Tannic acid-poloxamer self-assembled nanoparticles for advanced atherosclerosis therapy by regulation of macrophage polarization.

Atherosclerosis (AS) is a significant contributor to cardiovascular events. Advanced AS is particularly concerning, as it leads to the formation of high-risk vulnerable plaques. Current treatments for AS focus on antithrombotic and lipid-lowering interventions, which are effective in treating early-stage AS. Recent studies have shown that macrophage polarization plays a crucial role in the development of AS. This study presents a new biomedical application of natural tannic acid as an anti-inflammatory nanoplatform for advanced AS. Tannic acid-poloxamer nanoparticles (TPNP) are fabricated through self-assembly of tannic acid (TA) and poloxamer. TPNP has the potential to provide effective treatment for advanced AS. According to in vitro studies, TPNP has been found to suppress the inflammatory response in lipopolysaccharide-stimulated macrophages by scavenging reactive oxygen species (ROS), downregulating the expression levels of inflammatory cytokines (such as interleukin-10 and tumor necrosis factor-α) and regulating polarization of macrophages. In vivo studies further reveal that TPNP can retard the development of advanced atherosclerotic plaques by reducing ROS production and promoting M2 macrophage polarization in the aorta of ApoE-/- mice. Overall, these findings suggest that TPNP could be used to develop natural multifunctional nanoplatforms for molecular therapy of AS and other inflammation-related diseases.

Targeted therapy of atherosclerosis by zeolitic imidazolate framework-8 nanoparticles loaded with losartan potassium via simultaneous lipid-scavenging and anti-inflammation.

Atherosclerosis (AS) is a condition associated with dysfunctional lipid metabolism and an inflammatory immune microenvironment that remains the leading cause of severe cardiovascular events. Drugs exhibiting both anti-inflammatory and lipid-scavenging activity hold great promise for treating AS. In this study, zeolitic imidazolate framework-8 (ZIF-8) nanoparticles loaded with losartan potassium (LP) were developed as an anti-AS treatment to target both of these therapeutic arms simultaneously. LP@ZIF-8 accumulated within AS target tissues via the enhanced permeability and retention (EPR) effect, as confirmed via in vivo near-infrared fluorescence (NIRF) imaging and was disrupted in response to the low pH. ZIF-8 could activate autophagy, thus regulating lipid metabolism and restoring cholesterol homeostasis as previously reported, while the released LP served as an anti-inflammatory angiotensin receptor blocker (ARB) inhibitor, which was confirmed via the in vivo treatment studies. As such, our data highlight LP@ZIF-8 as a promising therapeutic agent capable of attenuating the severity of AS.

Prevalence and Associated Risk Factors of Pulmonary Embolism in Children and Young Adults With Nephrotic Syndrome: A Chinese Large Cohort Study.

PURPOSE: Nephrotic syndrome (NS) is highly associated with an increased risk of pulmonary embolism (PE) in children and young adults. However, few studies have specified the risk factors of PE in children and young adults with NS. We sought to determine the prevalence and associated factors of PE confirmed with computed tomography pulmonary angiography in Chinese children and young adults with NS. METHODS: Data from 444 children and young adults with NS who had computed tomography pulmonary angiography from December 2010 to October 2018 were retrospectively analyzed. The prevalence of PE was estimated for different age, sex, and histopathologic types of NS. Multivariable logistic regression was used to identify independent risk factors of PE in children and young adults with NS. Models incorporating the independent risk factors were evaluated using receiver operation characteristic curves. Area under the curve was used to determine the best-performing prognosticators for predicting PE. RESULTS: There were 444 patients in the study cohort (310 male patients, 134 female patients; mean age 19±3 y; range: 6 to 25 y). PE was present in 24.8% of the participants (110 of 444, 18.2% female). Children and young adult NS patients with PE tend to be older, male, to have a previous thromboembolism history and smoking, and have a higher level of proteinuria, D-dimer, and serum albumin (P<0.05 for all). Children and young adults with membranous nephropathy are likely to have a higher incidence of PE than those with other types of nephropathy. Membranous nephropathy and proteinuria were significant predictors of PE in children and young adults with NS (P<0.05 for all). The area under the curves of each model for the presence of PE in children and young adults with NS based on biochemical parameters and clinical information (model 1), adjusted for proteinuria (model 2), and adjusted for membranous nephropathy (model 3) were 0.578, 0.657, and 0.709, respectively. Compared with model 1, model 2, and model 3 showed statistically significant differences (model 1 vs. model 2, P=0.0336; model 1 vs. model 3, P=0.0268). There was no statistically significant difference between model 2 and model 3 (P=0.2947). CONCLUSION: This study identified membranous nephropathy and proteinuria as independent associated factors of PE in children and young adults with NS, which can be noted as a risk factor to guide clinician management in this population.

Pifithrin-µ incorporated in gold nanoparticle amplifies pro-apoptotic unfolded protein response cascades to potentiate synergistic glioblastoma therapy.

Conventional radiotherapy has a pivotal role in the treatment of glioblastoma; nevertheless, its clinical utility has been limited by radiation resistance. There is emerging evidence that upregulated heat shock protein A5 (HSPA5) in cancer cells maintains or restores the homeostasis of a cellular microenvironment and results in cancer resistance in various treatments. Therefore, we describe a bioresponsive nanoplatform that can deliver a HSPA5 inhibitor (pifithrin-µ, PES) and radiosensitizer (gold nanosphere, AuNS), to expand the synergistic photothermal therapy and radiotherapy, as well as to monitor the progression of cancer therapy using computer tomography/magnetic resonance imaging. The nanoplatform (PES-Au@PDA, 63.3 ± 3.1 nm) comprises AuNS coated with the photothermal conversion agent polydopamine (PDA) for enhanced radiotherapy and photothermal therapy, as well as PES (loading efficiency of PES approximately 40%), a small molecular inhibitor against HSPA5 to amplify the pro-apoptotic unfolded protein response (UPR). The reported nanoplatform enables hyperthermia-responsive release of PES. Results from in vitro and in vivo studies demonstrate that PES-Au@PDA can specially activate pro-apoptotic UPR cascades, leading to remarkably improved radiotherapy and photothermal therapy efficiencies. Considered together, a versatile theranostic nanosystem is reported for promoting the synergistic radiophotothermal therapy by selectively activating pro-apoptotic UPR cascade pathways.

Role of GRP78 inhibiting artesunate-induced ferroptosis in KRAS mutant pancreatic cancer cells.

Objective: To investigate the exact role of GRP78 in artesunate-induced ferroptosis in KRAS mutant pancreatic cancer cells. Methods: Artesunate-induced KRAS mutant human pancreatic cancer cells (AsPC-1 and PaTU8988) ferroptosis was confirmed by fluorescent staining experiments and CCK8. Western blot and short-hairpin RNA-based knockdown assays were conducted to detect GRP78 activity and its role in artesunate-induced ferroptosis. Results: Artesunate induced AsPC-1 and PaTU8988 cell death in ferroptosis manner, rather than necrosis or apoptosis. In addition, artesunate increased the mRNA and protein levels of GRP78 in a concentration-dependent manner in AsPC-1 and PaTU8988 cells. Knockdown GRP78 enhanced artesunate-induced ferroptosis of pancreatic cancer cells in vitro and in vivo. Conclusion: Combining artesunate with GRP78 inhibition may be a novel maneuver for effective killing of KRAS mutant pancreatic ductal adenocarcinoma cells.