Integration of network pharmacology and transcriptomics to explore the mechanism of isoliquiritigenin in treating heart failure induced by myocardial infarction.

BACKGROUND: The inflammatory response and myocardial remodeling play critical roles in the progression of heart failure (HF) following myocardial infarction (MI). Isoliquiritigenin (ISL) possesses anti-inflammatory properties and has been investigated in cardiovascular diseases such as atherosclerosis. However, the effects and mechanism of ISL on MI-induced HF remain unclear. This research aimed to explore the effects and mechanism of ISL in the treatment of HF on the basis of network pharmacology, transcriptomics, and experimental verification. METHODS AND RESULTS: We established an MI-induced HF mouse model in which ISL was administered via gavage for 28 days. Ultrasonic cardiogram data were collected from the mice, and pathological staining was conducted. Then, network pharmacology and molecular docking were performed. Transcriptomic analysis was also conducted on mouse myocardial tissue. Ultimately, we integrated transcriptomic data and network pharmacology to reveal the underlying mechanism, with the results verified through in vivo experiments. Our experiments indicated that ISL improved cardiac function, preserved myocardial structure, inhibited collagen fiber accumulation, reduced inflammatory factor secretion, and mitigated myocardial cell apoptosis in mice with MI-induced HF. A combination of transcriptomics and network pharmacology analysis revealed that core targets of ISL related to HF were significantly enriched in the Tumor Necrosis Factor (TNF) signaling pathway. Molecular docking validation demonstrated that ISL shows strong binding to these core targets. Additionally, in vivo experiments verified that ISL protects against HF post-MI by inhibiting the TNF signaling pathway. CONCLUSION: We clarified the anti-inflammatory and antimyocardial remodeling mechanisms of ISL in the treatment of HF post-MI, which involves the TNF signaling pathway.

Long-Term Prognosis of Patients Undergoing Percutaneous Coronary Intervention: The Impact of Serum Creatinine Levels on All-Cause Mortality.

BACKGROUND The correlation between serum creatinine levels and the long-term prognosis of patients undergoing percutaneous coronary intervention (PCI) has not yet been systematically investigated. This study aimed to evaluate the association between long-term prognosis and serum creatinine levels in patients after PCI. MATERIAL AND METHODS This was an observational cohort study of 2533 patients who received PCI and completed serum creatinine and other tests in China. The study's primary prognostic indicators were the frequency of clinical adverse events, all-cause death, cardiac death, acute myocardial infarction, and stroke. All-cause death referred to death from all causes during the follow-up period, whereas cardiac death was death due to cardiac injury resulting in severe cardiac dysfunction or failure. Clinical events included death, ischemia, and stroke. Yao et al completed the entire study and uploaded the data to the DATADRYAD website. We used only this data for secondary analysis. RESULTS The study involved 2533 participants, with a mean age of 59.9±11.1 years and a median follow-up of 29.8 months. The analysis, controlling for confounding factors, revealed a positive correlation between serum creatinine and all-cause death (OR: 2.178, 95% CI: 1.317-3.603, P<0.05), which was confirmed by the results of sensitivity analysis (P for trend <0.05). However, no direct linear correlation was found between serum creatinine and acute myocardial infarction, cardiac death, or stroke. CONCLUSIONS There was a linear correlation between serum creatinine and all-cause death in the long-term prognosis of patients after PCI, independent of acute myocardial infarction, cardiac death, and stroke.

Animal Experimental Study of Bioabsorbable Left Atrial Appendage Occluder.

