A New Event-Triggered Adaptive Fixed-Time Control Design for Uncertain Nonlinear Systems.

This article investigates the problem of dynamic memory event-triggered (DMET) fixed-time tracking control within time-varying asymmetric constraints for nonaffine nonstrict-feedback uncertain nonlinear systems with unmodeled dynamics and unknown disturbances. The existing dynamic event-triggered control methods cannot handle the nonlinear systems with unmodeled dynamics and nonaffine inputs, which greatly limits the applicability of the strategy. To this end, a novel DMET adaptive fuzzy fixed-time control protocol is constructed based on the idea of command filtered backstepping, in which a new dynamic signal function is established to deal with the unmodeled dynamics and an improved DMET mechanism (DMETM) is designed to solve the problem of nonaffine inputs. It is proved that the newly DMET control strategy ensures the tracking error converges to an arbitrarily small compact set in a fixed time and all the signals of the closed-loop systems are bounded. The effectiveness of the proposed approach is demonstrated by two simulation examples.

Chitosan-based oral nanoparticles as an efficient platform for kidney-targeted drug delivery in the treatment of renal fibrosis.

There is increasingly keen interest in developing orally delivered targeted drugs, especially for diseases that require long-term medication. Hence, we manufactured nanoparticles derived from methoxypolyethylene glycol-chitosan (PCS) to enhance the oral delivery and kidney-targeted distribution of salvianolic acid B (SalB), a naturally occurring renoprotective and anti-fibrotic compound, as a model drug for the treatment of renal fibrosis. Orally administered SalB-loaded PCS nanoparticles (SalB-PCS-NPs) maintained good stability in the gastrointestinal environment, improved mucus-penetrating capacity, and enhanced transmembrane transport through a Caco-2 cell monolayer. The relative oral bioavailability of SalB-PCS-NPs to free SalB and SalB-loaded chitosan nanoparticles (SalB-CS-NPs) was 367.0 % and 206.2 %, respectively. The structural integrity of SalB-PCS-NPs after crossing the intestinal barrier was also validated by Förster resonance energy transfer (FRET) in vitro and in vivo. Fluorescein isothiocyanate (FITC)-labeled SalB-PCS-NPs showed higher kidney accumulation than free FITC and FITC-labeled SalB-CS-NPs (4.6-fold and 2.1-fold, respectively). Significant improvements in kidney function, extracellular matrix accumulation, and pathological changes were observed in a unilateral ureter obstruction mouse model of renal fibrosis after once daily oral treatment with SalB-PCS-NPs for 14 days. Thus, oral administration of SalB-PCS-NPs represents a promising new strategy for kidney-targeted drug delivery.

Dysregulated glycolysis underpins high-fat-associated endometrial decidualization impairment during early pregnancy in mice.

Pregnancy complications are more likely to occur in obese women because of defective decidualization. However, the specific mechanism of glycolysis in decidual modulation associated with obesity remains unknown. Therefore, we explored the role of glycolysis in the endometrium of obese pregnant mice during decidualization. C57BL/6J mice were fed a high-fat diet (HFD) to induce obesity. All obesity related parameters were significantly higher in the HFD mice than control. Furthermore, the HFD mice had fewer implantation sites, a smaller decidual area growth, and decreased decidualization marker protein expression than control. The HFD mice also had significantly decreased lactate production and glycolytic enzyme expression. To confirm the functional role of glycolysis during the decidual period in obese pregnant mice, we extracted endometrial stromal cells (ESCs) and treated them with oleic acid (OA) and palmitic acid (PA) to mimic a high-fat environment. Decidualization and glycolysis were significantly restricted in the OA-and PA-treated groups. Moreover, we administered a glycolytic inhibitor, 2-DG, and an agonist, pioglitazone. 2-DG treatment considerably decreased the cells' glycolysis and decidualization. However, pioglitazone treatment improved glycolysis and alleviated defective decidualization. In conclusion, obesity-induced endometrial glycolysis modifications and key glycolytic enzyme downregulation during early pregnancy might cause abnormal decidualization, leading to an unsustainable pregnancy.

