Blockage of macrophage migration inhibitory factor (MIF) suppressed uric acid-induced vascular inflammation, smooth muscle cell de-differentiation, and remodeling.

Hyperuricemia contributes to vascular injury and dysfunction, yet the potential mechanisms are not well understood. Uric acid (UA) has been found to stimulate macrophage migration inhibitory factor (MIF) up-regulation in renal tubules from rats subjected to UA-induced nephropathy. Given that MIF is able to induce vascular smooth muscle cell (VSMC) de-differentiation (from contractile state to a secretory state), we thus hypothesized that UA-induced vascular injury is via up-regulating of MIF in VSMCs, which enhancing vascular inflammation and VSMC transition. Within a mouse model of UA injection (500 mg/kg, twice/day, 14 days), we measured circulating and vascular MIF levels under UA stimulation at 6 h, day 1, and 14. We tested the efficacy of MIF inhibitor (10 mg/kg, twice/day, 14 days) on UA-induced vascular inflammation and remodeling. High plasma level of UA induced vascular MIF release into the plasma at acute phase. In the chronic phase, the protein level of MIF is up-regulated in the vessels. MIF inhibitor suppressed vascular inflammatory responses, repressed VSMC de-differentiation, and attenuated vascular remodeling and dysfunction following UA stimulation. Knockdown of MIF in cultured VSMCs repressed UA-induced de-differentiation. Our results provided a novel mechanism for MIF-mediated vascular injury in response to UA stimulation, and suggested that anti-MIF interventions may be of therapeutic value in hyperuricemic patients.

Stereochemical considerations in pharmacokinetic processes of representative antineoplastic agents.

The vast majority of chemical drugs or drug candidates contain stereocenter(s) in their molecular structures. In these molecules, stereochemical properties are vital properties that influence or even determine their drug actions. Therefore, studying the stereochemical issues of drugs (or drug candidates) is necessary for rational drug use. These stereochemical issues are usually involved with the stereoselectivity in pharmacokinetic processes, especially in the metabolism process. Thus, the investigation of the stereochemical issues in drug metabolism process deserves great attention, especially in those chiral/prochiral antineoplastic agents exhibiting pharmacodynamics and toxicologic differences between stereoisomers. Published reviews concerning this certain issue are inspiring, however they were covering all drug types and only limited antineoplastic drugs were discussed. Here in this review, the research on stereochemical issues in pharmacokinetic processes of some representative antineoplastic agents were described, especially focusing on some newly developed compounds. We highlight the chemical transformations in pharmacokinetic processes of these chiral/prochiral compounds and discuss their different behaviors with metabolic enzymes or transporter proteins, to explicate the observed stereoselectivity intrinsically.

Catanionic lipid nanosystems improve pharmacokinetics and anti-lung cancer activity of curcumin.

Novel catanionic lipid nanosystems (CLNs) incorporating curcumin (CCM) were developed, and improvements in pharmacokinetics and enhanced anti-lung cancer activity were observed. CCM was present in a lipid matrix surrounded by cationic, anionic and zwitterionic surfactants, forming the core-shell nanosystems. Compared with free CCM, the CCM-CLNs had much higher oral and intravenous bioavailabilities due to enhanced absorption and reduced clearance. The CCM-CLNs exhibited greater cytotoxicity in Lewis lung cancer (LLC) cells, which might have been due to increased antiproliferative, proapoptotic and anti-invasive activities and induction of cell cycle arrest. The CCM-CLNs increased the antitumor efficacy of CCM and decreased the tumor growth rate in tumor-bearing mice. This is the first report of induction of apoptosis in LLC cells by CCM through the PI3K/Akt/FoxO1/Bim signaling pathway. Catanionic lipid nanocarriers show promise for the therapeutic delivery of insoluble anti-tumor drugs.

Subclinical highly pathogenic avian influenza virus infection among vaccinated chickens, China.

Subclinical infection of vaccinated chickens with a highly pathogenic avian influenza A(H5N2) virus was identified through routine surveillance in China. Investigation suggested that the virus has evolved into multiple genotypes. To better control transmission of the virus, we recommend a strengthened program of education, biosecurity, rapid diagnostics, surveillance, and elimination of infected poultry.

Risk factors from Framingham risk score for anthracyclines cardiotoxicity in breast cancer: A systematic review and meta-analysis.