Left atrial appendage (LAA) closure can prevent stroke in high-risk patients with atrial fibrillation.A bioabsorbable LAA occluder made of degradable polymer materials, such as polydioxanone (PDO) and poly-L-lactic acid (PLA), and nitinol wire was used. Occluders were successfully implanted in 18 Chinese rural dogs, 2 of which died within 48 hours after operation due to pericardial tamponade and hemorrhage, respectively. Follow-up observation was performed after transcatheter LAA closure. New tissue was found on the surface of the occluder 2 months after operation. No adjacent structures such as the mitral valve and the left superior pulmonary vein were affected by the occluder discs. Hematoxylin and eosin (HE) staining was performed at 3 months after operation, which showed intact intimal structure on the occluder surface, and unabsorbed PDO and PLA were observed. Scanning electron microscopy showed irregular arrangement of endothelial cells. New endothelial tissue was observed to completely cover the occluder at 6 months after operation. Most PDOs were replaced by fibrous connective tissue, and scanning electron microscopy showed regularly arranged endothelial cells. Pathological examination at 12 months showed only a small remnant of PDO. The gross specimens of the liver, spleen, and kidneys and pathological examination did not indicate thromboembolism.The bioabsorbable LAA occluder made of PDO, PLA, and nitinol wire was safe and effective for the occlusion of LAA in dogs. The surface of the occluder was endothelialized half a year after operation. The absorbable materials of the occluder were degraded after 1 year.

Efficacy and safety of self-made covered coronary stent in the treatment of coronary artery perforation.

OBJECTIVE: To observe the efficacy and safety of self-made covered coronary stent in the treatment of coronary artery perforation. METHODS: Covered coronary stent was prepared by wrapping 3 M film on the surface of coronary stents. The beagle dogs were divided into control group and experimental group. A drug-eluting stent (DES) was implanted in the control group. The covered stent was applied to block the coronary branches of beagle dogs. The CaIMR value after stent placement was calculated by FlashAngio software. The effect of blocking the coronary branches on blood flow was observed by coronary angiography (CAG). The condition of the implanted stent was observed by optical coherence tomography (OCT), and the histopathologic examination of the coronary vessel implanted stent was performed by HE staining. RESULTS: The best number of layers was 2. Compared with the control group, the CaIMR of the experimental group increased (p < 0.05). A lot of in-stent thrombosis were found in the experimental group and obvious blood flow obstruction during follow-up. HE staining showed that stents implanted in the two groups adhered well to the wall of the blood vessel, but in-stent thrombosis and intimal hyperplasia were founded in the experimental group, while the in-stent restenosis was not founded. CONCLUSION: The self-made coronary covered stent can effectively block the leakage caused by coronary perforation, but the stent endothelialization is poor, which easily causes stent thrombosis and restenosis, so it is not recommended as a routine remedy.

Wogonin alleviates BaP-induced DNA damage and oxidative stress in human airway epithelial cells by dual inhibiting CYP1A1 activity and expression.

Benzo[a]pyrene (BaP) is a common air pollutant that has been reported to cause oxidative stress and carcinogenesis. Wogonin, a flavonoid compound extracted from the roots of Scutellaria baicalensis, has been found to possess a variety of pharmacological activities, including anti-inflammatory and anti-cancer effects. The purpose of this study was to examine the ability of wogonin to alleviate the cytotoxicity induced by BaP in human airway epithelial cells and explore the corresponding mechanism. Our study found that wogonin treatment inhibited DNA damage and reactive oxygen species overproduction induced by BaP in human airway epithelial cells. In vitro enzyme assays showed that wogonin significantly inhibited the enzymatic activity of CYP1A1. In addition, wogonin decreased the basal level of CYP1A1 and inhibited the CYP1A1 overexpression induced by BaP, whereas overexpression of CYP1A1 partially reversed the effect of wogonin on BaP-induced DNA damage. Meanwhile, a CYP1A1 inhibitor and CYP1A1 knockdown also showed these same effects. Further studies showed that wogonin regulates CYP1A1 expression by inhibiting CDK7 and CDK9 activity. The use of CDK7 or CDK9 inhibitors decreased BaP-induced cytotoxicity and CYP1A1 expression. Finally, we found that the methoxy group of wogonin was crucial for its inhibitory activity. In conclusion, our data indicated that wogonin could effectively relieve BaP induced cytotoxicity, and its mechanism was related to the dual inhibition of CYP1A1 activity and expression.

Conformational variability of loops in the SARS-CoV-2 spike protein.