Event-Based Remote State Estimation for Nonlinear Systems: A Box Particle Filtering Method.

This article is concerned with the problem of event-based remote state estimation for nonlinear/non-Gaussian systems on a wireless network with limited bandwidth. To reduce unnecessary data transmissions, a novel event-triggering mechanism is developed by using the least-square technique. Based on this, an event-triggered box particle filtering scheme is designed to realize the minimum mean-squared error estimation at the remote estimator end, in which the posterior probability density functions are calculated separately according to the information of the event-triggered indicator to avoid the problem of excessive estimation error. Different from the existing approaches, the proposed algorithm does not depend on any Gaussian assumptions and reduces the computational complexity under the premise of ensuring the estimation performance. Finally, two simulation examples are performed to demonstrate the validity of the proposed algorithm.

Alternate Day Fasting Improves Endothelial Function in Type 2 Diabetic Mice: Role of Adipose-Derived Hormones.

Introduction: Intermittent fasting, including alternate day fasting (ADF), has grown in popularity as it can produce clinically significant metabolic benefits and is often considered to be easier to adhere to than other types of diets such as chronic calorie restriction. However, the effects of ADF on diabetes-associated vascular dysfunction, and the role of adipose-derived hormones, i.e., adipokines, in mediating its effects, remain largely unknown. Objective: We aimed to test the hypothesis that ADF protects against diabetes-associated endothelial dysfunction, at least partly through modulating adipokine profiles. Methods: Control mice (m Lepr db ) and diabetic mice (Leprdb ) were treated with 12-weeks of ADF. Glucose metabolism, endothelial function, and adipokine profile were assessed. Results: ADF reduced fasting blood glucose level and homeostatic model assessment for insulin resistance (HOMA-IR), and improved insulin sensitivity. ADF improved endothelium-dependent vasorelaxation of small mesenteric arteries (SMA) of Leprdb mice. The improvement in endothelial function was largely attenuated by incubation with the nitric oxide synthase inhibitor, L-NAME. These ADF-induced metabolic and vascular benefits were accompanied by increased circulating adiponectin. Adenovirus-mediated adiponectin supplementation improved endothelial function in Leprdb mice, supporting endothelial protective roles in diabetes-associated endothelial dysfunction. Protein tyrosine nitration is a post-translational modification that serves as a marker of oxidative stress. Nitrotyrosine protein levels in SMA and mesenteric adipose tissue (MAT) were elevated in Leprdb mice. ADF reduced nitrotyrosine protein in SMA, but not in MAT, of Leprdb mice. Conclusion: ADF exerts metabolic and endothelial protective benefits. The improvement of endothelial function was partly mediated by increased adiponectin, representing an important mechanism for the beneficial vascular effects resulting from ADF.

Development and Evaluation of the Quality of Life Scale for Children With Visual Impairments in China.

Background: Visual impairments related to non-correctable vision loss, including blindness and low vision, have been consistently shown to lower a person's health-related quality of life. This study assessed the reliability, validity, and discrimination of the Quality of Life Scale for Children with Visual Impairments (QOLS-CVI) in China. Methods: The Pediatric Quality of Life Inventory™ 4.0 and World Health Organization Quality of Life-Disability Scale for physical disability were selected to define conceptual frameworks and item libraries based on relevant existing studies. According to two rounds of expert consultations and group discussions, some items were modified, and the draft scale was developed. Two item selection processes based on classical test theory and item response theory were used to conduct a preliminary survey and a formal survey in special schools in Shanxi and Hebei Provinces. Finally, the reliability and validity of the quality of life scale for visually impaired children in China were verified. Results: The final QOLS-CVI consisted of 38 items, 10 subdomains, and 6 domains. Reliability was verified by Cronbach's alpha coefficient, split-half reliability, and test-retest reliability (Cronbach's alpha for the full scale, 0.841; split-half reliability, 0.629; and test-retest reliability, 0.888). The validity results showed that the multidimensional scale met expectations: exploratory factor analysis and confirmatory factor analysis indicated good fitting models for children with visual impairments. Conclusions: The QOLS-CVI was determined to be reliable and valid and to have strong feasibility and effectiveness. This scale can be used as an evaluation tool to study the QOL and social-participation ability of children with visual impairments.

