RAW 264.7 cells were treated for 5 days with live S. aureus, inactivated S. aureus, and S. aureus filtrate. Then, the formation of osteoclast-like cells and resorption pits was observed, and the expression of osteoclast-specific genes (TRAP, MMP-9, cathepsin K, CTR and Atp6v0d2) was detected by real-time PCR. Moreover, key proteins in the signaling pathway associated with osteoclast differentiation were detected with Western blot. RESULTS The data showed that live S. aureus, inactivated S. aureus, and S. aureus filtrate induced osteoclast formation, promoted bone resorption, and increased the expression of osteoclast-specific genes in a dose-dependent manner in the absence RANKL. In addition, we found that the S. aureus-induced osteoclastogenesis was related to the degradation of IκB-a, phosphorylation of NF-κB p65, and increased expression of NFATc1. Thus, we used JSH-23 to inhibit NF-κB transcriptional activity. The effect of the S. aureus-induced osteoclastogenesis and the expression of osteoclast-specific genes and NFATc1 were inhibited, which indicated that the NF-κB signaling pathway plays a role in S. aureus-induced osteoclastogenesis. CONCLUSIONS This study demonstrated that S. aureus induces osteoclastogenesis through its cell wall compound and secretion of small soluble molecules, and the NF-κB signaling pathway plays a role in this process.

Spatial patterns of Holocene temperature changes over mid-latitude Eurasia.

The Holocene temperature conundrum, the discrepancy between proxy-based Holocene global cooling and simulated global annual warming trends, remains controversial. Meanwhile, reconstructions and simulations show inconsistent spatial patterns of terrestrial temperature changes. Here we report Holocene alkenone records to address spatial patterns over mid-latitude Eurasia. In contrast with long-term cooling trends in warm season temperatures in northeastern China, records from southwestern Siberia are characterized by colder conditions before ~6,000 years ago, thus long-term warming trends. Together with existing records from surrounding regions, we infer that colder airmass might have prevailed in the interior of mid-latitude Eurasian continent during the early to mid-Holocene, perhaps associated with atmospheric response to remnant ice sheets. Our results challenge the proposed seasonality bias in proxies and modeled spatial patterns in study region, highlighting that spatial patterns of Holocene temperature changes should be re-considered in record integrations and model simulations, with important implications for terrestrial hydroclimate changes.

The Role of Polaronic States on the Spin Dynamics in Solution-Processed Two-Dimensional Layered Perovskite with Different Layer Thickness.

2D lead halide perovskites (LHPs) show strong excitonic and spin-orbit coupling effects, generating a facile spin injection. Besides, they possess a polaron character due to the soft crystal lattice, which can prolong the spin lifetime, making them favorable materials for spintronic applications. Here, the spin dynamics of 2D PEA2 PbI4 (MAPbI3 )n -l thin films with different layers by temperature- and pump fluence-dependent circularly polarization-resolved transient absorption (TA) measurements is studied. These results indicate that the spin depolarization mechanism is gradually converted from the Maialle-Silva-Sham (MSS) mechanism to the polaronic states protection mechanism with the layer number increasing from = 1 to 3, which is determined by the interplay between the strength of Coulomb exchange interaction and the strength of polaronic effect. While for ≥ 4, the Elliot-Yafet (EY) impurities mechanism is proposed, in which the formed polaronic states with free charge carriers no longer play the protective role.

The N6-methyladenosine METTL3 regulates tumorigenesis and glycolysis by mediating m6A methylation of the tumor suppressor LATS1 in breast cancer.

BACKGROUND: Posttranscriptional modification of tumor-associated factors plays a pivotal role in breast cancer progression. However, the underlying mechanism remains unknown. M6A modifications in cancer cells are dynamic and reversible and have been found to impact tumor initiation and progression through various mechanisms. In this study, we explored the regulatory mechanism of breast cancer cell proliferation and metabolism through m6A methylation in the Hippo pathway.  METHODS: A combination of MeRIP-seq, RNA-seq and metabolomics-seq was utilized to reveal a map of m6A modifications in breast cancer tissues and cells. We conducted RNA pull-down assays, RIP-qPCR, MeRIP-qPCR, and RNA stability analysis to identify the relationship between m6A proteins and LATS1 in m6A regulation in breast cancer cells. The expression and biological functions of m6A proteins were confirmed in breast cancer cells in vitro and in vivo. Furthermore, we investigated the phosphorylation levels and localization of YAP/TAZ to reveal that the activity of the Hippo pathway was affected by m6A regulation of LATS1 in breast cancer cells.  RESULTS: We demonstrated that m6A regulation plays an important role in proliferation and glycolytic metabolism in breast cancer through the Hippo pathway factor, LATS1. METTL3 was identified as the m6A writer, with YTHDF2 as the reader protein of LATS1 mRNA, which plays a positive role in promoting both tumorigenesis and glycolysis in breast cancer. High levels of m6A modification were induced by METTL3 in LATS1 mRNA. YTHDF2 identified m6A sites in LATS1 mRNA and reduced its stability. Knockout of the protein expression of METTL3 or YTHDF2 increased the expression of LATS1 mRNA and suppressed breast cancer tumorigenesis by activating YAP/TAZ in the Hippo pathway. CONCLUSIONS: In summary, we discovered that the METTL3-LATS1-YTHDF2 pathway plays an important role in the progression of breast cancer by activating YAP/TAZ in the Hippo pathway.