The SARS-CoV-2 spike (S) protein facilitates viral infection, and has been the focus of many structure determination efforts. Its flexible loop regions are known to be involved in protein binding and may adopt multiple conformations. This article identifies the S protein loops and studies their conformational variability based on the available Protein Data Bank structures. While most loops had essentially one stable conformation, 17 of 44 loop regions were observed to be structurally variable with multiple substantively distinct conformations based on a cluster analysis. Loop modeling methods were then applied to the S protein loop targets, and the prediction accuracies discussed in relation to the characteristics of the conformational clusters identified. Loops with multiple conformations were found to be challenging to model based on a single structural template.

Effects and mechanism of renal denervation on ventricular arrhythmia after acute myocardial infarction in rats.

BACKGROUND: Renal denervation (RDN) can reduce ventricular arrhythmia after acute myocardial infarction (AMI), but the mechanism is not clear. The purpose of this study is to study its mechanism. METHODS: Thirty-two Sprague-Dawley rats were divided into four groups: control group, AMI group, RDN-1d + AMI group, RDN-2w + AMI group. The AMI model was established 1 day after RDN in the RDN-1d + AMI group and 2 weeks after RDN in the RDN-2w + AMI group. At the same time, 8 normal rats were subjected to AMI modelling (the AMI group). The control group consisted of 8 rats without RDN intervention or AMI modelling. RESULTS: The study confirmed that RDN can reduce the occurrence of ventricular tachycardia in AMI rats, reduce renal sympathetic nerve discharge, and inhibit the activity of local sympathetic nerves and cell growth factor (NGF) protein expression in the heart after AMI. In addition, RDN decreased the expression of norepinephrine (NE) and glutamate in the hypothalamus,and NE in cerebrospinal fluid, and increased the expression level of γ aminobutyric acid (GABA) in the hypothalamus after AMI. CONCLUSION: RDN can effectively reduce the occurrence of ventricular arrhythmia after AMI, and its main mechanism may be via the inhibition of central sympathetic nerve discharge.

Construction and Characterization of CRISPR/Cas9 Knockout Rat Model of Carboxylesterase 2a Gene.

Carboxylesterase (CES) 2, an important metabolic enzyme, plays a critical role in drug biotransformation and lipid metabolism. Although CES2 is very important, few animal models have been generated to study its properties and functions. Rat Ces2 is similar to human CES2A-CES3A-CES4A gene cluster, with highly similar gene structure, function, and substrate. In this report, CRISPR-associated protein-9 (CRISPR/Cas9) technology was first used to knock out rat Ces2a, which is a main subtype of Ces2 mostly distributed in the liver and intestine. This model showed the absence of CES2A protein expression in the liver. Further pharmacokinetic studies of diltiazem, a typical substrate of CES2A, confirmed the loss of function of CES2A both in vivo and in vitro. At the same time, the expression of CES2C and CES2J protein in the liver decreased significantly. The body and liver weight of Ces2a knockout rats also increased, but the food intake did not change. Moreover, the deficiency of Ces2a led to obesity, insulin resistance, and liver fat accumulation, which are consistent with the symptoms of nonalcoholic fatty liver disease (NAFLD). Therefore, this rat model is not only a powerful tool to study drug metabolism mediated by CES2 but also a good disease model to study NAFLD. SIGNIFICANCE STATEMENT: Human carboxylesterase (CES) 2 plays a key role in the first-pass hydrolysis metabolism of most oral prodrugs as well as lipid metabolism. In this study, CRISPR/Cas9 technology was used to knock out Ces2a gene in rats for the first time. This model can be used not only in the study of drug metabolism and pharmacokinetics but also as a disease model of nonalcoholic fatty liver disease (NAFLD) and other metabolic disorders.

Characterization of a Novel CYP1A2 Knockout Rat Model Constructed by CRISPR/Cas9.

