Nanofibrous Dressing with Nanocomposite Monoporous Microspheres for Chemodynamic Antibacterial Therapy and Wound Healing.

The excessive use of antibiotics and consequent bacterial resistance have emerged as crucial public safety challenges for humanity. As a promising antibacterial treatment, using reactive oxygen species (ROS) can effectively address this problem and has the advantages of being highly efficient and having low toxicity. Herein, electrospinning and electrospraying were employed to fabricate magnesium oxide (MgO)-based nanoparticle composited polycaprolactone (PCL) nanofibrous dressings for the chemodynamic treatment of bacteria-infected wounds. By utilizing electrospraying, erythrocyte-like monoporous PCL microspheres incorporating silver (Ag)- and copper (Cu)-doped MgO nanoparticles were generated, and the unique microsphere-filament structure enabled efficient anchoring on nanofibers. The composite dressings produced high levels of ROS, as confirmed by the 2,7-dichloriflurescin fluorescent probe. The sustained generation of ROS resulted in efficient glutathione oxidation and a remarkable bacterial killing rate of approximately 99% against Staphylococcus aureus (S. aureus). These dressings were found to be effective at treating externally infected wounds. The unique properties of these composite nanofibrous dressings suggest great potential for their use in the medical treatment of bacteria-infected injuries.

Large-Scale Fabrication of Tunable Sandwich-Structured Silver Nanowires and Aramid Nanofiber Films for Exceptional Electromagnetic Interference (EMI) Shielding.

The recent advancements in communication technology have facilitated the widespread deployment of electronic communication equipment globally, resulting in the pervasive presence of electromagnetic pollution. Consequently, there is an urgent necessity to develop a thin, lightweight, efficient, and durable electromagnetic interference (EMI) shielding material capable of withstanding severe environmental conditions. In this paper, we propose an innovative and scalable method for preparing EMI shielding films with a tunable sandwich structure. The film possesses a nylon mesh (NM) backbone, with AgNWs serving as the shielding coating and aramid nanofibers (ANFs) acting as the cladding layer. The prepared film was thin and flexible, with a thickness of only 0.13 mm. AgNWs can easily form a conductive network structure, and when the minimum addition amount was 0.2 mg/cm2, the EMI SE value reached 28.7 dB, effectively shielding 99.884% of electromagnetic waves and thereby meeting the commercial shielding requirement of 20 dB. With an increase in dosage up to 1.0 mg/cm2, the EMI SE value further improved to reach 50.6 dB. The NAAANF film demonstrated remarkable robustness in the face of complex usage environments as a result of the outstanding thermal, acid, and alkali resistance properties of aramid fibers. Such a thin, efficient, and environmentally resistant EMI shielding film provided new ideas for the broad EMI shielding market.

Anchoring silver nanoparticles on nanofibers by thermal bonding to construct functional surface.

Generally, the anchoring of inorganic nanoparticles onto the surface of fibers faces the problem of poor stability, which limits the wide application of nanoparticle functionalized fibers. Herein, nanofibers with shell-core structures were constructed by coaxial electrospinning of two polymers with different melting points (Tm). Polyglycolic acid (PGA, Tm = 225 °C) was employed as the core layer, while polycaprolactone (PCL, Tm = 60 °C) was used as the shell layer. Silver nanoparticles (AgNPs) were electrosprayed on the nanofibers and the shell layer (PCL) was heated and melted to bond the AgNPs, thus realizing a stable AgNP-composited nanofiber for the construction of antibacterial functional surface. By regulating the shell-core flow ratio and the condition for heat treatment, the appropriate thickness of the shell layer was obtained with a flow ratio of 3:1 (PCL:PGA). The optimal composite structure was constructed when the thermal bonding was taken under 80 °C for 5 min. Furthermore, it was found that the composite nanofibers prepared by thermal bonding had better hydrophilicity, mechanical property, and AgNPs bonding stability, and their antibacterial rate against Staphylococcus aureus (S. aureus) reached over 97%. Overall, a facile and universal method for the preparation of nanoparticle-anchored nanofibers was established in this study. The robust nanoparticle-composited nanofibers are promising for applications in optoelectronic devices, electrode materials, and so on.