Exciton-Phonon Coupling of Chiral One-Dimensional Lead-Free Hybrid Metal Halides at Room Temperature.

The interaction between organic cations and inorganic metal halide octahedral units strongly affects the properties of organic-inorganic hybrid metal halides. The "soft" property of the lattice provides the possibility of its strong exciton-phonon interaction. Here we report one-dimensional (1D) lead-free chiral organic-inorganic hybrid metal halide single crystals of (R/S)-methylbenzylamine bismuth iodide (R/S-MBA)2Bi2I8, which exhibits a high level of octahedral bond distortion. The introduction of chiral amines leads to a strong chiroptical response in the range of 200-600 nm. The strong exciton-phonon coupling can be observed through the coherent oscillation spectrum of transient absorption dynamics at room temperature. The coherent phonon oscillation frequencies are ∼97 and ∼130 cm-1, corresponding to the symmetrical stretching or bending of the Bi-I octahedron. Our work provides new insights for the study of exciton-phonon coupling in 1D chiral hybrid metal halides.

Inhibition of RFX6 Suppresses the Invasive Ability of Tumor Cells Through the Notch Pathway and Affects Tumor Immunity in Hepatocellular Carcinoma.

BACKGROUND: The DNA-binding protein RFX6 was overexpressed in hepatocellular carcinoma, and its expression level was correlated with the prognosis and immune cell infiltration in liver hepatocellular carcinoma. However, the mechanism of the abnormal expression and the biological effects of RFX6 in liver cancer remains unknown. METHODS: To understand the specific expression mechanism of RFX6 in liver cancer, we performed bioinformatic prediction, CHIP-qPCR assay, co-IP, and dual-luciferase assay to assess the regulating mechanism of RFX6. In the meantime, a series of biological experiments in vivo and in vitro were conducted to analyze the biological significance of RFX6 in hepatocellular carcinoma. RESULTS: We demonstrated that knockdown of RFX6 in liver cancer cells significantly suppressed the proliferation, migration, and invasion of cancer cells. Moreover, inhibition of RFX6 could affect the immune response of T cells. Among a number of interacting proteins, we revealed that RFX6 directly binds to DTX2, a regulator of the Notch signaling pathway by targeting NOTCH1, and helps in its transcription stability. Furthermore, we discovered that miRNA-542-3p, the expression of which was decreased in hepatocellular carcinoma, was directly involved in the negative regulation of the expression of RFX6. CONCLUSION: In summary, we discovered that the miRNA-542-3p-RFX6-DTX2-NOTCH1 regulatory pathway played significant roles in the tumor progression of liver hepatocellular carcinoma.

NEAT1 promotes cell proliferation and invasion in hepatocellular carcinoma by negative regulating miR-613 expression.

BACKGROUND: Long non-coding RNA nuclear-enriched abundant transcript 1 (NEAT1) was found to be participated in tumorigenesis in various cancers including hepatocellular carcinoma (HCC). However, the clinical implication and underling function of NEAT1 in HCC have not been fully known. METHODS: The relative NEAT1 expression was examined by qRT-PCR in HCC tissues and cells, compared with adjacent normal tissues and normal human hepatocyte (LO2) cells, respectively. Cell proliferation and invasion were examined by MTT, cell colony formation and transwell assays. Luciferase reporter assay was performed to verify miR-613 was a direct target of NEAT1. Western blot analysis was also performed. RESULTS: NEAT1 was notably upregulated in HCC tissues and cells. Higher NEAT1 expression associated with larger tumor size and vascular invasion of HCC patients. Knockdown of NEAT1 significantly suppressed HCC cell proliferation, colony formation and cell invasion. Interestingly, lower miR-613 expression negatively associated with the NEAT1 expression in HCC tissues and was regulated by NEAT1. Additionally, we demonstrated that NEAT1 promoted HCC cell proliferation and invasion by regulating miR-613 expression. CONCLUSION: These results implied that inhibition of NEAT1 may be a potential therapeutic strategy for HCC patients.

