Modulation of fried spring roll wrapper quality upon treatment of batter with maltogenic amylase, transglutaminase and bromelain.

BACKGROUND: Fried foods are favored for their unique crispiness, golden color and flavor, but they also face great challenge because of their high oil content, high calories and the existence of compounds such as acrylamide and polycyclic aromatic hydrocarbons. Long-term consumption of fried foods may adversely affect health. Therefore, it is necessary to explore fried foods with lower oil contents and a high quality to meet the demand. RESULTS: A method of enzyme treatment was explored to investigate the effects of maltogenic amylase (MA), transglutaminase (TG) and bromelain (BRO) on the physicochemical properties of the batter and the quality of fried spring roll wrapper (FSRW). The results showed that the MA-, TG- or BRO-treated batters had a significant shear-thinning behavior, especially with an increase in viscosity upon increasing TG contents. FSRW enhanced its fracturability from 419.19 g (Control) to 616.50 g (MA-6 U g-1), 623.49 g (TG-0.75 U g-1) and 644.96 g (BRO-10 U g-1). Meanwhile, in comparison with BRO and MA, TG-0.5 U g-1 endowed batter with the highest density and thermal stability. MA-15 U g-1 and TG-0.5 U g-1 displayed FSRW with uniform and dense pores, and significantly reduced its oil content by 18.05% and 25.02%, respectively. Moreover, compared to MA and TG, BRO-50 U g-1 improved the flavor of FSRW. CONCLUSION: MA, TG or BRO played a key role in affecting the physicochemical properties of the batter and the quality of FSRW. TG-0.5 U g-1 remarkly reduced the oil content of FSRW with a great potential in practical application. © 2024 Society of Chemical Industry.

The complete chloroplast genome sequence of Thladiantha nudiflora Hemsl. ex F.B.Forbes & Hemsl. 1887 (Cucurbitaceae).

Thladiantha nudiflora Hemsl. ex F.B.Forbes & Hemsl. 1887 (Cucurbitaceae) has been widely known as a traditional medicine plant. In this study, we sequenced, assembled, and annotated the complete chloroplast genome of T. nudiflora. The chloroplast genome of T. nudiflora is 156,824 base pair (bp) in length, containing a large single-copy region of 86,566 bp and a small single-copy region of 18,070 bp, separated by a pair of inverted repeats of 26,094 bp. The chloroplast genome contains 132 genes, including 87 protein-coding, 37 transfer RNA, and eight ribosomal RNA genes. Phylogenetic analysis of the chloroplast genome revealed that species of the genus Thladiantha were clustered together in the phylogenetic trees. This study will not only shed light on T. nudiflora's evolutionary position but also provide valuable chloroplast genomic information for future studies into the origins and diversification of the genus Thladiantha and the Cucurbitaceae family.

Preparation and epitope mapping of monoclonal antibodies against African swine fever virus p22 protein.

African swine fever (ASF), caused by the African swine fever virus (ASFV), is now widespread in many countries and severely affects the commercial rearing of swine. Rapid and early diagnosis is crucial for the prevention of ASF. ASFV mature virions comprise the inner envelope protein, p22, making it an excellent candidate for the serological diagnosis and surveillance of ASF. In this study, the prokaryotic-expressed p22 recombinant protein was prepared and purified for immunization in mice. Four monoclonal antibodies (mAbs) were identified using hybridoma cell fusion, clone purification, and immunological assays. The epitopes of mAbs 14G1 and 22D8 were further defined by alanine-scanning mutagenesis. Our results showed that amino acids C39, K40, V41, D42, C45, G48, E49, and C51 directly bound to 14G1, while the key amino acid epitope for 22D8 included K161, Y162, G163, D165, H166, I167, and I168. Homologous and structural analysis revealed that these sites were highly conserved across Asian and European ASFV strains, and the amino acids identified were located on the surface of p22. Thus, our study contributes to a better understanding of the antigenicity of the ASFV p22 protein, and the results could facilitate the prevention and control of ASF.

Long-Term Prognosis of Different Reperfusion Strategies for ST-Segment Elevation Myocardial Infarction in Chinese County-Level Hospitals: Insight from China Acute Myocardial Infarction Registry.

