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Cellular reprogramming can manipulate the identity of cells to generate the desired cell types1-3. The use of cell intrinsic components, including oocyte cytoplasm and transcription factors, can enforce somatic cell reprogramming to pluripotent stem cells4-7. By contrast, chemical stimulation by exposure to small molecules offers an alternative approach that can manipulate cell fate in a simple and highly controllable manner8-10. However, human somatic cells are refractory to chemical stimulation owing to their stable epigenome2,11,12 and reduced plasticity13,14; it is therefore challenging to induce human pluripotent stem cells by chemical reprogramming. Here we demonstrate, by creating an intermediate plastic state, the chemical reprogramming of human somatic cells to human chemically induced pluripotent stem cells that exhibit key features of embryonic stem cells. The whole chemical reprogramming trajectory analysis delineated the induction of the intermediate plastic state at the early stage, during which chemical-induced dedifferentiation occurred, and this process was similar to the dedifferentiation process that occurs in axolotl limb regeneration. Moreover, we identified the JNK pathway as a major barrier to chemical reprogramming, the inhibition of which was indispensable for inducing cell plasticity and a regeneration-like program by suppressing pro-inflammatory pathways. Our chemical approach provides a platform for the generation and application of human pluripotent stem cells in biomedicine. This study lays foundations for developing regenerative therapeutic strategies that use well-defined chemicals to change cell fates in humans.
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Diferenciación Celular , Reprogramación Celular , Células Madre Pluripotentes Inducidas , Linaje de la Célula , Humanos , Células Madre Pluripotentes Inducidas/citologíaRESUMEN
The lower critical solution temperature (LCST) transition in water and the upper critical solution temperature (UCST) transition in ethanol of poly(oligo(ethylene glycol) acrylate) (POEGA)-based core cross-linked star (CCS) polymers have been investigated and compared by employing turbidity, dynamic light scattering (DLS), (1)H NMR and FTIR measurements. Macroscopic phase transitions in water and in ethanol were observed to occur when passing through the transition temperature, as revealed by DLS and turbidity measurements. Analysis by IR indicated that the interactions between the polymer chains and solvent molecules in water are stronger than those in ethanol such that the CCS polymer arm chains in water adopt more extended conformations. Moreover, hydrophobic interaction among the aliphatic groups plays a predominant role in the LCST-type transition in water whereas weak solvation of the polymer chains results in the UCST-type transition in ethanol. Additionally, the LCST-type transition in water was observed to be much more abrupt and complete than the UCST-type transition in ethanol, as suggested by (1)H NMR and IR at the molecular level. Finally, an abnormal "forced hydration" phenomenon was observed during the LCST transition upon heating. This study provides a detailed understanding of the subtle distinctions between the thermal transitions of CCS polymers in two commonly used solvents, which may be useful to guide future materials design for a wide range of applications.
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A pH-responsive core cross-linked star (CCS) polymer containing poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA) arms was used as an interfacial stabilizer for emulsions containing toluene (80 v%) and water (20 v%). In the pH range of 12.1-9.3, ordinary water-in-oil emulsions were formed. Intermediate multiple emulsions of oil-in-water-in-oil and water-in-oil-in-water were formed at pH 8.6 and 7.5, respectively. Further lowering the pH resulted in the formation of gelled high internal phase emulsions of oil-in-water type in the pH range of 6.4-0.6. The emulsion behavior was correlated with interfacial tension, conductivity and configuration of the CCS polymer at different pH.
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Reactivos de Enlaces Cruzados/química , Metacrilatos/química , Nylons/química , Aceites/química , Agua/química , Reactivos de Enlaces Cruzados/síntesis química , Emulsiones/química , Concentración de Iones de Hidrógeno , Metacrilatos/síntesis química , Nylons/síntesis química , Tamaño de la Partícula , Propiedades de SuperficieRESUMEN
A glucose-responsive insulin delivery system that sustains blood glucose equilibrium for an extended duration can address the low therapeutic window of insulin in diabetes treatment. Herein, insulin is loaded in a water-in-oil-in-water (W1/O/W2) gelled multiple emulsion using poly (4-vinylphenylboronic acid) (PVPBA) homopolymer as an effective emulsifier. The gelled multiple emulsion exhibits a high encapsulation efficiency (99%), enhanced stability and remarkable shear-thinning behavior, making it easy to inject. Under hyperglycemic conditions, the gelled emulsion system instantly binds to glucose molecules and reduces the hydrogen bonds of the PVPBA homopolymer, resulting in insulin release. In a streptozotocin-induced type 1 diabetic mouse model, a single subcutaneous injection of the gelled emulsion rapidly responds to high blood glucose concentration (BGC) and release insulin in a glucose dependent manner, thus prolonging the antihyperglycemic effect compared with free insulin.
