Protective effects of curcumin on corneal endothelial cell PANoptosis and monocyte adhesion induced by tumor necrosis factor-alpha and interferon-gamma in rats.

Decrease of human corneal endothelial cell (CEC) density leads to corneal edema, progressive corneal opacity, and reduced visual acuity. A reduction in CEC density may be related to elevated levels of inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interferon (INF)-γ. PANoptosis, characterized by the activation of apoptosis, necroptosis, and pyroptosis, could be a factor in the loss of CECs driven by TNF-α and INF-γ. Cytokines also stimulate monocytes adhesion to endothelium. It has been shown in previous research that curcumin plays protective roles against numerous corneal inflammatory diseases. However, it is not determined whether curcumin acts as an anti-PANoptotic agent or if it mitigates monocyte adhesion to CECs. Therefore, this research aimed to explor the potential therapeutic effects of curcumin and its underlying mechanisms in the loss of CECs. CEC injury models were established, and curcumin was injected subconjunctivally. Clinical evaluation of the corneas was conducted using a scoring system and anterior segment photography. Corneal observation was performed with hematoxylin and eosin staining and immunostaining of zona occludens-1(ZO-1). Apoptotic cells within the corneal endothelium were observed using TUNEL staining. The detection of primary proteins expression was accomplished through Western blot analysis. Interleukin (IL)-1ß and macrophage chemotactic protein 1 (MCP-1) levels were determined via ELISA, while the expression of cleaved caspase-3, gasdermin-D (GSDMD), phosphor-mixed lineage kinase domain-like protein (p-MLKL) and intercellular cell adhesion molecule-1 were confirmed by immunofluorescence. Myeloperoxidase (MPO) activity was measured in aqueous humors. Curcumin treatment attenuated the loss of CECs and corneal edema caused by TNF-α and IFN-γ. Besides, it decreased the count of TUNEL-positive cells, and inhibited the upregulation of cleaved caspase-3, cleaved caspase-6, cleaved caspase-7, and cleaved poly (ADP-ribose) polymerase. Moreover, both the expression and phosphorylation of MLKL and receptor-interacting protein 3 were decreased in curcumin-treated rats. Furthermore, curcumin also lowered the expression of cleaved caspase-1, diminished the levels of IL1ß and MCP-1, and inhibited the activity of MPO. Besides, the expression of intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, as well as the number of CD11b-positive cells adhered to the CECs decreased for the administration of curcumin.

Nanoplastics Detected in Commercial Sea Salt.

People of all ages consume salt every day, but is it really just salt? Plastic nanoparticles [nanoplastics (NPs)] pose an increasing environmental threat and have begun to contaminate everyday salt in consumer goods. Herein, we developed a combined surface enhanced Raman scattering (SERS) and stimulated Raman scattering (SRS) approach that can realize the filtration, enrichment, and detection of NPs in commercial salt. The Au-loaded (50 nm) anodic alumina oxide substrate was used as the SERS substrate to explore the potential types of NP contaminants in salts. SRS was used to conduct imaging and quantify the presence of the NPs. SRS detection was successfully established through standard plastics, and NPs were identified through the match of the hydrocarbon group of the nanoparticles. Simultaneously, the NPs were quantified based on the high spatial resolution and rapid imaging of the SRS imaging platform. NPs in sea salts produced in Asia, Australasia, Europe, and the Atlantic were studied. We estimate that, depending on the location, an average person could be ingesting as many as 6 million NPs per year through the consumption of sea salt alone. The potential health hazards associated with NP ingestion should not be underestimated.

Brain endothelial CXCL12 attracts protective natural killer cells during ischemic stroke.

