Salvianolic Acid B Alleviates High Glucose-Induced Vascular Smooth Muscle Cell Inflammation by Upregulating the miR-486a-5p Expression.

The macrovascular complications of diabetes cause high mortality and disability in patients with type 2 diabetes mellitus (T2DM). The inflammatory response of vascular smooth muscle cell (VSMC) runs through its pathophysiological process. Salvianolic acid B (Sal B) exhibits beneficial effects on the cardiovascular system. However, its role and mechanism in diabetic vascular inflammatory response remain unclear. In this study, we found that Sal B reduced vascular inflammation in diabetic mice and high glucose- (HG-) induced VSMC inflammation. Subsequently, we found that Sal B reduced HG-induced VSMC inflammation by downregulating FOXO1. Furthermore, miR-486a-5p expression was obviously reduced in HG-treated VSMC. Sal B attenuated HG-induced VSMC inflammation by upregulating miR-486a-5p. Loss- and gain-of-function experiments had proven that the transfection of the miR-486a-5p mimic inhibited HG-induced VSMC inflammation whereas that of the miR-486a-5p inhibitor promoted HG-induced VSMC inflammation, thereby leading to the amelioration of vascular inflammation in the diabetic mice. Furthermore, studies had shown that miR-486a-5p inhibited FOXO1 expression by directly targeting its 3'-UTR. In conclusion, Sal B alleviates the inflammatory response of VSMC by upregulating miR-486a-5p and aggravating its inhibition of FOXO1 expression. Sal B exerts a significant anti-inflammatory effect in HG-induced VSMC inflammation by modulating the miR-486a-5p/FOXO1 axis.

17ß-estradiol reduces NF-κB expression induced by increased crosstalk between KLF5 and ERα in murine vascular smooth muscle cells.

Pathological vascular remodeling and cell proliferation play vital roles in many proliferative vascular diseases. Estrogen can protect the cardiovascular system, but its exact molecular mechanism is unknown. Here we report that 17ß-estradiol (E2) suppressed vascular smooth muscle cells (VSMCs) proliferation and inflammation. qRT-PCR and Western blot demonstrated that E2 decreased NF-κB p50 expression and reduced VSMCs proliferation and inflammation. Mechanistically, a dual luciferase reporter assay and chromatin immunoprecipitation suggested that KLF5 promoted NF-κB p50 expression by binding to the NF-κB p50 promoter, whereas E2 reduced the effect of KLF5 binding to the NF-κB p50 promoter and inhibited NF-κB p50 expression. Furthermore, a coimmunoprecipitation assay and immunofluorescence staining showed that the interaction between KLF5 and ERα increased in VSMCs treated with E2, which in turn decreased NF-κB p50 expression levels. Altogether, we reveal that E2 inhibits VSMCs proliferation and inflammation by reducing NF-κB expression induced by an increased interaction between KLF5 and ERα. These data provide further insights into how E2 inhibits vascular proliferation and inflammation.

Arbitrary superposition of plasmonic orbital angular momentum states with nanostructures.

A kind of plasmonic nanostructure is proposed that can generate the arbitrary superposition of orbital angular momentum (OAM) states in surface plasmons (SPs), which is achieved by combining the segmented spirals with nanoslit pairs. The structures can independently modulate both the phase and amplitude of SP waves, and thus enable the superposition of two OAM states with arbitrary topological charges (TCs) as well as free control of their relative amplitudes. Superposed states distributed over the entire Bloch sphere and hybrid superposed states with different TCs were constructed and experimentally demonstrated. This work will offer more opportunities for multifunctional plasmonic devices.

PRMT5-mediated histone arginine methylation antagonizes transcriptional repression by polycomb complex PRC2.

Protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetric di-methylation of arginine residues in histones H3 and H4, marks that are generally associated with transcriptional repression. However, we found that PRMT5 inhibition or depletion led to more genes being downregulated than upregulated, indicating that PRMT5 can also act as a transcriptional activator. Indeed, the global level of histone H3K27me3 increases in PRMT5 deficient cells. Although PRMT5 does not directly affect PRC2 enzymatic activity, methylation of histone H3 by PRMT5 abrogates its subsequent methylation by PRC2. Treating AML cells with an EZH2 inhibitor partially restored the expression of approximately 50% of the genes that are initially downregulated by PRMT5 inhibition, suggesting that the increased H3K27me3 could directly or indirectly contribute to the transcription repression of these genes. Indeed, ChIP-sequencing analysis confirmed an increase in the H3K27me3 level at the promoter region of a quarter of these genes in PRMT5-inhibited cells. Interestingly, the anti-proliferative effect of PRMT5 inhibition was also partially rescued by treatment with an EZH2 inhibitor in several leukemia cell lines. Thus, PRMT5-mediated crosstalk between histone marks contributes to its functional effects.

Different roles of E proteins in t(8;21) leukemia: E2-2 compromises the function of AETFC and negatively regulates leukemogenesis.

The AML1-ETO fusion protein, generated by the t(8;21) chromosomal translocation, is causally involved in nearly 20% of acute myeloid leukemia (AML) cases. In leukemic cells, AML1-ETO resides in and functions through a stable protein complex, AML1-ETO-containing transcription factor complex (AETFC), that contains multiple transcription (co)factors. Among these AETFC components, HEB and E2A, two members of the ubiquitously expressed E proteins, directly interact with AML1-ETO, confer new DNA-binding capacity to AETFC, and are essential for leukemogenesis. However, the third E protein, E2-2, is specifically silenced in AML1-ETO-expressing leukemic cells, suggesting E2-2 as a negative factor of leukemogenesis. Indeed, ectopic expression of E2-2 selectively inhibits the growth of AML1-ETO-expressing leukemic cells, and this inhibition requires the bHLH DNA-binding domain. RNA-seq and ChIP-seq analyses reveal that, despite some overlap, the three E proteins differentially regulate many target genes. In particular, studies show that E2-2 both redistributes AETFC to, and activates, some genes associated with dendritic cell differentiation and represses MYC target genes. In AML patients, the expression of E2-2 is relatively lower in the t(8;21) subtype, and an E2-2 target gene, THPO, is identified as a potential predictor of relapse. In a mouse model of human t(8;21) leukemia, E2-2 suppression accelerates leukemogenesis. Taken together, these results reveal that, in contrast to HEB and E2A, which facilitate AML1-ETO-mediated leukemogenesis, E2-2 compromises the function of AETFC and negatively regulates leukemogenesis. The three E proteins thus define a heterogeneity of AETFC, which improves our understanding of the precise mechanism of leukemogenesis and assists development of diagnostic/therapeutic strategies.

Generation of vector beams of Bell-like states by manipulating vector vortex modes with plasmonic metasurfaces.

Metasurfaces with orthogonal nano-slit pairs arranged on spirals are proposed to generate vector beams (VBs) of Bell-like states and slanted polarizations. The design of the metasurfaces is based on the theoretically derived parameter condition for manipulation of the two vector vortex modes, which is satisfied by matching the three parameters of rotation order m, the spiral order n, and incident polarization helicity σ. The linear polarization states of the VBs are controlled by the initial orientation angle φ0 of slit pairs. VBs of satisfying quality are experimentally obtained, with the analytical and simulated results validated.

Hydrophobic Surface Coating Can Reduce Toxicity of Zinc Oxide Nanoparticles to the Marine Copepod Tigriopus japonicus.

Coated zinc oxide nanoparticles (ZnO-NPs) are more commonly applied in commercial products but current risk assessments mostly focus on bare ZnO-NPs. To investigate the impacts of surface coatings, this study examined acute and chronic toxicities of six chemicals, including bare ZnO-NPs, ZnO-NPs with three silane coatings of different hydrophobicity, zinc oxide bulk particles (ZnO-BKs), and zinc ions (Zn-IONs), toward a marine copepod, Tigriopus japonicus. In acute tests, bare ZnO-NPs and hydrophobic ZnO-NPs were less toxic than hydrophilic ZnO-NPs. Analyses of the copepod's antioxidant gene expression suggested that such differences were governed by hydrodynamic size and ion dissolution of the particles, which affected zinc bioaccumulation in copepods. Conversely, all test particles, except the least toxic hydrophobic ZnO-NPs, shared similar chronic toxicity as Zn-IONs because they mostly dissolved into zinc ions at low test concentrations. The metadata analysis, together with our test results, further suggested that the toxicity of coated metal-associated nanoparticles could be predicted by the hydrophobicity and density of their surface coatings. This study evidenced the influence of surface coatings on the physicochemical properties, toxicity, and toxic mechanisms of ZnO-NPs and provided insights into the toxicity prediction of coated nanoparticles from their coating properties to improve their future risk assessment and management.