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This study aimed to explore the effects of Bacillus amyloliquefaciens (BA) as one woody forage addition (as a probiotic, 1 × 107 CFU/g) on tilapia (Oreochromis niloticus). Woody forage is one kind of fishery feed that could significantly enhance the growth, feed utilization, and digestibility of tilapia. At first, tilapia was divided into eight groups and fed with control, control + BA, Moringa oleifera, M. oleifera + BA, Neolamarckia cadamba, N. cadamba + BA, Broussonetia papyrifera, and B. papyrifera + BA diets, respectively. After dieting for 8 weeks, the intestinal morphology of tilapia in the eight groups was observed, and the effects of the B. amyloliquefaciens addition and wordy forage on the intestine functions were analyzed by two-way ANOVA. As no significant negative effects were found on the woody forage on tilapia, the villus height, density and width, and epithelial goblet cells in the posterior intestines of tilapia with BA supplementation were greater than those in the groups without BA supplementation, suggesting B. amyloliquefaciens SCAU-070 could promote the growth and development of tilapia intestinal tracts. Furthermore, it was found that B. amyloliquefaciens SCAU-070 enhanced the antioxidation capacity of tilapia posterior intestine tissue by promoting the activity of superoxide dismutase and content of malondialdehyde. In addition, the result of high-throughput sequencing (16S rDNA) showed that the beneficial bacteria Cetobacterium and Romboutsia in the probiotic groups increased significantly, while the potential pathogenic bacteria Acinetobacter decreased significantly.
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Lipid nanoparticle-assisted mRNA inhalation therapy necessitates addressing challenges such as resistance to shear force damage, mucus penetration, cellular internalization, rapid lysosomal escape, and target protein expression. Here, we introduce the innovative "LOOP" platform with a four-step workflow to develop inhaled lipid nanoparticles specifically for pulmonary mRNA delivery. iLNP-HP08LOOP featuring a high helper lipid ratio, acidic dialysis buffer, and excipient-assisted nebulization buffer, demonstrates exceptional stability and enhanced mRNA expression in the lungs. By incorporating mRNA encoding IL-11 single chain fragment variable (scFv), scFv@iLNP-HP08LOOP effectively delivers and secretes IL-11 scFv to the lungs of male mice, significantly inhibiting fibrosis. This formulation surpasses both inhaled and intravenously injected IL-11 scFv in inhibiting fibroblast activation and extracellular matrix deposition. The HP08LOOP system is also compatible with commercially available ALC0315 LNPs. Thus, the "LOOP" method presents a powerful platform for developing inhaled mRNA nanotherapeutics with potential for treating various respiratory diseases, including idiopathic pulmonary fibrosis.
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Fibrosis Pulmonar Idiopática , Nanopartículas , ARN Mensajero , Anticuerpos de Cadena Única , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/inmunología , Animales , Administración por Inhalación , ARN Mensajero/administración & dosificación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Nanopartículas/química , Masculino , Ratones , Anticuerpos de Cadena Única/administración & dosificación , Humanos , Pulmón/metabolismo , Pulmón/patología , Ratones Endogámicos C57BL , Lípidos/química , Modelos Animales de Enfermedad , LiposomasRESUMEN
T cell exhaustion has emerged as a major hurdle that impedes the clinical translation of stimulator of interferon genes (STING) agonists. It is crucial to explore innovative strategies to rejuvenate exhausted T cells and potentiate the antitumor efficacy. Here, we propose an approach utilizing MSA-2 as a STING agonist, along with nanoparticle-mediated delivery of mRNA encoding interleukin-12 (IL-12) to restore the function of T cells. We developed a lipid nanoparticle (DMT7-IL12 LNP) that encapsulated IL12 mRNA. Our findings convincingly demonstrated that the combination of MSA-2 and DMT7-IL12 LNP can effectively reverse the exhausted T cell phenotype, as evidenced by the enhanced secretion of cytokines, such as tumor necrosis factor alpha, interferon gamma, and Granzyme B, coupled with reduced levels of inhibitory molecules such as T cell immunoglobulin and mucin domain-3 and programmed cell death protein-1 on CD8+ T cells. Furthermore, this approach led to improved survival and tumor regression without causing any systemic toxicity in melanoma and lung metastasis models. These findings suggest that mRNA encoding IL-12 in conjunction with STING agonists has the potential to confer superior clinical outcomes, representing a promising advancement in cancer immunotherapy.
