Clinical Interventions and Hemodynamic Monitoring in the Setting of Left Ventricular Systolic Heart Failure in Children: Insights From a Physiologic Simulator.

BACKGROUND: In pediatric critical care, vasoactive/inotropic support is widely used in patients with heart failure, but it remains controversial because the influence of multiple medications and the interplay between their inotropic and vasoactive effects on a given patient are hard to predict. Robust evidence supporting their use and quantifying their effects in this group of patients is scarce. STUDY QUESTION: The aim of this study was to characterize the effect of vasoactive medications on various cardiovascular parameters in pediatric patient with decreased ejection fraction. STUDY DESIGN: Clinical-data based physiologic simulator study. MEASURE AND OUTCOMES: We used a physics-based computer simulator for quantifying the response of cardiovascular parameters to the administration of various types of vasoactive/inotropic medications in pediatric patients with decreased ejection fraction. The simulator allowed us to study the impact of increasing medication dosage and the simultaneous administration of some vasoactive agents. Correlation and linear regression analyses yielded the quantified effects on the vasoactive/inotropic support. RESULTS: Cardiac output and systemic venous saturation significantly increased with the administration of dobutamine and milrinone in isolation, and combination of milrinone with dobutamine, dopamine, or epinephrine. Both parameters decreased with the administration of epinephrine and norepinephrine in isolation. No significant change in these hemodynamic parameters was observed with the administration of dopamine in isolation. CONCLUSIONS: Milrinone and dobutamine were the only vasoactive medications that, when used in isolation, improved systemic oxygen delivery. Milrinone in combination with dobutamine, dopamine, or epinephrine also increased systemic oxygen delivery. The induced increment on afterload can negatively affect systemic oxygen delivery.

Dopamine-modified hyaluronic acid (DA-HA) as a novel dopamine-mimetics with minimal autoxidation and cytotoxicity.

Dopamine-modified hyaluronic acid (DA-HA) has been initially developed as an efficient coating and adhesion material for industrial uses. However, the biological activity and safety of DA-HA in the brain have not been explored yet. Here, we report a series of evidence that DA-HA exhibits similar functionality as dopamine (DA), but with much lower toxicity arising from autoxidation. DA-HA shows very little autoxidation even after 48-h incubation. This is profoundly different from DA and its derivatives including l-DOPA, which all induce severe neuronal death after pre-autoxidation, indicating that autoxidation is the cause of neuronal death. Furthermore, in vivo injection of DA-HA induces significantly lower toxicity compared to 6-OHDA, a well-known oxidized and toxic form of DA, and alleviates the apomorphine-induced rotational behavior in the 6-OHDA animal model of Parkinson's disease. Our study proposes that DA-HA with DA-like functionalities and minimal toxicity has a great potential to treat DA-related disease.

DNA tetrahedral nanocages as a promising nanocarrier for dopamine delivery in neurological disorders.

Dopamine is a neurotransmitter in the central nervous system that is essential for many bodily and mental processes, and a lack of it can cause Parkinson's disease. DNA tetrahedral (TD) nanocages are promising in bio-nanotechnology, especially as a nanocarrier. TD is highly programmable, biocompatible, and capable of cell differentiation and proliferation. It also has tissue and blood-brain barrier permeability, making it a powerful tool that could overcome potential barriers in treating neurological disorders. In this study, we used DNA TD as a carrier for dopamine to cells and zebrafish embryos. We investigated the mechanism of complexation between TD and dopamine hydrochloride using gel electrophoresis, fluorescence and circular dichroism (CD) spectroscopy, atomic force microscopy (AFM), and molecular dynamic (MD) simulation tools. Further, we demonstrate that these dopamine-loaded DNA TD nanostructures enhanced cellular uptake and differentiation ability in SH-SY5Y neuroblastoma cells. Furthermore, we extended the study to zebrafish embryos as a model organism to examine survival and uptake. The research provides valuable insights into the complexation mechanism and cellular uptake of dopamine-loaded DNA tetrahedral nanostructures, paving the way for further advancements in nanomedicine for Parkinson's disease and other neurological disorders.

Application of In Situ Mucoadhesive Hydrogel with Anti-Inflammatory and Pro-Repairing Dual Properties for the Treatment of Chemotherapy-Induced Oral Mucositis.

Chemotherapy-induced oral mucositis (CIOM) is a prevalent complication of chemotherapy and significantly affects the treatment process. However, effective treatment for CIOM is lacking due to the unique environment of the oral cavity and the single effect of current drug delivery systems. In this present study, we propose an innovative approach by combining a methacrylate-modified human recombinant collagen III (rhCol3MA) hydrogel system with hyaluronic acid-epigallocatechin gallate (HA-E) and dopamine-modified methacrylate-alginate (AlgDA-MA). HA-E is used as an antioxidant and anti-inflammatory agent and synergizes with AlgDA-MA to improve the wet adhesion of hydrogel. The results of rhCol3MA/HA-E/AlgDA-MA (Col/HA-E/Alg) hydrogel demonstrate suitable physicochemical properties, excellent wet adhesive capacity, and biocompatibility. Notably, the hydrogel could promote macrophage polarization from M1 to M2 and redress human oral keratinocyte (HOK) inflammation by inhibiting NF-κB activation. Wound healing evaluations in vivo demonstrate that the Col/HA-E/Alg hydrogel exhibits a pro-repair effect by mitigating inflammatory imbalances, fostering early angiogenesis, and facilitating collagen repair. In summary, the Col/HA-E/Alg hydrogel could serve as a promising multifunctional dressing for the treatment of CIOM.