Objective: To evaluate the long-term prognosis of patients with ST-segment elevation myocardial infarction (STEMI) treated with different reperfusion strategies in Chinese county-level hospitals. Methods: A total of 2,514 patients with STEMI from 32 hospitals participated in the China Acute Myocardial Infarction registry between January 2013 and September 2014. The success of fibrinolysis was assessed according to indirect measures of vascular recanalization. The primary outcome was 2-year mortality. Results: Reperfusion therapy was used in 1,080 patients (42.9%): fibrinolysis ( n= 664, 61.5%) and primary percutaneous coronary intervention (PCI) ( n= 416, 38.5%). The most common reason for missing reperfusion therapy was a prehospital delay > 12 h (43%). Fibrinolysis [14.5%, hazard ratio ( HR): 0.59, 95% confidence interval ( CI) 0.44-0.80] and primary PCI (6.8%, HR= 0.32, 95% CI: 0.22-0.48) were associated with lower 2-year mortality than those with no reperfusion (28.5%). Among fibrinolysis-treated patients, 510 (76.8%) achieved successful clinical reperfusion; only 17.0% of those with failed fibrinolysis underwent rescue PCI. There was no difference in 2-year mortality between successful fibrinolysis and primary PCI (8.8% vs. 6.8%, HR = 1.53, 95% CI: 0.85-2.73). Failed fibrinolysis predicted a similar mortality (33.1%) to no reperfusion (33.1% vs. 28.5%, HR= 1.30, 95% CI: 0.93-1.81). Conclusion: In Chinese county-level hospitals, only approximately 2/5 of patients with STEMI underwent reperfusion therapy, largely due to prehospital delay. Approximately 30% of patients with failed fibrinolysis and no reperfusion therapy did not survive at 2 years. Quality improvement initiativesare warranted, especially in public health education and fast referral for mechanical revascularization in cases of failed fibrinolysis.

Multifunctional Covalent Organic Framework-Based Microneedle Patch for Melanoma Treatment.

Melanoma is resistant to conventional chemotherapy and radiotherapy. Therefore, it is essential to develop a targeted, low-toxic, and minimally invasive treatment. Here, DTIC/ICG-Fe3O4@TpBD BSP/HA microneedles (MNs) were designed and fabricated, which can enhance targeting to melanoma and perform photothermal therapy (PTT) and chemotherapy simultaneously to synergistically exert anticancer effects. The system consisted of magnetic nanoparticles (DTIC/ICG-Fe3O4@TpBD), dissoluble matrix (Bletilla polysaccharide (BSP)/hyaluronic acid (HA)), and a polyvinyl alcohol backing layer. Due to the good magnetic responsiveness of Fe3O4@TpBD, dacarbazine (DTIC) and indocyanine green (ICG) can be better targeted to the tumor tissue and improve the therapeutic effect. BSP and HA have good biocompatibility and transdermal ability, so that the MNs can completely penetrate the tumor tissue, be dissolved by the interstitial fluid, and release DTIC and ICG. Under near-infrared (NIR) light irradiation, ICG converts light energy into thermal energy and induces ablation of B16-OVA melanoma cells. In vivo results showed that DTIC/ICG-Fe3O4@TpBD BSP/HA MNs combined with chemotherapy and PTT could effectively inhibit the growth of melanoma without tumor recurrence or significant weight loss in mice. Therefore, DTIC/ICG-Fe3O4@TpBD BSP/HA MNs are expected to provide new ideas and therapeutic approaches for the clinical treatment of melanoma.

Triglyceride glucose index predicts in-hospital mortality in patients with ST-segment elevation myocardial infarction who underwent primary angiography.

OBJECTIVES: To assess the correlation between triglyceride glucose (TyG) index and in-hospital mortality in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: A total of 2190 patients with STEMI who underwent primary angiography within 12 h from symptom onset were selected from the prospective, nationwide, multicenter CAMI registry. TyG index was calculated with the formula: Ln [fasting triglycerides (mmol/L) × fasting glucose (mmol/L)/2]. Patients were divided into three groups according to the tertiles of TyG index. The primary endpoint was in-hospital mortality. RESULTS: Overall, 46 patients died during hospitalization, in-hospital mortality was 1.5%, 2.2%, 2.6% for tertile 1, tertile 2, and tertile 3, respectively. However, TyG index was not significantly correlated with in-hospital mortality in single-variable logistic regression analysis. Nonetheless, after adjusting for age and sex, TyG index was significantly associated with higher mortality when regarded as a continuous variable (adjusted OR = 1.75, 95% CI: 1.16-2.63) or categorical variable (tertile 3 vs. tertile 1: adjusted OR = 2.50, 95% CI: 1.14-5.49). Furthermore, TyG index, either as a continuous variable (adjusted OR = 2.54, 95% CI: 1.42-4.54) or categorical variable (tertile 3 vs. tertile 1: adjusted OR = 3.57, 95% CI: 1.24-10.29), was an independent predictor of in-hospital mortality after adjusting for multiple confounders in multivariable logistic regression analysis. In subgroup analysis, the prognostic effect of high TyG index was more significant in patients with body mass index < 18.5 kg/m2 (P interaction = 0.006). CONCLUSIONS: This study showed that TyG index was positively correlated with in-hospital mortality in STEMI patients who underwent primary angiography, especially in underweight patients.