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Interleucina-12 , Ratones Endogámicos C57BL , ARN Mensajero , Interleucina-12/genética , Animales , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratones , Nanopartículas/química , Proteínas de la Membrana/agonistas , Proteínas de la Membrana/genética , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Humanos , Femenino , Antineoplásicos/farmacología , Antineoplásicos/química , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Línea Celular Tumoral , Agotamiento de Células TRESUMEN
The ischemic stroke is a major global health concern, with high mortality and disability rates. Unfortunately, there is a dearth of effective clinical interventions for managing poststroke neuroinflammation and blood-brain barrier (BBB) disruption that are crucial for the brain injury evolving and neurological deficits. By leveraging the pathological progression of an ischemic stroke, we developed an M2 microglia-targeting lipid nanoparticle (termed MLNP) approach that can selectively deliver mRNA encoding phenotype-switching interleukin-10 (mIL-10) to the ischemic brain, creating a beneficial feedback loop that drives microglial polarization toward the protective M2 phenotypes and augments the homing of mIL-10-loaded MLNPs (mIL-10@MLNPs) to ischemic regions. In a transient middle cerebral artery occlusion (MCAO) mouse model of an ischemic stroke, our findings demonstrate that intravenously injected mIL-10@MLNPs induce IL-10 production and enhance the M2 polarization of microglia. The resulting positive loop reinforces the resolution of neuroinflammation, restores the impaired BBB, and prevents neuronal apoptosis after stroke. Using a permanent distal MCAO mouse model of an ischemic stroke, the neuroprotective effects of mIL-10@MLNPs have been further validated by the attenuation of the sensorimotor and cognitive neurological deficits. Furthermore, the developed mRNA-based targeted therapy has great potential to extend the therapeutic time window at least up to 72 h poststroke. This study depicts a simple and versatile LNP platform for selective delivery of mRNA therapeutics to cerebral lesions, showcasing a promising approach for addressing an ischemic stroke and associated brain conditions.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Ratones , Animales , Microglía/patología , Microglía/fisiología , Barrera Hematoencefálica/patología , Isquemia Encefálica/tratamiento farmacológico , Enfermedades Neuroinflamatorias , Accidente Cerebrovascular/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patologíaRESUMEN
Core cross-linked star (CCS) polymers become increasingly important in polymer science and are evaluated in many value-added applications. However, limitations exist to varied degrees for different synthetic methods. It is clear that improvement in synthetic efficiency is fundamental in driving this field moving even further. Here, the most recent advances are highlighted in synthetic strategies, including cross-linking with cross-linkers of low solubility, polymerization-induced self-assembly in aqueous-based heterogeneous media, and cross-linking via dynamic covalent bonds. The understanding of CCS polymers is also further refined to advocate their role as an intermediate between linear polymers and polymeric nanoparticles, and their use as interfacial stabilizers is rationalized within this context.