BACKGROUND: The innate lymphoid cell (ILC) family consists of NK cells, ILC type 1, 2, 3 and lymphoid tissue inducer cells. They have been shown to play important roles in homeostasis and immune responses and are generally considered tissue resident. Not much is known about the presence of ILC members within the central nervous system and whether they are tissue resident in this organ too. Therefore, we studied the presence of all ILC members within the central nervous system and after ischemic brain insult. METHODS: We used the photothrombotic ischemic lesion method to induce ischemic lesions within the mouse brain. Using whole-mount immunofluorescence imaging, we established that the ILCs were present at the rim of the lesion. We quantified the increase of all ILC members at different time-points after the ischemic lesion induction by flow cytometry. Their migration route via chemokine CXCL12 was studied by using different genetic mouse models, in which we induced deletion of Cxcl12 within the blood-brain barrier endothelium, or its receptor, Cxcr4, in the ILCs. The functional role of the ILCs was subsequently established using the beam-walk sensorimotor test. RESULTS: Here, we report that ILCs are not resident within the mouse brain parenchyma during steady-state conditions, but are attracted towards the ischemic stroke. Specifically, we identify NK cells, ILC1s, ILC2s and ILC3s within the lesion, the highest influx being observed for NK cells and ILC1s. We further show that CXCL12 expressed at the blood-brain barrier is essential for NK cells and NKp46+ ILC3s to migrate toward the lesion. Complementary, Cxcr4-deficiency in NK cells prevents NK cells from entering the infarct area. Lack of NK cell migration results in a higher neurological deficit in the beam-walk sensorimotor test. CONCLUSIONS: This study establishes the lack of ILCs in the mouse central nervous system at steady-state and their migration towards an ischemic brain lesion. Our data show a role for blood-brain barrier-derived CXCL12 in attracting protective NK cells to ischemic brain lesions and identifies a new CXCL12/CXCR4-mediated component of the innate immune response to stroke.

Clinical Outcomes of Descemet Membrane Endothelial Keratoplasty for Iridocorneal Endothelial Syndrome With a Glaucoma Drainage Device.

PURPOSE: The purpose of this study was to evaluate the feasibility and clinical outcomes of Descemet membrane endothelial keratoplasty (DMEK) for treating iridocorneal endothelial (ICE) syndrome with a glaucoma drainage device (GDD). METHODS: In this retrospective, interventional case series, data of ICE eyes with a GDD treated with DMEK were collected at the Zhongshan Ophthalmic Center. A total of 24 patients (24 eyes) with mild-to-moderate ocular anterior segment anomalies together with good intraocular pressure (IOP) control preoperatively were included between March 10, 2014, and November 11, 2021. Cases were performed DMEK with concomitantly procedures, such as goniosynechialysis, an entire recipient's Descemet stripping, trimming of glaucoma tubes, and an inferiorly peripheral iridotomy. Graft survival, corrected distance visual acuity (CDVA), endothelial cell loss, IOP, and surgical complications were documented. RESULTS: The mean length of follow-up after surgery was 30.8 ± 7.8 months. Postoperative CDVA improved significantly. At 1 and 2 years postoperatively, 10 (50%) of 20 eyes and 7 (47%) of 15 eyes achieved a CDVA of 20/32 or better, cumulative graft success rates by Kaplan-Meier survival analysis were 89% and 67%, and endothelial cell loss were (59 ± 10)% and (71 ± 7)%, respectively. Within the follow-up period, IOP elevation and progressive peripheral anterior synechiae occurred in 7 (29%) and 5 (21%) of 24 eyes, respectively. CONCLUSIONS: With specific technical modifications, DMEK had not increased the risk of postoperative complications and provided comparable clinical outcomes in the treatment of ICE eyes with a GDD with those observed in the treatment of ICE eyes without a GDD.

Clinical outcomes of endothelial keratoplasty with an entire recipient's Descemet stripping for iridocorneal endothelial syndrome.

PURPOSE: To investigate whether entire recipient's Descemet stripping reduced endothelial cell loss (ECL) following Descemet membrane endothelial keratoplasty (DMEK) for iridocorneal endothelial (ICE) syndrome DESIGN: Randomized controlled clinical trial SETTING: Zhongshan Ophthalmic Center PATIENT: Forty-eight patients (48 eyes) with ICE syndrome were enrolled between March 10, 2014, and May 11, 2022. The eligible patients were divided into the entire recipient's Descemet stripping group (the entire stripping group, 24 eyes) or the standard technique group (the standard group, 24 eyes). INTERVENTIONS: DMEK was performed in all cases with concomitantly procedures. The entire recipient's Descemet membrane or the central 8.0 or 8.25-mm diameter of the Descemet membrane was removed intraoperatively. MAIN OUTCOMES MEASURES: ECL, corrected distance visual acuity (CDVA), intraocular pressure (IOP), graft survival, and surgical complications were compared 9, 12 and 24 months after surgery. RESULTS: After a 9 months follow-up, ECL was significantly lower in the entire stripping group than in the standard group. At 2 years postoperatively, the ECL rate was 66±5% and 74±4% (95%confidence interval (CI): -0.04 to 0.01; p = 0.040), with a cumulative graft success rate of 83% and 67% (95%CI: -0.07 to 0.39; p = 0.318) in the entire stripping group and the standard group, respectively. Postoperative CDVA level was comparable between the 2 groups throughout the follow-up period. No significant differences were observed in the incidence of main complications between the 2 groups. CONCLUSIONS: Entire recipient's Descemet stripping may delay the pathological progression of ICE syndrome, thereby reducing ECL following DMEK.

