Hyaluronic Acid Nanoparticles as a Topical Agent for Treating Psoriasis.

Although conventional topical approaches for treating psoriasis have been offered as an alternative, there are still unmet medical needs such as low skin-penetrating efficacy and off-target adverse effects. A hyaluronic acid nanoparticle (HA-NP) formed by self-assembly of HA-hydrophobic moiety conjugates has been broadly studied as a nanocarrier for long-term and target-specific delivery of drugs, owing to their excellent physicochemical and biological characteristics. Here, we identify HA-NPs as topical therapeutics for treating psoriasis using in vivo skin penetration studies and psoriasis animal models. Transcutaneously administered HA-NPs were found to be accumulated and associated with pro-inflammatory macrophages in the inflamed dermis of a psoriasis mouse model. Importantly, HA-NP exerted potent therapeutic efficacy against psoriasis-like skin dermatitis in a size-dependent manner by suppressing innate immune responses and restoring skin barrier function without overt toxicity signs. The therapeutic efficacy of HA-NPs on psoriasis-like skin dermatitis was due to the outermost hydrophilic HA shell layer of HA-NPs, independent of the molecular weight of HA and hydrophobic moiety, and comparable with that of other conventional psoriasis therapeutics widely used in the clinical settings. Overall, HA-NPs have the potential as a topical nanomedicine for treating psoriasis effectively and safely.

Self-assembled hyaluronic acid nanoparticles for osteoarthritis treatment.

Although osteoarthritis (OA) is the most prevalent degenerative joint disease, there is no effective disease-modifying therapy. We report an empty self-assembled hyaluronic acid nanoparticle (HA-NP) as a potential therapeutic agent for OA treatment. In mouse primary articular chondrocytes, HA-NPs blocked the receptor-mediated cellular uptake of free low-molecular-weight HA, and the cellular uptake of HA-NPs increased by ectopic expression of CD44, using an adenoviral delivery system (Ad-Cd44). HA-NP showed in vitro resistance to digestion with hyaluronidase and in vivo long-term retention ability in knee joint, compared with free high-molecular-weight (HMW) HA. CD44 expression increased in the damaged articular cartilage of patients and mice with OA. Ad-Cd44 infection and IL-1ß treatment induced in vitro phenotypes of OA by enhancing catabolic gene expression in primary articular chondrocytes, and these effects were attenuated by HA-NP, but not HMW HA. Both Cd44 deficiency and intra-articular injection of HA-NP protected joint cartilage against OA development in the OA mouse model. NF-κB was found to mediate CD44-induced catabolic factor expression and HA-NP inhibited CD44-induced NF-κB activation in chondrocytes. Our results identify an empty HA-NP as a potential therapeutic agent targeting CD44 for OA treatment, and the CD44-NF-κB-catabolic gene axis as an underlying mechanism of destructive cartilage disorders.

Homeopathic Rhus toxicodendron Induces Cell Adhesions in the Mouse Pre-osteoblast Cell Line MC3T3-e1.

BACKGROUND: Rhus toxicodendron (R. tox) has been used as a homeopathic remedy for the treatment of inflammatory conditions. Previously, we reported that R. tox modulated inflammation in the mouse chondrocyte and pre-osteoblastic MC3T3-e1 cell line. During the inflammatory process, cells adhere to the extracellular matrix (ECM) and then migrate to the inflammation site. We examine here the process of cell adhesion in MC3T3-e1 cells after their stimulation with homeopathic R. tox. METHODS: For the cell-substrate adhesion assay, the cultured MC3T3-e1 cells were trypsinized, starved for 1 h in serum-free media, and plated onto culture plates coated with fibronectin (FN), 30c R. tox or gelatin, respectively. The cells were allowed to adhere for 20 min incubation and unattached cells were washed out. Adherent cells were measured using the water-soluble tetrazolium salt-8 assay. The intracellular signals after stimulation of R. tox were examined by analyzing the tyrosine phosphorylation of focal adhesion kinase (FAK), Src kinase, and Paxillin using immunoblot assay. Formation of focal adhesion (FA, an integrin-containing multi-protein structure that forms between intracellular actin bundles and the ECM) was analyzed by immunocytochemistry using NIH ImageJ software. RESULTS: Cell adhesion increased after stimulation with R. tox (FN, 20.50%; R. tox, 44.80%; and gelatin, 17.11% vs. uncoated cells [control]). Tyrosine phosphorylation of FAK, Paxillin, and Src increased compared with that of gelatin when stimulated with R. tox. Additionally, R. tox-stimulated cells formed many FAs (number of FAs per cell, 35.82 ± 7.68) compared with gelatin-stimulated cells (number of FAs per cell, 19.80 ± 7.18) and exhibited extensive formation of actin stress fibers anchored by FAs formed at the cell periphery. CONCLUSION: Homeopathic R. tox promotes the formation of cell adhesions in vitro.