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Nanopartículas/química , Polímeros/química , Ácidos Borónicos/química , Reacción de Cicloadición , Emulsionantes/química , Nanotubos/química , Polimerizacion , Polímeros/síntesis química , SolubilidadRESUMEN
Atherosclerosis is a common pathology present in many cardiovascular diseases. Although the current therapies (including statins and inhibitors of the serine protease PCSK9) can effectively reduce low-density lipoprotein (LDL) cholesterol levels to guideline-recommended levels, major adverse cardiovascular events still occur frequently. Indeed, the subendothelial retention of lipoproteins in the artery wall triggers multiple events of inflammation in macrophages and is a major contributor to the pathological progression of atherosclerosis. It has been gradually recognized that modulating inflammation is, therefore, an attractive avenue to forestall and treat atherosclerosis and its complications. Unfortunately, challenges with specificity and efficacy in managing plaque inflammation have hindered progress in atherosclerosis treatment. Herein, we report an NP-mediated mRNA therapeutic approach to target atherosclerotic lesional macrophages, modulating inflammation in advanced atherosclerotic lesions for the treatment of atherosclerosis. We demonstrated that the targeted NPs containing IL-10 mRNA colocalized with M2-like macrophages and induced IL-10 production in atherosclerotic plaques following intravenous administration to Western diet (WD)-fed Ldlr-/- mice. Additionally, the lesions showed a significantly alleviated inflammatory response, as evidenced by reduced oxidative stress and macrophage apoptosis, resulting in decreased lipid deposition, diminished necrotic areas, and increased fiber cap thickness. These results demonstrate the successful delivery of mRNA therapeutics to macrophage-enriched plaques in a preclinical model of advanced atherosclerosis, showing that this targeted NP inflammation management approach has great potential for translation into a wide range of clinical applications.
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Aterosclerosis , Placa Aterosclerótica , Animales , Ratones , Placa Aterosclerótica/tratamiento farmacológico , Proproteína Convertasa 9 , Interleucina-10 , Aterosclerosis/tratamiento farmacológico , InflamaciónRESUMEN
Human somatic cells can be reprogrammed to pluripotent stem cells by small molecules through an intermediate stage with a regeneration signature, but how this regeneration state is induced remains largely unknown. Here, through integrated single-cell analysis of transcriptome, we demonstrate that the pathway of human chemical reprogramming with regeneration state is distinct from that of transcription-factor-mediated reprogramming. Time-course construction of chromatin landscapes unveils hierarchical histone modification remodeling underlying the regeneration program, which involved sequential enhancer recommissioning and mirrored the reversal process of regeneration potential lost in organisms as they mature. In addition, LEF1 is identified as a key upstream regulator for regeneration gene program activation. Furthermore, we reveal that regeneration program activation requires sequential enhancer silencing of somatic and proinflammatory programs. Altogether, chemical reprogramming resets the epigenome through reversal of the loss of natural regeneration, representing a distinct concept for cellular reprogramming and advancing the development of regenerative therapeutic strategies.
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Células Madre Pluripotentes Inducidas , Células Madre Pluripotentes , Humanos , Epigenoma , Epigénesis Genética , Reprogramación Celular/genética , Células Madre Pluripotentes/metabolismo , Factores de Transcripción/metabolismo , Células Madre Pluripotentes Inducidas/metabolismoRESUMEN
Interleukin-11 (IL-11) is a profibrotic cytokine essential for the differentiation of fibroblasts into collagen-secreting, actin alpha 2, smooth muscle-positive (ACTA2+) myofibroblasts, driving processes underlying the pathogenesis of idiopathic pulmonary fibrosis (IPF). Here, we developed an inhalable and mucus-penetrative nanoparticle (NP) system incorporating siRNA against IL11 (siIL11@PPGC NPs) and investigated therapeutic potential for the treatment of IPF. NPs are formulated through self-assembly of a biodegradable PLGA-PEG diblock copolymer and a self-created cationic lipid-like molecule G0-C14 to enable efficient transmucosal delivery of siIL11. Noninvasive aerosol inhalation hindered fibroblast differentiation and reduced ECM deposition via inhibition of ERK and SMAD2. Furthermore, siIL11@PPGC NPs significantly diminished fibrosis development and improved pulmonary function in a mouse model of bleomycin-induced pulmonary fibrosis without inducing systemic toxicity. This work presents a versatile NP platform for the locally inhaled delivery of siRNA therapeutics and exhibits promising clinical potential in the treatment of numerous respiratory diseases, including IPF.