ApoE Mimetic Peptide COG1410 Exhibits Strong Additive Interaction with Antibiotics Against Mycobacterium smegmatis.

Background: Drug-resistant tuberculosis (TB) is an emerging threat to public health worldwide. Antimicrobial peptide (AMP) is a promising solution to solve the antimicrobial resistance crisis. The apolipoprotein E mimetic peptide COG1410 has been confirmed to simultaneously have neuroprotective, anti-inflammatory, and antibacterial activity. However, whether it is effective to inhibit growth of mycobacteria has not been investigated yet. Methods: The peptide COG1410 was synthesized with conventional solid-phase peptide synthesis and qualified by HPLC and mass spectrometry. Micro-dilution method was used to determine the minimal inhibitory concentration. A time-kill assay was used to determine the bactericidal dynamics of antimicrobial peptide and relative antibiotics. Static biofilm formation was conducted in 24-well plate and the biofilm was separated from planktonic cells and collected. The mechanism of action of COG1410 was explored by TEM observation and ATP leak assay. The localization of COG1410 was observed by confocal laser scan microscopy. The drug-drug interaction was determined by a checkerboard assay. Results: COG1410 was a potent bactericidal agent against M. smegmatis in vitro and within the macrophages with MIC 16 µg/mL, but invalid against M. abscess and M. tuberculosis. A time-kill assay showed that COG1410 killed M. smegmatis as potent as clarithromycin, but faster than LL-37, another short synthetic cationic peptide. 1× MIC COG1410 almost reduced 90% biofilm formation of M. smegmatis. Additionally, COG1410 was able to penetrate the cell membrane of macrophage and inhibit intracellular M. smegmatis growth. TEM observation and ATP leak assay found that COG1410 disrupted cell membrane and caused release of cell contents. Confocal fluorescence microscopy showed that FITC-COG1410 aggregated around cell membrane instead of entering the cytoplasm. Although COG1410 had relative high cytotoxicity, it exhibited strong additive interaction with regular anti-TB antibiotics, which reduced the working concentration of COG1410 and expanding safety window. After 30 passages, there was no induced drug resistance for COG1410. Conclusion: COG1410 was a novel and potent AMP against M. smegmatis by disrupting the integrity of cell membrane.

Infrared radiation blanching-inhibited browning and extended shelf life of pecan kernels.

To evaluate infrared radiation (IR) blanching in comparison to conventional hot water (HW) blanching in inhibiting the browning and extending the shelf life of pecan kernels, the technology of IR blanching at 500-700 W for 90-45 s or HW blanching at 90°C for 60 s, and subsequently drying with hot air at 60, 70, and 80°C, respectively, was used, and then the activities of lipoxidase (LOX) and polyphenol oxidase (PPO), antioxidant capacities, color change, microscopic structure, and the shelf life of kernels were analyzed. Results showed that IR blanching not only significantly decreased the subsequent drying time but also effectively inactivated the activities of LOX and PPO, showing a lower residual activity of 15.74%-40.41% and 16.75%-56.25%, respectively. A higher retention of total phenolics was observed in kernels subjected to IR blanching, from 25.03 ± 0.04 to 29.50 ± 0.96 mg GAE/g compared with HW blanching (14.43 ± 0.07 mg GAE/g). Meanwhile, IR-blanched samples showed lower peroxide values, p-anisidine values, total color difference values, browning index, quinones contents, and lipofuscin-like pigments levels but had higher 2,2-diphenyl-1-picrylhydrazyl inhibition rate and better storage stabilities than HW-blanched samples. The technology of IR blanching at 600 W for 60 s followed by drying with hot air at 70°C for 40 min is suitable for producing pecan kernels with better qualities and a longer shelf life, through inactivating the endogenous enzymatic reactions and inhibiting the formation of lipofuscin-like pigments. PRACTICAL APPLICATION: Blanching is an essential pretreatment of food processing. Conventional blanching is achieved by hot water, which has some disadvantages of low-intensity enzyme inactivation, loss of water-soluble substances, etc. In this study, the potential of using infrared blanching, prior to drying, was studied to find solutions to improve the nutritional value, and the shelf life of pecan kernels. The results showed that infrared blanching at 600 W for 60 s followed by drying with hot air at 70°C for 40 min could inhibit the color degradation, improve the oxidation resistance, and prolong the shelf life of kernels.