Background: Framingham risk score (FRS) is an effective tool for evaluating the 10-year risk of cardiovascular diseases. However, the sensitivity of FRS for anthracycline-induced cardiotoxicity is unclear. This meta-analysis aims to evaluate the correlation between risk factors (hypertension, hyperlipidemia, diabetes, smoking, and obesity) in FRS and anthracycline-induced cardiotoxicity in breast cancer. Methods: We searched PubMed, EMBASE, and Cochrane Library for studies published from inception to January 2022 which reported cardiotoxicity due to anthracycline. Cardiotoxicity defined as any cardiac events were used as the primary endpoint. A total of 33 studies involving 55,708 breast cancer patients treated with anthracyclines were included in this meta-analysis. Results: At least one risk factor was identified at baseline for the 55,708 breast cancer patients treated with anthracycline. Hypertension [I 2 = 45%, Fixed, RR (95% CI) = 1.40 (1.22, 1.60), p < 0.00001], hyperlipidemia [I 2 = 0%, Fixed, RR (95% CI): 1.35 (1.12, 1.62), p = 0.002], diabetes [I 2 = 0%, Fixed, RR (95% CI): 1.29 (1.05, 1.57), p = 0.01], and obesity [I 2 = 0%, Fixed, RR (95% CI): 1.32 (1.05, 1.67), p = 0.02] were associated with increased risks of cardiac events. In addition, smoking was also associated with reduced left ventricular ejection fraction (LVEF) during anthracycline chemotherapy [I 2 = 0%, Fixed, OR (95% CI): 1.91 (1.24, 2.95), p = 0.003] in studies that recorded only the odds ratio (OR). Conclusion: Hypertension, hyperlipidemia, diabetes, smoking, and obesity are associated with increased risks of anthracycline-induced cardiotoxicity. Therefore, corresponding measures should be used to manage cardiovascular risk factors in breast cancer during and after anthracycline treatment.

Lycopene Ameliorates Hypoxic Pulmonary Hypertension via Suppression of Oxidative Stress.

Hypoxic pulmonary hypertension (HPH) is a progressive cardiopulmonary system disease characterized by pulmonary vascular remodeling. Its occurrence and progression are closely related to oxidative stress. Lycopene, extracted from red vegetables and fruits, exhibits a particularly high antioxidant capacity that is beneficial for cardiovascular diseases. Nevertheless, the role and mechanism of lycopene in HPH remain unknown. Here, we found that lycopene reversed the elevated right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and pulmonary vascular remodeling induced by hypoxia in rats. In vitro, lycopene caused lower proliferation and migration of PASMCs, with higher apoptosis. Consistent with the antiproliferative result of lycopene on hypoxic PASMCs, the hippo signaling pathway associated with cell growth was activated. Furthermore, lycopene reduced malondialdehyde (MDA) levels and enhanced superoxide dismutase (SOD) activity in the lungs and serum of rats under hypoxia conditions. The expression of NOX4 in the lungs was also significantly decreased. Hypoxic PASMCs subjected to lycopene showed decreased reactive oxygen species (ROS) production and NOX4 expression. Importantly, lycopene repressed HIF-1α expression both in the lungs and PASMCs in response to hypoxia in the absence of a significant change of HIF-1α mRNA. Compared with 2ME2 (a HIF-1α inhibitor) alone treatment, lycopene treatment did not significantly change PASMC proliferation, NOX4 expression, and ROS production after 2ME2 blocked HIF-1α, suggesting the inhibitory effect of lycopene on HIF-1α-NOX4-ROS axis and the targeted effect on HIF-1α. After CHX blocked protein synthesis, lycopene promoted the protein degradation of HIF-1α. MG-132, a proteasome inhibitor, notably reversed the decrease in HIF-1α protein level induced by lycopene in response to hypoxia. Therefore, lycopene suppressed hypoxia-induced oxidative stress through HIF-1α-NOX4-ROS axis, thereby alleviating HPH. Our findings will provide a new research direction for clinical HPH therapies.

MicroRNA-150 affects endoplasmic reticulum stress via MALAT1-miR-150 axis-mediated NF-κB pathway in LPS-challenged HUVECs and septic mice.