Staphylococcus aureus Protein A induces osteoclastogenesis via the NF­κB signaling pathway.

Staphylococcus aureus (S. aureus) is the most common organism causing osteomyelitis, and Staphylococcus aureus protein A (SpA) is an important virulence factor anchored in its cell wall. However, the precise mechanisms underlying the bone loss caused by SpA have not been well understood. The present study aimed to investigate the effect of SpA on osteoclast differentiation, and the probable mechanism was investigated. Raw264.7 cells were treated with SpA in the absence or presence of receptor­activated (NF)­κB ligand for 5 days, and morphological and biochemical assays were used to assess osteoclastogenesis and explore the underlying mechanisms. Data demonstrated that SpA induced osteoclast differentiation and promoted bone resorption in a dose­dependent manner in the absence or presence of RANKL. In addition, the expression of osteoclast­specific genes, such as the tartrate resistant acid phosphatase, matrix metalloproteinase­9, cathepsin K, calcitonin receptors and d2 isoform of the vacuolar ATPase Vo domain, were enhanced by SpA. Furthermore, the SpA­induced osteoclast differentiation was associated with the degradation of inhibitor of κB­α, phosphorylation of NF­κB p65 and increased expression of nuclear factor of activated T­cells. However, by treatment with JSH­23, an NF­κB inhibitor, the formation of osteoclast­like cells and resorption pits was significantly reduced, and the expression of osteoclast­specific genes was also inhibited. Collectively, in the present study SpA induced osteoclast differentiation, promoted bone resorption, and the NF­κB signaling pathway was involved in this process.

Combined identification of long non-coding RNA CCAT1 and HOTAIR in serum as an effective screening for colorectal carcinoma.

Long non-coding RNAs (lncRNAs) CCAT1 and HOTAIR have been shown to play an important regulatory role in cancer biology, and CCAT1 and HOTAIR are upregulated in several cancers, however, its value in the diagnosis of colorectal cancer (CRC) is unclear. Therefore, the aim of this study is to evaluate the clinical significance of plasma CCAT1 and HOTAIR as a biomarker in the screening of CRC. In our study, we found that the levels of HOTAIR (P < 0.05) and CCAT1 (P < 0.05) were significantly higher in plasma of CRC patients than that of the healthy control. Moreover, the levels of lincRNA-p21 (P < 0.05) were obviously decreased in plasma of CRC patients as compared to those of healthy control. There was highly correlated for CCAT1 (R = 0.752, mean differences = -0.06 ± 1.20), HOTAIR (R = 0.739, mean differences = -0.26 ± 0.76) and lincRNA-p21 (R = 0.848, mean differences = -0.41 ± 0.89) in plasma and serum. By receiver operating characteristic curve (ROC) analysis, plasma CCAT1 provided the higher diagnostic performance for detection of CRC (the area under the ROC curve (AUC), 0.836; P < 0.001; sensitivity, 75.7%; specificity, 85.3%). Moreover, CCAT1 combining with HOTAIR could provide a more effective diagnosis performance (AUC, 0.954, P < 0.001, sensitivity, 84.3%; specificity, 80.2%). Most importantly, this combination was effective to detect CRC at an early stage (85%). In conclusion, our results demonstrated that increased plasma HOTAIR and CCAT1 could be used as a predictive biomarker for CRC screening, and that combination of HOTAIR and CCAT1 had a higher positive diagnostic rate of CRC than HOTAIR or CCAT1 alone.

Onset of frequent dust storms in northern China at ~AD 1100.

Dust storms in northern China strongly affect the living and health of people there and the dusts could travel a full circle of the globe in a short time. Historically, more frequent dust storms occurred during cool periods, particularly the Little Ice Age (LIA), generally attributed to the strengthened Siberian High. However, limited by chronological uncertainties in proxy records, this mechanism may not fully reveal the causes of dust storm frequency changes. Here we present a late Holocene dust record from the Qaidam Basin, where hydrological changes were previously reconstructed, and examine dust records from northern China, including the ones from historical documents. The records, being broadly consistent, indicate the onset of frequent dust storms at ~AD 1100. Further, peaked dust storm events occurred at episodes of high total solar irradiance or warm-dry conditions in source regions, superimposed on the high background of frequent dust storms within the cool LIA period. We thus suggest that besides strong wind activities, the centennial-scale dust storm events over the last 1000 years appear to be linked to the increased availability of dust source. With the anticipated global warming and deteriorating vegetation coverage, frequent occurrence of dust storms in northern China would be expected to persist.