Association of sdLDL-C With Incident Carotid Plaques With Stable and Vulnerable Morphology: A Prospective Cohort Study.

BACKGROUND: Small dense low-density lipoprotein cholesterol (sdLDL-C) particles are more atherogenic than large and intermediate low-density lipoprotein cholesterol (LDL-C) subfractions. We sought to investigate the association of sdLDL-C and the sdLDL-C/LDL-C ratio with incident carotid plaques with stable and vulnerable morphology in rural China. METHODS: This community-based cohort study used data from the RICAS study (Rose Asymptomatic Intracranial Artery Stenosis), which enrolled 887 participants (aged ≥40 years) who were living in Kongcun Town, Pingyin County, Shandong, and free of carotid plaques and had no history of clinical stroke or transient ischemic attack at baseline (2017). Incident carotid plaques and their vulnerability were detected by carotid ultrasound at follow-up (2021). Multivariable logistic regression models were used to explore the association of sdLDL-C or sdLDL-C/LDL-C ratio with incident carotid plaques while adjusting for demographic factors, vascular risk factors, and follow-up time. RESULTS: Of the 887 participants (mean age [SD], 53.89 [8.67%] years; 54.34% women), 179 (20.18%) were detected with incident carotid plaques during an average follow-up of 3.94 years (SD=0.14). Higher sdLDL-C or sdLDL-C/LDL-C ratio, but not LDL-C, was significantly associated with an increased risk of incident carotid plaques. The upper tertile of sdLDL-C (versus lower tertile) was associated with the multivariate-adjusted odds ratio of 2.48 (95% CI, 1.00-6.15; P=0.049; P for linear trend=0.046) for carotid plaques with vulnerable morphology (n=41), and the association remained significant in participants with normal LDL-C (<130 mg/dL; n=693; upper versus lower tertile: odds ratio, 3.38 [95% CI, 1.15-9.90]; P=0.027; P for linear trend=0.025). Moreover, the sdLDL-C/LDL-C ratio was associated with a higher odds ratio of incident carotid plaques in participants without diabetes (P for interaction=0.014). CONCLUSIONS: Higher sdLDL-C was associated with an increased risk of incident carotid plaques, especially carotid plaques with vulnerable morphology, even in participants with normal LDL-C. This suggests the potential of sdLDL-C as a therapeutic target for stroke prevention. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR1800017197.

Synergistic effects of the KDM4C inhibitor SD70 and the menin inhibitor MI-503 against MLL::AF9-driven acute myeloid leukaemia.

MLL-rearranged (MLL-r) leukaemia is observed in approximately 10% of acute myeloid leukaemia (AML) and is associated with a relatively poor prognosis, highlighting the need for new treatment regimens. MLL fusion proteins produced by MLL rearrangements recruit KDM4C to mediate epigenetic reprogramming, which is required for the maintenance of MLL-r leukaemia. In this study, we used a combinatorial drug screen to selectively identify synergistic treatment partners for the KDM4C inhibitor SD70. The results showed that the drug combination of SD70 and MI-503, a potent menin-MLL inhibitor, induced synergistically enhanced apoptosis in MLL::AF9 leukaemia cells without affecting normal CD34+ cells. In vivo treatment with SD70 and MI-503 significantly prolonged survival in AML xenograft models. Differential gene expression analysis by RNA-seq following combined pharmacological inhibition of SD70 and MI-503 revealed changes in numerous genes, with MYC target genes being the most significantly downregulated. Taken together, these data provide preclinical evidence that the combination of SD70 and MI-503 is a potential dual-targeted therapy for MLL::AF9 AML.

Twist family BHLH transcription factor 1 is required for the maintenance of leukemia stem cell in MLL-AF9+ acute myeloid leukemia.

Leukemia stem cells (LSC) are a rare population capable of limitless self-renewal and are responsible for the initiation, maintenance, and relapse of leukemia. Elucidation of the mechanisms underlying the regulation of LSC function could provide novel treatment strategies. Here, we show that TWIST1 is extremely highly expressed in the LSC of MLL-AF9+ acute myeloid leukemia (AML), and its upregulation is positively regulated by KDM4C in a H3K9me3 demethylation-dependent manner. We further demonstrate that TWIST1 is essential for the viability, dormancy, and self-renewal capacities of LSC, and that it promotes the initiation and maintenance of MLL-AF9-mediated AML. In addition, TWIST1 directly interacts and collaborates with HOXA9 in inducing AML in mice. Mechanistically, TWIST1 exerts its oncogenic function by activating the WNT5a/RAC1 axis. Collectively, our study uncovers a critical role of TWIST1 in LSC function and provides new mechanistic insights into the pathogenesis of MLL-AF9+ AML.