Prevalence and risk factors of severe postpartum hemorrhage: a retrospective cohort study.

BACKGROUND: Although maternal deaths are rare in developed regions, the morbidity associated with severe postpartum hemorrhage (SPPH) remains a major problem. To determine the prevalence and risk factors of SPPH, we analyzed data of women who gave birth in Guangzhou Medical Centre for Critical Pregnant Women, which received a large quantity of critically ill obstetric patients who were transferred from other hospitals in Southern China. METHODS: In this study, we conducted a retrospective case-control study to determine the prevalence and risk factors for SPPH among a cohort of women who gave birth after 28 weeks of gestation between January 2015 and August 2019. SPPH was defined as an estimated blood loss ≥1000 mL and total blood transfusion≥4 units. Logistic regression analysis was used to identify independent risk factors for SPPH. RESULTS: SPPH was observed in 532 mothers (1.56%) among the total population of 34,178 mothers. Placenta-related problems (55.83%) were the major identified causes of SPPH, while uterine atony without associated retention of placental tissues accounted for 38.91%. The risk factors for SPPH were maternal age < 18 years (adjusted OR [aOR] = 11.52, 95% CI: 1.51-87.62), previous cesarean section (aOR = 2.57, 95% CI: 1.90-3.47), history of postpartum hemorrhage (aOR = 4.94, 95% CI: 2.63-9.29), conception through in vitro fertilization (aOR = 1.78, 95% CI: 1.31-2.43), pre-delivery anemia (aOR = 2.37, 95% CI: 1.88-3.00), stillbirth (aOR = 2.61, 95% CI: 1.02-6.69), prolonged labor (aOR = 5.24, 95% CI: 3.10-8.86), placenta previa (aOR = 9.75, 95% CI: 7.45-12.75), placenta abruption (aOR = 3.85, 95% CI: 1.91-7.76), placenta accrete spectrum (aOR = 8.00, 95% CI: 6.20-10.33), and macrosomia (aOR = 2.30, 95% CI: 1.38-3.83). CONCLUSION: Maternal age < 18 years, previous cesarean section, history of PPH, conception through IVF, pre-delivery anemia, stillbirth, prolonged labor, placenta previa, placental abruption, PAS, and macrosomia were risk factors for SPPH. Extra vigilance during the antenatal and peripartum periods is needed to identify women who have risk factors and enable early intervention to prevent SPPH.

17ß-Estradiol Attenuates LPS-Induced Macrophage Inflammation In Vitro and Sepsis-Induced Vascular Inflammation In Vivo by Upregulating miR-29a-5p Expression.

Excessive release of cytokines such as IL-1ß and other inflammatory mediators synthesized and secreted by macrophages is the fundamental link of uncontrolled inflammatory response in sepsis. 17ß-Estradiol (E2) plays anti-inflammatory and vascular protective effects by regulating leukocyte infiltration and the expression of chemokines or cytokines induced by injury. However, the role of E2 in the inflammatory response of macrophages in sepsis and its mechanism are still not fully understood. In the present study, we show that E2 alleviates vascular inflammation in sepsis mice induced by cecal ligation puncture (CLP). E2 significantly decreases RAW 264.7 cell inflammation response by downregulating the expression of NLRP3. Furthermore, we found that miR-29a-5p was significantly downregulated in LPS-treated macrophages. Treating RAW 264.7 cells with E2 markedly upregulated the miR-29a-5p expression level. More importantly, we demonstrated that miR-29a-5p repressed NLRP3 expression by directly targeting its 3'-UTR. Loss- and gain-of-function experiments revealed that transfection of the miR-29a-5p mimic abrogates LPS-induced macrophage inflammation. Moreover, depletion of miR-29a-5p by its inhibitor largely promotes LPS-induced macrophage inflammation. In summary, miR-29a-5p upregulation induced by E2 alleviated RAW 264.7 cell inflammation response by aggravating miR-29a-5p repression of NLRP3 expression. E2 exerts significant anti-inflammatory efficacy in macrophages by regulating the miR-29a-5p/NLRP3 axis. Targeting miR-29a-5p may be a novel therapeutic strategy to suppress sepsis-induced vascular inflammation.

