Vitexin inhibits APEX1 to counteract the flow-induced endothelial inflammation.

Vascular endothelial cells are exposed to shear stresses with disturbed vs. laminar flow patterns, which lead to proinflammatory vs. antiinflammatory phenotypes, respectively. Effective treatment against endothelial inflammation and the consequent atherogenesis requires the identification of new therapeutic molecules and the development of drugs targeting these molecules. Using Connectivity Map, we have identified vitexin, a natural flavonoid, as a compound that evokes the gene-expression changes caused by pulsatile shear, which mimics laminar flow with a clear direction, vs. oscillatory shear (OS), which mimics disturbed flow without a clear direction. Treatment with vitexin suppressed the endothelial inflammation induced by OS or tumor necrosis factor-α. Administration of vitexin to mice subjected to carotid partial ligation blocked the disturbed flow-induced endothelial inflammation and neointimal formation. In hyperlipidemic mice, treatment with vitexin ameliorated atherosclerosis. Using SuperPred, we predicted that apurinic/apyrimidinic endonuclease1 (APEX1) may directly interact with vitexin, and we experimentally verified their physical interactions. OS induced APEX1 nuclear translocation, which was inhibited by vitexin. OS promoted the binding of acetyltransferase p300 to APEX1, leading to its acetylation and nuclear translocation. Functionally, knocking down APEX1 with siRNA reversed the OS-induced proinflammatory phenotype, suggesting that APEX1 promotes inflammation by orchestrating the NF-κB pathway. Animal experiments with the partial ligation model indicated that overexpression of APEX1 negated the action of vitexin against endothelial inflammation, and that endothelial-specific deletion of APEX1 ameliorated atherogenesis. We thus propose targeting APEX1 with vitexin as a potential therapeutic strategy to alleviate atherosclerosis.

Aristolochic acid I promoted clonal expansion but did not induce hepatocellular carcinoma in adult rats.

Aristolochic acid I (AAI) is a well-known nephrotoxic carcinogen, which is currently reported to be also associated with hepatocellular carcinoma (HCC). Whether AAI is a direct hepatocarcinogen remains controversial. In this study we investigated the association between AAI exposure and HCC in adult rats using a sensitive rat liver bioassay with several cofactors. Formation of glutathione S-transferase placental form-positive (GST-P+) foci was used as the marker for preneoplastic lesions/clonal expansion. We first conducted a medium-term (8 weeks) study to investigate whether AAI had any tumor-initiating or -promoting activity. Then a long-term (52 weeks) study was conducted to determine whether AAI can directly induce HCC. We showed that oral administration of single dose of AAI (20, 50, or 100 mg/kg) in combination with partial hepatectomy (PH) to stimulate liver proliferation did not induce typical GST-P+ foci in liver. In the 8-week study, only high dose of AAI (10 mg · kg-1 · d-1, 5 days a week for 6 weeks) in combination with PH significantly increased the number and area of GST-P+ foci initiated by diethylnitrosamine (DEN) in liver. Similarly, only high dose of AAI (10 mg· kg-1· d-1, 5 days a week for 52 weeks) in combination with PH significantly increased the number and area of hepatic GST-P+ foci in the 52-week study. No any nodules or HCC were observed in liver of any AAI-treated groups. In contrast, long-term administration of AAI (0.1, 1, 10 mg· kg-1· d-1) time- and dose-dependently caused death due to the occurrence of cancers in the forestomach, intestine, and/or kidney. Besides, AAI-DNA adducts accumulated in the forestomach, kidney, and liver in a time- and dose-dependent manner. Taken together, AAI promotes clonal expansion only in the high-dose group but did not induce any nodules or HCC in liver of adult rats till their deaths caused by cancers developed in the forestomach, intestine, and/or kidney. Findings from our animal studies will pave the way for further large-scale epidemiological investigation of the associations between AA and HCC.

DNA methyltransferase 1 and Krüppel-like factor 4 axis regulates macrophage inflammation and atherosclerosis.