AIMS: Sepsis is a systemic inflammatory complication, which is the common cause of death in critical patients. This study aimed to evaluate the potential regulatory mechanisms of miR-150 in lipopolysaccharide (LPS)-challenged HUVECs and cecal ligation and puncture (CLP)-induced septic mice. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were challenged with LPS. Pulmonary arterial endothelial cells (PAECs) were isolated from CLP-induced septic mice. The mRNA and protein levels of target molecules were detected by RT-qPCR and Western blotting. Apoptosis of HUVECs was determined by Annexin V/PI staining on a flow cytometry. The interaction between miR-150 and MALAT1 was assessed by luciferase reporter assay, RIP and RNA pull-down assay. KEY FINDINGS: MiR-150 was downregulated in LPS-induced HUVECs. MiR-150 mimics restrained LPS-induced inflammatory response by reducing TNF-α and IL-6 levels, but increasing IL-10 level. Moreover, miR-150 mimics downregulated endoplasmic reticulum (ER) stress-related proteins, GRP78 and CHOP levels in LPS-exposed HUVECs. Additionally, LPS-induced apoptosis was suppressed by miR-150 mimics via decreasing cleaved caspase-3 and Bax levels, while enhancing Bcl-2 level. Mechanistically, MALAT1 could competitively bind to miR-150. LPS-induced apoptosis, ER stress and inflammation were promoted by MALAT1 overexpression, but reversed by siMALAT1. Furthermore, miR-150 inhibitor strengthened LPS-induced apoptosis, ER stress and inflammation, which could be attenuated by siMALAT1 via regulating NF-κB pathway. Finally, agomiR-150 repressed ER stress and inflammatory response in PAECs isolated from septic mice via decreasing MALAT1 level. SIGNIFICANCE: Our findings suggest that miR-150 affects sepsis-induced endothelial injury by regulating ER stress and inflammation via MALAT1-mediated NF-κB pathway.

Association between plasma endothelial microparticles and contrast-induced nephropathy in patients underwent coronary angiography.

ABSTRACT: We aim to investigate the association between plasma endothelial microparticles (EMPs) and contrast-induced nephropathy of patients underwent coronary angiography.The patients were divided into normal renal function group and renal dysfunction group based on the estimated glomerular filtration rate (eGFR). Among the 180 cases, 117 received determination of EMP and serum creatinine after percutaneous coronary intervention (PCI) and/or coronary angiography. The patients were divided into contrast-induced-nephropathy (CIN) group and non-CIN group. EMPs collection and determination were performed, together with biochemical analysis and digital subtraction angiography (DSA) analysis.Spearman correlation showed that the expression of EMP was negatively correlated with eGFR (r = -0.201, P < .01). The serum hypersensitive C-reactive protein (hs-CRP), cystatin C (Cys-C), uric acid (UA) were significantly higher in CIN group than that in the non CIN group. Spearman correlation showed that the expression of EMP was positively correlated with serum interleukin-6 (IL-6, r = 0.393, P < .01). The expression of EMP was positively correlated with serum hs-CRP (r = 0.360, P < .01). Logistic regression analysis showed that the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), eGFR, UA, and Cys-C were correlated with the incidence of contrast induced nephropathy.In patients with contrast-induced-nephropathy, the plasma EMPs were significantly increased after coronary angiography. The expression of plasma EMPs may play a role in the occurrence of contrast-induced-nephropathy.

Flexural Behavior of Fire-Damaged Prefabricated RC Hollow Slabs Strengthened with CFRP versus TRM.

In this paper, carbon fiber reinforced polymer (CFRP) and textile reinforced mortar (TRM) strengthening techniques were proposed to retrofit and strengthen fire-damaged prefabricated concrete hollow slabs. A total of six slabs, from an actual multi-story masonry building, were tested to investigate the flexural performance of reinforced concrete (RC) hollow slabs strengthened with TRM and CFRP. The investigated parameters included the strengthening method (CFRP versus TRM), the number of CFRP layers, and with or without fire exposure. One unstrengthened slab and one TRM strengthened slab served as the control specimens without fire exposure. The remaining four slabs were first exposed to ISO-834 standard fire for 1 h, and then three of them were strengthened with CFRP or TRM. Through the four-point bending tests at ambient temperature, the failure modes, load and deformation response were recorded and discussed. Both CFRP and TRM strengthening methods can significantly increase the cracking load and peak load of the fire-damaged hollow slabs, as well as the stiffness in the early stage. The prefabricated hollow slabs strengthened by CFRP have better performance in the ultimate bearing capacity, but the ductility reduced with the increase of CFRP layers. Meanwhile, the TRM strengthening technique is a suitable method for the performance improvement of fire-damaged hollow slabs, in terms of not only the load capacity, especially the cracking load, but also the flexural stiffness and deformation capacity.

Sarpogrelate and rosuvastatin synergistically ameliorate aortic damage induced by hyperlipidemia in apolipoprotein E-deficient mice.