Categorical perception of speech sounds in adults who stutter.

Stuttering is often attributed to the impaired speech production system, however, there is growing evidence implicating issues in speech perception. Our previous research showed that children who stutter have similar patterns but slower categorical perception (i.e. the ability to categorise different acoustic variations of the speech sounds into the same or different phonemic categories) compared to the children who do not stutter. This study aimed to extend our previous research to adults who stutter (AWS) using the same categorical perception paradigm. Fifteen AWS and 15 adults who do not stutter (A WNS) were recruited to complete identification and discrimination tasks involving acoustic variations of Cantonese speech sounds in four stimulus contexts: consonants (varying in voice onset times, VOTs), lexical tones, vowels and pure tones. The results showed similar categorical perception between the two groups in terms of the boundary position and width in the identification task and between-category benefits in the discrimination task. However, there were some trends for lower discrimination accuracy (overall d' scores) and slower discrimination of the between-category stimuli versus within-category stimuli for AWS than AWNS. These results partially confirm our previous finding on children in terms of a comparable pattern of categorical perception between the two groups, but slower processing speed to access the phoneme representations in speech perception among AWS than AWNS.

Caspase-3 controls AML1-ETO-driven leukemogenesis via autophagy modulation in a ULK1-dependent manner.

AML1-ETO (AE), a fusion oncoprotein generated by t(8;21), can trigger acute myeloid leukemia (AML) in collaboration with mutations including c-Kit, ASXL1/2, FLT3, N-RAS, and K-RAS. Caspase-3, a key executor among its family, plays multiple roles in cellular processes, including hematopoietic development and leukemia progression. Caspase-3 was revealed to directly cleave AE in vitro, suggesting that AE may accumulate in a Caspase-3-compromised background and thereby accelerate leukemogenesis. Therefore, we developed a Caspase-3 knockout genetic mouse model of AML and found that loss of Caspase-3 actually delayed AML1-ETO9a (AE9a)-driven leukemogenesis, indicating that Caspase-3 may play distinct roles in the initiation and/or progression of AML. We report here that loss of Caspase-3 triggers a conserved, adaptive mechanism, namely autophagy (or macroautophagy), which acts to limit AE9a-driven leukemia. Furthermore, we identify ULK1 as a novel substrate of Caspase-3 and show that upregulation of ULK1 drives autophagy initiation in leukemia cells and that inhibition of ULK1 can rescue the phenotype induced by Caspase-3 deletion in vitro and in vivo. Collectively, these data highlight Caspase-3 as an important regulator of autophagy in AML and demonstrate that the balance and selectivity between its substrates can dictate the pace of disease.

Novel 2, 8-bit derivatives of quinolines attenuate Pseudomonas aeruginosa virulence and biofilm formation.

Signal molecules are stimulators of multiple quroum-sensing virulence and biofilm formation. Small molecule analogues have been suspected as a potent inhibitor in therapeutic strategy. Herein, we synthesized a series of small molecule compounds from the 2, 8-bit derivatives of quinoline by Suzuki coupling reaction. We found that these compounds have the biofilm inhibitory effect in normal condition instead of phosphate limitation state. Furthermore, lacZ reporter strain assay and rhamnolipids as well as pyocyanin experiments showed that these compounds did not affect las and pqs system but reduced the expression of rhl. All these results suggest that quinoline derivatives can be treated as potent inhibitors against biofilm and reduce virulence through the rhl system. This research will be useful in designing new quorum sensing inhibitors to attenuate the infection of bacteria.

Accidental Spill of Palm Stearin Poses Relatively Short-Term Ecological Risks to a Tropical Coastal Marine Ecosystem.