Salicylaldehyde-derived piperazine-functionalized hydrazone ligand-based Pt(II) complexes: inhibition of EZH2-dependent tumorigenesis in pancreatic ductal adenocarcinoma, synergism with PARP inhibitors and enhanced apoptosis.

Piperazine is an important functional unit of many clinically approved drugs, including chemotherapeutic agents. In the current study, methyl piperazine was incorporated and eight salicylaldehyde-derived piperazine-functionalized hydrazone ONN-donor ligands (L) and their Pt(II) complexes (L-PtCl) were prepared. The structures of all these ligands (L1-L8) and Pt(II) complexes (C1-C8) were determined using 1H and 13C NMR, UV-vis, FT-IR and HR-ESI MS analyses, whereas the structures of C1, C5, C6, C7 and C8 were determined in the solid state using single crystal X-ray diffraction analysis. Solution state stabilities of C3, C4, C5 and C6 were determined via time-dependent UV-vis spectroscopy. All these complexes (C1-C8) were studied for their anticancer effect in pancreatic ductal adenocarcinoma cells, including BxPC3, MIAPaCa-2 and PANC1 cells. C1-C8 displayed a potential cytotoxic effect in all these cancer cells, among which C5, C6 and C8 showed the strongest inhibitory effect in comparison with standard chemotherapeutic agents, including 5-fluorouracil (5-FU), cisplatin (CP), oxaliplatin and doxorubicin (DOX). C5, C6 and C8 suppressed the growth of pancreatic cancer cells in a dose-dependent manner. Moreover, C5, C6 and C8 inhibited clonogenic potential and invasion ability and induced apoptosis in PANC1 cells. Importantly, C5, C6 and C8 synergized the anticancer effect with PARP inhibitors, including olaparib, veliparib and niraparib, in pancreatic cancer cells, thus suggesting an important role of C5, C6 and C8 in induction of apoptosis in combination with PARP inhibitors. C5 combined with PARP inhibitors induced caspase3/7 activity and suppressed ATP production. Mechanistically, C5, C6 and C8 inhibited EZH2 protein expression to suppress EZH2-dependent tumorigenesis. Overall, these results highlighted the importance of these piperazine-functionalized Pt(II) complexes as potential anticancer agents to suppress pancreatic ductal adenocarcinoma tumorigenesis by targeting the EZH2-dependent pathway.

Effect of PCSK9 on atherosclerotic cardiovascular diseases and its mechanisms: Focus on immune regulation.

Atherosclerosis is a basic pathological characteristic of many cardiovascular diseases, and if not effectively treated, patients with such disease may progress to atherosclerotic cardiovascular diseases (ASCVDs) and even heart failure. The level of plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) is significantly higher in patients with ASCVDs than in the healthy population, suggesting that it may be a promising new target for the treatment of ASCVDs. PCSK9 produced by the liver and released into circulation inhibits the clearance of plasma low-density lipoprotein-cholesterol (LDL-C), mainly by downregulating the level of LDL-C receptor (LDLR) on the surface of hepatocytes, leading to upregulated LDL-C in plasma. Numerous studies have revealed that PCSK9 may cause poor prognosis of ASCVDs by activating the inflammatory response and promoting the process of thrombosis and cell death independent of its lipid-regulatory function, yet the underlying mechanisms still need to be further clarified. In patients with ASCVDs who are intolerant to statins or whose plasma LDL-C levels fail to descend to the target value after treatment with high-dose statins, PCSK9 inhibitors often improve their clinical outcomes. Here, we summarize the biological characteristics and functional mechanisms of PCSK9, highlighting its immunoregulatory function. We also discuss the effects of PCSK9 on common ASCVDs.

Using optimized particle imaging of micro-Raman to characterize microplastics in water samples.