Dopamine enhances GABAA receptor-mediated current amplitude in a subset of intrinsically photosensitive retinal ganglion cells.

Neuromodulation in the retina is crucial for effective processing of retinal signal at different levels of illuminance. Intrinsically photosensitive retinal ganglion cells (ipRGCs), the neurons that drive nonimage-forming visual functions, express a variety of neuromodulatory receptors that tune intrinsic excitability as well as synaptic inputs. Past research has examined actions of neuromodulators on light responsiveness of ipRGCs, but less is known about how neuromodulation affects synaptic currents in ipRGCs. To better understand how neuromodulators affect synaptic processing in ipRGC, we examine actions of opioid and dopamine agonists have on inhibitory synaptic currents in ipRGCs. Although µ-opioid receptor (MOR) activation had no effect on γ-aminobutyric acid (GABA) currents, dopamine [via the D1-type dopamine receptor (D1R)]) amplified GABAergic currents in a subset of ipRGCs. Furthermore, this D1R-mediated facilitation of the GABA conductance in ipRGCs was mediated by a cAMP/PKA-dependent mechanism. Taken together, these findings reinforce the idea that dopamine's modulatory role in retinal adaptation affects both nonimage-forming and image-forming visual functions.NEW & NOTEWORTHY Neuromodulators such as dopamine are important regulators of retinal function. Here, we demonstrate that dopamine increases inhibitory inputs to intrinsically photosensitive retinal ganglion cells (ipRGCs), in addition to its previously established effect on intrinsic light responsiveness. This indicates that dopamine, in addition to its ability to intrinsically modulate ipRGC activity, can also affect synaptic inputs to ipRGCs, thereby tuning retina circuits involved in nonimage-forming visual functions.

Smart zwitterionic coatings with precise pH-responsive antibacterial functions for bone implants to combat bacterial infections.

Hydrophilic antifouling coatings based on zwitterionic polymers have been widely applied for the surface modification of bone implants to combat biofilm formation and reduce the likelihood of implant-related infections. However, their long-term effectiveness is significantly limited by the lack of effective and precise antibacterial activity. Here, a pH-responsive smart zwitterionic antibacterial coating (PSB/GS coating) was designed and robustly fabricated onto titanium-base bone implants by using a facile two-step method. First, dopamine (DA) and a poly(sulfobetaine methacrylate-co-dopamine methacrylamide) (PSBDA) copolymer were deposited on implants via mussel-inspired surface chemistry, resulting in a hydrophilic base coating with abundant catechol residues. Next, an amino-rich antibiotic, gentamicin sulfate (GS), was covalently linked to the coating through the formation of acid-sensitive Schiff base bonds between the amine groups of GS and the catechol residues present in both the zwitterionic polymer and the DA component. During the initial implantation period, the hydrophilic zwitterionic polymers demonstrated the desired anti-fouling properties that could effectively reduce protein and bacterial adhesion by over 90%. With time, the bacterial proliferation led to a decrease in the microenvironment pH value, resulting in the hydrolysis of the acid-sensitive Schiff base bonds, thereby releasing GS on demand and effectively enhancing the anti-biofilm properties of coatings. Benefiting from this synergistic antifouling and smart antibacterial activities, the PSB/GS coating exerted an excellent anti-infective activity in both in vivo preoperative and postoperative infection rat models. This proposed facile yet effective coating strategy is expected to provide a promising solution to combat bone implant-related infections.

Basal release of 6-cyanodopamine from rat isolated vas deferens and its role on the tissue contractility.

6-Cyanodopamine is a novel catecholamine released from rabbit isolated heart. However, it is not known whether this catecholamine presents any biological activity. Here, it was evaluated whether 6-cyanodopamine (6-CYD) is released from rat vas deferens and its effect on this tissue contractility. Basal release of 6-CYD, 6-nitrodopamine (6-ND), 6-bromodopamine, 6-nitrodopa, and 6-nitroadrenaline from vas deferens were quantified by LC-MS/MS. Electric-field stimulation (EFS) and concentration-response curves to noradrenaline, adrenaline, and dopamine of the rat isolated epididymal vas deferens (RIEVD) were performed in the absence and presence of 6-CYD and /or 6-ND. Expression of tyrosine hydroxylase was assessed by immunohistochemistry. The rat isolated vas deferens released significant amounts of both 6-CYD and 6-ND. The voltage-gated sodium channel blocker tetrodotoxin had no effect on the release of 6-CYD, but it virtually abolished 6-ND release. 6-CYD alone exhibited a negligible RIEVD contractile activity; however, at 10 nM, 6-CYD significantly potentiated the noradrenaline- and EFS-induced RIEVD contractions, whereas at 10 and 100 nM, it also significantly potentiated the adrenaline- and dopamine-induced contractions. The potentiation of noradrenaline- and adrenaline-induced contractions by 6-CYD was unaffected by tetrodotoxin. Co-incubation of 6-CYD (100 pM) with 6-ND (10 pM) caused a significant leftward shift and increased the maximal contractile responses to noradrenaline, even in the presence of tetrodotoxin. Immunohistochemistry revealed the presence of tyrosine hydroxylase in both epithelial cell cytoplasm of the mucosae and nerve fibers of RIEVD. The identification of epithelium-derived 6-CYD and its remarkable synergism with catecholamines indicate that epithelial cells may regulate vas deferens smooth muscle contractility.