In early August 2017, a serious palm stearin pollution accident occurred in the Pearl River Estuary, South China. While there were already several palm oil related spills around the world, the ecological effects and risks of such accidents to coastal marine environments remain largely unknown. In this study, we found that all seawater and sediment samples collected from six coastal sites were heavily contaminated by palm stearin within 1 week of the accident, and their levels significantly decreased to preaccident levels after four months. Waterborne exposure to palm stearin resulted in growth inhibition to four microalgal species (range of EC50: 9.9-212.6 mg/L) and acute mortality to four invertebrate species (range of LC50: 4.6-409.3 mg/L), while adverse chronic effects of palm stearin on the survival, development, and fecundity of Tigriopus japonicus and on the growth of Oryzias melastigma were observed. On the basis of these results, its interim-predicted no effect concentration was determined as 0.141 mg/L. The hazard quotient of palm stearin greatly exceeded 1 at all sites in August 2017 but returned to <1 at four sites and <2 at the other two sites in November 2017, indicating that its ecological risk was relatively transient and short-term.

Enhancement of Oral Bioavailability and Anti-hyperuricemic Activity of Isoliquiritigenin via Self-Microemulsifying Drug Delivery System.

The aim of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) for enhancement of the oral bioavailability of isoliquiritigenin (ISL) as well as evaluate its in vivo anti-hyperuricemic effect in rats. The ISL-loaded self-microemulsifying drug delivery system (ISL-SMEDDS) was comprised of ethyl oleate (EO, oil phase), Tween 80 (surfactant), and PEG 400 (co-surfactant). The ISL-SMEDDS exhibited an acceptable narrow size distribution (44.78 ± 0.35 nm), negative zeta potential (- 10.67 ± 0.86 mV), and high encapsulation efficiency (98.17 ± 0.24%). The in vitro release study indicated that the release rates of the formulation were obviously higher in different release media (HCl, pH 1.2; PBS, pH 6.8; double-distilled water, pH 7.0) compared with the ISL solution. The oral bioavailability of the ISL-SMEDDS was enhanced by 4.71 times in comparison with the free ISL solution. More importantly, ISL-SMEDDS significantly reduced uric acid level by inhibiting xanthine oxidase (XOD) activity in the model rats. Collectively, the prepared ISL-SMEDDS proved to be potential carriers for enhancing the solubility and oral bioavailability of ISL, as well as ameliorating its anti-hyperuricemic effect.

Differential role of Id1 in MLL-AF9-driven leukemia based on cell of origin.

Inhibitor of DNA binding 1 (Id1) functions as an E protein inhibitor, and overexpression of Id1 is seen in acute myeloid leukemia (AML) patients. To define the effects of Id1 on leukemogenesis, we expressed MLL-AF9 in fetal liver (FL) cells or bone marrow (BM) cells isolated from wild-type, Id1(-/-), p21(-/-), or Id1(-/-)p21(-/-) mice, and transplanted them into syngeneic recipient mice. We found that although mice receiving MLL-AF9-transduced FL or BM cells develop AML, loss of Id1 significantly prolonged the median survival of mice receiving FL cells but accelerated leukemogenesis in recipients of BM cells. Deletion of Cdkn1a (p21), an Id1 target gene, can rescue the effect of Id1 loss in both models, suggesting that Cdkn1a is a critical target of Id1 in leukemogenesis. It has been suggested that the FL transplant model mimics human fetal-origin (infant) MLL fusion protein (FP)-driven leukemia, whereas the BM transplantation model resembles postnatal MLL leukemia; in fact, the analysis of clinical samples from patients with MLL-FP(+) leukemia showed that Id1 expression is elevated in the former and reduced in the latter type of MLL-FP(+) AML. Our findings suggest that Id1 could be a potential therapeutic target for infant MLL-AF9-driven leukemia.

Pioglitazone Use and Risk of Bladder Cancer: an In Vitro Study.