CYP1A2, as one of the most important cytochrome P450 isoforms, is involved in the biotransformation of many important endogenous and exogenous substances. CYP1A2 also plays an important role in the development of many diseases because it is involved in the biotransformation of precancerous substances and poisons. Although the generation of Cyp1a2 knockout (KO) mouse model has been reported, there are still no relevant rat models for the study of CYP1A2-mediated pharmacokinetics and diseases. In this report, CYP1A2 KO rat model was established successfully by CRISPR/Cas9 without any detectable off-target effect. Compared with wild-type rats, this model showed a loss of CYP1A2 protein expression in the liver. The results of pharmacokinetics in vivo and incubation in vitro of specific substrates of CYP1A2 confirmed the lack of function of CYP1A2 in KO rats. In further studies of potential compensatory effects, we found that CYP1A1 was significantly upregulated, and CYP2E1, CYP3A2, and liver X receptor ß were downregulated in KO rats. In addition, CYP1A2 KO rats exhibited a significant increase in serum cholesterol and free testosterone accompanied by mild liver damage and lipid deposition, suggesting that CYP1A2 deficiency affects lipid metabolism and liver function to a certain extent. In summary, we successfully constructed the CYP1A2 KO rat model, which provides a useful tool for studying the metabolic function and physiologic function of CYP1A2. SIGNIFICANCE STATEMENT: Human CYP1A2 not only metabolizes clinical drugs and pollutants but also mediates the biotransformation of endogenous substances and plays an important role in the development of many diseases. However, there are no relevant CYP1A2 rat models for the research of pharmacokinetics and diseases. This study successfully established CYP1A2 knockout rat model by using CRISPR/Cas9. This rat model provides a powerful tool to study the function of CYP1A2 in drug metabolism and diseases.

CYP3A deficiency alters bile acid homeostasis and leads to changes in hepatic susceptibility in rats.

Cytochrome P450 3A (CYP3A) as an important enzyme metabolizes many drugs and a variety of endogenous substances. Bile acids (BA) regulate physiological function by activating BA receptors. In this study, CYP3A1/2 gene knockout (KO) and wild-type (WT) rats were used to investigate the regulatory effects of CYP3A on BA homeostasis and liver function. Compared with WT rats, BA concentrations in serum, liver and small intestine of CYP3A1/2 KO rats increased significantly, which was due to the decrease of catabolism and the increase of synthesis. In particular, the composition of serum BA (overall hydrophobicity) presented an age- and CYP3A-dependent manner. With the aging of WT rats, the serum BA became more hydrophobic, while this trend was delayed in CYP3A1/2 KO rats. Moreover, the level of serum total cholesterol, the precursor of BA synthesis, decreased by about 20% in CYP3A1/2 KO rats, which is due to the low synthesis but high biotransformation rate. The increase of BA pool further led to the change of transcription level of BA receptor in liver (pregnane X receptor) and small intestine (Takeda G-protein receptor 5), and affected the function and morphology of CYP3A1/2 KO rat liver. In conclusion, CYP3A is a key regulator of BA homeostasis in rats, especially in regulating BA pool size, composition and balance of anabolism, and prevents susceptibility to hepatotoxicity under BA overload.

TRIM28 and TRIM27 are required for expressions of PDGFRß and contractile phenotypic genes by vascular smooth muscle cells.

Vascular smooth muscle cells (VSMCs) in the normal arterial media continually express contractile phenotypic markers which are reduced dramatically in response to injury. Tripartite motif-containing proteins are a family of scaffold proteins shown to regulate gene silencing, cell growth, and differentiation. We here investigated the biological role of tripartite motif-containing 28 (TRIM28) and tripartite motif-containing 27 (TRIM27) in VSMCs. We observed that siRNA-mediated knockdown of TRIM28 and TRIM27 inhibited platelet-derived growth factor (PDGF)-induced migration in human VSMCs. Both TRIM28 and TRIM27 can regulate serum response element activity and were required for maintaining the contractile gene expression in human VSMCs. At the same time, TRIM28 and TRIM27 knockdown reduced the expression of PDGF receptor-ß (PDGFRß) and the phosphorylation of its downstream signaling components. Immunoprecipitation showed that TRIM28 formed complexes with TRIM27 through its N-terminal RING-B boxes-Coiled-Coil domain. Furthermore, TRIM28 and TRIM27 were shown to be upregulated and mediate the VSMC contractile marker gene and PDGFRß expression in differentiating human bone marrow mesenchymal stem cells. In conclusion, we identified that TRIM28 and TRIM27 cooperatively maintain the endogenous expression of PDGFRß and contractile phenotype of human VSMCs.

