Nanoparticle-mediated endothelial cell-selective delivery of pitavastatin induces functional collateral arteries (therapeutic arteriogenesis) in a rabbit model of chronic hind limb ischemia

ObjectivesWe recently demonstrated in a murine model that nanoparticle-mediated delivery of pitavastatin into vascular endothelial cells effectively increased therapeutic neovascularization. For the development of a clinically applicable approach, further investigations are necessary to assess whether this novel system can induce the development of collateral arteries (arteriogenesis) in a chronic ischemia setting in larger animals.MethodsChronic hind limb ischemia was induced in rabbits. They were administered single injections of nanoparticles loaded with pitavastatin (0.05, 0.15, and 0.5 mg/kg) into ischemic muscle.ResultsTreatment with pitavastatin nanoparticles (0.5 mg/kg), but not other nanoparticles, induced angiographically visible arteriogenesis. The effects of intramuscular injections of phosphate-buffered saline, fluorescein isothiocyanate (FITC)-loaded nanoparticles, pitavastatin (0.5 mg/kg), or pitavastatin (0.5 mg/kg) nanoparticles were examined. FITC nanoparticles were detected mainly in endothelial cells of the ischemic muscles for up to 4 weeks. Treatment with pitavastatin nanoparticles, but not other treatments, induced therapeutic arteriogenesis and ameliorated exercise-induced ischemia, suggesting the development of functional collateral arteries. Pretreatment with nanoparticles loaded with vatalanib, a vascular endothelial growth factor receptor (VEGF) tyrosine kinase inhibitor, abrogated the therapeutic effects of pitavastatin nanoparticles. Separate experiments with mice deficient for VEGF receptor tyrosine kinase demonstrated a crucial role of VEGF receptor signals in the therapeutic angiogenic effects.ConclusionsThe nanotechnology platform assessed in this study (nanoparticle-mediated endothelial cell-selective delivery of pitavastatin) may be developed as a clinically feasible and promising strategy for therapeutic arteriogenesis in patients.Clinical RelevanceRestoration of tissue perfusion in patients with critical limb ischemia is a major therapeutic goal. Recent clinical trials designed to induce neovascularization by administering exogenous angiogenic growth factors or cells failed to demonstrate a decisive clinical benefit. A controlled drug delivery system for a new approach to therapeutic neovascularization therefore would be more favorable. In the present study, we applied nanoparticle-mediated delivery system and report that endothelial cell-selective delivery of pitavastatin increased the development of collateral arteries and improved exercise-induced ischemia in a rabbit model of chronic hind limb ischemia. This nanotechnology platform is a promising strategy for the treatment of patients with severe organ ischemia and represents a significant advance in therapeutic arteriogenesis over current approaches

Anti-inflammatory Nanomedicine for Cardiovascular Disease

Coronary artery disease, in the development of which inflammation mediated by innate immune cells plays a critical role, is one of the leading causes of death worldwide. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are a widely used lipid-lowering drug that has lipid-independent vasculoprotective effects, such as improvement of endothelial dysfunction, antioxidant properties, and inhibitory effects on inflammation. Despite recent advances in lipid-lowering therapy, clinical trials of statins suggest that anti-inflammatory therapy beyond lipid-lowering therapy is indispensible to further reduce cardiovascular events. One possible therapeutic option to the residual risk is to directly intervene in the inflammatory process by utilizing a nanotechnology-based drug delivery system (nano-DDS). Various nano-sized materials are currently developed as DDS, including micelles, liposomes, polymeric nanoparticles, dendrimers, carbon nanotubes, and metallic nanoparticles. The application of nano-DDS to coronary artery disease is a feasible strategy since the inflammatory milieu enhances incorporation of nano-sized materials into mononuclear phagocytic system and permeability of target lesions, which confers nano-DDS on “passive-targeting” property. Recently, we have developed a polymeric nanoparticle-incorporating statin to maximize its anti-inflammatory property. This statin nanoparticle has been tested in various disease models, including plaque destabilization and rupture, myocardial ischemia-reperfusion injury, and ventricular remodeling after acute myocardial infarction, and its clinical application is in progress. In this review, we present current development of DDS and future perspective on the application of anti-inflammatory nanomedicine to treat life-threatening cardiovascular diseases