MicroRNA-362-5p promotes the proliferation and inhibits apoptosis of trophoblast cells via targeting glutathione-disulfide reductase.

Gestational diabetes mellitus (GDM), a common complication of pregnancy, harms the health of pregnant women and fetuses. MicroRNAs (miRNAs) dysregulation in placenta is involved in GDM. Herein, we explored the roles of miR-362-5p in GDM. After high glucose (HG) treated HTR-8/SVneo cells, CCK-8 and flow cytometry were conducted to assess the capability of the proliferation and apoptosis, respectively. The data demonstrated that HG inhibited proliferation and induced apoptosis of HTR-8/SVneo cells. MiR-362-5p level was reduced in HG-treated cells and placenta tissues of GDM patients, measured by qPCR. Overexpressed miR-362-5p accelerated the proliferation and restrained apoptosis of HG-treated cells. Furthermore, glutathione-disulfide reductase (GSR) was verified as a target of miR-362-5p, through TargetScan database and dual-luciferase reporter assay. GSR was upregulated in GDM placenta tissues and was negatively regulated by miR-362-5p. Enforced GSR level abolished the effects of miR-362-5p overexpression on the proliferation and apoptosis of HTR-8/SVneo cells. Furthermore, miR-362-5p increased p-PI3K, p-AKT and bcl-2, while reduced bax and cleaved caspase3, which were abolished by GSR. In conclusion, miR-362-5p promoted cell proliferation and inhibited apoptosis via targeting GSR and activating PI3K/AKT pathway. The findings mentioned above suggested that miR-362-5p might be a therapy target of GDM.

Molecular modeling studies of benzothiophene-containing derivatives as promising selective estrogen receptor downregulators: a combination of 3D-QSAR, molecular docking and molecular dynamics simulations.

Selective estrogen receptor downregulators (SERDs) for the treatment of positive breast cancer can act both as estrogen alpha receptor (ERα) antagonists and degraders. In this study, the optimal antagonist models (CoMFA-A, q2 = 0.660, r2 = 0.996; CoMSIA-A, q2 = 0.728, r2 = 0.992) and degrader models (CoMFA-D, q2 = 0.850, r2 = 0.996; CoMSIA-D, q2 = 0.719, r2 = 0.995) of a series of potent benzothiophene-containing SERDs were constructed to explore the three-dimensional quantitative structure-activity relationship. Internal and external validation indicated that all models exhibited good applicability, high predictive ability and robustness. Contour maps revealed the relationships between the essential structural features and antagonistic and degradation activities. Additionally, molecular docking, molecular dynamics and free energy calculation studies were further performed to investigate the detailed binding mode. Results indicated that several key residues, ARG394, GLU353, PHE404 and ILE424, were crucial for the stability of the ligand binding domain. The hydrophobic, electrostatic and Van der Waals interactions played significant effect on the binding affinity. Finally, ten novel compounds were designed based on above findings, where the predicted activity of compound D8 was equivalent to that of the compound LSZ102. 3D-QSAR, ADMET and bioavailability predictions indicated that all designed compounds with good predicted activity, good physicochemical and bioavailability could be potential candidates for SERDs. These results and combinations of computational methods provided guidance for the rational drug design of novel potential SERDs.Communicated by Ramaswamy H. Sarma.

Design of novel dopamine D2 and serotonin 5-HT2A receptors dual antagonists toward schizophrenia: An integrated study with QSAR, molecular docking, virtual screening and molecular dynamics simulations.