Association between atherogenic index of plasma and asymptomatic intracranial arterial stenosis in middle-aged and elderly women: A cross-sectional study in Shandong, China.

BACKGROUND AND AIMS: The atherogenic index of plasma (AIP) is associated with progression of atherosclerosis and used to describe how pro- or anti-atherogenic components are balanced. However, the association of AIP with asymptomatic intracranial arterial stenosis (aICAS) is uncertain. The purpose of this study is to investigate the association between AIP and aICAS in rural China. METHODS AND RESULTS: A total of 1990 participants aged ≥40 years free of stroke or transient ischemic attack were enrolled in this study. The presence of aICAS was examined by Transcranial Doppler ultrasound and confirmed by magnetic resonance angiography. The adjusted AIP (aAIP) was calculated according to the ratio of TG and HDL-C and further separated into 4 quartiles. Multiple logistic regression was used to investigate the association between aAIP and aICAS, and the dose-response relationship was explored by restricted cubic spline. After adjusting for conventional confounders, aAIP was significantly higher in the aICAS group than that in the non-aICAS group. Furthermore, the common odds ratios for aICAS risk increased with increasing aAIP quartiles. Multivariate logistic regression revealed that aAIP was independently associated with aICAS in female or middle-aged and elderly (age ≥50 years), and superior to other lipid profiles. Multiple-adjusted spline regression showed the dose-response association between aAIP levels and aICAS prevalence. CONCLUSIONS: AIP might be independently and positively associated with the prevalence of aICAS in middle-aged and elderly women, which might be superior to traditional and nontraditional lipid profiles in rural China.

TWIST1 preserves hematopoietic stem cell function via the CACNA1B/Ca2+/mitochondria axis.

Mitochondria of hematopoietic stem cells (HSCs) play crucial roles in regulating cell fate and preserving HSC functionality and survival. However, the mechanism underlying HSC regulation remains poorly understood. Here, we identify transcription factor TWIST1 as a novel regulator of HSC maintenance through modulation of mitochondrial function. We demonstrate that Twist1 deletion results in significantly decreased lymphoid-biased HSC frequency, markedly reduced HSC dormancy and self-renewal capacity, and skewed myeloid differentiation in steady-state hematopoiesis. Twist1-deficient HSCs are more compromised in tolerance of irradiation- and 5-fluorouracil-induced stresses and exhibit typical phenotypes of senescence. Mechanistically, Twist1 deletion induces transactivation of voltage-gated calcium channel (VGCC) Cacna1b, which exhausts lymphoid-biased HSCs, impairs genotoxic hematopoietic recovery, and enhances mitochondrial calcium levels, metabolic activity, and reactive oxygen species production. Suppression of VGCC by a calcium channel blocker largely rescues the phenotypic and functional defects in Twist1-deleted HSCs under both steady-state and stress conditions. Collectively, our data, for the first time, characterize TWIST1 as a critical regulator of HSC function acting through the CACNA1B/Ca2+/mitochondria axis and highlight the importance of Ca2+ in HSC maintenance. These observations provide new insights into the mechanisms for the control of HSC fate.

GADD45g acts as a novel tumor suppressor, and its activation suggests new combination regimens for the treatment of AML.

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy for which there is an unmet need for novel treatment strategies. Here, we characterize the growth arrest and DNA damage-inducible gene gamma (GADD45g) as a novel tumor suppressor in AML. We show that GADD45g is preferentially silenced in AML, especially in AML with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations and mixed-lineage leukemia (MLL)-rearrangements, and reduced expression of GADD45g is correlated with poor prognosis in patients with AML. Upregulation of GADD45g impairs homologous recombination DNA repair, leading to DNA damage accumulation, and dramatically induces apoptosis, differentiation, and growth arrest and increases sensitivity of AML cells to chemotherapeutic drugs, without affecting normal cells. In addition, GADD45g is epigenetically silenced by histone deacetylation in AML, and its expression is further downregulated by oncogenes FLT3-ITD and MLL-AF9 in patients carrying these genetic abnormalities. Combination of the histone deacetylase 1/2 inhibitor romidepsin with the FLT3 tyrosine kinase inhibitor AC220 or the bromodomain inhibitor JQ1 exerts synergistic antileukemic effects on FLT3-ITD+ and MLL-AF9+ AML, respectively, by dually activating GADD45g. These findings uncover hitherto unreported evidence for the selective antileukemic role of GADD45g and provide novel strategies for the treatment of FLT3-ITD+ and MLL-AF9+ AML.