Novel lncRNA-prader willi/angelman region RNA, SNRPN neighbour (PWARSN) aggravates tubular epithelial cell pyroptosis by regulating TXNIP via dual way in diabetic kidney disease.

OBJECTIVES: Elevated thioredoxin-interacting protein (TXNIP)-induced pyroptosis contributes to the pathology of diabetic kidney disease (DKD). However, the molecular mechanisms in dysregulated TXNIP in DKD remain largely unclear. MATERIALS AND METHODS: Transcriptomic analysis identified a novel long noncoding RNA-Prader Willi/Angelman region RNA, SNRPN neighbour (PWARSN)-which was highly expressed in a proximal tubular epithelial cell (PTEC) under high glucose conditions. We focused on revealing the functions of PWARSN in regulating TXNIP-mediated pyroptosis in PTECs by targeting PWARSN expression via lentivirus-mediated overexpression and CRISPR-Cas9-based knockout in vitro and overexpressing PWARSN in the renal cortex by AAV-9 targeted injection in vivo. A number of molecular techniques disclosed the mechanisms of PWARSN in regulating TXNIP induced-pyroptosis in DKD. RESULTS: TXNIP-NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and PTEC pyroptosis were activated in the renal tubules of patients with DKD and in diabetic mice. Then we explored that PWARSN enhanced TXNIP-driven PTECs pyroptosis in vitro and in vivo. Mechanistically, cytoplasmic PWARSN sponged miR-372-3p to promote TXNIP expression. Moreover, nuclear PWARSN interacted and facilitated RNA binding motif protein X-linked (RBMX) degradation through ubiquitination, resulting in the initiation of TXNIP transcription by reducing H3K9me3-enrichment at the TXNIP promoter. Further analysis indicated that PWARSN might be a potential biomarker for DKD. CONCLUSIONS: These findings illustrate distinct dual molecular mechanisms for PWARSN-modulated TXNIP and PTECs pyroptosis in DKD, presenting PWARSN as a promising therapeutic target for DKD.

A novel intelligent displacement prediction model of karst tunnels.

Karst is a common engineering environment in the process of tunnel construction, which poses a serious threat to the construction and operation, and the theory on calculating the settlement without the assumption of semi-infinite half-space is lack. Meanwhile, due to the limitation of test conditions or field measurement, the settlement of high-speed railway tunnel in Karst region is difficult to control and predict effectively. In this study, a novel intelligent displacement prediction model, following the machine learning (ML) incorporated with the finite difference method, is developed to evaluate the settlement of the tunnel floor. A back propagation neural network (BPNN) algorithm and a random forest (RF) algorithm are used herein, while the Bayesian regularization is applied to improve the BPNN and the Bayesian optimization is adopted for tuning the hyperparameters of RF. The newly proposed model is employed to predict the settlement of Changqingpo tunnel floor, located in the southeast of Yunnan Guizhou Plateau, China. Numerical simulations have been performed on the Changqingpo tunnel in terms of variety of karst size, and locations. Validations of the numerical simulations have been validated by the field data. A data set of 456 samples based on the numerical results is constructed to evaluate the accuracy of models' predictions. The correlation coefficients of the optimum BPNN and BR model in testing set are 0.987 and 0.925, respectively, indicating that the proposed BPNN model has more great potential to predict the settlement of tunnels located in karst areas. The case study of Changqingpo tunnel in karst region has demonstrated capability of the intelligent displacement prediction model to well predict the settlement of tunnel floor in Karst region.

Safety and Efficacy of Drug-Coated Balloons in Patients with Acute Coronary Syndromes and Vulnerable Plaque.