Microtubule associated tumor suppressor 1 interacts with mitofusins to regulate mitochondrial morphology in endothelial cells.

Mitochondria are dynamic organelles that are able to change their morphology and cellular distribution by either fission or fusion. However, the molecular mechanisms controlling mitochondrial dynamics in vascular endothelial cells (ECs) remain largely unknown. In this study, we observed that knockdown of microtubule-associated tumor suppressor 1 (MTUS1) in ECs inhibited tube formation and migration, accompanied with decreased promigratory signalings. We showed that MTUS1 was localized in the outer membrane of mitochondria in ECs. Knockdown of MTUS1 disturbed the elongated mitochondrial network and induced the formation of perinuclear clusters of mitochondria. Importantly, mitochondrial motility and fusion were suppressed, whereas generation of reactive oxygen species was increased in MTUS1 knockdown ECs. Mechanistically, we showed that the N-terminal coiled-coil domain of MTUS1 interacted with the mitochondrial membrane proteins, mitofusin-1 and mitofusin-2, to maintain mitochondrial morphology in ECs. This study illustrated a novel role of MTUS1 in mitochondrial morphology and EC angiogenic responses.-Wang, Y., Huang, Y., Liu, Y., Li, J., Hao, Y., Yin, P., Liu, Z., Chen, J., Wang, Y., Wang, N., Zhang, P. Microtubule associated tumor suppressor 1 interacts with mitofusins to regulate mitochondrial morphology in endothelial cells.

NR6A1 regulates lipid metabolism through mammalian target of rapamycin complex 1 in HepG2 cells.

BACKGROUND: Lipogenesis is required for the optimal growth of many types of cancer cells, it is shown to control the biosynthesis of the lipid bilayer membrane during rapid proliferation and metastasis, provides cancer cells with signaling lipid molecules to support cancer development and make cancer cells more resistant to oxidative stress-induced cell death. Though multiple lipogenic enzymes have been identified to mediate this metabolic change, how the expression of these lipogenic enzymes are transcriptionally regulated remains unclear. METHODS: Gain- and loss-of-function experiments were conducted to assess the role of transcriptional repressor, nuclear receptor sub-family 6, group A, member 1 (NR6A1) in HepG2 cells. RT-qPCR method was performed to investigate target gene of NR6A1. Western blot was employed to determine the mechanisms by which NR6A1 regulates lipid accumulation in HepG2 cells. RESULTS: We provide evidence that NR6A1 is a novel regulator of lipid metabolism in HepG2 cells. NR6A1 knockdown can increase lipid accumulation as well as insulin-induced proliferation and migration of HepG2 cells. The lipogenic effect correlated well with the expression of lipogenic genes, including fatty acid synthase (FAS), diglyceride acyltransferase-2 (DGAT2), malic enzyme 1 (ME1), microsomal triglyceride transfer protein (MTTP) and phosphoenolpyruvate carboxykinase (PEPCK). NR6A1 knockdown also increased the expression of carnitine palmitoyltransferase 1A (CPT1a), the rate-limiting enzyme in fatty acid oxidation. Furthermore, NR6A1 knockdown induced lipid accumulation through mammalian target of rapamycin complex 1 (mTORC1), but not mTORC2. Moreover, siRNA-mediated knockdown of NR6A1 increased expression of insulin receptor (INSR) and potentitated insulin-induced phosphorylation of mTOR and AKT partly via miR-205-5p in HepG2 cells. CONCLUSIONS: These findings provide important new insights into the role of NR6A1 in the lipogenesis in HepG2 cells. .