Macrophage-mediated inflammatory responses occur throughout all stages of atherosclerosis. DNA methylation is one of the critical epigenetic mechanisms and is associated with the development of atherosclerosis. The underlying mechanism of epigenetic regulation of macrophage inflammation (M1 activation) remains unclear. Here we aim to study the role of DNA methyltransferase 1 (DNMT1) in modulating macrophage inflammation and atherosclerosis. DNMT1 expression is up-regulated in THP-1-derived macrophages upon treatment with lipopolysaccharide (LPS) and interferon-gamma (IFN-γ). Overexpression of DNMT1 promotes the LPS- and IFN-γ-induced M1 activation whereas inhibition of DNMT1 attenuates it. Consistently, DNMT1 expression is elevated in macrophages in atherosclerotic plaques from human and mouse specimens; compared with the Dnmt1wild-type, myeloid Dnmt1 deficiency in mice in an Apolipoprotein E (ApoE) knockout background or receiving AAV-PSCK9 injection and carotid partial ligation results in ameliorated atheroma formation and suppressed plaque inflammation. The promoter regions of atheroprotective Krüppel-like factor 4 (KLF4) are hypermethylated in M1- activated macrophages. DNMT1 down-regulates the expression of KLF4, probably through catalyzing DNA methylation of the promoter regions of KLF4. Gain- and loss-of function study of KLF4 indicates that the DNMT1-mediated macrophage M1 activation is dependent on KLF4. Our data demonstrate a proatherogenic role for DNMT1 as a defining factor in macrophage inflammation both in vitro and in vivo. DNMT1 promotes macrophage M1 activation by suppressing KLF4 expression. Thus macrophage-specific DNMT1 inhibition may provide an attractive therapeutic potential to prevent or reduce atherosclerosis.

Enhanced molecular recognition for imprinted monolithic column containing polyhedral oligomeric silsesquioxanes by dendritic effect of mesoporous molecular sieve scaffolds.

The dendritic effect of nano mesoporous molecular sieve was first used to enhance molecular recognition of molecularly imprinted polymers (MIPs)-based polyhedral oligomeric silsesquioxanes (POSS). In this study, the MIPs were made using S-naproxen (S-NAP) as template molecule, 4-vinylpyridine (4-VP) as functional monomer, ethylene glycol dimethacrylate as cross-linker, 1-butyl-3-methylimidazoliumtetrafluoroborate ([BMIM]BF4)/DMSO as binary porogens, 1-propylmethacrylate-heptaisobutyl substituted as POSS monomer, and mesoporous molecular sieve (Mobil composition of matter No. 41, MCM-41) as dendritic scaffold. The influence of synthesis parameters on the imprinting effect, including the content of POSS monomer and derivatized MCM-41-MPS, the ratio of template to monomer, and the ratio of binary porogens were also investigated, respectively. The morphology of the polymers was characterized by scanning electron microscopy, nitrogen adsorption, and X-ray powder diffraction. The results showed that POSS&MCM-41-MPS MIP had a stronger imprinting effect with an imprinting factor 6.86, which is approximately 2.4, 2.3, and 3 times than that of POSS MIP, MCM-41-MPS MIP, and conventional MIP, respectively. The increase of affinity might be attributed to impediment of the chain motion of polymer due to improved POSS aggregation and the dipole interaction between the POSS units by introduce of MCM-41-MPS as scaffolds. The resulting POSS&MCM-41-MPS MIP was used as adsorbent for the enrichment of S-NAP in solid-phase extraction with a high recovery of 97.65% and the value of RSD was 0.94%.

[Effect of Compound Medicine of Tanshinone 2A and Resveratrol on Peak Bone Mass in Growing Rats].

Objective To study the effect of the compound medicine of tanshinone 2A and resveratrol on peak bone mass in growing rats and to explore its possible mechanism,so as to explore anti-osteoporosis mechanisms of new traditional Chinese medicine (TCM) drugs. Methods Totally 40 1-month-old female Wistar rats were randomly divided into tanshinone 2A group,resveratrol group,compound group (tanshinone 2A and resveratrol),and normal control group,with 10 rats in each group. Body weight was measured once every two weeks,and the whole body bone mineral density was measured with dual-energy X-ray monthly. When the whole-body bone mineral density became statistically significant between medication groups and control group,all animals were sacrificed to determine the bone mineral density of vertebrae and right femoral bone. The biomechanical properties of femur and vertebrae were measured by AGS-X series universal test,then the bone morphology was analyzed with Fuchsin picric acid staining. Finally,the levels of tartrate-resistant acid phosphatase 5b and osteocalcin were measured with enzyme-linked immunosorbent assay.Results The body weights were not statistically significant among all groups (P>0.05). The whole-body bone mineral density showed no significant difference (P>0.05) after feeding for 1 month;however,two months later,it was significantly different between medication groups and control group;in particular,the whole-body (P=0.016),femoral (P=0.001),and vertebral bone mineral density (P=0.034),bone trabecular number (P=0.024),thickness (P=0.040),and area (P=0.038) were significantly increased in the compound group,along with the significantly decreased trabecular separation degree (P=0.032). Compared with the control group,the compound group had significantly increased osteocalcin (P=0.033) and tartrate-resistant acid phosphatase 5b (P=0.028) levels in serum.Conclusion The compound of tanshinone 2 A and resveratrol can improve the bone density and bone quality in rats,and such effect is higher than either tanshinone 2 A monomer or resveratrolmonomer.

