Role of macrophages and their exosomes in orthopedic diseases.

Exosomes are vesicles with a lipid bilayer structure that carry various active substances, such as proteins, DNA, non-coding RNA, and nucleic acids; these participate in the immune response, tissue formation, and cell communication. Owing to their low immunogenicity, exosomes play a key role in regulating the skeletal immune environment. Macrophages are important immune cells that swallow various cellular and tissue fragments. M1-like and M2-like macrophages differentiate to play pro-inflammatory, anti-inflammatory, and repair roles following stimulation. In recent years, the increase in the population base and the aging of the population have led to a gradual rise in orthopedic diseases, placing a heavy burden on the social medical system and making it urgent to find effective solutions. Macrophages and their exosomes have been demonstrated to be closely associated with the pathogenesis and prognosis of orthopedic diseases. An in-depth understanding of their mechanisms of action and the interaction between them will be helpful for the future clinical treatment of orthopedic diseases. This review focuses on the mechanisms of action, diagnosis, and treatment of orthopedic diseases involving macrophages and their exosomes, including fracture healing, diabetic bone damage, osteosarcoma, and rheumatoid arthritis. In addition, we discuss the prospects and major challenges faced by macrophages and their exosomes in clinical practice.

Engineering EHD1-Targeted Natural Borneol Nanoemulsion Potentiates Therapeutic Efficacy of Gefitinib against Nonsmall Lung Cancer.

Despite the effective targeting of the epidermal growth factor receptor (EGFR), the use of gefitinib (GFT) for nonsmall cell lung cancer (NSCLC) treatment meets a failure because of the insufficient drug accumulation in the tumor region. Therefore, developing chemosensitizers of GFT with synergistic therapeutic effects is urgently needed for advanced cancer therapy. Herein, a natural chemosensitizer, natural borneol (NB), is reformulated as an oil-in-water nanoemulsion to enhance its solubility, distribution, and to ultimately increase the therapeutic index with GFT. The nanolization of NB (NBNPs) displays stronger targeted delivery and cytotoxicity than NB by selectively identifying eight specific protein targets in A549 NSCLC cells as revealed by the proteomic studies. Consistently, NBNPs realize stronger chemosensitization effects than NB with GFT by effectively regulating EGFR/EHD1-mediated apoptosis in A549 NSCLC cells. Owing to the satisfying synergistic effect between NBNPs and GFT, the combined therapy not only enhances the anticancer ability of GFT against NSCLC proliferation but also avoids heavy double toxicity in vivo. This finding demonstrates the effective synergism between NBNPs and GFT with clear mechanistic investigation and is expected to extend the application of NBNPs as a novel chemosensitizer for advanced cancer chemotherapy.

A uPAR targeted nanoplatform with an NIR laser-responsive drug release property for tri-modal imaging and synergistic photothermal-chemotherapy of triple-negative breast cancer.

In the present work, an iridium (Ir) complex loaded theranostic nanoplatform was designed for high-efficiency triple-negative breast cancer (TNBC) therapy. For this purpose, the Ir complex was firstly loaded on a photothermal agent of gold nanostars (GNS) by simply mixing followed by functionalization using a urokinase-type plasminogen activator receptor (uPAR) targeted polyetherimide-AE105 peptide conjugate (P-AE105) with the formation of GNS@Ir@P-AE105. It was demonstrated that the resultant GNS@Ir@P-AE105 was a multifunctional nanoplatform with advantages of (1) NIR laser controlled release of the Ir complex; (2) precise delivery of the Ir complex to TNBC cells; (3) excellent photothermal (PT)/photoacoustic (PA)/X-ray computed tomography (CT) tri-modal imaging ability; and (4) a synergistic photothermal-chemotherapeutic effect. An in-depth investigation of the mechanism revealed that binding forces of the Ir complex-GNS and P-AE105-GNS were significantly diminished upon NIR laser irradiation, which conferred an NIR laser-responsive Ir complex release property to the nanoplatform. Moreover, the nanoplatform exerted high efficiency anti-TNBC effects via a ROS-induced p53 apoptotic pathway. Specifically, combinational photothermal-chemotherapeutic treatments stimulated intracellular ROS generation, which significantly up-regulated apoptotic-relative p53 gene expression either by causing severe DNA damage or inducing an arrest effect on the sub-G1 phase of the cell cycle. Taken together, our work provides a novel theranostic nanoplatform for efficient and simultaneous diagnosis and therapy of TNBC.

[Change of early serum TNF-alpha and IL-6 levels in acute cerebral infarction and its significances].

OBJECTIVE: To investigate the change of early serum TNF-alpha and IL-6 levels in acute cerebral infarction and its significances. METHODS: Serum TNF-alpha and IL-6 levels in 30 health subjects and 35 patients with acute cerebral infarction (ACI) within 6 hours of onset were measured by enzyme linked immunosorbent assay (ELISA); neurological deficits scores (NDS) in all cases were determined, and Spearman test was used for correlation. RESULTS: The serum levels of TNF-alpha and IL-6 in ACI group were markedly higher than those in health subjects and there was a positive correlation of TNF-alpha and IL-6 levels with 6 h NDS (rs=0.89 and 0.93, P<0.001) and with NDS progression (rs=0.90 and 0.91, P<0.001). Early serum TNF-alpha and IL-6 levels in progressive cerebral infarction (PCI) group were evidently higher than those in stable cerebral infarction (SCI)[(49.56+/-12.12) pg/L compared with (24.30+/-7.4) ng/L and (39.76+/-7.88) ng/L compared with (20.78+/-6.28) ng/L, respectively, P<0.01)]. CONCLUSION: The early serum levels of TNF-alpha and IL-6 in ACI markedly increase and are closely correlated with disease severity; which may be of value in PCI risk evaluation.