The extrapyramidal side effects of schizophrenia treatment can be significantly reduced by simultaneously targeting dopamine D2 and serotonin 5-HT2A receptors. In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) models of D2 receptor (CoMFA-1, q2 = 0.767, r2 = 0.969; CoMSIA-1, q2 = 0.717, r2 = 0.978) and 5-HT2A receptor antagonists (CoMFA-2, q2 = 0.703, r2 = 0.946; CoMSIA-2, q2 = 0.675, r2 = 0.916) were successfully constructed using 35 tetrahydropyridopyrimidinone derivatives. Topomer CoMFA and HQSAR models were then constructed to further validate and supplement above models. Results showed that all models had good predictive power and stability. Contour map analysis revealed that the electrostatic and hydrophobic fields played vital roles in the bioactivity of dual antagonists. Molecular docking and molecular dynamic studies also suggested that the hydrogen bonding, electrostatic and hydrophobic interactions played key roles in the formation of stable binding sites. Meanwhile, several key residues like ASP114, TRP100, PHE389 of dopamine D2 receptor and ASP134, PHE328, TRP324 of serotonin 5-HT2A receptor were identified. Based on above findings, seven compounds were obtained through bioisostere replacement and ten compounds were designed by contour map analysis, in which the predicted activity of compounds S6 and DS2 were equivalent to that of the template compound 15. 3D-QSAR and ADMET predictions indicated that all newly designed compounds had great biological activity and physicochemical properties. Moreover, based on the best pharmacophore model, four compounds (Z1, Z2, Z3 and Z4) with new backbones were obtained by virtual screening. Overall, this study could provide theoretical guidance for the structural optimization, design and synthesis of novel dopamine D2 and serotonin 5-HT2A receptors dual antagonists. Abbreviations3D-QSARThree-dimensional quantitative structure-activity relationship5-HT2ARSerotonin 5-hydroxytryptamine 5-HT2A receptor5-HT2CRSerotonin 5-hydroxytryptamine 5-HT2C receptor receptorCADDComputer-aided drug designCoMFAComparative molecular field analysisCoMSIAComparative molecular similarity index analysisD2RDopamine D(2) receptorGPCRG-protein coupled receptorPLSPartial least squares regressionHQSARHologram quantitative structure-activity relationship. Communicated by Ramaswamy H. Sarma.

Event-Triggered Adaptive Output Feedback Control for a Class of Uncertain Nonlinear Systems With Actuator Failures.

This paper investigates the event-triggered adaptive output feedback control problem for a class of uncertain nonlinear systems in the presence of actuator failures and unknown control direction. By utilizing the adaptive backstepping technique, an event-based output feedback controller is developed together with a time-variant event-triggered rule. In this design, the radial basis function neural network algorithms are first introduced to identify the unknown terms of the systems. Then, a new state observer with adaptive compensation is designed to estimate the state vector. The overall control strategy guarantees that the output signal tracks the reference signal and all the signals of the closed-loop systems are bounded. Unlike the existing methods, the proposed control scheme can handle the coupling term incurred by the loss of effectiveness fault of the actuator, the event-triggered rule, and unknown control direction. Finally, an example is performed to demonstrate the validity of the proposed strategy.

Interaction of IL-6 and TNF-α contributes to endothelial dysfunction in type 2 diabetic mouse hearts.