[Effect of Xianling Gubao capsule on bone metabolism in ovariectomized rats].

To investigate the effect of Xianling Gubao capsule in preventing postmenopausal osteoporosis, forty-eight female Wistar rats were randomly divided into four groups: sham group (Sham), ovariectomized group (OVX), ethinylestradiol group (EE) and Xianling Gubao capsule group (XLGB). Rats in each group received ovariectomy, except for sham group. The XLGB group received Xianling Gubao capsule at the dose of 378 mg·kg⁻¹·d⁻¹. The dosage of EE group was 200 µg·kg⁻¹·d⁻¹, and OVX and Sham groups were only fed with equal volume of distilled water. All of the rats were put to death two months later. Bone mineral density, bone biomechanics, bone histomorphometry Micro-CT scanning and organ index of vital organs were calculated and pathologically observed. There was no significant difference in the body weight of rats and organ indexes of lung, kidney, heart and spleen in the experimental groups. There was also no significant change in their pathological observation, but the uterine index of OVX group and XLGB group was significantly lower than that of Sham group. According to the results of BMD test, compared with the OVX group, femurs and vertebrae BMD of the other three groups were increased, with statistically significant differences. On the basis of the results of bone biomechanical test, compared with OVX group, the maximum load values of femur and vertebrae of the other three groups were increased, with statistically significant differences, while the change of elastic modulus was not statistically significant. According to the bone histomorphometry results of VG staining, compared with Sham group, the number of trabecular bone was significantly lower than that in OVX group. Compared with OVX group, the number of trabecular bone in EE group and XLGB group was increased, but with no significant difference between EE and XLGB groups. The results of serum biochemical indexes showed that compared with Sham group, osteocalcin (OC) decreased, while tartrate resistant acid phosphatase 5b (TRACP 5b) increased in OVX group, with statistically significant differences. Compared with OVX group, the OC content of XLGB group and EE group increased, while the content of TRACP 5b decreased, with statistically significant differences. On the basis of the results of Micro-CT scanning, the change trends of femur volume BMD, number of trabecular bone (Tb.N), trabecular bone thickness (Tb.Th), trabecular bone separation (Tb.Sp), bone volume/tissue volume (BV/TV) in the groups were consistent with those of bone histomorphometry. There was no significant change in femoral cortical bone between the two groups. Xianling Gubao capsule can prevent osteoporosis in ovariectomized rats. The possible mechanism is the dual activity of inhibiting bone resorption and improving bone formation.

The Effect and Mechanism of Transdermal Penetration Enhancement of Fu's Cupping Therapy: New Physical Penetration Technology for Transdermal Administration with Traditional Chinese Medicine (TCM) Characteristics.