Corrigendum to "MicroRNA-30-5p Suppresses Inflammatory Factor-Induced Endothelial Cell Injury by Targeting TCF21".

[This corrects the article DOI: 10.1155/2019/1342190.].

Post-translational regulation of PGC-1α modulates fibrotic repair.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease associated with mitochondrial oxidative stress. Mitochondrial reactive oxygen species (mtROS) are important for cell homeostasis by regulating mitochondrial dynamics. Here, we show that IPF BAL cells exhibited increased mitochondrial biogenesis that is, in part, due to increased nuclear expression of peroxisome proliferator-activated receptor-É£ (PPARÉ£) coactivator (PGC)-1α. Increased PPARGC1A mRNA expression directly correlated with reduced pulmonary function in IPF subjects. Oxidant-mediated activation of the p38 MAPK via Akt1 regulated PGC-1α activation to increase mitochondrial biogenesis in monocyte-derived macrophages. Demonstrating the importance of PGC-1α in fibrotic repair, mice harboring a conditional deletion of Ppargc1a in monocyte-derived macrophages or mice administered a chemical inhibitor of mitochondrial division had reduced biogenesis and increased apoptosis, and the mice were protected from pulmonary fibrosis. These observations suggest that Akt1-mediated regulation of PGC-1α maintains mitochondrial homeostasis in monocyte-derived macrophages to induce apoptosis resistance, which contributes to the pathogenesis of pulmonary fibrosis.

pH-Sensitive Membranes with Smart Cleaning Capability for Efficient Emulsion Separation and Pollutant Removal.

Since anionic dyes and surfactants abundantly exist in oily wastewater, both the separation of oil/water mixture and removal of low-molecular-weight pollutants are important to realize the advanced purification of water. By grafting poly(2-dimethylaminoethyl methacrylate) (pDMAEMA) onto polyethylene (PP) membrane via ultraviolet (UV)-initiated polymerization, the obtained PP-g-pDMAEMA membrane presented positively in water and negatively in an alkaline buffer (pH 9.0), respectively. Due to the switchable surface charge, the membrane had high emulsion separation efficiency and flux recovery ratio (approximately 100%). Besides, the dye (reactive black 5, RB-5) adsorption capacity reached 140 mg/m2 in water, and approximately 90% RB-5 could be released in pH 9.0. The anionic surfactant (sodium dodecyl benzene sulfonate, SDBS) was also reversely interpreted and released by the membrane via manipulating the ambient pH. The membrane constructed in this study is supposed to realize emulsion separation with smart cleaning capability, as well as the removal of dyes and surfactants, which could be utilized for multifunctional water purification.

The efficacy of baroreflex activation therapy for heart failure: A meta-analysis of randomized controlled trials.

INTRODUCTION: The efficacy of baroreflex activation therapy for heart failure is elusive. This meta-analysis aims to evaluate the impact of baroreflex activation therapy on treatment efficacy of heart failure. METHODS: Several databases including PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases have been searched, and we include randomized controlled trials (RCTs) regarding the efficacy of baroreflex activation therapy for patients with heart failure. RESULTS: This meta-analysis includes 4 RCTs. Baroreflex activation therapy shows significantly positive impact on the quality of life score (standard mean difference SMD = -4.61; 95% confidence interval CI = -6.24 to -2.98; P < .00001), 6-minute hall walk (6MHW) distance (SMD = 2.83; 95% CI = 1.44- 4.22; P < .0001), New York Heart Association (NYHA) Class (SMD = -3.23; 95% CI = -4.76 to -1.69; P < .0001), N-terminal pro-brain natriuretic peptide (NT-proBNP) (SMD = -1.24; 95% CI = -1.58 to -0.89; P < .00001) and the duration of hospitalization (SMD = -1.65; 95% CI = -2.90 to -0.39; P = .01) compared with control group for heart failure, but has no obvious effect on left ventricular ejection fraction (LVEF) (SMD = 1.43; 95% CI = -0.15-3.01; P = .08), or the number of hospitalization per year (SMD = -1.17; 95% CI = -2.56-0.22; P = .10). CONCLUSIONS: Baroreflex activation therapy can improve the treatment efficacy for heart failure.