OBJECTIVES: Inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), are individually considered as important contributors to endothelial dysfunction in obesity and type 2 diabetes (T2D). However, their interactions in coronary arteriole endothelial dysfunction are uncertain. Therefore, this study aimed to determine the effects of TNF-α and IL-6 interactions on coronary endothelial dysfunction in experimental T2D. METHODS: The studies used wild type (WT), diabetic mice (db/db), db/db null for TNF (dbTNF-/dbTNF-), and db/db mice treated with neutralizing antibody to IL-6 (anti-IL-6). Endothelium-dependent (acetylcholine [ACh], or luminal flow-induced shear stress) and endothelium-independent (sodium nitroprusside [SNP]) vasodilation of isolated and pressurized coronary arterioles were determined. Quantitative PCR, Western blot, and immunofluorescence staining were utilized for mechanistic studies. RESULTS: Relative to WT, arteriolar dilation to both ACh and flow was attenuated in db/db mice and dbTNF-/dbTNF-. Treatment of dbTNF-/dbTNF- and db/db mice with anti-IL-6 improved arteriolar dilation compared to db/db mice. Immunofluorescence staining illustrated localization of IL-6 within the endothelial cells of coronary arterioles. In db/db mice, mRNA and protein expression of IL-6 and superoxide (O2-) production were higher, but reduced by anti-IL-6 treatment. Also, in db/db mice, mRNA and protein expression of TNF-α suppressed by the anti-IL-6 treatment and the reduced expression of mRNA and protein expression of IL-6 by the genetic deletion of TNF-α both supported a reciprocal regulation between TNF-α and IL-6. Superoxide dismutase 2 (SOD2) expression and phosphorylation of eNOS (p-eNOS/eNOS) were lower in db/db mice coronary arterioles and were restored in db/db+Anti-IL-6 and dbTNF-/dbTNF- mice. CONCLUSION: The interactions between TNF-α and IL-6 exacerbate oxidative stress and reduce phosphorylation of eNOS, thereby contributing to coronary endothelial dysfunction in T2D mice.

Micro-structural evolution and biomineralization behavior of carbon nanofiber/bioactive glass composites induced by precursor aging time.

Bioactive glass (BG)-containing carbon nanofibers (CNFs) are promising orthopaedic biomaterials. Herein, CNF composites were produced from electrospinning of polyacrylonitrile (PAN)/BG sol-gel precursor solution, followed by carbonization. Choosing 58S-type BG (mol%: 58.0% SiO2-26.3% CaO-15.7% P2O5) as the model, micro-structural evolution of CNF/BG composites was systematically evaluated in relating to aging times of BG precursor solution. With aging time prolonging, BG precursors underwent morphological changes from small sol clusters with loosely and randomly branched structure to highly crosslinked Si-network structure, showing continuous increase in solution viscosity. BG precursor solution with low viscosity could mix well with PAN solution, resulting in CNF composite with homogeneously distributed BG component. Whereas, BG precursor gel with densely crosslinked Si-network structure led to uneven distribution of BG component along final CNFs due to its significant phase separation from PAN component. Meanwhile, BG nanoparticles in CNFs demonstrated micro-structural evolution that they transited from weak to strong crystal state along with longer aging time. Biomineralization in simulated body fluid and in vitro osteoblasts proliferation were then applied to determine the bioactivity of CNF/BG composites. CNF/BG composites prepared from shorter aging time could induce both faster apatite deposition and cell proliferation rate. It was suggested weakly crystallized BG nanoparticles along CNFs dissolved fast and was able to provide numerous nucleation sites for apatite deposition, which also favored the proliferation of osteoblasts cells. Aging time could thus be a useful tool to regulate the biological features of CNF/BG composites.

Regulation of Coronary Endothelial Function by Interactions between TNF-α, LOX-1 and Adiponectin in Apolipoprotein E Knockout Mice.

BACKGROUND/AIMS: Although individual contributions of TNF-α, LOX-1 and adiponectin to the regulation of endothelial function were previously studied, their interactions in the regulation of coronary endothelial function remain unclear. The aim of this study is to investigate the interactions between TNF-α, LOX-1 and adiponectin in endothelial dysfunction in atherosclerosis. METHODS: Vasodilator function was assessed in coronary arterioles isolated from wild-type, apolipoprotein (ApoE) knockout (KO) mice, ApoE KO null for TNF-α (ApoE KOTNF-/TNF-) and ApoE KO mice treated with neutralizing antibodies to either TNF-α and LOX-1, or recombinant adiponectin. Western blot analysis and immunofluorescence staining were used for mechanistic studies. RESULTS: Acetylcholine (Ach) dilation was impaired in ApoE KO mice. KO of TNF-α, anti-TNF-α anti-LOX-1 or adiponectin restored impaired ACh vasodilation without affecting endothelium-derived hyperpolarizing factor-mediated vasodilation. Immunofluorescence staining demonstrated colocalization of TNF-α with vascular smooth muscle cells, and adiponectin with endothelial cells. ApoE KO mice showed increased protein expression of LOX-1, NF-x03BA;B, NADPH oxidase subunit NOX4 and nitrotyrosine (N-Tyr) levels in coronary arterioles. Treatment with anti-TNF-α, anti-LOX-1 and adiponectin suppressed protein expression of LOX-1, NOX4, NF-x03BA;B and N-Tyr levels. CONCLUSION: Adiponectin, anti-TNF-α and anti-LOX-1 exert vasoprotective effects in atherosclerotic ApoE KO mice.