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Fibrosis Pulmonar Idiopática , Nanopartículas , Animales , Bleomicina , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/genética , Interleucina-11/uso terapéutico , Ratones , Ratones Endogámicos C57BL , ARN Interferente Pequeño/genéticaRESUMEN
Osteoarthritis (OA), a chronic and degenerative joint disease, remains a challenge in treatment due to the lack of disease-modifying therapies. As a promising therapeutic agent, adipose-derived stem cells (ADSCs) have an effective anti-inflammatory and chondroprotective paracrine effect that can be enhanced by genetic modification. Unfortunately, direct cell delivery without matrix support often results in poor viability of therapeutic cells. Herein, a hydrogel implant approach that enabled intra-articular delivery of gene-engineered ADSCs was developed for improved therapeutic outcomes in a surgically induced rat OA model. An injectable extracellular matrix (ECM)-mimicking hydrogel was prepared as the carrier for cell delivery, providing a favorable microenvironment for ADSC spreading and proliferation. The ECM-mimicking hydrogel could reduce cell death during and post injection. Additionally, ADSCs were genetically modified to overexpress transforming growth factor-ß1 (TGF-ß1), one of the paracrine factors that exert an anti-inflammatory and pro-anabolic effect. The gene-engineered ADSCs overexpressing TGF-ß1 (T-ADSCs) had an enhanced paracrine effect on OA-like chondrocytes, which effectively decreased the expression of tumor necrosis factor-alpha and increased the expression of collagen II and aggrecan. In a surgically induced rat OA model, intra-articular injection of the T-ADSC-loaded hydrogel markedly reduced cartilage degeneration, joint inflammation, and the loss of the subchondral bone. Taken together, this study provides a potential biomaterial strategy for enhanced OA treatment by delivering the gene-engineered ADSCs within an ECM-mimicking hydrogel.
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Hidrogeles , Osteoartritis , Adipocitos , Tejido Adiposo , Animales , Osteoartritis/terapia , Ratas , Células MadreRESUMEN
Age-related macular degeneration (AMD) is a leading cause of irreversible visual loss among elderly persons, of which wet AMD is characterized by choroidal neovascularization (CNV). We herein developed nanoparticles with good biosafety for effective treatment of choroidal neovascularization (CNV). S-PEG-ICG-RGD-RBZ NPs were synthesized and characterized by ZP, DLS, UV-Vis, TEM and Coomassie Brilliant Blue staining analyses. In our study, the S-PEG-ICG-RGD-RBZ NPs exhibited good biocompatibility in vitro and in vivo. There was no cellular toxicity, dead cells, apoptosis or genotoxicity in the studied concentration range in vitro; meanwhile, intravenous injection of the designed NPs did not cause histological damage or apoptosis in the organs in vivo, including the heart, liver, spleen, lung, kidneys and brain. The designed NPs inhibited VEGF-induced proliferation, cell migration, tube formation and expression of CD31 and VEGF in vitro. Meanwhile, in vivo studies also indicated the inhibition of CNV development by NPs. What's more, the CNV area was imaged after intravenous injection of NPs modified with indocyanine green. The NPs were mainly targeted to CNV areas and did not remain in the other organs. In summary, S-PEG modified with RGD was designed as a powerful carrier to deliver anti-VEGF agents to CNV areas. The smart NPs, which have good cellular compatibility, hold great potential for drug delivery in CNV treatment.