Characterizing the chemical properties, morphologies, size, and quantities of microplastics (MPs) in water samples with high precision is critically important for understanding the environmental behaviors of MPs. Traditional detection methods, such as Fourier transform infrared spectroscopy (FTIR) and Raman spectroscopy point-by-point detection, provide worthy reference techniques but are time- and labor-consuming. We established a super time-saving and high-precision technique to characterize MPs using micro-Raman automatic particle identification (MR-API). Based on the identification of PS spheres, screen magnification, exposure time, and the number of scans are selected as crucial detection parameters for MR-API analysis, which highly affect the precision of the results. Detecting particles down to 1 µm requires magnification of the mosaic until the scale showed 200 µm. The recommended setting parameters were 83.33 or 100 ms exposure time, 20 scans, 7 mW laser power, and 1 µm image pixel size, suitable for polystyrene (PS), polypropylene (PP), polyethylene terephthalate (PET), polyethylene (PE), polyvinyl chloride (PVC), and polyamide (PA) particles detection. With the complete procedure of MR-API measurements, the recovery of MPs was 61.67-90.00 %. To validate the feasibility of the MR-API, the method was used to detect samples of known plastic types (mask leachates) and unknown plastic types (urban lake). A total of 4540 particles in the sample of mask leachates consuming 35 h 50 min 43 s, and 0.92 ± 0.49 % of particles were identified as MPs. The urban river sample efficiently identified PP, PET, PE, PVC, PS, EVA, and VC/VAC MPs using this method. The detected MPs size ranged from 8.3 to 5000 µm, saving 75.03 % and 58.38 % of the time compared to the conventional micro-FTIR and micro-Raman point-by-point methods, respectively. Therefore, this method is effective for detecting MPs in the environmental samples and has excellent prospects.

Disposable face masks release micro particles to the aqueous environment after simulating sunlight aging: Microplastics or non-microplastics?

This study focuses on characterizing microplastics and non-microplastics released from surgical masks (SMs), N95 masks (N95), KN95 masks (KN95), and children's masks (CMs) after simulating sunlight aging. Based on micro-Raman spectrum analysis, it was found that the dominant particles released from masks were non-microplastics (66.76-98.85%). Unfortunately, CMs released the most microplastics, which is 8.92 times more than SMs. The predominant size range of microplastics was 30-500 µm, and the main polymer types were PP and PET. Compared with the whole SMs, the microplastic particles released from the cutting-SMs increased conspicuously, which is 12.15 times that of the whole SMs. The main components of non-microplastics include ß-carotene, microcrystalline cellulose 102, and eight types of minerals. Furthermore, non-microplastics were mainly fibrous and fragmented in appearance, similar to the morphology of microplastics. After 15 days of UVA-aging, the fibers of the face layers had cracks to varying degrees. It was estimated that these four types of masks can release at least 31.5 trillion microplastics annually in China. Overall, this study demonstrated that the masks could release a large quantity of microplastics and non-microplastics to the environment after sunlight aging, deserving urgent attention in the future study.

Resveratrol regulates macrophage recruitment and M1 macrophage polarization and prevents corneal allograft rejection in rats.

Introduction: Resveratrol is an immune modulator that can reduce M1 macrophage polarization in vitro. Reducing macrophage recruitment and M1 polarization can prevent corneal allograft rejection (CGR). In this study, rat corneal allograft rejection models were established to explore the effects of resveratrol on CGR and macrophages and the underlying mechanisms after corneal transplantation. Methods: Corneal allograft models were established, and 100 mg/kg resveratrol was injected intraperitoneally. The corneal allografts were assessed clinically using the Holland rejection scoring system, anterior segment photography, and anterior segment optical coherence tomography. Corneal macrophages, pro-inflammatory cytokines, and corneal lymphatic vessels were detected using hematoxylin and eosin staining, immunofluorescence staining, and real-time quantitative polymerase chain reaction (qRT-PCR). Dendritic cells (DCs) in cervical lymph nodes were explored using flow cytometry. RNA sequencing experiments were conducted to identify the mechanisms through which resveratrol affected CGR. The results were verified using Simple Western analysis. Pro-inflammatory cytokines by macrophages in vitro were measured using qRT-PCR and enzyme-linked immunosorbent assays. Results: Resveratrol significantly prolonged the survival of corneal grafts and reduced graft edema and central corneal thickness. Corneal macrophage recruitment and M1 macrophage polarization decreased significantly after corneal transplantation in the resveratrol group. Resveratrol also reduced pro-inflammatory cytokines in corneal grafts and suppressed the early generation of cornea lymphatic vessels and the recruitment of cornea inflammatory cells 14 days after surgery. Resveratrol decreased the proportion of DCs in ipsilateral cervical lymph nodes. The effect of resveratrol on CGR was related to the phosphatidylinositol 3-kinase/protein kinase-B (PI3K/Akt) pathway. Resveratrol reduced the secretion of pro-inflammatory cytokines by M1 macrophages in vitro. Conclusion: Our findings suggest that resveratrol can reduce corneal macrophage recruitment and M1 macrophage polarization after corneal transplantation in rats and prevent CGR. The PI3K/Akt pathway may be an important mechanism that warrants further research.