BACKGROUND: In this paper, a new type of physical penetration technology for transdermal administration with traditional Chinese medicine (TCM) characteristics is presented. Fu's cupping therapy (FCT), was established and studied using in vitro and in vivo experiments and the penetration effect and mechanism of FCT physical penetration technology was preliminarily discussed. METHODS: With 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-ylacetic acid (indomethacin, IM) as a model drug, the establishment of high, medium, and low references was completed for the chemical permeation system via in vitro transdermal tests. Furthermore, using chemical penetration enhancers (CPEs) and iontophoresis as references, the percutaneous penetration effect of FCT for IM patches was evaluated using seven species of in vitro diffusion kinetics models and in vitro drug distribution; the IM quantitative analysis method in vivo was established using ultra-performance liquid chromatography-tandem mass spectrometry technology (UPLC-MS/MS), and pharmacokinetic parameters: area under the zero and first moment curves from 0 to last time t (AUC0-t, AUMC0-t), area under the zero and first moment curves from 0 to infinity (AUC0-∞, AUMC0-∞), maximum plasma concentration (Cmax) and mean residence time (MRT), were used as indicators to evaluate the percutaneous penetration effect of FCT in vivo. Additionally, we used the 3K factorial design to study the joint synergistic penetration effect on FCT and chemical penetration enhancers. Through scanning electron microscopy (SEM) and transmission electron microscope (TEM) imaging, micro- and ultrastructural changes on the surface of the stratum corneum (SC) were observed to explore the FCT penetration mechanism. RESULTS: In vitro and in vivo skin permeation experiments revealed that both the total cumulative percutaneous amount and in vivo percutaneous absorption amount of IM using FCT were greater than the amount using CPEs and iontophoresis. Firstly, compared with the control group, the indomethacin skin percutaneous rate of the FCT low-intensity group (FCTL) was 35.52%, and the enhancement ratio (ER) at 9 h was 1.76X, roughly equivalent to the penetration enhancing effect of the CPEs and iontophoresis. Secondly, the indomethacin percutaneous ratio of the FCT middle-intensity group (FCTM) and FCT high-intensity group (FCTH) were 47.36% and 54.58%, respectively, while the ERs at 9 h were 3.58X and 8.39X, respectively. Thirdly, pharmacokinetic data showed that in vivo indomethacin percutaneous absorption of the FCT was much higher than that of the control, that of the FCTM was slightly higher than that of the CPE, and that of the FCTM group was significantly higher than all others. Meanwhile, variance analysis indicated that the combination of the FCT penetration enhancement method and the CPE method had beneficial effects in enhancing skin penetration: the significance level of the CPE method was 0.0004, which was lower than 0.001, meaning the difference was markedly significant; the significance level of the FCT was also below 0.0001 and its difference markedly significant. The significance level of factor interaction A × B was lower than 0.0001, indicating that the difference in synergism was markedly significant. Moreover, SEM and TEM images showed that the SC surfaces of Sprague-Dawley rats treated with FCT were damaged, and it was difficult to observe the complete surface structure, with SC pores growing larger and its special "brick structure" becoming looser. This indicated that the barrier function of the skin was broken, thus revealing a potentially major route of skin penetration. CONCLUSION: FCT, as a new form of transdermal penetration technology, has significant penetration effects with TCM characteristics and is of high clinical value. It is worth promoting its development.

[Pharmacokinetics of bullatine A in Aconitum brachypodum total alkaloids gel in transdermal delivery].

In this study, the changes of bullatine A in plasma and skin of mice with time in microemulsion gel and ordinary gel of Aconitum brachypodum total alkaloids were compared through UPLC-MS/MS, and their pharmacokinetic parameters were also compared and analyzed, to investigate the feasibility of microemulsion agent in the transdermal drug delivery. UPLC-MS/MS method for simultaneous determination of bullatine A in plasma and skin had high sensitivity and was in line with the pharmacokinetic study requirements for transdermal drug delivery. The main pharmacokinetic parameters for microemulsion gel in the plasma were as follows: Cmax=(37.62±14.31) µg•L⁻¹, Tmax=(3.40±1.34) h, AUC0-∞=(1 027.7±260) µg•L⁻¹â€¢h⁻¹, MRT=(34.80±12.31) h, MRTlast=(10.68±0.57) h, t1/2=(23.11±9.20) h; main pharmacokinetic parameters for ordinary gel in the blood: Cmax=(52.23±15.90) µg•L⁻¹, Tmax=(4.00±0.00) h, AUC0-∞=(728.60±280.80) µg•L⁻¹â€¢h⁻¹, MRT=(20.69±3.98) h, MRTlast=(9.34±0.42) h, t1/2=(14.69±3.15) h. The results showed that the microemulsion gel had more stable transdermal absorption, longer duration of action and higher bioavailability than ordinary gel, indicating that the microemulsion gel had a good and stable transdermal effect. There was no significant difference in bioavailability of bullatine A in skin between microemulsion gel and ordinary gel.

High temperature induces apoptosis and oxidative stress in pufferfish (Takifugu obscurus) blood cells.