Nanoporous structured carbon nanofiber-bioactive glass composites for skeletal tissue regeneration.

Bioactive glass (BG) decorated nanoporous composite carbon nanofibers (PCNF-BG) were prepared for the purpose of obtaining effective substrates for skeletal tissue regeneration. The preparation was conducted by electrospinning of polyacrylonitrile (PAN)-polymethylmethacrylate (PMMA) blends with the addition of sol-gel precursors of 58s-type (mol%: 58% SiO2-38% CaO-4% P2O5) BG, followed by high temperature thermal treatment. The removal of PMMA during the carbonization of PAN generated numerous slit-like nanoporous structures along CNFs, leading to a significant enhancement in the specific surface area, surface roughness and pore volume, which was confirmed by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and Brunauer-Emmett-Teller (BET) characterizations. PCNF-BG composites with different specific surface areas were biologically evaluated by experiments of biomineralization in simulated body fluid (SBF), in vitro MC3T3-E1 osteoblast proliferation and osteogenic differentiation. Compared to non-porous CNF/BG, the nanoporous structure distinctively enlarged the interfacial reaction area of the BG component with a medium environment and thus enhanced the bioactivity of CNFs by accelerating the dissolution of the BG component and providing abundant nucleation sites for hydroxyapatite depositions. The released ions displayed distinct promotion in proliferation and osteogenic differentiation of osteoblast cells, which promoted the osteocompatibility of carbon-based materials significantly.

Vascular transcriptional alterations produced by juvenile obesity in Ossabaw swine.

We adopted a transcriptome-wide microarray analysis approach to determine the extent to which vascular gene expression is altered as a result of juvenile obesity and identify obesity-responsive mRNAs. We examined transcriptional profiles in the left anterior descending coronary artery (LAD), perivascular fat adjacent to the LAD, and descending thoracic aorta between obese (n = 5) and lean (n = 6) juvenile Ossabaw pigs (age = 22 wk). Obesity was experimentally induced by feeding the animals a high-fat/high-fructose corn syrup/high-cholesterol diet for 16 wk. We found that expression of 189 vascular cell genes in the LAD and expression of 165 genes in the thoracic aorta were altered with juvenile obesity (false discovery rate ≤ 10%) with an overlap of only 28 genes between both arteries. Notably, a number of genes found to be markedly upregulated in the LAD of obese pigs are implicated in atherosclerosis, including ACP5, LYZ, CXCL14, APOE, PLA2G7, LGALS3, SPP1, ITGB2, CYBB, and P2RY12. Furthermore, pathway analysis revealed the induction of proinflammatory and pro-oxidant pathways with obesity primarily in the LAD. Gene expression in the LAD perivascular fat was minimally altered with juvenile obesity. Together, we provide new evidence that obesity produces artery-specific changes in pretranslational regulation with a clear upregulation of proatherogenic genes in the LAD. Our data may offer potential viable drug targets and mechanistic insights regarding the molecular precursors involved in the origins of overnutrition and obesity-associated vascular disease. In particular, our results suggest that the oxidized LDL/LOX-1/NF-κB signaling axis may be involved in the early initiation of a juvenile obesity-induced proatherogenic coronary artery phenotype.

Structural diversity directed by switchable coordination of substitute groups in a ternary Cu(II)-triazole-sulfoisophthalate self-assembly system: synthesis, crystal structures and magnetic behavior.