Association of plaque characteristics with long-term stroke recurrence in patients with intracranial atherosclerotic disease: a 3D high-resolution MRI-based cohort study.

OBJECTIVES: To evaluate the predictive ability of plaque characteristics for long-term stroke recurrence among patients with symptomatic intracranial atherosclerotic disease (ICAD). METHODS: This cohort study included 132 patients with acute ischemic stroke (AIS) attributed to ICAD who were recruited between July 2017 and December 2020 and followed until stroke recurrence or December 2021. Plaque surface irregularity, degree of stenosis, plaque burden, remodeling ratio, enhancement ratio, and intraplaque hemorrhage were assessed with 3-dimensional high-resolution magnetic resonance vessel wall imaging (3D HR-MRI). Data were analyzed using Cox models, receiver operating characteristic (ROC) curves, and Kaplan-Meier survival analysis. RESULTS: Of the 132 patients, during a median follow-up of 2.8 years, stroke recurrence occurred in 35 patients. The multivariable-adjusted hazard ratio (95% confidence interval) of stroke recurrence was 3.15 (1.34-7.42) per 10% increase in plaque burden and 2.17 (1.27-3.70) for enhancement ratio. The area under the curve (AUC) to predict stroke recurrence was 0.725 (95% CI 0.629-0.822) for plaque burden, 0.692 (95% CI 0.593-0.792) for enhancement ratio, and only 0.595 (95% CI 0.492-0.699) for the Essen stroke risk score. The Kaplan-Meier survival analysis further demonstrated significant differences in survival of free recurrent stroke between patients with plaque burden or enhancement ratio below and above the optimum cut-offs (both p < 0.001). CONCLUSION: Higher plaque burden and enhancement ratio are independent risk factors for long-term stroke recurrence among patients with symptomatic ICAD, and valuable imaging markers for predicting and stratifying risk of stroke recurrence. CLINICAL RELEVANCE STATEMENT: In patients with symptomatic ICAD, the results of this high-resolution magnetic resonance vessel wall imaging study have potential implications for optimal management of intracranial plaques and secondary prevention of stroke recurrence based on plaque burden and enhancement ratio. KEY POINTS: • Identification of intracranial plaque characteristics responsible for stroke recurrence is essential to preventing stroke recurrence in patients with symptomatic intracranial atherosclerotic disease. • Higher plaque burden and enhancement ratio are independent risk factors for stroke recurrence. • Plaque burden and enhancement ratio are valuable imaging markers in the prediction and stratification of the risk of stroke recurrence.

Association of visceral adiposity index with asymptomatic intracranial arterial stenosis: a population-based study in Shandong, China.

BACKGROUND AND OBJECTIVE: The visceral adiposity index (VAI), as a composite indictor to evaluate visceral adipose function, has been demonstrated to be correlated with atherosclerosis. The study objective was to explore the association between asymptomatic intracranial arterial stenosis (aICAS) and VAI in Chinese rural dwellers. METHODS: The cross-sectional study consisted of 1942 participants ≥ 40 years old who were living in Pingyin County, Shandong Province and free from history of clinical stroke and transient ischemic attack. The aICAS in the study was diagnosed by transcranial doppler ultrasound combined with magnetic resonance angiography. The multivariate logistic regression models were deployed to explore the correlation of VAI with aICAS, and receiver operating characteristic (ROC) curve were plotted to compare the performance of models. RESULTS: The participants with aICAS comparing to those without had a significantly higher VAI. After adjusting for confounding factors including age, hypertension, DM, sex, drinking habit, LDL-C, hsCRP, and smoking habit, the VAI-Tertile 3 (vs. VAI-Tertile 1) was positively associated with aICAS (OR, 2.15; 95% CI, 1.25-3.65; P = 0.005). The VAI-Tertile 3 was still markedly associated with aICAS among the underweight and normal weight (BMI ≤ 23.9 kg/m2) participants (OR, 3.17; 95% CI, 1.15-8.71; P = 0.026) with an AUC = 0.684. A similar relationship between VAI and aICAS was obtained among the participants with no abdominal obesity (WHR < 1, OR, 2.03; 95% CI, 1.14-3.62; P = 0.017). CONCLUSIONS: The possible correlation between VAI and aICAS was found to be positive for the first time among Chinese rural residents over 40 years old. A higher VAI was found to be significantly associated with aICAS among the participants who were underweight or normal weight, and these results may provide additional risk stratification information for aICAS.