Engineering extracellular vesicles with macrophage membrane fusion for ameliorating imiquimod-induced psoriatic skin inflammation.

INTRODUCTION: Herein, we developed an engineered extracellular vehicle (EV)-based method for ameliorating inflammatory responses in psoriasis. METHODS: EVs, derived from annexin A1 (ANXA1) overexpressing T cells, were co-extruded with M2 macrophage membrane to obtain engineered EVs. In vitro, the effect of engineered EVs on macrophage polarization was evaluated by real-time PCR. In imiquimod (IMQ)-induced psoriasis-like mouse model, the efficacy of engineered EVs in ameliorating psoriatic inflammation was evaluated by Psoriasis Area and Severity Index (PASI) score and immunohistochemistry staining after subcutaneous injection of EVs. RESULTS: The engineered EVs not only preserved the high stability of M2 macrophage membrane but also retained the macrophage reprogramming potential of ANXA1 overexpressed in T cells. In the psoriasis-like mouse model, subcutaneous injection of engineered EVs successfully reduced the PASI score and the levels of pro-inflammatory cytokines, including IL-1ß, IL-6, and TNF-α. Along with high biosafety, the administration of EVs also rescued the histomorphological changes of spleen, liver, and kidney. CONCLUSIONS: The engineered EVs exhibited the potential to alleviate inflammation of psoriasis, providing new insights and potential strategies for the immunotherapies of psoriasis.

Effects of Oil Viscosity and the Solution Gas-Oil Ratio on Foamy Oil Flow in Solution Gas Drive.

The anomalously high recovery of solution gas drive in some heavy oil reservoirs has been associated with foamy oil. The effects of external factors such as temperature, permeability, and the pressure depletion rate on foamy oil flow have been studied sufficiently, but few studies are available on the effect of heavy oil itself. In order to investigate the effect of oil viscosity and the solution gas-oil ratio on foamy oil, 11 tests of solution gas drive through a sandpack were carried out in this work. The results show that a typical foamy oil solution gas drive exists in three stages, which are the oil phase expansion stage, the foamy oil flow stage, and the oil-gas two-phase flow stage. As the oil viscosity decreases, the foamy oil flow stage shortens, resulting in reduced recovery of this stage significantly. In the experiment with an oil viscosity of 200 mPa·s, foamy oil flow was not observed. A lower limit of oil viscosity should exist for steady flow of foamy oil, which is considered to be approximately 600 mPa·s according to the experimental results. As the solution gas-oil ratio increases, the oil recovery first increases and then decreases. Foamy oil flow could be observed clearly when the solution gas-oil ratio was between 10 and 26 Sm3/m3, which indicates that there is an optimal range of solution gas-oil ratios for foamy oil solution gas drive. The test with a solution gas-oil ratio of 35 Sm3/m3 showed that oil-gas two-phase flow followed the oil phase expansion stage as a result of the production of a quantity of gas, which illustrates that excess solution gas is unbeneficial to foamy oil flow on the contrary. The investigation revealed that oil viscosity and the solution gas-oil ratio are essential for foamy oil flow, which provides theoretical support for foamy oil production.

A randomized non-inferiority study of low-dose and standard-dose ticagrelor after intervention for acute coronary syndrome: study protocol for the TIGER STUDY.