Tripartite motif-containing 28 bridges endothelial inflammation and angiogenic activity by retaining expression of TNFR-1 and -2 and VEGFR2 in endothelial cells.

Angiogenesis and inflammation are regarded as important factors in the pathogenesis of chronic inflammation, cancer, and wound healing. Recent studies have supported prior evidence that common signaling pathways are involved in angiogenesis and inflammatory responses; however, key factors controlling both processes remain unclear. Although tripartite motif-containing (TRIM)-28 is known to have an immunosuppressive role in immune cells, its expression level and role in endothelial cells (ECs) are still unclear. In this study, we investigated the role of TRIM28 in inflammatory responses and angiogenic activity of ECs for the first time. We showed that TRIM28 is the most abundant TRIM family member and is localized in nuclei of ECs. Small interfering RNA-mediated knockdown of TRIM28 strikingly suppressed expression of TNF receptor (TNFR)-1 and -2, decreased TNF-α-induced phosphorylation of IKKα/ß and IκBα and degradation of IκBα and nuclear translocation of p65, and suppressed basal level and TNF-α-induced expression of chemokines and adhesion molecules, including VCAM-1, IL-6, ICAM-1, E-selectin, and monocyte chemoattractant protein (MCP)-1. Unexpectedly, IL-8 was potentiated by TRIM28 knockdown in ECs in an NF-κB-inducing kinase-dependent manner. Meanwhile, knockdown of TRIM28 inhibited expression of VEGF receptor 2 and suppressed VEGF-induced proliferation and tube formation by ECs. Finally, knockdown of TRIM28 suppressed recruitment of ECs in vivo in a murine synthetic basement membrane model. In summary, we found that TRIM28 acts as a central factor in controlling endothelial inflammatory responses and angiogenic activities by retaining expression of TNFR-1 and -2 and VEGF receptor 2 in ECs.-Wang, Y., Li, J., Huang Y., Dai, X., Liu, Y., Liu, Z., Wang, Y., Wang, N., Zhang, P. Tripartite motif-containing 28 bridges endothelial inflammation and angiogenic activity by retaining expression of TNFR1 and -2 and VEGFR2 in endothelial cells.

Protective Effects of Salvianolate on Contrast-Induced Nephropathy after Primary Percutaneous Coronary Intervention: A Prospective Multicenter Randomized Controlled Trial.

OBJECTIVES: This study's aim was to evaluate the protective effects of salvianolate on contrast-induced nephropathy after primary percutaneous coronary intervention (PPCI) compared with normal saline (NS) hydration. METHODS: We enrolled patients with acute myocardial infarction who underwent PPCI in 3 centers in Shanghai. The patients were randomly assigned to the salvianolate group or the NS group. The incidence of CIN, the changes in renal function parameters, and the occurrence of adverse events after the procedure were compared between the 2 groups. We used a multivariate logistic regression analysis to determine the independent correlates of CIN after PPCI. RESULTS: A total of 484 patients were finally included in the statistical analysis. Compared with the control group, salvianolate reduced the incidence of CIN (9.1 vs. 16.3%, p = 0.018) after PPCI. The renal function parameters after PPCI in the salvianolate group were superior to those of the control group (p < 0.05). The composite adverse events rate was significantly lower in the salvianolate group within 1 month after the procedure (9.5 vs. 15.5%, p = 0.046). A higher peak of troponin I and loop diuretic therapy were the independent correlates of CIN after PPCI. CONCLUSIONS: Salvianolate reduces the incidence of CIN and protects renal function after PPCI, and the effects were superior to those of NS hydration.

MTUS1 silencing promotes E-selectin production through p38 MAPK-dependent CREB ubiquitination in endothelial cells.