Water temperature is an important environmental factor in aquaculture farming that affects the survival and growth of organisms. The change in culture water temperature may not only modify various chemical and biological processes but also affect the status of fish populations. In previous studies, high temperature induced apoptosis and oxidative stress. However, the precise mechanism and the pathways that are activated in fish are still unclear. In the present study, we investigated the effects of high temperature (34°C) on the induction of apoptosis and oxidative stress in pufferfish (Takifugu obscurus) blood cells. The data showed that high temperature exposure increased oxygen species (ROS), cytoplasmic free-Ca(2+) concentration and cell apoptosis. To test the apoptotic pathway, the expression pattern of some key apoptotic related genes including P53, Bax, caspase 9 and caspase 3 were examined. The results showed that acute high temperature stress induced up-regulation of these genes, suggesting that the p53-Bax pathway and the caspase-dependent apoptotic pathway could be involved in apoptosis induced by high temperature stress. Furthermore, the gene expression of antioxidant enzymes (Cu/Zn-SOD, Mn-SOD, CAT, GPx, and GR) and heat shock proteins (HSP90 and HSP70) in the blood cells were induced by high temperature stress. Taken together, our results showed that high temperature-induced oxidative stress may cause pufferfish blood cells apoptosis, and cooperatively activated p53-Bax and caspase-dependent apoptotic pathway.

Effect of acute ammonia exposure on expression of GH/IGF axis genes GHR1, GHR2 and IGF-1 in pufferfish (Takifugu obscurus).

Waterborne ammonia has become a persistent pollutant of aquatic habitats. The exposure to ammonia stress can reduce growth in a wide range of aquatic organisms. To assess the effect of ammonia exposure on the growth hormone/insulin-like growth factors (GH/IGF) axis, we identified and characterized GHR1, GHR2 and IGF-1 from pufferfish. Comparative analysis showed that these genes shared high identity and similarity with corresponding genes in other fish species. The transcripts of these genes were widely expressed in all tested tissues. The highest level of GHR1 mRNA was found in the brain, whereas GHR2 and IGF-1 mRNA levels were the highest in the liver. Following acute ammonia exposure (100 mg/L total ammonia-nitrogen), GHR2 expression in the liver did not change at 6 h and then significantly decreased at 12, 24 and 48 h, whereas GHR1 and IGF-1 expressions were significantly down-regulated at 6, 12, 24 and 48 h, respectively. These results indicated that ammonia stress decreased the expression of GH/IGF axis genes, which might have negative effect on the growth and development of pufferfish.

Identification, characterization and functional analysis of anti-apoptotic protein BCL-2-like gene from pufferfish, Takifugu obscurus, responding to bacterial challenge.

Apoptosis plays a crucial role in many biological processes, including development, cellular homeostasis and immune responses. The BCL-2 family is a key regulator of the mitochondrial response to apoptotic signals in the intrinsic pathway. In this study, we identified and characterized the cDNA and expression pattern of pufferfish BCL-2 (PfBCL-2). The full-length cDNA of PfBCL-2 was 1412 bp with an open reading frame of 657 bp encoding a putative protein of 219 amino acids (Accession no: KP898414). The calculated molecular mass of the PfBCL-2 was 24.2 kDa with a predicted isoelectric point of 5.27. The deduced PfBCL-2 protein exhibited four highly conserved BCL-2 homology domains, suggesting that PfBCL-2 may play a similar role in the apoptotic-signaling pathway as in other species. Real-time PCR results showed that PfBCL-2 transcript was expressed in a wide range of tissues but exhibited the greatest level of expression in blood. Transcriptional responses of PfBCL-2 exhibited different spatial and temporal expression profiles in liver and blood after bacterial infection. PfBcl-2 transcript was significantly up-regulated in liver at 6, 12, 24 and 48 h (with maximum induction at 48 h) and was up-regulated in blood at 3, 6, 12 and 24 h (with maximum induction at 12 h). Meanwhile, recombinant PfBCL-2 fused with His6 tag was efficiently expressed in Escherichia coli BL21 (DE3) and purified using Ni-nitrilotriacetic acid resin. Western blot analysis indicated that its protein level appeared to be elevated during the initial bacterial infection. These results suggest that PfBCL-2 plays important roles in immune responses against bacteria challenge.

Neuron-secreted NLGN3 ameliorates ischemic brain injury via activating Gαi1/3-Akt signaling.