Clinical characteristics and fatal outcomes of hypertension in patients with severe COVID-19.

The aim of this study is to investigate clinical characteristics and fatal outcomes of hypertension as well as the role of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) use in patients with severe coronavirus disease 2019 (COVID-19). A total of 220 (female: 51.8%) patients with severe COVID-19 were included. The mean age of included patients was 59.5 years and 70 (31.8%) patients had a history of hypertension. There were 23 patients (32.9%) receiving ACEI/ARB therapy. Patients with hypertension were older and had more comorbidities, and were more likely to suffer from severe inflammatory response and acute cardiac injury. Moreover, patients with hypertension were associated with significantly higher risk of in-hospital mortality than patients without hypertension. After adjustment of potential confounders, the independent correlation was still observed. In addition, ACEI/ARB users were associated with lower level of high-sensitivity cardiac troponin I and creatinine kinase-myocardial band, and lower risk of acute cardiac injury than ACEI/ARB non-users. In conclusion, patients with hypertension were more likely to suffer from severe inflammatory response, acute cardiac injury and had high risk of in-hospital mortality in severe COVID-19. The use of ACEI/ARB may protect patients with COVID-19 from acute cardiac injury.

Technical advance: The use of tree shrews as a model of pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease with a high morbidity and mortality. Some of the mechanisms of fibrosis development have been described using rodent models; however, the relevance of findings in these animal models is difficult to assess. New innovative models are needed that closely mimic IPF disease pathology. METHODS: To overcome this unmet need of investigating IPF with a relevant model, we utilized tree shrews, which are genetically, anatomically, and metabolically similar to primates and humans. Using human antibodies and primers, we investigated the role of macrophage phenotypic switching in normal and IPF subjects and bleomycin-injured tree shrews. RESULTS: Bronchoalveolar lavage (BAL) cells from tree shrews expressed human markers, and there was recruitment of monocyte-derived macrophages (MDMs) to the lung in IPF subjects and bleomycin-injured tree shrews. MDMs were polarized to a profibrotic phenotype in IPF and in bleomycin-injured tree shrews. Resident alveolar macrophages (RAMs) expressed proinflammatory markers regardless of bleomycin exposure. Tree shrews developed bleomycin-induced pulmonary fibrosis with architectural distortion in parenchyma and widespread collagen deposition. CONCLUSION: The profibrotic polarization of macrophages has been demonstrated to be present in IPF subjects and in fibrotic mice. Although the lung macrophages have long been considered to be homogeneous, recent evidence indicates that these cells are heterogeneous during multiple chronic lung diseases. Here, we show new data that indicate a critical and essential role for macrophage-fibroblast crosstalk promoting fibroblast differentiation and collagen production. in the development and progression of fibrosis. The current data strongly suggest development of therapeutics that attenuate of the profibrotic activation of MDMs may mitigate macrophage-fibroblast interaction. These observations demonstrate that tree shrews are an ideal animal model to investigate the pathogenesis of IPF as they are genetically, anatomically, and metabolically closer to humans than the more commonly used rodent models.

Combination of luteolin and lycopene effectively protect against the "two-hit" in NAFLD through Sirt1/AMPK signal pathway.