Aims: Whether pioglitazone (PIO), a peroxisome proliferator-activated receptor-gamma agonist, increases the risk of developing bladder cancer has been debated for several years. The aim of this study was to investigate the in vitro effects of PIO on normal urothelial transitional epithelium (NUTE) cells and bladder cancer (J82) cells to further evaluate the risk. Methods: NUTE cells were obtained from Sprague-Dawley rats. NUTE and J82 cells were treated with different concentrations of PIO for various time periods. Cell proliferation was tested by the MTT assay. Cell apoptosis was evaluated by flow cytometry. The expressions of p53, cyclin D1, Bcl-2, and Bax were determined by qRT-PCR and western blots. Results: After 24 hours, the treatment of NUTE cells with 10 µmol/L PIO led to morphological changes, without changes in J82 cells. Moreover, PIO inhibited the proliferation and induced apoptosis of NUTE cells, but not J82 cells, in a time- and dose-dependent manner. However, PIO did not alter the growth of cells from other tissues. In addition, treatment with PIO for up to 72 hours did not result in changes in the expressions of p53, cyclin D1, Bcl-2, and Bax in NUTE cells and J82 cells. Interestingly, PIO significantly downregulated the protein levels of p53 and cyclin D1 in J82 cells, but not NUTE cells after more than 192 hours of treatment. Conclusions: PIO did not promote malignant alterations of NUTE cells or stimulate proliferation of J82 cells. PIO decreased the expression of p53 and cyclin D1 in J82 cells after long-term culture, which suggested that PIO may be helpful for diabetic patients with bladder cancer.

Regulation of AKT signaling by Id1 controls t(8;21) leukemia initiation and progression.

Transcriptional regulators are recurrently altered through translocations, deletions, or aberrant expression in acute myeloid leukemia (AML). Although critically important in leukemogenesis, the underlying pathogenetic mechanisms they trigger remain largely unknown. Here, we identified that Id1 (inhibitor of DNA binding 1) plays a pivotal role in acute myeloid leukemogenesis. Using genetically modified mice, we found that loss of Id1 inhibited t(8;21) leukemia initiation and progression in vivo by abrogating protein kinase B (AKT)1 activation, and that Id1 interacted with AKT1 through its C terminus. An Id1 inhibitor impaired the in vitro growth of AML cells and, when combined with an AKT inhibitor, triggered even greater apoptosis and growth inhibition, whereas normal hematopoietic stem/progenitor cells were largely spared. We then performed in vivo experiments and found that the Id1 inhibitor significantly prolonged the survival of t(8;21)(+) leukemic mice, whereas overexpression of activated AKT1 promoted leukemogenesis. Thus, our results establish Id1/Akt1 signaling as a potential therapeutic target in t(8;21) leukemia.

Delineation of the molecular basis of borderline hemoglobin A2 in Chinese individuals.

BACKGROUND: The "gray zone" of borderline hemoglobin A2 (Hb A2) may be present in a large section of the population, especially in countries where thalassemia is common. However, very little is currently known of the molecular basis of borderline Hb A2 in Chinese individuals. METHOD: In this study, we performed a comprehensive analysis of the globin genotypes and KLF1 gene mutations associated with borderline Hb A2 in 165 Chinese subjects. RESULT: Fifteen (9.1%) were positive for a molecular defect in the α-,ß-globin genes, of whom, α-thalassemia mutations and α-globin gene triplication were found in eleven cases, accounting for about 73.3% of these globin gene defects. Twenty (12.1%) were positive for a molecular defect in the KLF1 gene. Eight different mutations were identified, six of which are here reported for the first time. The most common is the G176AfsX179 mutation, accounting for 50% of the total. CONCLUSIONS: The molecular characterization of borderline Hb A2 in Chinese individuals is significantly different than in Italian population. Our data is conductive to provision of genetic counseling for Chinese individuals with borderline Hb A2.

Exceptional points enhance sensing in silicon micromechanical resonators.

Exceptional points (EPs) have recently emerged as a new method for engineering the response of open physical systems, that is, systems that interact with the environment. The systems at the EPs exhibit a strong response to a small perturbation. Here, we show a method by which the sensitivity of silicon resonant sensors can be enhanced when operated at EPs. In our experiments, we use a pair of mechanically coupled silicon micromechanical resonators constituting a parity-time (PT)-symmetric dimer. Small perturbations introduced on the mechanically coupled spring cause the frequency to split from the EPs into the PT-symmetric regime without broadening the two spectrum linewidths, and this frequency splitting scales with the square root of the perturbation strength. The overall signal-to-noise ratio is still greatly enhanced, although the measured noise spectral density of the EP sensing scheme has a slight increase comparable to the traditional counterpart. Our results pave the way for resonant sensors with ultrahigh sensitivity.