We here tested the potential activity and the underlying mechanisms of neuroligin-3 (NLGN3) against ischemia-reperfusion-induced neuronal cell injury. In SH-SY5Y neuronal cells and primary murine cortical neurons, NLGN3 activated Akt-mTOR and Erk signalings, and inhibited oxygen and glucose deprivation (OGD)/re-oxygenation (OGD/R)-induced cytotoxicity. Akt activation was required for NLGN3-induced neuroprotection. Gαi1/3 mediated NLGN3-induced downstream signaling activation. NLGN3-induced Akt-S6K1 activation was largely inhibited by Gαi1/3 silencing or knockout. Significantly, NLGN3-induced neuroprotection against OGD/R was almost abolished by Gαi1/3 silencing or knockout. In vivo, the middle cerebral artery occlusion (MCAO) procedure induced NLGN3 cleavage and secretion, and increased its expression and Akt activation in mouse brain tissues. ADAM10 (A Disintegrin and Metalloproteinase 10) inhibition blocked MCAO-induced NLGN3 cleavage and secretion, exacerbating ischemic brain injury in mice. Neuronal silencing of NLGN3 or Gαi1/3 in mice also inhibited Akt activation and intensified MCAO-induced ischemic brain injury. Conversely, neuronal overexpression of NLGN3 increased Akt activation and alleviated MCAO-induced ischemic brain injury. Together, NLGN3 activates Gαi1/3-Akt signaling to protect neuronal cells from ischemia-reperfusion injury.

[Causes of stopping subcutaneous specific immunotherapy in asthmatic children].

OBJECTIVE: To improve the compliance with subcutaneous specific immunotherapy (SCIT) by analyzing the causes of stopping SCIT in asthmatic children. METHODS: A telephone follow-up was conducted in the asthmatic children who received SCIT but did not finished the 3-year course of treatment from June 2005 to October 2010, so as to analyze the causes of stopping SCIT. RESULTS: A total of 616 asthmatic children received SCIT, and 322 (52.2%) of them stopped SCIT.A total of 127 cases (39.4%) of the 322 children received telephone follow-up. In the 127 children, 53 (41.8%) stopped the SCIT for the reason of bad effecacy, 29 (22.8%) for remission of asthma,12 (9.4%) for expensive fees, 10 (7.9%) for complex process of treatment, 10 (7.9%) for adverse reaction, 9 (7.1%) for long distance from the hospital, and 4 (3.1%) for having no time for treatment. And 69 (54.3%) of them stopped SCIT in the first year, 28 (22.1%) in the second year, and 30 (23.6%) in the third year. Currently, 85 cases (66.9%) of the 127 asthmatic children were up to the control level, and the other 42 cases were not. There was significant difference in the control level of asthma berween the group receiving treatment with regular inhaled corticosteroids (ICS) and the group receiving treatment with irregular ICS (P<0.01). CONCLUSIONS: Bad efficacy, remission of asthma, expensive fees, complex process of treatment, and adverse reaction are the main reasons contributing to the stop of SCIT in asthmatic children. To improve the compliance with SCIT, It is important to make the patients and their parents understand the long treatment course and slow effect of SCIT, encourage them to use objective indices for evaluating the state of asthma, and effectively prevent and treat the adverse reactions.

The Global Burden of Disease attributable to low physical activity and its trends from 1990 to 2019: An analysis of the Global Burden of Disease study.

Introduction: Low physical activity (LPA) is associated with several major non-communicable diseases (NCDs) and premature mortality. In this study, we aimed to assess the global burden and trends in disease attributable to LPA (DALPA) from 1990 to 2019. Methods: Annual age-standardized disability-adjusted life years (DALYs) and death rates of DALPA [all-cause and five specific causes (ischaemic heart disease, diabetes mellitus, stroke, colon and rectal cancer, and breast cancer)] by sex, age, geographical region and social deprivation index (SDI) score from 1990 to 2019 were available from the Global Burden of Disease (GBD) study 2019. The estimated annual percentage changes (EAPCs) were calculated to quantify the changing trend. A generalized linear model (GLM) was used to explore the relationship between DALYs/death rates of DALPA and sociodemographic factors. Results: Globally, in 2019, the age-standardized DALYs and death rates of DALPA were 198.42/100,000 (95% UI: 108.16/100,000-360.32/100,000) and 11.10/100,000 (95% UI: 5.66/100,000-19.51/100,000), respectively. There were 15.74 million (8.51-28.61) DALYs and 0.83 million (0.43-1.47) deaths attributable to LPA. Overall, age-standardized DALYs and death rates presented significant downward trends with EAPCs [-0.68% (95% CI: -0.85- -0.50%) for DALYs and -1.00% (95% CI: -1.13- -0.86%) for deaths] from 1990 to 2019. However, age-standardized DALYs and death rates of diabetes mellitus attributable to LPA were substantially increased [EAPC: 0.76% (95% CI: 0.70-0.82%) for DALYs and 0.33% (95% CI: 0.21-0.51%) for deaths]. In the 15-49 age group, DALPA presented significant upward trends [EAPC: 0.74% (95% CI: 0.58-0.91%) for DALYs and 0.31% (95% CI: 0.1-0.51%) for deaths]. The GLM revealed that higher gross domestic product and current health expenditure (% of GDP) were negatively associated with DALYs and death rates of DALPA. Conclusion: Although global age-standardized DALYs and death rates of DALPA presented downward trends, they still cause a heavy burden worldwide. These rates showed upward trends in the diabetic and 15-49 age groups, which need more attention and health interventions.