AIM: Luteolin and lycopene are common natural products, widely existing in nature, and both of which were reported to have various biological functions including anti-inflammatory, anti-obesity and anti-NAFLD. In the present study, we aimed to evaluate the therapeutic efficacy of luteolin and lycopene in combination and its latent molecular mechanisms in vitro and in vivo models of NAFLD. MAIN METHODS: Sodium palmitate (PA)-induced steatotic HepG2 cells and primary hepatocytes, and high-fat diet-induced C57BL/6J obese mice were treated with luteolin, lycopene and their combination. Metabolic parameters were measured. KEY FINDINGS: We found that luteolin (20 µM) + lycopene (10 µM) was the best therapeutic combination in PA-induced HepG2 cells, and significantly improve cell viability and lipid accumulation in PA-induced HepG2 cells and primary hepatocytes. In addition, luteolin (20 mg/kg) + lycopene (20 mg/kg) could ameliorate increased body weight and hepatocyte steatosis; regulate serum triglycerides, serum total cholesterol, hepatic triglycerides and hepatic total cholesterol; decrease serum alanine transaminase and aspartate transaminase. Furthermore, in vivo and in vitro, luteolin, lycopene and their combination had no effect on Sirt1 expression, but all of them could upregulate the expression of NAMPT, which could increase the level of NAD+, the co-substrate of Sirt1, indirectly activating Sirt1/AMPK pathway, and then inhibited lipogenesis and increased ß-oxidation, defensing the "first hit"; they also inactivated nuclear factor-κB (NF-κB) and decreased the levels of IL-6, IL-1ß and TNF-α, defensing the "second hit". SIGNIFICANCE: Thus, luteolin and lycopene in combination can effectively ameliorate "two-hit" in NAFLD through activation of the Sirt1/AMPK pathway.

Prognostic value of NT-proBNP in patients with severe COVID-19.

BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China has been declared a public health emergency of international concern. The cardiac injury is a common condition among the hospitalized patients with COVID-19. However, whether N terminal pro B type natriuretic peptide (NT-proBNP) predicted outcome of severe COVID-19 patients was unknown. METHODS: The study initially enrolled 102 patients with severe COVID-19 from a continuous sample. After screening out the ineligible cases, 54 patients were analyzed in this study. The primary outcome was in-hospital death defined as the case fatality rate. Research information and following-up data were obtained from their medical records. RESULTS: The best cut-off value of NT-proBNP for predicting in-hospital death was 88.64 pg/mL with the sensitivity for 100% and the specificity for 66.67%. Patients with high NT-proBNP values (> 88.64 pg/mL) had a significantly increased risk of death during the days of following-up compared with those with low values (≤88.64 pg/mL). After adjustment for potential risk factors, NT-proBNP was independently correlated with in-hospital death. CONCLUSION: NT-proBNP might be an independent risk factor for in-hospital death in patients with severe COVID-19. TRIAL REGISTRATION: ClinicalTrials, NCT04292964. Registered 03 March 2020.

Investigating the Role of FlhF Identifies Novel Interactions With Genes Involved in Flagellar Synthesis in Campylobacter jejuni.

FlhF is a key protein required for complete flagellar synthesis, and its deletion results in the complete absence of a flagella and thus motility in Campylobacter jejuni. However, the specific mechanism still remains unknown. In this study, RNA-Seq, EMSAs, ChIP-qPCR and ß-Galactosidase assays were performed to elucidate the novel interactions between FlhF and genes involved in flagellar synthesis. Results showed that FlhF has an overall influence on the transcription of flagellar genes with an flhF mutant displaying down-regulation of most flagellar related genes. FlhF can directly bind to the flgI promoter to regulate its expression, which has significant expression change in an flhF mutant. The possible binding site of FlhF to the flgI promoter was explored by continuously narrowing the flgI promoter region and performing further point mutations. Meanwhile, FlhF can directly bind to the promoters of rpoD, flgS, and fliA encoding early flagellin regulators, thereby directly or indirectly regulating the synthesis of class I, II, and III flagellar genes, respectively. Collectively, this study demonstrates that FlhF may directly regulate the transcription of flagellar genes by binding to their promoters as a transcriptional regulator, which will be helpful in understanding the mechanism of FlhF in flagellar biosynthetic and bacterial flagellation in general.

Neuronal Wiskott-Aldrich syndrome protein regulates Pseudomonas aeruginosa-induced lung vascular permeability through the modulation of actin cytoskeletal dynamics.

