Anti-Acidification and Immune Regulation by Nano-Ceria-Loaded Mg-Al Layered Double Hydroxide for Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disease featuring an abnormal immune microenvironment and resultant accumulation of hydrogen ions (H+ ) produced by activated osteoclasts (OCs). Currently, clinic RA therapy can hardly achieve sustained or efficient therapeutic outcomes due to the failures in generating sufficient immune modulation and manipulating the accumulation of H+ that deteriorates bone damage. Herein, a highly effective immune modulatory nanocatalytic platform, nanoceria-loaded magnesium aluminum layered double hydroxide (LDH-CeO2 ), is proposed for enhanced immune modulation based on acid neutralization and metal ion inherent bioactivity. Specifically, the mild alkaline LDH initiates significant M2 repolarization of macrophages triggered by the elevated antioxidation effect of CeO2 via neutralizing excessive H+ in RA microenvironment, thus resulting in the efficient recruitment of regulatory T cell (Treg) and suppressions on T helper 17 cell (Th 17) and plasma cells. Moreover, the osteogenic activity is stimulated by the Mg ion released from LDH, thereby promoting the damaged bone healing. The encouraging therapeutic outcomes in adjuvant-induced RA model mice demonstrate the high feasibility of such a therapeutic concept, which provides a novel and efficient RA therapeutic modality by the immune modulatory and bone-repairing effects of inorganic nanocatalytic material.

Nebulized Therapy of Early Orthotopic Lung Cancer by Iron-Based Nanoparticles: Macrophage-Regulated Ferroptosis of Cancer Stem Cells.

Cancer stem cells (CSCs) within protumorigenic microlesions are a critical driver in the initiation and progression of early stage lung cancer, where immune cells provide an immunosuppressive niche to strengthen the CSC stemness. As the mutual interactions between CSCs and immune cells are increasingly recognized, regulating the immune cells to identify and effectively eliminate CSCs has recently become one of the most attractive therapeutic options, especially for abundant tumor-associated macrophages (TAMs). Herein, we developed a nebulized nanocatalytic medicine strategy in which iron-based nanoparticle-regulated TAMs effectively target CSC niches and trigger CSC ferroptosis in the early stage of lung cancer. Briefly, the iron-based nanoparticles can effectively accumulate in lung cancer microlesions (minimum 122 µm in diameter) through dextran-mediated TAM targeting by nebulization administration, and as a result, nanoparticle-internalized TAMs can play a predominant role of the iron factory in elevating the iron level surrounding CSC niches and destroying redox equilibrium through downregulating glucose-6-phosphate metabolite following their lysosomal degradation and iron metabolism. The altered microenvironment results in the enhanced sensitivity of CSCs to ferroptosis due to their high expression of the CD44 receptor mediating iron endocytosis. In an orthotopic mouse model of lung cancer, the initiation and progression of early lung cancer are significantly suppressed through ferroptosis-induced stemness reduction of CSCs by nebulization administration. This work presents a nebulized therapeutic strategy for early lung cancer through modulation of communications between TAMs and CSCs, which is expected to be a general approach for regulating primary microlesions and micrometastatic niches of lung cancer.

Dual Tumor Exosome Biomarker Co-recognitions Based Nanoliquid Biopsy for the Accurate Early Diagnosis of Pancreatic Cancer.

Pancreatic cancer, with extremely limited treatment options and poor prognosis, urgently needs a breakthrough in early diagnosis and monitoring. Tumor exosomes (T-Exos) detection is presently one of the most clinically significant liquid biopsy approaches for non-invasive pancreatic cancer early diagnosis, which, unfortunately, cannot be applied as a routine diagnostic tool until a number of obstacles, such as unsatisfactory specificity and sensitivity, as well as labor-intensive purification and analysis procedures by ultracentrifugation and enzyme-linked immunosorbent assay, are overcome. Here, we report a facile nanoliquid biopsy assay for the especially specific, ultrasensitive yet economical T-Exos detection by a dual specific biomarker antigen co-recognition and capturing strategy, which is enabled by grafting two corresponding capture antibodies on magnetic nanoparticles and gold nanoparticles, for the accurate detection of target tumor exosomes. This approach exhibits excellent specificity and ultrahigh sensitivity of detecting as low as 78 pg/mL pancreatic cancer exosome specific protein GPC1. Successful screening of 21 pancreatic cancer samples from 22 normal control cases with the enhanced specificity and sensitivity ensures the promising non-invasive monitoring and diagnosis for early stage pancreatic cancer.