Thermally Assisted Heterogeneous Cavitation through Gas Supersaturation.

We demonstrate that besides gaseous pockets also a gas supersaturated spot on a substrate can be a nucleus for cavitation. The supersaturation is achieved by either a formerly dissolved bubble or by heating locally the surface below the boiling temperature. The experiments are conducted in a thin film of water; one side of the water film is in contact with a gold coated substrate that is heated by a continuous laser through plasmonic heating. For nucleation of a bubble, the pressure at the heated spot is reduced by a transient rarefaction wave. The experimental findings suggest that the local gas supersaturation is responsible to nucleate cavitation and thus connects the phase transitions of cavitation and boiling. Additionally, the pressure waves in the liquid gap are studied numerically.

How sodium chloride extends lifetime of bulk nanobubbles in water.

We present a molecular dynamics simulation study on the effects of sodium chloride addition on stability of a nitrogen bulk nanobubble in water. We find that the lifetime of the bulk nanobubble is extended in the presence of NaCl and reveal the underlying mechanisms. We do not observe spontaneous accumulation or specific arrangement of ions/charges around the nanobubble. Importantly, we quantitatively show that the N2 molecule selectively diffuses through water molecules rather than pass by any ions after it leaves the nanobubble due to the much weaker water-water interactions than ion-water interactions. The strong ion-water interactions cause hydration effects and disrupt hydrogen bond networks in water, which leave fewer favorable paths for the diffusion of N2 molecules, and by that reduce the degree of freedom in the dissolution of the nanobubble and prolong its lifetime. These results demonstrate that the hydration of ions plays an important role in stability of the bulk nanobubble by affecting the dynamics of hydrogen bonds and the diffusion properties of the system, which further confirm and interpret the selective diffusion path of N2 molecules and the extension of lifetime of the nanobubble. The new atomistic insights obtained from the present research could potentially benefit the practical application of bulk nanobubbles.

The pathogenesis of prevalent aerobic bacteria in aerobic vaginitis and adverse pregnancy outcomes: a narrative review.

BACKGROUND: Aerobic vaginitis is a common cause of vaginal discharge in reproductive-age women, increasing the risk of negative pregnancy outcomes such as premature delivery, abortion, premature rupture of membranes and stillbirth. However, the aetiology and pathogenesis of aerobic vaginitis causing negative pregnancy outcomes are still unclear, and there is no unified and standardized treatment method for aerobic vaginitis in the pregnancy period. METHODS: We conducted a literature search of published studies in the English language focusing on aerobic vaginitis and its association with adverse pregnancy outcomes utilizing PubMed and Web of Science from January 1973 through June 2021. The common pathogenic bacteria of aerobic vaginitis during pregnancy, such as group B Streptococcus, Escherichia coli, Staphylococcus aureus, Enterococcus faecalis and Klebsiella pneumoniae, as well as the related adverse pregnancy outcomes and existing treatments were reviewed. RESULTS: A total of 4534 articles were identified, and 97 studies that had inclusion criteria were subjected to careful review. The pathogenic bacteria of aerobic vaginitis can produce different toxins or affect the local immunity of patients and then lead to the occurrence of infection. Fresh wet mount microscopy is the preferred diagnostic method for aerobic vaginitis. Clindamycin is a common antibiotic used for aerobic vaginitis in pregnant women. The use of products combining probiotics has achieved excellent treatment success. CONCLUSIONS: Future research in this field can provide insights regarding the mechanism of aerobic vaginitis-induced adverse pregnancy outcomes in humans and ways to prevent their occurrence.