BACKGROUND: Percutaneous coronary intervention (PCI) is the main treatment option for acute coronary syndromes (ACS) often related to the progression and rupture of vulnerable plaques. While drug-eluting stents (DES) are now routinely used in PCI, drug-coated balloons (DCB) are a new strategy to PCI and their practice in the treatment of ACS with vulnerable plaques has not been reported. This study aimed to evaluate the safety and efficacy of DCB in ACS complicated with vulnerable plaque lesions. METHODS: 123 patients were retrospectively analyzed and diagnosed with ACS and given PCI in our Cardiology Department from December 2020 to July 2022. Vulnerable plaques were confirmed by intravenous ultrasound (IVUS) in all patients. According to individual treatment plan, patients were entered into either DCB (n = 55) or DES (n = 68) groups. The results of coronary angiography and IVUS before and immediately after percutaneous coronary intervention were analyzed. The occurrence of major adverse cardiovascular events (MACE) and the results of coronary angiography were also evaluated during follow-up. RESULTS: There were no significant differences in baseline clinical characteristics, preoperative minimal luminal diameter (MLD), and preoperative diameter stenosis (DS) between the two groups. Also, there were no differences in IVUS plaque burden (PB), vessel area, and lumen area in the two groups before and immediately after PCI. The efficacy analysis showed that immediately after PCI, the DCB group had smaller MLD and higher degrees of lumen stenosis than the DES group (P < 0.05). However, during follow-up, no significant differences in MLD and DS were seen in two groups; relatively, late loss in luminal diameter（LLL）in the DCB group was smaller (P＜0.05). Safety analysis showed that during follow-up, 9 patients developed restenosis after DCB implantation while restenosis occurred in 10 patients with DES treatment, no statistical difference in the incidence of restenosis in the two groups. Besides, there was no statistical difference in the incidence of major adverse cardiac events（MACE）during hospitalization and follow-up in the DCB group (7.3% (4/55)) and the DES group (8.8% (6/68)). CONCLUSION: DCB is safe and effective for ACS complicated with vulnerable plaque and has an advantage over DES in LLL.

Apolipoprotein E mimetic peptide COG1410 combats pandrug-resistant Acinetobacter baumannii.

The emergence of pandrug-resistant bacteria breaks through the last line of defense and raises fear among people of incurable infections. In the post-antibiotic era, the pharmaceutical field turns to seek non-conventional anti-infective agents. Antimicrobial peptides are considered a prospective solution to the crisis of antimicrobial resistance. In this study, we evaluated the antimicrobial efficiency of an ApoE mimetic peptide, COG1410, which has been confirmed to exhibit strong neural protective activity and immunomodulatory function. COG1410 showed potent antimicrobial activity against pandrug-resistant Acinetobacter baumannii, even eliminating large inocula (108 CFU/ml) within 30 min. LC99.9 in PBS and 50% pooled human plasma was 2 µg/ml (1.4 µM) and 8 µg/ml (5.6 µM), respectively. Moreover, COG1410 exhibited biofilm inhibition and eradication activity, excellent stability in human plasma, and a low propensity to induce resistance. Although COG1410 easily entered bacterial cytoplasm and bound to DNA nonspecifically, the major mechanism of COG1410 killing was to disrupt the integrity of cell membrane and lead to leakage of cytoplasmic contents, without causing obvious pores on the cell surface or cell lysis. Additionally, transcriptome analysis showed that treatment with COG1410-enriched genes involved a series of oxidation-reduction processes. DCFH-DA probe detected an increased ROS level in the presence of COG1410, indicating ROS was another hit of this AMP. Furthermore, the action of COG1410 did not depend on the electronic interaction with the LPS layer, in contrast to polymyxin B. The strong synergistic interaction between COG1410 and polymyxin B dramatically reduced the working concentration of COG1410, expanding the safety window of the application. C. elegans infection model showed that combined therapy of COG1410 and polymyxin B was capable of significantly rescuing the infected nematodes. Taken together, our study demonstrates that COG1410 is a promising drug candidate in the battle against pandrug-resistant A. baumannii.

Clinical Outcomes Following Hemodynamic Parameter or Intravascular Imaging-Guided Percutaneous Coronary Intervention in the Era of Drug-Eluting Stents: An Updated Systematic Review and Bayesian Network Meta-Analysis of 28 Randomized Trials and 11,860 Patients.