Acute glucose fluctuation promotes RAGE expression via reactive oxygen species­mediated NF­κB activation in rat podocytes.

Diabetic nephropathy (DN) is a common chronic complication of diabetes, for which acute glucose fluctuation (AGF) is a potential risk factor. Fluctuating hyperglycemia has been confirmed to induce more serious kidney damage than hyperglycemia in diabetic rats; however, the mechanism remains unknown. The purpose of this study was to explore the potential role of AGF in the progression of DN. Viability of rat podocytes following 72­h AGF treatment was detected using Cell Counting­Kit­8. The rates of apoptosis and the level of reactive oxygen species (ROS) in rat podocytes were assessed by flow cytometry. Western blotting and reverse transcription­quantitative PCR were performed to measure relative protein and mRNA expression levels, respectively. Transfection with an mRFP­GFP­LC3 adenoviral vector was used to track autophagic flux under confocal microscopy. The results indicated that AGF could inhibit cell proliferation, promote TNF­α, interleukin­1ß (IL­1ß), and reactive oxygen species (ROS) generation, and increase autophagy in rat podocytes. Moreover, AGF upregulated receptor for advanced glycation end products (RAGE) expression via activation of NF­κB/p65 and IκBα. Pretreatment with 5 mM N­Acetyl­L­cysteine or 10 µM pyrrolidine dithiocarbamate effectively reduced cellular damage and inhibited activation of the NF­κB/RAGE signaling pathway. Thus, AGF induces rat podocyte injury by aggravating oxidative stress, promoting the inflammatory response, and regulating ROS­mediated NF­κB/RAGE activation.

Alisol B 23-Acetate Ameliorates Lipopolysaccharide-Induced Cardiac Dysfunction by Suppressing Toll-Like Receptor 4 (TLR4)/NADPH Oxidase 2 (NOX2) Signaling Pathway.

BACKGROUND Cardiac dysfunction during endotoxemia is a major cause of cardiovascular disease with high morbidity and mortality. Alisol B 23-acetate (AB23A) is a triterpenoid extracted from the Rhizoma Alismatis, a kind of traditional Chinese medicine, exhibits anti-inflammatory activity on endotoxemia. This investigation aimed to uncover the protective effects of AB23A against sepsis-induced cardiac dysfunction. MATERIAL AND METHODS Adult male C57BL/6 mice received lipopolysaccharide (LPS) (20 mg/kg intravenous) stimulation, with or without pre-treatment of AB23A (10 mg/kg, 20 mg/kg, or 40 mg/kg). Histopathological staining and cardiac function were performed 4 hours after LPS stimulation. Then the levels of interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-alpha were monitored with enzyme-linked immunosorbent assay (ELISA). In addition, H9C2 cells were treated with LPS (5 µg/mL) with or without pre-treated with AB23A (0.1 µM, 1 µM, or 10 µM), and the production of reactive oxygen species (ROS) was detected by DCFH-DA combined with flow cytometry. The expression of Toll-like receptor 4 (TLR4), NADPH oxidase 2 (NOX2), NOX4, P38, p-P38, extracellular-signal-regulated kinase (ERK), and p-ERK were assessed by western blotting. RESULTS AB23A improved the survival rate and ameliorated myocardial injury, decreased inflammatory infiltration and the level of IL-6, IL-1ß, and TNF-alpha in the LPS-stimulated mouse model. Moreover, AB23A inhibited the ROS production in LPS-treated H9C2 cells. In addition, AB23A suppressed the levels of TLR4 and NOX2 as well as the activation levels of P38 and ERK both in vivo and in vitro. CONCLUSIONS AB23A reduced LPS-induced myocardial dysfunction by inhibiting inflammation and ROS production through the TLR4/NOX2 pathway.