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Neovascularización Coroidal , Anciano , Neovascularización Coroidal/tratamiento farmacológico , Humanos , Verde de Indocianina , Rayos Láser , Oligopéptidos , PolímerosRESUMEN
Macrophages are attractive therapeutic targets due to their contributions to many pathological processes including cancers, atherosclerosis, obesity, diabetes and other inflammatory diseases. Macrophage-targeted gene therapy is an effective strategy for regulating macrophage function at the site of inflammation to treat related diseases. However, macrophages are recognized as difficult to transfect cells and non-specific delivery would inevitably cause unwanted systemic side effects. Herein, we prepared a series of macrophage-targeted nanoparticles (NPs) using cationic lipid-like compound G0-C14 and different carbohydrates-modified poly(lactide-co-glycolide) (PLGA) or poly(lactide-coglycolide)-b-poly(ethylene glycol) (PLGA-PEG) for gene delivery by a robust self-assembly method. The yielded NPs were decorated with carbohydrate-based targeting moieties including mannose, galactose, dextran, and a mixture of mannose and galactose. EGFP messenger RNA (mRNA) and GFP plasmid DNA (pDNA) were used as reporter genes to evaluate NP-mediated gene transfection in macrophages. Experimental results of macrophage phagocytosis demonstrated that more carbohydrate-decorated NPs were endocytosed by Raw 264.7 cells than the ones without carbohydrate modification. Mannose-decorated NPs showed better targeting ability to macrophages than NPs decorated with galactose only and a blended mixture of mannose and galactose. It is worth noting that polysaccharide dextran-modified NPs also exhibited evident targeting effects. CCK-8 assay revealed that no cytotoxicity was observed for all tested NP concentrations up to 2.8 mg/mL. The carbohydrate-decorated polymer/G0-C14 exhibited strong entrapment of mRNA and pDNA with an encapsulation efficiency of above 95%. The targeted NPs significantly improved cellular internalization and transfection efficiency in macrophages, depending on the type and content of the carbohydrate moieties presented on the NP surface. Interestingly, dextran-decorated NPs showing higher endocytosis at various concentrations in macrophages also demonstrated more efficient mRNA transfection, suggesting that the NP-mediated mRNA transfection efficiency was consistent with the endocytosis results.
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Nanopartículas , Carbohidratos , Terapia Genética , Macrófagos , PolietilenglicolesRESUMEN
A hydrophobic CCS polymer of poly(benzyl methacrylate) (PBzMA) was prepared in toluene by reversible addition-fragmentation chain transfer (RAFT)-mediated dispersion polymerization. The CCS polymer, with poly(benzyl methacrylate) as the arm and crosslinked N, N'-bis(acryloyl)cystamine (BAC) as the core, was confirmed by characterization with gel permeation chromatography (GPC) and nuclear magnetic resonance (NMR) spectroscopy. Three kinds of oils (toluene, anisole and styrene) were chosen to study the emulsification properties of PBzMA CCS polymer. The oils can be emulsified by CCS polymer to form water-in-oil (w/o) emulsions. Moreover, w/o high internal phase emulsions (HIPEs) can be obtained with the increase of toluene and styrene volume fractions from 75% to 80%. Porous polystyrene monolith and microparticles were prepared from the emulsion templates and characterized by the scanning electronic microscopy (SEM). With the internal phase volume fraction increased, open-pore porous monolith was obtained.
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OBJECTIVE: To investigate the effects of exogenous recombinant human brain natriuretic peptide (rhBNP) after primary percutaneous coronary intervention (PCI) on non-invasive hemodynamic in acute myocardial infarction patients with left ventricular failure. METHODS: A number of 96 acute myocardial infarction patients accompanied with heart failure after PCI hospitalized in the People's Hospital of Sanya during February 2012 to October 2015 were selected. They were randomly divided into the therapy group (n = 50) and control group (n = 46). On the basis of routine treatment, patients in the therapy group were treated with intravenous rhBNP (1.5 µg/kg was intravenous injection with uniform speed of 3 min, followed by continuous infusion 0.0075 µg/kg·min for 72 h), while the control group received conventional treatment. BioZ-2011 non-invasive hemodynamic real-time monitoring system was used to monitor the hemodynamic parameters changes and the leaves of plasma pro-BNP, serum creatinine, serum potassium, serum sodium and urine volume of each group before and after treating for 30 min, 1 h, 3 h, 6 h, 12 h, 24 h, 48 h, 72 h. RESULTS: Patients in the therapy group showed no effect on heart rate, while after 30 min of intravenous injection of rhBNP, CO, CI, SV, and SI increased significantly and LVET and TFC reduced at the same time, which had certain effect on blood pressure (SBP/DBP). Compared with the control group, the therapy group showed a faster and more effective improvement on hemodynamics. CONCLUSIONS: Acute myocardial infarction patients complicated with left heart failure after primary PCI can significantly improve hemodynamics by treating with rhBNP.