BACKGROUND: Endothelial cell activation is thought to be a key event in atherosclerosis. p38 mitogen-activated protein kinase (p38 MAPK) plays an important role in regulating pro-inflammatory cytokine production in endothelial cells (ECs), however, how p38 MAPK is controlled in EC activation remain unclear. In this study, we investigated the effect of mitochondrial tumor suppressor 1 (MTUS1) on p38 MAPK activation, cytokine induction and the underlying molecular mechanisms in ECs. METHODS AND RESULTS: Using qPCR and ELISA methods, we found that knockdown of MTUS1 led to a marked increase in the mRNA and protein expression of E-selectin (SELE) and monocyte chemotactic protein-1 in ECs, which is accompanied with increased phosphorylation of p38 MAPK (Thr180/Tyr182), MKK3/6 (Ser 189) and IκBα (Ser 32). Using luciferase reporter assay, we found that MTUS1 silencing also activated NF-κB transcriptional activity. The inhibition of p38 MAPK and NF-κB pathway was shown to abrogate MTUS1 silencing-induced cytokine expression in ECs. Furthermore, MTUS1 silencing induced p38 MAPK-dependent ubiquitination of cAMP-response element binding protein (CREB) which potentiated CREB-binding protein-mediated NF-κB p65 acetylation and binding to the promoter of the SELE gene. Conversely, adenovirus-mediated overexpression of MTUS1 inhibited p38 MAPK activation in ECs in vitro and in vivo. Importantly, decreased expression of MTUS1 and CREB, accompanied with induced activation of p38 MAPK were observed in aortas of apoE-/- mice after high-fat diet challenge. CONCLUSIONS: Our findings showed that MTUS1 regulates the p38 MAPK-mediated cytokine production in ECs. MTUS1 gene probably plays a protective role against pro-inflammatory response of ECs.

pH-Responsive drug release and NIR-triggered singlet oxygen generation based on a multifunctional core-shell-shell structure.

A multifunctional platform with pH-responsive drug release and near-infrared (NIR) light-triggered photodynamic therapy (PDT) was designed and prepared using the novel core-shell-shell structure. The multifunctional platform consists of an upconversion nanoparticle (UCNP) emission core, a photosensitizer methylene blue (MB) embedded dense silica sandwich shell, and a polyethyleneimine conjugated folic acid (PEI-FA) gated mesoporous silica (MS) outmost shell with doxorubicin hydrochloride (DOX) loaded inside. The simulated drug release experiments revealed that DOX will release from the nanoparticles because of the distortion in the PEI-FA layer under acidic conditions. Moreover, under 980 nm NIR irradiation, a 660 nm red light emission was excited, activating MB to generate a singlet oxygen (1O2), which acts as the PDT drug. The multifunctional platform integrated pH-responsive drug release and UCNP-based PDT drug together show promising potential in nanomedicine for future chemotherapy and NIR-triggered PDT.

Differential contribution of endothelium-derived relaxing factors to vascular reactivity in conduit and resistance arteries from normotensive and hypertensive rats.

The endothelium contributes to the maintenance of vasodilator tone by releasing nitric oxide (NO), prostacyclin (PGI2), and endothelium-derived hyperpolarizing factor (EDHF). In hypertension, endothelium-dependent relaxation is attenuated (a phenomenon referred to as endothelial dysfunction) and contributes to the increased peripheral resistance. However, which vasodilator among NO, PGI2, and EDHF is impaired in hypertension remains largely unknown. The present study was designed to study the exact contribution of NO, PGI2, and EDHF to vascular reactivity in conduit and resistance artery, under physiological and pathological conditions. The aorta and the second-order mesenteric artery from spontaneous hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were used to measure the vasorelaxation with myograph technology, in the presence or absence of different inhibitors. The results showed that the endothelium-dependent vasodilatation in the conduit artery was mediated mainly by NO, whereas the resistant artery by NO, PGI2, and EDHF together. In hypertension, both NO-mediated relaxation in the conduit artery and NO-, PGI2-, and EDHF-mediated dilation in the resistant artery were markedly impaired. Furthermore, the endothelium-dependent and the endothelium-independent vasorelaxation in conduit artery was attenuated more pronouncedly than that in the resistant artery from hypertensive rats, suggesting that the conduit artery is more vulnerable to hypertensive condition. In conclusion, vasodilators including NO, PGI2, and EDHF contribute distinctively to endothelium-dependent relaxation in conduit and resistance artery under physiological and pathological conditions.