Pulmonary edema associated with increased vascular permeability is a severe complication of Pseudomonas (P.) aeruginosa-induced acute lung injury. The mechanisms underlying P aeruginosa-induced vascular permeability are not well understood. In the present study, we investigated the role of neuronal Wiskott Aldrich syndrome protein (N-WASP) in modulating P aeruginosa-induced vascular permeability. Using lung microvascular endothelial and alveolar epithelial cells, we demonstrated that N-WASP downregulation attenuated P aeruginosa-induced actin stress fiber formation and prevented paracellular permeability. P aeruginosa-induced dissociation between VE-cadherin and ß-catenin, but increased association between N-WASP and VE-cadherin, suggesting a role for N-WASP in promoting P aeruginosa-induced adherens junction rupture. P aeruginosa increased N-WASP-Y256 phosphorylation, which required the activation of Rho GTPase and focal adhesion kinase. Increased N-WASP-Y256 phosphorylation promotes N-WASP and integrin αVß6 association as well as TGF-ß-mediated permeability across alveolar epithelial cells. Inhibition of N-WASP-Y256 phosphorylation by N-WASP-Y256F overexpression blocked N-WASP effects in P aeruginosa-induced actin stress fiber formation and increased paracellular permeability. In vivo, N-WASP knockdown attenuated the development of pulmonary edema and improved survival in a mouse model of P aeruginosa pneumonia. Together, our data demonstrate that N-WASP plays an essential role in P aeruginosa-induced vascular permeability and pulmonary edema through the modulation of actin cytoskeleton dynamics.

Increased flux through the mevalonate pathway mediates fibrotic repair without injury.

Macrophages are important in mounting an innate immune response to injury as well as in repair of injury. Gene expression of Rho proteins is known to be increased in fibrotic models; however, the role of these proteins in idiopathic pulmonary fibrosis (IPF) is not known. Here, we show that BAL cells from patients with IPF have a profibrotic phenotype secondary to increased activation of the small GTPase Rac1. Rac1 activation requires a posttranslational modification, geranylgeranylation, of the C-terminal cysteine residue. We found that by supplying more substrate for geranylgeranylation, Rac1 activation was substantially increased, resulting in profibrotic polarization by increasing flux through the mevalonate pathway. The increased flux was secondary to greater levels of acetyl-CoA from metabolic reprogramming to ß oxidation. The polarization mediated fibrotic repair in the absence of injury by enhancing macrophage/fibroblast signaling. These observations suggest that targeting the mevalonate pathway may abrogate the role of macrophages in dysregulated fibrotic repair.

Effects of ivabradine hydrochloride combined with trimetazidine on myocardial fibrosis in rats with chronic heart failure.

Effects of ivabradine hydrochloride (Iva) and trimetazidine on myocardial fibrosis (MF) in rats with chronic heart failure (CHF) werφe explored. Fifty Wistar rats were randomly divided into sham operation, model, Iva, trimetazidine and combined drug group with 10 rats each. All rats except those in sham operation group were subjected to establish CHF model by constricting the abdominal aorta. After successful modeling, rats in the sham operation and model group received normal saline (10 mg/kg) gavage daily, the Iva group received Iva (10 mg/kg) gavage, the trimetazidine group received trimetazidine (10 mg/kg) gavage, and the combined drug group were given Iva (10 mg/kg) and trimetazidine (10 mg/kg) gavage for 12 weeks. The changes of hemodynamic indexes and heart rate, connective tissue growth factor (CTGF) and superoxide dismutase (SOD) levels as well as transforming growth factor ß1 (TGF-ß1) and collagen I (COL-I) expression levels in myocardial tissue of each group were detected. Compared with sham operation group, the left ventricular end-diastolic pressure (LVEDP) level, CTGF expression, TGF-ß1 mRNA and COL-I mRNA expression levels in model group increased significantly, but the ± dp/dtmax and SOD content in myocardial tissue decreased significantly. Compared with model group, the LVEDP level, CTGF expression, TGF-ß1 mRNA and COL-I mRNA expression levels in Iva group, trimetazidine group and combined drugs decreased significantly, but the ± dp/dtmax and the SOD content in myocardial tissue increased significantly (P<0.05). Changes in the combined drug group were the most notable (P<0.05). Iva combined with trimetazidine reduces LVEDP in rat with CHF, increases SOD content, and inhibits CTGF expression and TGF-ß1 and COL-I expression levels in myocardial tissues, thus achieving the inhibitory effect on MF.

MicroRNA-30-3p Suppresses Inflammatory Factor-Induced Endothelial Cell Injury by Targeting TCF21.