Background: Coronary angiography (CAG) is the standard imaging modality for guiding percutaneous coronary interventions (PCI). Intracoronary imaging techniques such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT), and hemodynamic parameter like fractional flow reserve (FFR) can overcome some limitations of CAG. Objective: We sought to explore the clinical outcomes of different PCI guidance modalities in the era of drug-eluting stent (DES). Methods: A network meta-analysis of 28 randomized trials and 11,860 patients undergoing different modalities-guided PCI in the era of DES was performed. Odds ratio (OR) with 95% credible interval (CrI) were calculated. Results: In comparison with CAG, IVUS was associated with a significant reduction in major adverse cardiovascular events (MACE, OR: 0.60; 95% CrI: 0.46-0.79), cardiovascular death (OR: 0.46; 95% CrI: 0.20-0.94), target vessel/lesion revascularization (TVR/TLR, OR: 0.55; 95% CrI: 0.41-0.74), and a trend toward decreased risk of stent thrombosis (OR: 0.44; 95% CrI: 0.17 to 1.00). FFR/quantitative flow ratio (QFR) could significantly reduce stroke compared with CAG, IVUS, and OCT/optical frequency domain imaging (OFDI). However, myocardial infarction (MI), all-cause death, stent thrombosis, and any revascularization presented similar risks for different PCI guidance modalities. Conclusion: In the era of DES, IVUS led to lower risks of MACE than CAG, which was mainly due to lower risks of cardiovascular death and TVR/TLR. A trend toward decreased risk of stent thrombosis was also observed with IVUS. Hemodynamic parameter (FFR/QFR)-guided PCI could significantly reduce the stroke risk compared with CAG, IVUS, and OCT/OFDI. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42021291442].

Antagonism of histamine H3 receptor promotes angiogenesis following focal cerebral ischemia.

Our previous study showed that H3 receptor antagonists reduced neuronal apoptosis and cerebral infarction in the acute stage after cerebral ischemia, but through an action independent of activation of histaminergic neurons. Because enhanced angiogenesis facilitates neurogenesis and neurological recovery after ischemic stroke, we herein investigated whether antagonism of H3R promoted angiogenesis after brain ischemia. Photothrombotic stroke was induced in mice. We showed that administration of H3R antagonist thioperamide (THIO, 10 mg·kg-1·d-1, i.p., from D1 after cerebral ischemia) significantly improved angiogenesis assessed on D14, and attenuated neurological defects on D28 after cerebral ischemia. Compared with wild-type mice, Hrh3-/- mice displayed more blood vessels in the ischemic boundary zone on D14, and THIO administration did not promote angiogenesis in these knockout mice. THIO-promoted angiogenesis in mice was reversed by i.c.v. injection of H3R agonist immepip, but not by H1 and H2 receptor antagonists, histidine decarboxylase inhibitor α-fluoromethylhistidine, or histidine decarboxylase gene knockout (HDC-/-), suggesting that THIO-promoted angiogenesis was independent of activation of histaminergic neurons. In vascular endothelial cells (bEnd.3), THIO (10-9-10-7 M) dose-dependently facilitated cell migration and tube formation after oxygen glucose deprivation (OGD), and H3R knockdown caused similar effects. We further revealed that H3R antagonism reduced the interaction between H3R and Annexin A2, while knockdown of Annexin A2 abrogated THIO-promoted angiogenesis in bEnd.3 cells after OGD. Annexin A2-overexpressing mice displayed more blood vessels in the ischemic boundary zone, which was reversed by i.c.v. injection of immepip. In conclusion, this study demonstrates that H3R antagonism promotes angiogenesis after cerebral ischemia, which is independent of activation of histaminergic neurons, but related to the H3R on vascular endothelial cells and its interaction with Annexin A2. Thus, H3R antagonists might be promising drug candidates to improve angiogenesis and neurological recovery after ischemic stroke.

Pyruvate Upregulates Hepatic FGF21 Expression by Activating PDE and Inhibiting cAMP-Epac-CREB Signaling Pathway.

Fibroblast growth factor 21 (FGF21) functions as a polypeptide hormone to regulate glucose and lipid metabolism, and its expression is regulated by cellular metabolic stress. Pyruvate is an important intermediate metabolite that acts as a key hub for cellular fuel metabolism. However, the effect of pyruvate on hepatic FGF21 expression and secretion remains unknown. Herein, we examined the gene expression and protein levels of FGF21 in human hepatoma HepG2 cells and mouse AML12 hepatocytes in vitro, as well as in mice in vivo. In HepG2 and AML12 cells, pyruvate at concentrations above 0.1 mM significantly increased FGF21 expression and secretion. The increase in cellular cAMP levels by adenylyl cyclase activation, phosphodiesterase (PDE) inhibition and 8-Bromo-cAMP administration significantly restrained pyruvate-stimulated FGF21 expression. Pyruvate significantly increased PDE activities, reduced cAMP levels and decreased CREB phosphorylation. The inhibition of exchange protein directed activated by cAMP (Epac) and cAMP response element binding protein (CREB) upregulated FGF21 expression, upon which pyruvate no longer increased FGF21 expression. The increase in plasma pyruvate levels in mice induced by the intraperitoneal injection of pyruvate significantly increased FGF21 gene expression and PDE activity with a reduction in cAMP levels and CREB phosphorylation in the mouse liver compared with the control. In conclusion, pyruvate activates PDEs to reduce cAMP and then inhibits the cAMP-Epac-CREB signaling pathway to upregulate FGF21 expression in hepatocytes.