Four magnetic samples with different building blocks and dimensionalities, {[Cu(4)(atr)(2)(µ(3)-OH)(2)(sip)(2)]·4H(2)O}(n) (1), {[Cu(4)(atr)(2)(H(2)O)(8)(µ-OH)(2)(sip)(2)]·1.3CH(3)OH·0.7H(2)O}(n) (2), {[Cu(3)(atr)(4)(H(2)O)(2)(sip)(2)]·4H(2)O}(n) (3) and {[Cu(3)(atr)(4)(H(2)O)(2)(µ(3)-OH)(sip)(Hsip)]·2CH(3)OH·2.75H(2)O}(n) (4) (atr = 4-amino-1,2,4-triazole and sip(3-) = 5-sulfoisophthalate), were obtained and characterized structurally and magnetically. Complex 1 exhibits a three-dimensional (3D) robust framework with butterfly-like Cu(II)(4) clusters periodically extended by tetratopic sip(3-) connectors. Complex 2 possesses a 2D layer with alternating Cu(II)(3) + Cu(II)(1) chains crosslinked by pairs of ditopic sip(3-) linkers. By contrast, the latter two entities feature 1D broad ribbons with linear (for 3) and triangular Cu(II)(3) cores (for 4) propagated by bidirectional sip(3-) connectors. Structural analysis reveals that the diverse building blocks and dimensionalities of 1-4 are significantly dominated by the tunable coordination of exocyclic amino- and/or sulfonate-group of the mixed ligands. Magnetically, antiferromagnetic interactions with variable strength transmitted by -NN- moiety of atr and hydroxyl mediators result in overall S = 0 (for 1) and 1/2 (for 3 and 4) spin ground states. These interesting results indicate that coordinative side group in the ternary metal ion-azolate-carboxylate system can be utilized to generate aesthetically pleasing building units and variably polytopic connectors, leading to differently extended superstructures and magnetic behavior.

Physical activity opposes coronary vascular dysfunction induced during high fat feeding in mice.

The study's purpose was to investigate if physical activity initiated with the start of high-fat feeding would oppose development of endothelial dysfunction, and if it does, then to determine some potential mechanisms. C57BL/6 female mice were randomly divided into three groups: (1) control low-fat diet (LF-SED; 15% of calories from fat), (2) high-fat diet (HF-SED; 45% of calories from fat), and (3) HF diet given access to a voluntary running wheel (HF-RUN). Our hypothesis was that HF-RUN would differ in multiple markers of endothelial dysfunction from HF-SED after 10 weeks of 45%-fat diet, but would not differ from LF-SED. HF-RUN differed from HF-SED in nine determinations in which HF-SED either had decreases in (1) acetylcholine (ACh)-induced and flow-induced vasodilatations in isolated, pressurized coronary arterioles, (2) heart phosphorylated endothelial nitric oxide synthase (p-eNOS/eNOS) protein, (3) coronary arteriole leptin (ob) receptor protein, (4) phosphorylated signal transducer and activator of transcription 3 (p-STAT3/STAT3) protein, and (5) coronary arteriole superoxide dismutase 1 protein; or had increases in (6) percentage body fat, (7) serum leptin, (8) coronary arteriole suppressor of cytokine signalling 3 (SOCS3) protein, and (9) coronary arteriole gp91(phox) protein. Higher endothelium-dependent vasodilatation by ACh or leptin was abolished with incubation of NOS inhibitor N(G)-nitro-l-arginine-methyl ester (l-NAME) in LF-SED and HF-RUN groups. Further, impaired ACh-induced vasodilatation in HF-SED was normalized by apocynin or TEMPOL to LF-SED and HF-RUN. These findings demonstrate multiple mechanisms (eNOS, leptin and redox balance) by which voluntary running opposes the development of impaired coronary arteriolar vasodilatation during simultaneous high-fat feeding.

Adiponectin abates diabetes-induced endothelial dysfunction by suppressing oxidative stress, adhesion molecules, and inflammation in type 2 diabetic mice.