Imaging Characteristics of Invasive Pulmonary Fungal Infection Secondary to Hematological Diseases and Comparison before and after Treatment.

Fungal infections have become crucial factors that threaten the prognosis and survival of blood disease patients. Here, we aim to analyze the epidemiological characteristics and early and advanced CT (computed tomography) manifestations of patients with invasive pulmonary fungal infections secondary to blood system diseases. 65 hospitalized patients from October 2018 to October 2020 with invasive pulmonary fungal infections secondary to blood diseases were enrolled. Blood diseases were recorded according to clinical and imaging data, and the serum galactomannan test (GM test) was conducted. Two senior radiologists analyzed the CT data and recorded the distribution of the lesions and CT signs. We analyzed and counted the first chest CT scan images of patients with nodule/mass type secondary to hematological diseases and invasive pulmonary fungal infection. The first CT nodules or mass-type lesions were statistically significant in nodule size, the number of lesions, distribution, and accompanying signs. Pulmonary fungal infection was common in both lungs during 7-day, 14-day, and 30-day follow-up CT. We also found that the nodular mass type was the main manifestation in the positive group of the GM test. Both the positive group and the negative group had the highest incidence of nodules. The incidence of air crescent signs in nodules or mass lesions in the positive group was higher than in the negative group, and the difference was statistically significant. To conclude, follow-up CT signs after antifungal treatment were highly sensitive to the early diagnosis of hematological diseases and secondary invasive pulmonary Eumycetes infection, which could be used for clinical treatment to provide help. GM test results were also related to CT manifestations such as air crescent sign, cavity, and halo sign.

Evaluation of the clinical application of the Postpartum Depression Predictors Inventory-Revised for postpartum women in China.

AIM: This study was designed to assess the clinical applicability of the Postpartum Depression Predictors Inventory-Revised (PDPI-R) during the 1st month following delivery among women in China and to survey the prevalence of postpartum depression (PPD)-related risk factors included in the PDPI-R in this population. METHODS: This was a cross-sectional study which recruited 447 women from the People's Liberation Army Hospital in Hefei of Anhui province. All participants completed the Chinese version of the PDPI-R (PDPI-R-C) and the Chinese version of the Edinburgh Postnatal Depression Scale (C-EPDS) within 1 month of delivery. The predictive ability of the PDPI-R was then evaluated through receiver operating characteristic (ROC) curve analyses. RESULTS: The PDPI-R-C was able to accurately predict 73.2% of PPD cases (area under the ROC curve = 0.732; 95% CI 0.69-0.78) using a cut-off score of 5.5, as defined by a C-EPDS score of ≥10 (sensitivity = 62.8%; specificity = 73.5%; positive predictive value = 74.5%; negative predictive value = 61.5%). All 13 risk factors in the PDPI-R-C other than socioeconomic status and marital status were associated with the risk of PPD. CONCLUSIONS: The PDPI-R-C was found to be an effective and easy-to-implement tool that has promise as a means of screening for PPD in Chinese populations.

Mitigation of acute radiation-induced brain injury in a mouse model using anlotinib.

BACKGROUND: With the development of radiological technologies, radiotherapy has been gradually widely used in the clinic to intracranial tumours and become standardised. However, the related central nervous system disorders are still the most obvious complications after radiotherapy. This study aims to quantify the effectiveness of anlotinib, a small molecule inhibitor of multiple receptor tyrosine kinases, in mitigating acute phase of radiation-induced brain injury (RBI) in a mouse model. METHODS: The onset and progression of RBI were investigated in vivo. All mice, (except for the sham group) were irradiated at a single-fraction of 20 Gy and treated with different doses of anlotinib (0, 0.2 and 0.8 mg/kg, respectively). The expression levels of glial fibrillary acidic protein (GFAP), hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and phosphorylated vascular endothelial growth factor receptor-2 (p-VEGFR2) were assessed by western blot. Histological changes were identified by luxol fast blue (LFB) staining. RESULTS: The expression levels of GFAP, HIF-1α, and VEGF were downregulated following treatment with anlotinib. However, anlotinib failed to inhibit the development of demyelination. Cerebral edema [as measured by brain water content (BWC)] was also mitigated following treatment with anlotinib. CONCLUSIONS: In summary, treatment with anlotinib significantly mitigated the adverse effects of acute RBI in a dose-dependent manner by downregulating the activation of astrocytes, improving brain hypoxia, and alleviating cerebral edema.