BACKGROUND: Current guidelines recommend that patients with acute coronary syndrome (ACS) who have successfully undergone percutaneous coronary intervention (PCI) should continue to use dual antiplatelet therapy (DAPT) for 12 months. The long-term use of standard-dose dual antiplatelet therapy will increase the risk of bleeding. An optimized antiplatelet strategy that can prevent ischemic events and reduce the risk of bleeding remains to be explored. METHODS: The study is a prospective, multicenter, randomized, open-label, controlled study involving 2090 patients from six clinical centers in China. Through the interactive web response system (IWRS), ACS patients undergoing successful PCI will be randomly divided into the low-dose ticagrelor group or the normal-dose ticagrelor group, after taking 100 mg aspirin and 90 mg ticagrelor bid for 1 week. The primary endpoint is a composite of cardiovascular death, non-fatal myocardial infarction, stent thrombosis, repeat revascularization, and stroke. The secondary endpoints are bleeding events of grade 2 or higher according to Bleeding Academic Research Consortium [BARC] criteria, cardiovascular death, acute myocardium infarction, and coronary revascularization at 1 year. DISCUSSION: Recent studies have confirmed that 90 mg ticagrelor alone can safely and effectively reduce bleeding without increasing ischemic events of patients with ACS after PCI. Compared with standard-dose DAPT, whether low-dose ticagrelor combined with aspirin can ensure the anti-ischemic effect while reducing the bleeding risk remains unclear in Chinese patients. The TIGER study will be the first large-scale, multicenter study to compare the efficacy and safety of low-dose and standard-dose ticagrelor combined with aspirin in ACS patients 1 week after successful PCI. TRIAL REGISTRATION: Clinicaltrials.gov NCT04255602. Registered on 5 February 2020.

Multiple imputation of maritime search and rescue data at multiple missing patterns.

Based on the missing situation and actual needs of maritime search and rescue data, multiple imputation methods were used to construct complete data sets under different missing patterns. Probability density curves and overimputation diagnostics were used to explore the effects of multiple imputation. The results showed that the Data Augmentation (DA) algorithm had the characteristics of high operation efficiency and good imputation effect, but the algorithm was not suitable for data imputation when there was a high data missing rate. The EMB algorithm effectively restored the distribution of datasets with different data missing rates, and was less affected by the missing position; the EMB algorithm could obtain a good imputation effect even when there was a high data missing rate. Overimputation diagnostics could not only reflect the data imputation effect, but also show the correlation between different datasets, which was of great importance for deep data mining and imputation effect improvement. The Expectation-Maximization with Bootstrap (EMB) algorithm had a poor estimation effect on extreme data and failed to reflect the dataset's variability characteristics.

TANK Promotes Pressure Overload Induced Cardiac Hypertrophy via Activating AKT Signaling Pathway.

Background: TANK (TRAF family member associated NF-κB activator) acts as a member of scaffold proteins participated in the development of multiple diseases. However, its function in process of cardiac hypertrophy is still unknown. Methods and Results: In this study, we observed an increased expression of TANK in murine hypertrophic hearts after aortic banding, suggesting that TANK may be involved in the pathogenesis of cardiac hypertrophy. We generated cardiac-specific TANK knockout mice, and subsequently subjected to aortic banding for 4-8 weeks. TANK knockout mice showed attenuated cardiac hypertrophy and dysfunction compared to the control group. In contrast, cardiac-specific TANK transgenic mice showed opposite signs. Consistently, in vitro experiments revealed that TANK knockdown decreased the cell size and expression of hypertrophic markers. Mechanistically, AKT signaling was inhibited in TANK knockout mice, but activated in TANK transgenic mice after aortic banding. Blocking AKT signaling with a pharmacological AKT inhibitor alleviated the cardiac hypertrophy and dysfunction in TANK transgenic mice. Conclusions: Collectively, we identified TANK accelerates the progression of pathological cardiac hypertrophy and is a potential therapeutic target.

Embryonic Stem Cell-Derived Exosomes Attenuate Transverse Aortic Constriction Induced Heart Failure by Increasing Angiogenesis.