SPIN90, an adaptor protein, alters the proximity between Rab5 and Gapex5 and facilitates Rab5 activation during EGF endocytosis.

During ligand-mediated receptor endocytosis, the small GTPase Rab5 functions in vesicle fusion and trafficking. Rab5 activation is known to require interactions with its guanine nucleotide-exchange factors (GEFs); however, the mechanism regulating Rab5 interactions with GEFs remains unclear. Here, we show that the SH3-adapter protein SPIN90 participates in the activation of Rab5 through the recruitment of both Rab5 and its GEF, Gapex5, to endosomal membranes during epidermal growth factor (EGF)-mediated endocytosis. SPIN90 strongly interacts with the inactive Rab5/GDI2 complex through its C-terminus. In response to EGF signaling, extracellular signal-regulated kinase (ERK)-mediated phosphorylation of SPIN90 at Thr-242 enables SPIN90 to bind Gapex5 through its N-terminal SH3 domain. Gapex5 is a determinant of Rab5 membrane targeting, while SPIN90 mediates the interaction between Gapex5 and Rab5 in a phosphorylation-dependent manner. Collectively, our findings suggest that SPIN90, as an adaptor protein, simultaneously binds inactive Rab5 and Gapex5, thereby altering their spatial proximity and facilitating Rab5 activation.

Long-term clinical outcomes after a percutaneous coronary intervention with a drug-eluting stent in patients with unprotected left main coronary artery disease excluded from clinical trials.

BACKGROUND: Major randomized clinical trials assessing clinical outcomes in patients who underwent a percutaneous coronary intervention (PCI) for left main coronary artery disease excluded some high-risk subsets. Whether the effectiveness and safety of a percutaneous approach in this group of patients are comparable with those observed in clinical trials is unclear. We aimed to explore the long-term outcomes of contemporary drug-eluting stent (DES)-based revascularization for left main coronary artery disease in patients presenting with one or more clinical or angiographic characteristics who would have precluded inclusion in randomized trials. PATIENTS AND METHODS: Between April 2003 and December 2011, 340 consecutive patients with unprotected left main coronary artery stenosis of at least 50% who underwent successful PCI with DES at Sejong General Hospital (Bucheon, Republic of Korea) were included in this retrospective study. Patients were classified into the exclusion group (group E; n=120) and the inclusion group (group I; n=220) according to the prespecified inclusion and exclusion criteria utilized in clinical trials. RESULTS: During the median follow-up of 86 (52-114) months, major adverse cardiac or cerebrovascular events occurred in 69 (31.4%) patients in group I and 46 (38.3%) patients in group E (P=0.155). In the propensity score-matched population, group E was not associated with a higher incidence of major adverse cardiac or cerebrovascular events (hazard ratio: 1.42, 95% confidence interval: 0.76-2.65, P=0.758). Definite or probable stent thrombosis occurred in five patients of group I, with no cases in group E. CONCLUSION: In our real-world registry, about a third of patients who underwent PCI for unprotected left main coronary artery stenosis had one or more high-risk characteristics or comorbid conditions that represent exclusion criteria of previous randomized trials. PCI using DES is feasible in these patients.

Acute ST Elevated Myocardial Injury due to Coronary Thrombosis during Thoracic Endovascular Aortic Repair in Patient with Protein S Deficiency.

A 71-year-old woman who had suffered from pulmonary thromboembolism with deep vein thrombosis for 12 years presented the hospital with a huge thoracic aortic aneurysm. During thoracic endovascular therapy, she had a sudden coronary artery occlusion without having organized stenosis or plaque rupture even under the dual antiplatelet treatment and heparinization. She turned out to be having a protein S deficiency. A procedure related thrombotic adverse event in patient with protein S deficiency is very rare, so we report a case with literature review.

Right coronary artery to left ventricular fistula associated with infective endocarditis of the mitral valve.

A 27-year-old man with bacterial endocarditis of the mitral valve and embolic episodes was bound to have a large right coronary artery fistula communicating with the left ventricle, immediately inferior to the posterior mitral annulus. The perforation of the posterior leaflet and coronary arteriovenous fistula was identified using two-dimensional Doppler echocardiography. The diagnosis was confirmed by coronary angiography, and the patient underwent a successful operation.