VAMP3 and SNAP23 as Potential Targets for Preventing the Disturbed Flow-Accelerated Thrombus Formation.

Disturbed blood flow has been recognized to promote platelet aggregation and thrombosis via increasing accumulation of von Willebrand factor (VWF) at the arterial post-stenotic sites. The mechanism underlying the disturbed-flow regulated endothelial VWF production remains elusive. Here we described a mouse model, in which the left external carotid artery (LECA) is ligated to generate disturbed flow in the common carotid artery. Ligation of LECA increased VWF accumulation in the plasma. Carotid arterial thrombosis was induced by ferric chloride (FeCl3) application and the time to occlusion in the ligated vessels was reduced in comparison with the unligated vessels. In vitro, endothelial cells were subjected to oscillatory shear (OS, 0.5 ± 4 dynes/cm2) or pulsatile shear (PS, 12 ± 4 dynes/cm2). OS promoted VWF secretion as well as the cell conditioned media-induced platelet aggregation by regulating the intracellular localization of vesicle-associated membrane protein 3 (VAMP3) and synaptosomal-associated protein 23 (SNAP23). Disruption of vimentin intermediate filaments abolished the OS-induced translocation of SNAP23 to the cell membrane. Knockdown of VAMP3 and SNAP23 reduced the endothelial secretion of VWF. Systemic inhibition of VAMP3 and SNAP23 by treatment of mice with rapamycin significantly ameliorated the FeCl3-induced thrombogenesis, whereas intraluminal overexpression of VAMP3 and SNAP23 aggravated it. Our findings demonstrate VAMP3 and SNAP23 as potential targets for preventing the disturbed flow-accelerated thrombus formation.

The "BURP" maneuver improves the glottic view during laryngoscopy but remains a difficult procedure.

OBJECTIVE: We investigated the "BURP" maneuver's effect on the association between difficult laryngoscopy and difficult intubation, and predictors of a difficult airway. METHODS: Adult patients who underwent general anesthesia and tracheal intubation from September 2016 to May 2018 were included. The "BURP" maneuver was performed when glottic exposure was classified as Cormack-Lehane grade 3 or 4, suggesting difficult laryngoscopy. The thyromental distance, modified Mallampati score, and interincisor distance were assessed before anesthesia. RESULTS: Among this study's 2028 patients, the "BURP" maneuver decreased difficult laryngoscopies from 428 (21.1%) to 124 (6.1%) cases and increased the difficult intubation to difficult laryngoscopy ratio from 53/428 (12.4%) to 52/124 (41.9%). For laryngoscopies classified as difficult without the "BURP" maneuver, the area under the curve (AUC) of the thyromental distance, modified Mallampati score, and interincisor distance was 0.60, 0.57, and 0.66, respectively. In difficult laryngoscopies using the "BURP" maneuver, the AUC of the thyromental distance, modified Mallampati score, and interincisor distance was 0.71, 0.67, and 0.76, respectively. CONCLUSIONS: The "BURP" maneuver improves the laryngoscopic view and assists in difficult laryngoscopies. Compared with difficult laryngoscopies without the "BURP" maneuver, those with the "BURP" maneuver are more closely associated with difficult intubations and are more predictable. Trial registration: www.chictr.org.cn identifier: ChiCTR-ROC- 16009050.

Correction: Inhibition of Stat3 signaling pathway by nifuroxazide improves antitumor immunity and impairs colorectal carcinoma metastasis.

Since publication of this article, the authors have noticed that there were errors in Fig. 1b (the CT 26 cells colony formation images) and Fig. 7c (the vehicle group images). As a result of the misfiling of the data during preparation of figures, incorrect images were inadvertently inserted in these figures.An amendment to this paper has been published and can be accessed via a link at the top of the paper.