Aerobic vaginitis is an infection of the vagina that increases the risk of negative pregnancy outcomes. The aetiology and pathogenesis of aerobic vaginitis causing negative pregnancy outcomes are still unclear. This paper reviews the common pathogenic bacteria of aerobic vaginitis during pregnancy, and the related adverse pregnancy outcomes. We also review the existing treatment. Currently, it is believed that the microflora in aerobic vaginitis is composed of commensal aerobic microorganisms of intestinal origin, and the most frequently encountered bacteria are group B Streptococcus, Escherichia coli, Staphylococcus aureus, Enterococcus faecalis and Klebsiella pneumoniae. The pathogenic bacteria of aerobic vaginitis can produce different toxins or affect the local immunity of patients and then lead to the occurrence of infection. Fresh wet mount microscopy is the preferred diagnostic method for aerobic vaginitis. Clindamycin is a common antibiotic used for aerobic vaginitis in pregnant women. The use of products combining probiotics has achieved excellent treatment success. This study provides a reference for future research and early diagnosis and treatment during pregnancy. Future research in this field can provide insights regarding the mechanisms of aerobic vaginitis-induced adverse pregnancy outcomes in humans and ways to prevent their occurrence.

Twist1 promotes dendritic cell-mediated antitumor immunity.

Dendritic cells (DCs) play a central role in autoimmunity, immune homeostasis, and presentation of tumor antigens to T cells in order to prime antitumor responses. The number of tumor-infiltrating DCs is associated with survival and prognosis in cancer. Twist1 is a well-known regulator of tumor initiation and promotion, but whether and how DC-derived Twist1 regulates antitumor responses remains poorly understood. Here, we generated a mouse line with Twist1 conditionally depleted in DCs and found that Twist1-deficiency in DCs did not affect the DCs and T cell homeostasis under steady-state conditions; however, in melanoma models, the proportion of conventional DCs (cDCs) in draining lymph nodes (DLNs) was significantly decreased. Accordingly, a decreased ratio and number of tumor-infiltrating cDCs were observed, which reduced the recruitment of tumor-infiltrating T cells. Furthermore, production of IFN-γ, a crucial antitumor factor, by T cells, was dramatically decreased, which can further dampen the T cell antitumor functions. Collectively, our data indicate that Twist1 in DCs regulates antitumor functions by maintain the number of tumor-infiltrating DCs and T cells, and their antitumor activity.

Association of triglyceride-glucose index and high-sensitivity C-reactive protein with asymptomatic intracranial arterial stenosis: A cross-sectional study.

BACKGROUND AND AIMS: Triglyceride-glucose index (TyG) and high-sensitivity C-reactive protein (hsCRP) have been shown to play important roles in the pathophysiological mechanisms of atherogenesis. However, the cumulative value of TyG and hsCRP in identifying asymptomatic intracranial arterial stenosis (aICAS), as well as its severity and numerical burden, is uncertain. This study seeks to fill this knowledge gap. METHODS AND RESULTS: This study included 1938 participants aged ≥40 years who were free of stroke or transient ischemic attack. All participants were classified into four groups based on the participants' TyG and hsCRP levels, including low-TyG and low-hsCRP, low-TyG and high-hsCRP, high-TyG and low-hsCRP, and high-TyG and high-hsCRP groups. The presence of aICAS was screened via transcranial Doppler ultrasound and confirmed by magnetic resonance angiography. The TyG was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. We used multinomial logistic regression analysis to investigate the cumulative value of TyG and hsCRP on identifying the severity of aICAS or its numerical burden. After adjustment for conventional confounders, isolated high-hsCRP, isolated high-TyG, and high-TyG combined with high-hsCRP were independently associated with moderate-to-severe aICAS. Compared with the low-TyG and low-hsCRP group, participants with high-TyG and high-hsCRP had a 2.6 times higher odds ratio (OR) of having a single moderate-to-severe aICAS and a 3.3 times higher OR of having multiple moderate-to-severe aICASs. CONCLUSION: The cumulative value of TyG and hsCRP may better identify moderate-to-severe aICAS as well as its numerical burden.

Metabolomics and Lipidomics Profiling in Asymptomatic Severe Intracranial Arterial Stenosis: Results from a Population-Based Study.

