Oxidative stress and inflammatory signaling in cerulein pancreatitis

Oxidative stress is considered to be an important regulator of the pathogenesis of acute pancreatitis. Reactive oxygen species (ROS) regulate the activation of inflammatory cascades, the recruitment of inflammatory cells and tissue damage in acute pancreatitis. A hallmark of the inflammatory response in pancreatitis is the induction of cytokine expression, which is regulated by a number of signaling molecules including oxidant-sensitive transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinases (MAPKs). Cross-talk between ROS and pro-inflammatory cytokines is mediated by NF-κB, AP-1, STAT3, and MAPKs; this crosstalk amplifies the inflammatory cascade in acute pancreatitis. Therapeutic studies have shown that antioxidants and natural compounds can have beneficial effects for patients with pancreatitis and can also influence the expression of proinflammatory cytokines in cerulein-induced pancreatitis. Since oxidative stress may activate inflammatory signaling pathways and contribute to the development of pancreatitis, antioxidant therapy may alleviate the symptoms or prevent the development of pancreatitis. Since chronic administration of high doses of antioxidants may have deleterious effects, dosage levels and duration of antioxidant treatment should be carefully determined.

The KDM4B–CCAR1–MED1 axis is a critical regulator of osteoclast differentiation and bone homeostasis

Bone undergoes a constant and continuous remodeling process that is tightly regulated by the coordinated and sequential actions of bone-resorbing osteoclasts and bone-forming osteoblasts.Recent studies have shown that histone demethylases are implicated in osteoblastogenesis;however,little is known about the role of histone demethylases in osteoclast formation.Here,we identified KDM4B as an epigenetic regulator of osteoclast differentiation.Knockdown of KDM4B significantly blocked the formation of tartrate-resistant acid phosphatase-positive multinucleated cells.Mice with myeloid-specific conditional knockout of KDM4B showed an osteopetrotic phenotype due to osteoclast deficiency.Biochemical analysis revealed that KDM4B physically and functionally associates with CCAR1 and MED1 in a complex.Using genome-wide chromatin immunoprecipitation(ChIP)-sequencing,we revealed that the KDM4B–CCAR1–MED1 complex is localized to the promoters of several osteoclast-related genes upon receptor activator of NF-κB ligand stimulation.We demonstrated that the KDM4B–CCAR1–MED1 signaling axis induces changes in chromatin structure(euchromatinization)near the promoters of osteoclast-related genes through H3K9 demethylation,leading to NF-κB p65 recruitment via a direct interaction between KDM4B and p65.Finally,small molecule inhibition of KDM4B activity impeded bone loss in an ovariectomized mouse model.Taken together,our findings establish KDM4B as a critical regulator of osteoclastogenesis,providing a potential therapeutic target for osteoporosis.

Crushed Gold Shell Nanoparticles Labeled with Radioactive Iodine as a Theranostic Nanoplatform for Macrophage-Mediated Photothermal Therapy

Plasmonic nanostructure-mediated photothermal therapy(PTT) has proven to be a promising approach for cancer treatment,and new approaches for its effective delivery to tumor lesions are currently being developed.This study aimed to assess macrophage-mediated delivery of PTT using radioiodine-124-labeled gold nanoparticles with crushed gold shells(124I-Au@AuCBs) as a theranostic nanoplatform.124I-Au@AuCBs exhibited effective photothermal conversion effects both in vitro and in vivo and were efficiently taken up by macrophages without cytotoxicity.After the administration of 124I-Au@AuCB-labeled macrophages to colon tumors,intensive signals were observed at tumor lesions,and subsequent in vivo PTT with laser irradiation yielded potent antitumor effects.The results indicate the considerable potential of 124I-Au@AuCBs as novel theranostic nanomaterials and the prominent advantages of macrophage-mediated cellular therapies in treating cancer and other diseases.