Thrombotic vs. Bleeding Events of Interruption of Dual Antiplatelet Therapy within 12 Months among Patients with Stent-Driven High Ischemic Risk Definition following PCI.

BACKGROUND: There is a paucity of real-world data regarding the clinical impact of dual antiplatelet therapy (DAPT) interruption (temporary or permanent) among patients at high ischemic risk. The aim of this study was to assess the risk of cardiovascular events after interruption of DAPT in high-risk PCI population. METHODS: This study used data from the Fuwai PCI registry, a large, prospective cohort of consecutive patients who underwent PCI. We assessed 3,931 patients with at least 1 high ischemic risk criteria of stent-related recurrent ischemic events proposed in the 2017 ESC guidelines for focused update on DAPT who were free of major cardiac events in the first 12 months. The primary ischemic endpoint was 30-month major adverse cardiac and cerebrovascular events, and the key safety endpoints were BARC class 2, 3, or 5 bleeding and net adverse clinical events. RESULTS: DAPT interruption within 12 months occurred in 1,122 patients (28.5%), most of which were due to bleeding events or patients' noncompliance to treatment. A multivariate Cox regression model, propensity score (PS) matching, and inverse probability of treatment weighting (IPTW) based on the propensity score demonstrated that DAPT interruption significantly increased the risk of primary ischemic endpoint compared with prolonged DAPT (3.9% vs. 2.2%; Cox-adjusted hazard ratio (HR): 1.840; 95% confidence interval (CI): 1.247 to 2.716; PS matching-HR: 2.049 [1.236-3.399]; IPTW-adjusted HR: 1.843 [1.250-2.717]). This difference was driven mainly by all-cause death (1.8% vs. 0.7%) and MI (1.3% vs. 0.5%). Furthermore, the rate of net adverse clinical events (4.9% vs. 3.2%; Cox-adjusted HR: 1.581 [1.128-2.216]; PS matching-HR: 1.639 [1.075-2.499]; IPTW-adjusted HR: 1.554 [1.110-2.177]) was also higher in patients with DAPT interruption (≤12 months), whereas no significant differences between groups were observed in terms of BARC 2, 3, or 5 bleeding. These findings were consistent across various stent-driven high-ischemic risk subsets with respect to the primary ischemic endpoints, with a greater magnitude of harm among patients with diffuse multivessel diabetic coronary artery disease. CONCLUSIONS: In patients undergoing high-risk PCI, interruption of DAPT in the first 12 months occurred infrequently and was associated with a significantly higher adjusted risk of major adverse cardiovascular events and net adverse clinical events. 2017 ESC stent-driven high ischemic risk criteria may help clinicians to discriminate patient selection in the use of long-term DAPT when the ischemic risk certainly overcomes the bleeding one.

Astragaloside IV inhibits cell invasion and metastasis in vulvar squamous cell carcinoma through the TGF-ß1/FAK/AKT signaling pathway.

OBJECTIVES: To investigate the mechanism of astragaloside IV (AS-IV) inhibiting the invasion and metastasis of vulvar squamous cell carcinoma (VSCC). MATERIAL AND METHODS: MTT and plate colony-formation assays were used to examine the cell proliferation of VSCC (SW962 cell line). Transwell and scratch wound-healing assays were used to analyse cell migration and invasion. Western blot was used to detect the expression of relevant proteins in terms of cell proliferation, invasion and metastasis, as well as the TGF-ß1/FAK/AKT signaling pathway. RESULTS: The results showed that AS-IV inhibited the proliferation of SW962 cells in a concentration-dependent manner, as demonstrated by the upregulation of P53 and P21 expression and the downregulation of cyclin D1 expression. AS-IV decreased the ability of cell invasion and metastasis by the downregulation of MMP-2 and MMP-9 expression. When TGF-ß1 was added to SW962 cells, the expression of the N-cadherin and Vimentin were upregulated and that of the E-cadherin was downregulated. Subsequently, fibroblast-like elongated spindle-shaped cells appeared, which suggests that TGF-ß1 could induce EMT in SW962 cells. Furthermore, the expression of p-FAK, p-AKT, MMP-2 and MMP-9 were upregulated. The expression of these proteins exhibited the opposite effect after AS-IV intervention. Cell invasion and metastasis were suppressed. CONCLUSIONS: AS-IV inhibits cell invasion and metastasis in VSCC through the TGF-ß1/FAK/AKT signalling pathway.