Background: Although there are concerns regarding their clinical use, embryonic stem cells (ESCs) hold a great promise for cardiac repair. Exosomes deriving from ESCs constitute a promising alternative for heart restoration. However, their effects in hypertension-induced heart failure are still unknown. Objective and Methods: To investigate the effects of ESCs-derived exosomes on hypertension-induced heart failure and the underlying mechanisms, sustained transverse aortic constriction (TAC) was performed on 8-week-old C57BL/6 male mice. After 1 months, ESCs-derived exosomes were isolated and injected intravenously once a week for 6 weeks. Echocardiography, wheat germ agglutinin (WGA), Masson staining, immunohistochemistry, and tube formation assays were all involved in our study. Results: Proteomics analyses revealed that ESC-derived exosomes contain FGF2 protein. Tube formation induced by these exosomes could be inhibited by FGF2R siRNA interference. ESCs-derived exosomes evidently attenuated TAC-induced heart failure, improving cardiac function and promoting myocardial angiogenesis which can be attenuated by selective FGF2 inhibitor AZD4547. Conclusions: ESC-derived exosomes attenuate TAC-induced heart failure mostly by promoting myocardial angiogenesis. FGF2 signaling plays a vital role in the myocardial angiogenesis induced by ESC-derived exosomes.

Transdermal protein delivery by a coadministered peptide identified via phage display.

Efficient transdermal drug delivery of large hydrophilic drugs is challenging. Here we report that the short synthetic peptide, ACSSSPSKHCG, identified by in vivo phage display, facilitated efficient transdermal protein drug delivery through intact skin. Coadministration of the peptide and insulin to the abdominal skin of diabetic rats resulted in elevated systemic levels of insulin and suppressed serum glucose levels for at least 11 h. Significant systemic bioavailability of human growth hormone was also achieved when topically coadministered with the peptide. The transdermal-enhancing activity of the peptide was sequence specific and dose dependent, did not involve direct interaction with insulin and enabled penetration of insulin into hair follicles beyond a depth of 600 microm. Time-lapse studies suggested that the peptide creates a transient opening in the skin barrier to enable macromolecular drugs to reach systemic circulation.

Dendrimers as drug carriers: applications in different routes of drug administration.

Dendrimers have successfully proved themselves as useful additives in different routes of drug administration because they can render drugs greater water-solubility, bioavailability, and biocompatibility. This review demonstrated the potential of dendrimers to be applied in these detailed routes with particular reference to intravenous, oral, transdermal, and ocular delivery systems. As a necessary introduction, the structures, synthesis, and properties of dendrimers were presented. Furthermore, the interaction mechanisms between dendrimers and drug molecules, including simple encapsulation, electrostatic interaction, and covalent conjugation, were elaborated.

Polyamidoamine (PAMAM) dendrimers as biocompatible carriers of quinolone antimicrobials: an in vitro study.

Quinolones, an expanding class of clinically established potent antibiotics, is not freely soluble in water which prevents the design of liquid dosage forms and restricts their use in topical applications. In the present study we investigated the potential of polyamidoamine (PAMAM) dendrimers as drug carriers of quinolones (nadifloxacin and prulifloxacin) by aqueous solubility and antibacterial activity studies. Results showed that the aqueous solubility of nadifloxacin and prulifloxacin was significantly increased by PAMAM dendrimers. Microbiology studies showed that nadifloxacin and prulifloxacin still exhibit their strong antimicrobial activities in the presence of dendrimers. These studies indicated that PAMAM dendrimers might be considered as biocompatible carriers of quinolones under suitable conditions.

Evaluation of polyamidoamine (PAMAM) dendrimers as drug carriers of anti-bacterial drugs using sulfamethoxazole (SMZ) as a model drug.

Sulfamethoxazole (SMZ), a sulfonamide with well-known anti-bacterial properties, is not freely soluble in water and causes problems in its clinical applications. In the present study we investigated the potential of ethylenediamine (EDA) core polyamidoamine (PAMAM) dendrimers as drug carriers of SMZ by aqueous solubility, in vitro release as well as anti-bacterial activity studies. Results showed that the aqueous solubility of SMZ was approximately proportional to dendrimer concentration (a 40-fold increase in solubility in 10mg/ml G3 PAMAM dendrimer solutions compared with that in double-distilled water at 37 degrees C). The in vitro release of SMZ in the presence of PAMAM dendrimers was significantly slower compared to pure SMZ dissolved in ethanol. Microbiology studies showed that PAMAM dendrimers could increase the anti-bacterial activity of SMZ (a 4- or 8-fold increase in the anti-bacterial activity of SMZ in dendrimer solution compared to pure SMZ dissolved in dimethylsulfoxide (DMSO) or 0.01 M NaOH solution). The in vitro release behavior and anti-bacterial activity studies indicated that PAMAM dendrimers might be considered as potential drug carriers of sulfonamides with a sustained release behavior under suitable conditions.