The current study aimed to investigate whether sarpogrelate and rosuvastatin possess anti-arterial injury, and attempted to elucidate the mechanism of action underlying this activity. Sarpogrelate, a 5-hydroxytryptamine type 2A antagonist, is extensively used to prevent arterial thrombosis; however, its effects on atherosclerosis remain unknown. In the present study, sarpogrelate combined with rosuvastatin or rosuvastatin alone were administered to male ApoE-/- mice fed a high-fat diet (HFD) for 8 weeks. Metabolic parameters in the blood samples were analyzed using an automatic analyzer. Aortic tissues were stained with hematoxylin and eosin for morphological analysis. The expression levels of oxidized-low density lipoprotein (LDL) specific scavenging receptors, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and cluster of differentiation 68 were detected via immunostaining. mRNA expression levels of interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α were determined via reverse transcription-quantitative PCR analysis, while protein expression levels of LOX-1 and phosphor(p)-ERK were determined via western blot analysis. The results demonstrated that sarpogrelate combined with rosuvastatin treatment significantly decreased total cholesterol and LDL cholesterol levels in the serum, and alleviated intimal hyperplasia and lipid deposition, accompanied by decreased inflammatory cell infiltration and lower expression levels of inflammatory cytokines, compared with rosuvastatin monotherapy or HFD treatment. Furthermore, sarpogrelate combined with rosuvastatin treatment significantly decreased the expression levels of LOX-1 and p-ERK. Taken together, these results suggest that the positive effects of sarpogrelate combined with rosuvastatin treatment on aortic injury may be associated with the regulation of the LOX-1/p-ERK signaling pathway. Sarpogrelate and rosuvastatin synergistically decreased aortic damage in ApoE-/- HFD mice, and thus provide a basis for the treatment of aortic injury caused by hyperlipidemia with sarpogrelate.

MiR-373-3p enhances the chemosensitivity of gemcitabine through cell cycle pathway by targeting CCND2 in pancreatic carcinoma cells.

OBJECTIVE: This study aimed to detect the expression of miR-373-3p and CCND2 in gemcitabine-resistance pancreatic carcinoma (PC) cells, investigate the relationship between miR-373-3p and CCND2, and explore their effects on PC propagation, migration, invasion and apoptosis. METHODS: R software was applied for analyzing differentially expressed genes (DEGs) in cell samples. The potential biological pathway was determined by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, based on R software. The gemcitabine-resistance PC cells were screened out using MTT assay, and they were applied in the next experiments. MiR-373-3p and CCND2 expression in GEM-PANC-1 cells were measured by qRT-PCR. After transfection, the expression of CCND2 protein was examined via western blot assay. Cells viability and apoptosis were confirmed by MTT proliferation assay and Flow cytometry, whereas cells migration and invasion were analyzed by transwell assay. The targeting relationship between miR-373-3p and CCND2 was identified by dual-luciferase reporter assay. RESULTS: MiR-373-3p was found to be low expressed in GEM-PANC-1 cells while CCND2 was highly expressed in GEM-PANC-1 cells. MiR-373-3p negatively regulated CCND2 expression through KEGG_Cell_Cycle_Signaling_Pathway. The targeted relationship between miR-373-3p and CCND2 could be verified using dual luciferase reporter assay. MTT proliferation assay, transwell assay and Annexin V assay demonstrated that miR-373-3p suppressed GEM-PANC-1 cells propagation and invasion and promoted cell apoptosis, while CCND2 showed totally reverse effects compared with miR-373-3p. All the results suggested that miR-373-3p could enhance the chemosensitivity of GEM-PANC-1 cells by regulating CCND2. CONCLUSION: MiR-373-3p inhibited cell propagation, migration and invasion and boosted apoptosis in gemcitabine resistance pancreatic carcinoma cells by targeting CCND2.

Development of a simulation environment to study emergency department information technology.

INTRODUCTION: This article presents a simulation architecture for a patient tracking system simulator to study caregiver performance in emergency departments (EDs). The architecture integrates discrete event simulation modeling with clinical patient information. Evaluation components for electronic patient tracking system displays are also described. METHODS: A simulation of an ED electronic whiteboard was developed to study situation awareness metrics. Dynamic process data from an actual ED was used to generate simulation parameters including patient arrivals at various hours, distribution of severities, times required to treat the ED patients, and ancillary turnaround times (laboratory and radiology). A team of industrial engineers and ED physicians contributed demographic and clinical information for simulator patients. ED simulation parameters were combined with clinical information resulting in an event timeline database. Event timelines were used to populate a front-end patient-tracking system display simulation. RESULTS: The resulting patient-tracking system display simulation consists of underlying software, desktop and large-screen displays, a phone call/pager system, and typical tasks that enhance the realism of the simulation experience. The system can evaluate the impact of display parameters and ED operations on user performance. CONCLUSIONS: Modular design of the patient-tracking system display simulation helps adaptation for different studies to support various interface features and interaction types. The methodology described in this work exploits the benefits of discrete event simulation to iteratively design and test technologies such as electronic patient tracking systems and allows assessment of human performance measures.