A new rapamycin-abluminally coated chitosan/heparin stent system accelerates early re-endothelialisation and improves anti-coagulant properties in porcine coronary artery models.

PURPOSE: Drug-eluting stents (DES) in percutaneous coronary intervention are more effective in preventing in-stent restenosis compared with bare metal stents (BMS); however, DES may cause late stent thrombosis, which has limited its use. In this study, the functional properties of a newly developed DES (RAP/CS/HEP), in which rapamycin was abluminally-loaded onto a chitosan/heparin coating stent (CS/HEP), were investigated in large animal artery injury models. METHODS: The effectiveness of BMS, RAP (the traditional version of rapamycin DES), CS/HEP and RAP/CS/HEP stents in preventing coagulation and promoting re-endothelialisation was examined and compared in the porcine coronary artery models with arteriovenous shunt, high load thrombus and coronary balloon injury at day 7 and 28, respectively, after stent implantation. The re-endothelialisation on these stents was further evaluated in terms of endothelial gene expression using quantitative RT-PCR. RESULTS: In the porcine coronary artery injury models, both RAP and RAP/CS/HEP stents were potent in reducing neointimal thickness, thus enlarging lumen area efficiently in the stented artery region compared with BMS and CS/HEP. RAP/CS/HEP stents facilitated re-endothelialisation and inhibited thrombosis more efficiently than BMS and RAP. Consistent with this, the expression of endothelial genes, such as CD31, CD34, eNOS and VEGF, was significantly elevated with RAP/CS/HEP stents compared with RAP and BMS stents. CONCLUSION: Abluminal coating of rapamycin onto the endothelialisation-accelerated CS/HEP stent and may prove to be an efficient treatment for tackling the late stent thrombosis associated with the traditionally circumferential RAP stent. This new RAP/CS/HEP stent system exhibits considerably improved therapeutic activity.

[Effect of catheter-based renal sympathetic denervation in pigs with rapid pacing induced heart failure].

OBJECTIVE: This study investigated the effect of catheter-based renal sympathetic denervation (RDN) in pigs with rapid pacing induced heart failure. METHODS: Heart failure was induced by rapid right ventricular pacing in 12 pigs and pigs were randomly divided into RDN group (n = 6): pacing+RDN at 7 days post pacing; control group (n = 6): pacing only. Echocardiography examination (LVEF, LVEDD and LVESD) was performed before pacing and at 1 and 2 weeks post pacing. Serum biochemical markers including renin, aldosterone and creatinine were also measured at baseline, 1 and 2 weeks after pacing. Repeated renal artery angiography was performed at 1 week after RDN. All pigs were sacrificed to examine the heart and renal pathology and renal artery sympathetic nerve staining at 2 weeks post pacing. RESULTS: LVEF decreased 1 week after rapid pacing from (60.5 ± 6.0)% to (35.3 ± 9.8)%. LVEF was significantly higher [(42.8 ± 5.9) % vs. (33.4 ± 9.7)%, P = 0.001 8] while LVESD was significantly lower [(28.4 ± 3.7) mm vs. (33.0 ± 2.0) mm, P = 0.001 6] in the RDN group than in the control group at 2 weeks post pacing. At 2 weeks after pacing, plasma concentrations of renin and aldosterone were significantly lower in RDN group compared to the control group (all P < 0.05) . Kidney function and blood pressure were comparable between the two groups at 2 weeks post pacing. There were no signs of renal damages such as renal artery stenosis, dissection and thrombus in all pigs after 2 weeks pacing. Sympathetic neurons of adventitia were injured in RND group. CONCLUSION: RDN could significantly improve cardiac function and attenuate left ventricular remodeling via inhibiting renin-angiotensin-aldosterone system in this pacing induced pig heart failure model.