No data are available on the serum metabolomics and lipidomics profiles of people with asymptomatic intracranial arterial stenosis. We explored the characteristic metabolites of individuals with asymptomatic severe intracranial arterial stenosis (asICAS) using untargeted serum metabolomics and lipidomics analyses based on ultra-high-performance liquid chromatography high-resolution mass spectrometry (UPLC-HRMS). This case-control study included 25 participants with asICAS and 25 age- and sex-matched controls free of asICAS, who were all diagnosed by using magnetic resonance angiography and derived from the same population-based study. Serum metabolomics and lipidomics profiles were determined using UPLC-HRMS, and possible biomarker metabolites were identified. Compared with the control group, the asICAS group showed higher levels of free choline, glycerophosphocholine, uracil, taurine, and four peptide molecules and lower levels of free fatty acids, hydroxydodecanedioic acid, hydroxy valeryl carnitine, hydroxytetradecanedioic acid, and two sphingomyelin molecules. The serum metabolomics and lipidomics profiles for people with asICAS are characterized by abnormal metabolism of sphingomyelin, taurine/hypotaurine, pyrimidine, and protein (peptide). The biological changes in asICAS may mainly involve taurine/hypotaurine, glycerophospholipid, and sphingolipid metabolism pathways. Biofunctional analysis indicated that these differential metabolites were correlated with metabolic diseases such as early myocardial injury, heart failure, and diabetes.

Association between serum bilirubin and asymptomatic intracranial atherosclerosis: results from a population-based study.

INTRODUCTION: The effects of bilirubin on asymptomatic intracranial atherosclerosis (aICAS) remain uncertain. OBJECTIVES: To investigate the association between bilirubin and aICAS in rural-dwelling Chinese people. METHODS: This population-based study included 2013 participants from the Kongcun Town Study, which aimed to investigate the prevalence of aICAS in people aged ≥ 40 years who were free of stroke and hepatic and gall disease history. Baseline data were collected via interviews, clinical examinations, and laboratory tests. Total bilirubin (Tbil), direct bilirubin (Dbil), and indirect bilirubin (Ibil) levels were divided into high-concentration group and low-concentration group, respectively. We diagnosed aICAS and moderate-to-severe aICAS (m-saICAS) (≥ 50% stenosis) by integrating transcranial Doppler ultrasound with magnetic resonance angiography. The association between bilirubin and aICAS, as well as m-saICAS, was analyzed using logistic regression. RESULTS: Of the 2013 participants, those in the high-concentration group of Tbil (odds ratio (OR), 0.50; 95% confidence interval (CI), 0.42-0.87), Dbil (OR 0.60, 95%CI 0.41-0.87), and Ibil (OR 0.67; 95%CI 0.47-0.97) had a lower risk of aICAS than those in the low-concentration group after adjusting all confounders. The high concentrations of Tbil, Dbil, and Ibil were also negatively associated with m-saICAS. After stratification according to age, Tbil, Dbil, and Ibil were significantly negatively associated with aICAS among participants aged ≥ 60 years. CONCLUSION: Tbil, Dbil, and Ibil might be independent protective factors for aICAS and moderate-to-severe aICAS in rural-dwelling Chinese people, especially among older participants aged ≥ 60 years.

Carbon dots-embedded epitope imprinted polymer for targeted fluorescence imaging of cervical cancer via recognition of epidermal growth factor receptor.

A carbon dots-embedded epitope imprinted polymer (C-MIP) was fabricated for targeted fluorescence imaging of cervical cancer by specifically recognizing the epidermal growth factor receptor (EGFR). The core-shell C-MIP was prepared by a reverse microemulsion polymerization method. This method used silica nanoparticles embedded with carbon dots as carriers, acrylamide as the main functional monomer, and N-terminal nonapeptides of EGFR modified by palmitic acid as templates. A series of characterizations (transmission electron microscope, dynamic light scattering, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, zeta potential, and energy dispersive X-ray spectroscopy) prove the successful synthesis of C-MIP. The fluorescence of C-MIP is quenched by the epitopes of EGFR due to the specific recognition of epitopes of EGFR through their imprinted cavities (analytical excitation/emission wavelengths, 540 nm/610 nm). The linear range of fluorescence quenching is 2.0 to 15.0 µg mL-1 and the determination limit is 0.73 µg mL-1. The targeted imaging capabilities of C-MIP are demonstrated through in vitro and in vivo experiments. The laser confocal imaging results indicate that HeLa cells (over-expression EGFR) incubated with C-MIP show stronger fluorescence than that of MCF-7 cells (low-expression EGFR), revealing that C-MIP can target tumor cells overexpressing EGFR. The results of imaging experiments in tumor-bearing mice exhibit that C-MIP has a better imaging effect than C-NIP, which further proves the targeted imaging ability of C-MIP in vivo. Graphical abstract An oriented epitope imprinted polymer embedded with carbon dots was prepared for the determination of the epitopes of epidermal growth factor receptor and targeted fluorescence imaging of cervical cancer.