Atherosclerosis is one of the leading causes of mortality worldwide. Growing evidence suggested that miRNAs contributed to the progression of atherosclerosis. miR-30-5p was found involved in various diseases. However, the role of miR-30-5p in regulation of atherosclerosis is not known. Here, we aim to investigate the effects of miR-30-5p on regulating the progression of atherosclerosis. The expression levels of miR-30-5p in serum collected from atherosclerosis patients and normal healthy people were analyzed by qRT-PCR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway bioinformatics were carried out to reveal the possible signaling pathways involved in the mode of action of miR-30-5p. A potential target gene of miRNA-30-5p was searched and examined by a luciferase reporter assay. ELISA, Western blot, proliferation, and flow cytometry assays were performed to assess the biological functional role of miR-30-5p in vitro. Also, an in vitro monocyte-endothelial cell coculture model was used to study the functional role of miR-30-5p in atherosclerosis. We found that miR-30-5p was significantly decreased in serum samples from atherosclerosis patients compared with control subjects. GO and KEGG analysis results showed that miR-30-5p is highly associated with genetic profile of cardiovascular disease. TCF21 was verified as a target gene of miR-30-5p. Overexpression of miR-30-5p in THP-1 not only protected endothelial cell viability but also inhibited endothelial cell apoptosis, and similar results were observed in cells with that of TCF21 knocked down. Moreover, miR-30-5p decreased the expression levels of lactate dehydrogenase (LDH) and tumor necrosis factor-α (TNF-α) and reduced reactive oxygen species (ROS) accumulation. NF-κB and MAPK/p38 pathways played an indispensable role in the protection ability of miR-30-5p against atherosclerosis. Our results reveal that miR-30-5p suppresses the progression of atherosclerosis through targeting TCF21 in vitro. Therefore, the miR-30-5p-TCF21-MAPK/p38 signaling pathway may be a potential biomarker or therapeutic target in atherosclerosis.

Acidity-triggered charge-reversible multilayers for construction of adaptive surfaces with switchable bactericidal and bacteria-repelling functions.

The acidity of a microenvironment in infected sites was utilized as the trigger to manipulate the bacterial behavior on the surface. Multilayers composed of dopamine-anchored poly(acrylic acid) (PAA-dopa) and chitosan quaternary ammonium salt (Q-CS) were deposited onto a surface via the layer-by-layer (LBL) assembly technology. The multilayer was crosslinked through the reaction of catechol moieties. The surface charge of the multilayer reversibly shifted from positive to negative as the pH increased without influencing the chemical composition and wettability of the top layer. The precise manipulation of the surface charge, and therefore, the biological function was achieved by varying the acidity. The bactericidal efficiency increased 15 times for E. coli, while almost 90% dead S. aureus and 100% E. coli were released from the surface when the pH increased from 5.0 to 7.4. Therefore, the functional surface was regenerated, which is particularly essential during the long-term treatment of chronic wounds. This study presented a new adaptive material responding to microenvironment acidity of the infected sites for efficient and safe antibacterial therapies.

Angiotensin-converting enzyme defines matrikine-regulated inflammation and fibrosis.

The neutrophil chemoattractant proline-glycine-proline (PGP) is generated from collagen by matrix metalloproteinase-8/9 (MMP-8/9) and prolyl endopeptidase (PE), and it is concomitantly degraded by extracellular leukotriene A4 hydrolase (LTA4H) to limit neutrophilia. Components of cigarette smoke can acetylate PGP, yielding a species (AcPGP) that is resistant to LTA4H-mediated degradation and can, thus, support a sustained neutrophilia. In this study, we sought to elucidate if an antiinflammatory system existed to degrade AcPGP that is analogous to the PGP-LTA4H axis. We demonstrate that AcPGP is degraded through a previously unidentified action of the enzyme angiotensin-converting enzyme (ACE). Pulmonary ACE is elevated during episodes of acute inflammation, as a consequence of enhanced vascular permeability, to ensure the efficient degradation of AcPGP. Conversely, we suggest that this pathway is aberrant in chronic obstructive pulmonary disease (COPD) enabling the accumulation of AcPGP. Consequently, we identify a potentially novel protective role for AcPGP in limiting pulmonary fibrosis and suggest the pathogenic function attributed to ACE in idiopathic pulmonary fibrosis (IPF) to be a consequence of overzealous AcPGP degradation. Thus, AcPGP seemingly has very divergent roles: it is pathogenic in its capacity to drive neutrophilic inflammation and matrix degradation in the context of COPD, but it is protective in its capacity to limit fibrosis in IPF.