SET based experiments for HTSC materials: II

The cuprates seem to exhibit statistics, dimensionality and phase transitions in novel ways. The nature of excitations [i.e. quasiparticle or collective], spin-charge separation, stripes [static and dynamics], inhomogeneities, psuedogap, effect of impurity dopings [e.g. Zn, Ni] and any other phenomenon in these materials must be consistently understood. In this note we further discuss our original suggestion of using Single Electron Tunneling Transistor [SET] based experiments to understand the role of charge dynamics in these systems. Assuming that SET operates as an efficient charge detection system we can expect to understand the underlying physics of charge transport and charge fluctuations in these materials for a range of doping. Experiments such as these can be classed in a general sense as mesoscopic and nano characterization of cuprates and related materials. In principle such experiments can show if electron is fractionalized in cuprates as indicated by ARPES data. In contrast to flux trapping experiments SET based experiments are more direct in providing evidence about spin-charge separation. In addition a detailed picture of nano charge dynamics in cuprates may be obtained.Comment: 10 pages revtex plus four figures; ICMAT 2001 Conference Symposium P: P10-0

A paradigm shift for bone quality in dentistry: A literature review

Purpose: The aim of this study was to present the current concept of bone quality based on the proposal by the National Institutes of Health (NIH) and some of the cellular and molecular factors that affect bone quality. Study selection: This is a literature review which focuses on collagen, biological apatite (BAp), and bone cells such as osteoblasts and osteocytes. Results: In dentistry, the term “bone quality” has long been considered to be synonymous with bone mineral density (BMD) based on radiographic and sensible evaluations. In 2000, the NIH proposed the concept of bone quality as “the sum of all characteristics of bone that influence the bone’s resistance to fracture,” which is completely independent of BMD. The NIH defines bone quality as comprising bone architecture, bone turnover, bone mineralization, and micro-damage accumulation. Moreover, our investigations have demonstrated that BAp, collagen, and bone cells such as osteoblasts and osteocytes play essential roles in controlling the current concept of bone quality in bone around hip and dental implants. Conclusion: The current concept of bone quality is crucial for understanding bone mechanical functions. BAp, collagen and osteocytes are the main factors affecting bone quality. Moreover, mechanical loading dynamically adapts bone quality. Understanding the current concept of bone quality is required in dentistry

Perioperative changes in respiratory impedance in lobectomy and their clinical impact.

Background:Respiratory function declines after lung resection. However, perioperative changes in respiratory impedance and their clinical significance are unclear. The forced oscillation technique can measure respiratory impedance during quiet breathing and possibly early after surgery. We investigated respiratory impedance changes before and after lung lobectomy and examined the correlation of impedance with clinical factors.Methods:We prospectively included patients who underwent lobectomy between February 2018 and March 2020 and measured respiratory impedance by forced oscillation preoperatively and postoperative days 1 and 7. We statistically analyzed changes in perioperative forced oscillation measurements and their correlation with clinical factors, including subjective symptoms. The modified British Medical Research Council scale and the chronic obstructive pulmonary disease (COPD) assessment test were used for scoring subjective symptoms.Results:Forty-four subjects were included, in whom respiratory impedance could be measured from postoperative day 1. The respective mean values for forced oscillation measurements preoperatively and at postoperative days 1 and 7 were as follows: respiratory resistance, 5 Hz: 2.28, 2.77, and 2.75; respiratory resistance, 20 Hz: 2.00, 2.36, and 2.32; difference in respiratory resistance at 5 and 20 Hz: 0.28, 0.40, and 0.43; respiratory reactance, 5 Hz: -0.31, -0.65, and -0.56; resonant frequency: 7.45, 10.41, and 9.81; and low-frequency reactance area: 1.33, 3.27, and 2.84. These changes were statistically significant (P<0.01). Besides the difference in respiratory resistance at 5 and 20 Hz, all other measurements on postoperative day 7 were relatively weakly correlated with the modified Medical Research Council scale score at this time point (all P<0.05). Respiratory complications correlated with the respiratory resistance difference, respiratory reactance, and resonant frequency on day 7 (R =0.415, -0.421, and 0.441), while the latter also correlated with postoperative hypoxemia on day 1 (R =0.433).Conclusions:Respiratory impedance was measurable even early after surgery and significantly changed postoperatively. As the sample size was small and appeared to be biased, assessing respiratory impedance and clinical factors in detail was difficult. Since respiratory impedance is suggested to be associated with clinical factors that affect the postoperative course, it is necessary to accumulate cases and observe them over longer periods