Mass transfer during osmotic dehydration and its effect on anthocyanin retention of microwave vacuum-dried blackberries.

BACKGROUND: The combination of sugar osmotic dehydration and microwave vacuum drying is an effective method for the dehydration of blackberries, the retention of their antioxidant properties, and the extension of their shelf life. Mass transfer during the osmotic dehydration of blackberries in sugar solution was investigated together with its influence on microwave vacuum drying characteristics, and the retention rate of anthocyanins in dried frozen blackberries. RESULTS: The concentrations of the osmotic solutions that were tested contained 40%, 50%, and 60% sugar, and the osmotic solution temperatures were 30 °C, 40 °C, and 50 °C. The solution-to-blackberry mass ratio was 10:1 (w/w) and the process duration varied from 0 to 5 h. A two-parameter mathematical model was used to describe mass transfer in the osmotic dehydration of blackberry samples and estimate moisture loss and solid gain in the final equilibrium. The results showed that the dehydration rate and solid gain rate of the blackberries increased with an increase in osmotic concentration, osmotic time, and the temperature of the solution under certain experimental conditions. The effective diffusivity of moisture and solute were estimated using the analytical solution of Fick's second law of diffusion. The moisture and effective diffusivities of sugar in the above osmotic dehydration conditions were in the range of 1.77 × 10-9 -2.10 × 10-9 and 1.36 × 10-9 -1.60 × 10-9 m2 .s-1 , respectively. CONCLUSION: The pretreatment of sugar osmosis greatly reduced the microwave vacuum drying time in the latter part of the dehydration period and increased anthocyanin retention. © 2019 Society of Chemical Industry.

Microvesicles-mediated communication between endothelial cells modulates, endothelial survival, and angiogenic function via transferring of miR-125a-5p.

Endothelial cells (ECs) released microvesicles (EMVs) could modulate the functions of target cells by transferring their microRNAs (miRs). We have reported that miR-125a-5p protected EC function. In this study, we determined whether EMVs provided beneficial effects on ECs by transferring miR-125a-5p. Human brain microvessel ECs were transfected with miR-125a-5p mimic or miR-125a-5p short hairpin RNA to obtain miR-125a-5p overexpressing ECs and miR-125a-5p knockdown ECs, and their derived EMVs. For the functional study, ECs or hypoxia/reoxygenation injured ECs were coincubated with various EMVs. The survival and angiogenic function of ECs were measured. Western blot and quantitative real time polymerase chain reaction (qRT-PCR) were used for measuring the levels of phosphoinositide 3-kinase (PI3K), phosphorylation-Akt (p-Akt)/Akt, p-endothelial nitric oxide synthase (p-eNOS), cleaved caspase-3, and miR-125a-5p. PI3K inhibitor was used for pathway analysis. EMVs promoted the proliferation, migration, and tube formation ability of ECs, and alleviated the apoptotic rate of ECs. These effects were associated by an increase in p-Akt/Akt and p-eNOS, and a decrease in cleaved caspase-3 could be abolished by LY294002. Overexpression or downregulation of miR-125a-5p in EMVs promoted or inhibited those effects of EMVs. EMVs could enhance the survival and angiogenic function of ECs via delivering miR-125a-5p to modulate the expression of PI3K/Akt/eNOS pathway and caspase-3.

Proteomic profiling of plasma biomarkers in acute ischemic stroke due to large vessel occlusion.