Adiponectin (APN) can confer protection against metabolism-related illnesses in organs such as fat, the liver, and skeletal muscle. However, it is unclear whether APN improves endothelial-dependent nitric oxide-mediated vasodilation in type 2 diabetes and, if so, by what mechanism. We tested whether exogenous APN delivery improves endothelial function in type 2 diabetic mice and explored the mechanisms underlying the observed improvement. To test the hypothesis, we injected adenovirus APN (Ad-APN) or adenovirus ß-galactosidase (Ad-ßgal; control virus) via the tail vein in control (m Lepr(db)) and diabetic (Lepr(db); db/db) mice and studied vascular function of the aorta ex vivo. Ad-APN improved endothelial-dependent vasodilation in db/db mice compared with Ad-ßgal, whereas Ad-APN had no further improvement on endothelial function in control mice. This improvement was completely inhibited by a nitric oxide synthase inhibitor (N(G)-nitro-l-arginine methyl ester). Serum triglyceride and total cholesterol levels were increased in db/db mice, and Ad-APN significantly reduced triglyceride levels but not total cholesterol levels. Immunoblot results showed that interferon-γ, gp91(phox), and nitrotyrosine were markedly increased in the aorta of db/db mice. Ad-APN treatment decreased the expression of these proteins. In addition, mRNA expression of TNF-α, IL-6, and ICAM-1 was elevated in db/db mice, and Ad-APN treatment decreased these expressions in the aorta. Our findings suggest that APN may contribute to an increase in nitric oxide bioavailability by decreasing superoxide production as well as by inhibiting inflammation and adhesion molecules in the aorta in type 2 diabetic mice.

Role of inflammation in the regulation of coronary blood flow in ischemia and reperfusion: mechanisms and therapeutic implications.

A multitude of factors, including increased coronary vascular resistance and dysregulated coronary microcirculatory function, contribute to the impairment of coronary blood flow (CBF) regulation and the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. CBF is primarily determined by coronary vascular resistance, which is affected by the balance between various vasodilators and vasoconstrictors. Myocardial I/R causes reduced production of endogenous vasodilators, such as nitric oxide (NO), leaving unopposed vasoconstriction that is caused mainly by continued presence of endothelin-1 (ET-1) and serotonin (5-HT); this imbalance in turn enhances vascular tone, triggers inflammatory response, decreases CBF and exacerbates reperfusion injury. Various inflammatory cytokines participate in the regulation of coronary vasomotor function by affecting the balance between vasodilators and vasoconstrictors. In addition to the enhanced coronary vasoconstriction, coronary microembolization, inflammatory cell infiltration and post-ischemic hyperpermeability contribute to the impairment of coronary microcirculatory function and myocardial perfusion during I/R. Ongoing research examining the role of inflammation in the regulation of CBF and coronary microcirculatory function in myocardial I/R is expected to yield new insights that will lead to therapies for ameliorating the vascular inflammatory response in coronary artery diseases (CADs) in the clinical setting. This article is part of a Special Issue entitled "Coronary Blood Flow".

Vasoprotection by dietary supplements and exercise: role of TNFα signaling.

Vascular dysfunction contributes to the pathogenesis of various cardiovascular diseases. Dietary supplements, including fish oil, dietary fibers, and various natural products, and exercise training exert vasoprotective effects. However, the mechanisms underlying the vasoprotective benefits of dietary supplements and physical activity demand extensive investigation. Accumulating evidence suggests that inflammatory cytokine tumor necrosis factor-alpha (TNFα) plays a pivotal role in the dysregulation of macrovascular and microvascular function. TNFα induces vascular inflammation, monocyte adhesion to endothelial cells, vascular oxidative stress, apoptosis, and atherogenic response and participates in the regulation of thrombosis and coagulation through multiple signaling pathways involving NFκB, Sp1, activator protein 1, JNK, p38, STAT3, and so forth. Dietary supplements and exercise training decrease TNFα production and ameliorate TNFα-mediated pathological changes in vasculature. Thus, the inhibitory effects of dietary supplements and physical exercise on TNFα production and TNFα signaling may contribute to their vasoprotective properties.