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Large conductance Ca2+-activated potassium channels (BK) are targets for research that explores therapeutic means to various diseases, owing to the roles of the channels in mediating multiple physiological processes in various cells and tissues. We investigated the pharmacological effects of curcumin, a compound isolated from the herb Curcuma longa, on BK channels. As recorded by whole-cell patch-clamp, curcumin increased BK (α) and BK (α+ß1) currents in transfected HEK293 cells as well as the current density of BK in A7r5 smooth muscle cells in a dose-dependent manner. By incubating with curcumin for 24 hours, the current density of exogenous BK (α) in HEK293 cells and the endogenous BK in A7r5 cells were both enhanced notably, though the steady-state activation of the channels did not shift significantly, except for BK (α+ß1). Curcumin up-regulated the BK protein expression without changing its mRNA level in A7r5 cells. The surface expression and the half-life of BK channels were also increased by curcumin in HEK293 cells. These effects of curcumin were abolished by MG-132, a proteasome inhibitor. Curcumin also increased ERK 1/2 phosphorylation, while inhibiting ERK by U0126 attenuated the curcumin-induced up-regulation of BK protein expression. We also observed that the curcumin-induced relaxation in the isolated rat aortic rings was significantly attenuated by paxilline, a BK channel specific blocker. These results show that curcumin enhances the activity of the BK channels by interacting with BK directly as well as enhancing BK protein expression through inhibiting proteasomal degradation and activating ERK signaling pathway. The findings suggest that curcumin is a potential BK channel activator and provide novel insight into its complicated pharmacological effects and the underlying mechanisms.
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Canales de Potasio de Gran Conductancia Activados por el Calcio/biosíntesis , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Animales , Butadienos/farmacología , Curcumina , Células HEK293 , Humanos , Canales de Potasio de Gran Conductancia Activados por el Calcio/genética , Leupeptinas/farmacología , Sistema de Señalización de MAP Quinasas/genética , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Nitrilos/farmacología , Complejo de la Endopetidasa Proteasomal/genética , RatasRESUMEN
We report emulsion studies using poly(vinylphenyl boronic acid) (PVPBA) linear homopolymer as an effective emulsifier and gelator. Two stabilizing regimes were identified depending on the pH of PVPBA aqueous solutions, i.e., emulsions stabilized by the hompolymer nanoparticles (Pickering emulsions) at pH < pKa and emulsions stabilized by the homopolymer unimers at pH > pKa. In both cases, gelled emulsions were obtained from medium to high internal phase volume fractions with the unimers exhibiting more effective emulsification and gelling properties. Hydrogen bonding between the boronic acid units is proposed to account for the high strength of the emulsions. The emulsions were shown to be pH- and sugar-responsive. Finally, the stable emulsions were used as templates to directly prepare PVPBA macroporous materials and to fabricate multilayered capsules. This remarkable observation that a simple homopolymer can serve as an effective emulsifier and gelator may dramatically extend the scope of potential emulsifiers and inspire further research in the design of new types of efficient emulsifying agents.
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Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione], a polyphenolic compound isolated from the rhizomes of Curcuma longa (turmeric), has been shown to exhibit a wide range of pharmacological activities including anti-inflammatory, anti-cancer, anti-oxidant, anti-atherosclerotic, anti-microbial, and wound healing effects. These activities of curcumin are based on its complex molecular structure and chemical features, as well as its ability to interact with multiple signaling molecules. The ability of curcumin to regulate ion channels and transporters was recognized a decade ago. The cystic fibrosis transmembrane conductance regulator (CFTR) is a well-studied ion channel target of curcumin. During the process of studying its anti-cancer properties, curcumin was found to inhibit ATP-binding cassette (ABC) family members including ABCA1, ABCB1, ABCC1, and ABCG2. Recent studies have revealed that many channels and transporters are modulated by curcumin, such as voltage-gated potassium (Kv) channels, high-voltage-gated Ca(2+) channels (HVGCC), volume-regulated anion channel (VRAC), Ca(2+) release-activated Ca(2+) channel (CRAC), aquaporin-4 (AQP-4), glucose transporters, etc., In this review, we aim to provide an overview of the interactions of curcumin with different types of ion channels and transporters and to help better understand and integrate the underlying molecular mechanisms of the multiple pharmacological activities of curcumin.