Establishing the optimal duration of DAPT following PCI in high-risk TWILIGHT-like patients with acute coronary syndrome.

OBJECTIVES: To determine the association of extended-term (>12-month) versus short-term dual antiplatelet therapy (DAPT) with ischemic and hemorrhagic events in high-risk "TWILIGHT-like" patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) in clinical practice. BACKGROUND: Recent emphasis on shorter DAPT regimen after PCI irrespective of indication for PCI may fail to account for the substantial residual risk of recurrent atherothrombotic events in ACS patients. METHODS: All consecutive patients fulfilling the "TWILIGHT-like" criteria undergoing PCI were identified from the prospective Fuwai PCI Registry. High-risk patients (n = 8,358) were defined by at least one clinical and one angiographic feature based on TWILIGHT trial selection criteria. The primary ischemic endpoint was major adverse cardiac and cerebrovascular events at 30 months, composed of all-cause mortality, myocardial infarction, or stroke while BARC type 2, 3, or 5 bleeding was key secondary outcome. RESULTS: Of 4,875 high-risk ACS patients who remained event-free at 12 months after PCI, DAPT>12-month compared with shorter DAPT reduced the primary ischemic endpoint by 63% (1.5 vs. 3.8%; HRadj: 0.374, 95% CI: 0.256-0.548; HRmatched: 0.361, 95% CI: 0.221-0.590). The HR for cardiovascular death was 0.049 (0.007-0.362) and that for MI 0.45 (0.153-1.320) and definite/probable stent thrombosis 0.296 (0.080-1.095) in propensity-matched analyses. Rates of BARC type 2, 3, or 5 bleeding (0.9 vs. 1.3%; HRadj: 0.668 [0.379-1.178]; HRmatched: 0.721 [0.369-1.410]) did not differ significantly between two groups. CONCLUSIONS: Among high-risk ACS patients undergoing PCI, long-term DAPT, compared with shorter DAPT, reduced ischemic events without a concomitant increase in clinically meaning bleeding events, suggesting that prolonged DAPT can be considered in ACS patients who present with a particularly higher risk for thrombotic complications without excessive risk of bleeding.

Prognostic and Practical Validation of ESC/EACTS High Ischemic Risk Definition on Long-Term Thrombotic and Bleeding Events in Contemporary PCI Patients.

AIMS: The ESC/EACTS myocardial revascularization guidelines recently standardized the definition of patients at high ischemic risk (HIR). However, the ability of ESC/EACTS-HIR criteria to stratify ischemic and bleeding risk in a contemporary real-world East Asian cohort remains unexplored. METHODS: A total of 10,167 consecutive patients undergoing PCI from prospective Fuwai PCI Registry (January 2013 to December 2013) were reviewed. ESC/EACTS-HIR features was defined as having at least one of the eight clinical and angiographic characteristics. The primary ischemic endpoint was target vessel failure (cardiac death, target vessel myocardial infarction [MI], or target vessel revascularization [TVR]); bleeding outcome was assessed using the BARC type 2, 3, or 5 bleeding. Median follow-up was 29 months. RESULTS: Compared with non-HIR patients, HIR patients (n=5,149, 50.6%) were associated with increased risk for target vessel failure (adjusted hazard ratio [HRadjust]: 1.48 [1.25-1.74]) and patient-oriented composite outcome (HRadjust: 1.44 [1.28-1.63]), as well as cardiac death, MI, and TVR. By contrast, the risk of clinically relevant bleeding was not significantly different between the two groups. (HRadjust: 0.84 [0.66-1.06]). Greater than or equal to three implanted stents and diabetic patients with diffuse multivessel coronary disease emerged as independent predictors for long-term adverse outcomes. There was no significant interaction between high bleeding risk (HBR) status and clinical outcomes associated with ESC/EACTS-HIR criteria (all Pinteraction ＞0.05). CONCLUSION: The ESC/EACTS-HIR features identified patients at increased risk of thrombotic events, including cardiac death, but not for clinically relevant bleeding. Importantly, HBR did not modify cardiovascular risk subsequent to patients with ESC/EACTS-HIR features, suggesting its potential clinical applicability in tailoring antithrombotic therapy.