Dynamic Cross-Linking, Self-Healing, Antibacterial Hydrogel for Regenerating Irregular Cranial Bone Defects.

Given the widespread clinical demand, addressing irregular cranial bone defects poses a significant challenge following surgical procedures and traumatic events. In situ-formed injectable hydrogels are attractive for irregular bone defects due to their ease of administration and the ability to incorporate ceramics, ions, and proteins into the hydrogel. In this study, a multifunctional hydrogel composed of oxidized sodium alginate (OSA)-grafted dopamine (DO), carboxymethyl chitosan (CMCS), calcium ions (Ca2+), nanohydroxyapatite (nHA), and magnesium oxide (MgO) (DOCMCHM) was prepared to address irregular cranial bone defects via dynamic Schiff base and chelation reactions. DOCMCHM hydrogel exhibits strong adhesion to wet tissues, self-healing properties, and antibacterial characteristics. Biological evaluations indicate that DOCMCHM hydrogel has good biocompatibility, in vivo degradability, and the ability to promote cell proliferation. Importantly, DOCMCHM hydrogel, containing MgO, promotes the expression of osteogenic protein markers COL-1, OCN, and RUNX2, and stimulates the formation of new blood vessels by upregulating CD31. This study could provide meaningful insights into ion therapy for the repair of cranial bone defects.

Macrophage Membrane-Encapsulated Dopamine-Modified Poly Cyclodextrin Multifunctional Biomimetic Nanoparticles for Atherosclerosis Therapy.

Atherosclerotic plaques exhibit high cholesterol deposition and oxidative stress resulting from high reactive oxygen species (ROS). These are the major components in plaques and the main pro-inflammatory factor. Therefore, it is crucial to develop an effective therapeutic strategy that can simultaneously address the multiple pro-inflammatory factors via removing cholesterol and inhibiting the overaccumulated ROS. In this study, we constructed macrophage membrane-encapsulated biomimetic nanoparticles (MM@DA-pCD@MTX), which not only alleviate cholesterol deposition at the plaque lesion via reverse cholesterol transport but also scavenge the overaccumulated ROS. ß-Cyclodextrin (ß-CD) and the loaded methotrexate (MTX) act synergistically to induce cholesterol efflux for inhibiting the formation of foam cells. Among them, MTX up-regulated the expression of ABCA1, CYP27A1, and SR-B1. ß-CD increased the solubility of cholesterol crystals. In addition, the ROS scavenging property of dopamine (DA) was perfectly preserved in MM@DA-pCD@MTX, which could scavenge the overaccumulated ROS to alleviate the oxidative stress at the plaque lesion. Last but not least, MM-functionalized "homing" targeting of atherosclerotic plaques not only enables the targeted drug delivery but also prolongs in vivo circulation time and drug half-life. In summary, MM@DA-pCD@MTX emerges as a potent, multifunctional therapeutic platform for AS treatment, offering a high degree of biosafety and efficacy in addressing the complex pathophysiology of atherosclerosis.

A biomimetic lubricating nanosystem for synergistic therapy of osteoarthritis.

Failure of articular cartilage lubrication and inflammation are the main causes of osteoarthritis (OA), and integrated treatment realizing joint lubrication and anti-inflammation is becoming the most effective treat model. Inspired by low friction of human synovial fluid and adhesive chemical effect of mussels, our work reports a biomimetic lubricating system that realizes long-time lubrication, photothermal responsiveness and anti-inflammation property. To build the system, a dopamine-mediated strategy is developed to controllably graft hyaluronic acid on the surface of metal organic framework. The design constructs a biomimetic core-shell structure that has good dispersity and stability in water with a high drug loading ratio of 99%. Temperature of the solution rapidly increases to 55 °C under near-infrared light, and the hard-soft lubricating system well adheres to wear surfaces, and greatly reduces frictional coefficient by 75% for more than 7200 times without failure. Cell experiments show that the nanosystem enters cells by endocytosis, and releases medication in a sustained manner. The anti-inflammatory outcomes validate that the nanosystem prevents the progression of OA by down-regulating catabolic proteases and pain-related genes and up-regulating genes that are anabolic in cartilage. The study provides a bioinspired strategy to employ metal organic framework with controlled surface and structure for friction reduction and anti-inflammation, and develops a new concept of OA synergistic therapy model for practical applications.