BACKGROUND: Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. Proteins associated with acute LVO pathogenesis and endothelial function may appear in blood samples of AIS patients due to LVO, thus permitting development of blood-based biomarkers for its diagnosis and prognosis. METHODS: This study is a single-center, retrospective, observational case-control trial. Consecutive patients who presented at the Department of Neurology of Tongji Hospital were recruited from July 2016 to April 2018. In the discovery phase, a proteomic approach with iTRAQ-based LC-MS/MS was used to investigate the altered proteomic pattern in plasma from patients with AIS due to LVO. In the validation study, Western blots was used to identify biomarkers associated with stroke diagnosis as well as their prognostic value associated with different collateral statuses. RESULTS: For this exploratory study, the proteomic analysis of plasma from 40 patients with AIS due to LVO and 20 healthy controls revealed seven differentially expressed proteins with a 1.2/0.83-fold or greater difference between groups. The four elevated proteins, PPBP (1.58 ± 0.78 vs 0.98 ± 0.37; P < 0.001), THBS1 (1.13 ± 0.88 vs 0.43 ± 0.26; P < 0.001), LYVE1 (1.61 ± 0.55 vs 0.97 ± 0.50; P < 0.001), and IGF2 (1.19 ± 0.42 vs 0.86 ± 0.24; P < 0.001), were verified by Western blots analysis in an independent cohort including 33 patients and 33 controls. A strong interaction was observed between the four-protein panel and the diagnosis of AIS due to LVO (AUC 0.947; P < 0.001). Furthermore, IGF2, LYVE1, and THBS1 were closely associated with collateral status (IGF2 0.115, 95% CI 0.016-0.841, P = 0.033; LYVE1 0.183, 95% CI 0.036-0.918, P = 0.039; THBS1 4.257, 95% CI 1.273-14.228, P = 0.019), and proved to be independent predictors of good outcome (IGF2 0.115, 95% CI 0.015-0.866, P = 0.036; LYVE1 0.028, 95% CI 0.002-0.334, P = 0.005; THBS1 3.294, 95% CI 1.158-9.372, P = 0.025) at a 3-month follow-up. CONCLUSIONS: The identified 4-biomarker panel could provide diagnostic aid to the existing imaging modalities for AIS due to LVO, and the prognostic value of IGF2, LYVE1, and THBS1 was proved in predicting functional outcomes related to collateral status. Trial registration ClinicalTrials.gov NCT03122002. Retrospectively registered April 20, 2017. URL of trial registry record: https://www.clinicaltrials.gov/ct2/show/NCT03122002?term=NCT+03122002&rank=1.

Menstrual blood derived mesenchymal stem cells combined with Bushen Tiaochong recipe improved chemotherapy-induced premature ovarian failure in mice by inhibiting GADD45b expression in the cell cycle pathway.

BACKGROUND: To investigate the therapeutic effects of menstrual blood derived mesenchymal stem cells (MB-MSCs) combined with Bushen Tiaochong recipe (BSTCR) on epirubicin induced premature ovarian failure (POF) in mice. METHODS: Twenty-four female C57BL/6 mice of 6-8 weeks were intraperitoneally injected with epirubicin to induce POF, and then they were randomized into 4 groups of 6 mice each and treated with PBS, MB-MSCs, BSTCR, and MB-MSCs combined with BSTCR, respectively. Six mice of the same age were used as controls. Vaginal smear, TUNEL and hematoxylin-eosin staining were to observe estrous cycles, ovarian cell apoptosis and follicles. Enzyme-linked immunosorbent analysis determined serum estradiol, follicle-stimulating hormone (FSH) and anti-Müllerian hormone (AMH) levels. RT-qPCR and Western Blot analysis were to determine GADD45b, CyclinB1, CDC2 and pCDC2 expressions. RESULTS: Epirubicin treatment resulted in a decrease in the number of primordial, primary, secondary and antral follicles, an increase in the number of atretic follicles and ovarian cell apoptosis, a decrease in estradiol and AMH levels, an increase in FSH levels, and estrous cycle arrest. However, MB-MSCs combined with BSTCR rescued epirubicin induced POF through down-regulating GADD45b and pCDC2 expressions, and up-regulating CyclinB1 and CDC2 expressions. The combined treatment showed better therapeutic efficacy than BSTCR or MB-MSCs alone. CONCLUSIONS: MB-MSCs combined with BSTCR improved the ovarian function of epirubicin induced POF mice, which might be related to the inhibition of GADD45b expression and the promotion of CyclinB1 and CDC2 expressions. The combined treatment had better therapeutic efficacy than BSTCR or MB-MSCs alone.