αvß3 integrin receptor specific peptide modified, salvianolic acid B and panax notoginsenoside loaded nanomedicine for the combination therapy of acute myocardial ischemia.

PURPOSE: To achieve the combination therapy of acute myocardial ischemia, arginyl-glycyl-aspartic acid (RGD) conjugated lipid was synthesized and RGD modified, salvianolic acid B (Sal B) and panax notoginsenoside (PNS) co-loaded lipid-polymer hybrid nanoparticles (RGD-S/P-LPNs) was fabricated an evaluated. METHODS: RGD was conjugated to distearoyl phosphatidylethanolamine-polyethylene glycol (DSPE-PEG-NH2) through amide linkage. Lipid-polymer hybrid nanoparticles (LPNs) were fabricated by nanoprecipitation method. RGD-S/P-LPNs was characterized in terms of morphology, size, charge, drug loading, entrapment, stability, drug release and cytotoxicity in vitro. Cardiac distribution, pharmacokinetics study and infarct therapy effect were evaluated in vivo. RESULTS: The LPNs are generally spherical in shape with uniform size distribution, have sizes of 100-200nm and zeta potentials range from -30.7∼ -39.8. In vitro release behaviors of drugs loaded LPNs are in a sustained release manner, which does not exhibit obviously cytotoxicity against H9c2 cardiomyocytes. RGD-S/P-LPNs group shows the most significant cardiac distribution and infarct therapy effect in vivo. CONCLUSION: The results illustrated that RGD modified dual drugs co-loaded LPNs are stable, sustained release carriers. Cardiac distribution, pharmacokinetics, and infarct therapy effect results suggested that the RGD-S/P-LPNs could improve the in vivo therapeutic efficacy of the double drugs.

Tristetraprolin Down-Regulation Contributes to Persistent TNF-Alpha Expression Induced by Cigarette Smoke Extract through a Post-Transcriptional Mechanism.

RATIONALE: Tumor necrosis factor-alpha (TNF-α) is a potent pro-inflammatory mediator and its expression is up-regulated in chronic obstructive pulmonary disease (COPD). Tristetraprolin (TTP) is implicated in regulation of TNF-α expression; however, whether TTP is involved in cigarette smoke-induced TNF-α expression has not been determined. METHODS: TTP expression was examined by western blot analysis in murine alveolar macrophages and alveolar epithelial cells challenged without or with cigarette smoke extract (CSE). TNF-α mRNA stability, and the decay of TNF-α mRNA, were determined by real-time quantitative RT-PCR. TNF-α protein levels were examined at the same time in these cells. To identify the molecular mechanism involved, a construct expressing the human beta-globin reporter mRNA containing the TNF-α 3'-untranslated region was generated to characterize the TTP targeted site within TNF-α mRNA. RESULTS: CSE induced TTP down-regulation in alveolar macrophages and alveolar epithelial cells. Reduced TTP expression resulted in significantly increased TNF-α mRNA stability. Importantly, increased TNF-α mRNA stability due to impaired TTP function resulted in significantly increased TNF-α levels in these cells. Forced TTP expression abrogated the increased TNF-α mRNA stability and expression induced by CSE. By using the globin reporter construct containing TNF-α mRNA 3'-untranslated region, the data indicate that TTP directly targets the adenine- and uridine-rich region (ARE) of TNF-α mRNA and negatively regulates TNF-α expression at the post-transcriptional level. CONCLUSION: The data demonstrate that cigarette smoke exposure reduces TTP expression and impairs TTP function, resulting in significantly increased TNF-α mRNA stability and excessive TNF-α expression in alveolar macrophages and epithelial cells. The data suggest that TTP is a novel post-transcriptional regulator and limits excessive TNF-α expression and inflammatory response induced by cigarette smoke.