Liang Li

Background: CPT is a pentacyclic monoterpene alkaloid with a wide spectrum of antitumor activity. Its clinical application is restricted due to poor water solubility, instability, and high toxicity. We developed a new kind of multifunctional micelles to improve its solubility, reduce the side effecs, and obtain enhanced antitumor effects. Methods: We constructed HA-CPT nano-self-assembly prodrug micelles, which combined the advantages of pH-sensitivity, redox-sensitivity, and active targeting ability to CD44 receptor-overexpressing cancer cells. To synthesize dual sensitive HA-CPT conjugates, CPT was conjugated with HA by pH-sensitive histidine (His) and redox-sensitive 3,3′-dithiodipropionic acid (DTPA). In vitro, we studied the cellular uptake and antitumor effect for tumor cell lines. In vivo, we explored the bio-distribution and antitumor effects of the micelles in HCT 116 tumor bearing nude mice. Results: The dual-sensitive and active targeting HA-His-ss-CPT micelles was proved to be highly efficient in CPT delivery by the in vitro cellular uptake study. The HA-His-ss-CPT micelles escaped from endosomes of tumor cells within 4 h after cellular uptake due to the proton sponge effect of the conjugating His and then quickly released CPT in the cytosol by glutathione (GSH). In mice, HA-His-ss-CPT micelles displayed efficient tumor accumulation and conspicuous inhibition of tumor growth. Conclusions: The novel, dual-sensitive, active targeting nano-prodrug micelles exhibited high efficiency in drug delivery and cancer therapy. This “all in one” drug delivery system can be realized in an ingenious structure and avoid intricate synthesis. This construction strategy can illume the design of nanocarriers responding to endogenous stimuli in tumors.

Nonalcoholic steatohepatitis (NASH) is a subtype of nonalcoholic fatty liver disease (NAFLD) characterized by hepatic steatosis and evidence of hepatocyte injury (ballooning) and inflammation, with or without liver fibrosis. In this study, after 12 weeks of induction, the mice were treated with emodin succinyl ethyl ester (ESEE) for four weeks at doses of 10/30/90 mg/kg/day. The blood analysis of experimental endpoints showed that ESEE exhibited significant therapeutic effects on the progression of disorders of glycolipid metabolism and the induced liver injury in the model animals. Histopathological diagnosis of the liver and total triglyceride measurements revealed that ESEE had a significant therapeutic effect on the histopathological features of nonalcoholic fatty liver disease/hepatitis, such as cellular steatosis and activation of intrahepatic inflammation. Additionally, ESEE was able to improve hepatocyte fat deposition, steatosis, and the course of intrahepatic inflammatory activity. Furthermore, it showed some inhibitory effect on liver fibrosis in the model animals. In summary, this study confirms the therapeutic effects of ESEE on the NAFLD/NASH model in C57BL/6J mice induced by a high-fat, high cholesterol, and fructose diet. These effects were observed through improvements in liver function, inhibition of fibrosis, and inflammatory responses. Changes in blood glucose levels, blood lipid metabolism, liver histopathological staining, liver fibrosis staining, and related pathological scores further supported the therapeutic effects of ESEE. Therefore, this study has important implications for the exploration of novel drugs for nonalcoholic fatty liver disease.

Osteoclasts, bone-specified multinucleated cells produced by monocyte/macrophage, are involved in numerous bone destructive diseases such as arthritis, osteoporosis, and inflammation-induced bone loss. The osteoclast differentiation mechanism suggests a possible strategy to treat bone diseases. In this regard, we recently examined the in vivo impact of kalkitoxin (KT), a marine product obtained from the marine cyanobacterium Moorena producens (previously Lyngbya majuscula), on the macrophage colony-stimulating factor (M-CSF) and on the receptor activator of nuclear factor κB ligand (RANKL)-stimulated in vitro osteoclastogenesis and inflammation-mediated bone loss. We have now examined the molecular mechanism of KT in greater detail. KT decreased RANKL-induced bone marrow-derived macrophages (BMMs) tartrate-resistant acid phosphatase (TRAP)-multinucleated cells at a late stage. Likewise, KT suppressed RANKL-induced pit area and actin ring formation in BMM cells. Additionally, KT inhibited several RANKL-induced genes such as cathepsin K, matrix metalloproteinase (MMP-9), TRAP, and dendritic cell-specific transmembrane protein (DC-STAMP). In line with these results, RANKL stimulated both genes and protein expression of c-Fos and nuclear factor of activated T cells (NFATc1), and this was also suppressed by KT. Moreover, KT markedly decreased RANKL-induced p-ERK1/2 and p-JNK pathways at different time points. As a result, KT prevented inflammatory bone loss in mice, such as bone mineral density (BMD) and osteoclast differentiation markers. These experiments demonstrated that KT markedly inhibited osteoclast formation and inflammatory bone loss through NFATc1 and mitogen-activated protein kinase (MAPK) signaling pathways. Therefore, KT may have potential as a treatment for destructive bone diseases.

Background: Periodontitis is a common chronic inflammatory disease caused by bacteria which can result in periodontal tissue inflammation, as well as alveolar bone resorption. The purpose of this study was to evaluate the effects of omega‐3 fatty acids plus aspirin (ASA) on ligature‐induced periodontitis in rats.Methods: Ninety‐six male Sprague‐Dawley (SD) rats (age 6 weeks) were randomly divided into eight groups (n = 12 each) and had ligatures placed for 7 days, followed by daily treatment with specific drug regimens for 14 days. The rats were sacrificed 20 days after drug treatment, and their maxillary were subjected to histomorphometric analysis. RAW264.7 cells were cultured with lipopolysaccharide (LPS) or receptor activator (NF)‐κB ligand (RANKL), and treated with various concentrations of omega‐3 and ASA. Then, cyclooxygenase (COX‐2), inducible nitric oxide synthase (iNOS) protein expression and receptor activator of nuclear factor κ B (RANK), tartrate‐resistant acid phosphatase (TRAP), matrix metalloproteinase‐9 (MMP‐9), MMP‐2, and Cathepsin‐K gene expression were detected.Results: The administration of omega‐3 fatty acids and aspirin significantly inhibited tumor necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β) in serum of rats. Histomorphometric analysis showed omega‐3 fatty acids plus aspirin promoted alveolar bone increase. Omega‐3 fatty acids only, aspirin only, or omega‐3 fatty acids plus aspirin also inhibited the protein expressions of COX‐2 and iNOS in LPS‐stimulated RAW264.7 cells. In addition, omega‐3 combined with ASA also inhibited the RANKL‐induced gene expressions of MMPs in dose‐dependent manners.Conclusion: These results demonstrate that omega‐3 fatty acids plus aspirin could decrease alveolar bone loss, while simultaneously increasing the protection against periodontal inflammation.

The purpose of the present study was to explore the protective effect and functional mechanism of ginkgolide K (GK: C20H22O9) on cerebral ischemia. SH‑SY5Y cells were exposed to oxygen‑glucose deprivation (OGD) to simulate an ischemic model in vitro. Cell viability, reactive oxygen species (ROS), nuclear staining with Hoechst 33258 and mitochondrial membrane potential were detected following 4 h of exposure to OGD. Subsequently, the expression levels of the apoptosis‑related proteins, caspase‑9, caspase‑3, Bcl‑2, Bax, p53 and c‑Jun, as well as the mitogen‑activated protein kinases (MAPKs) signaling molecules were detected by western blot analysis. GK significantly elevated the cell viability and decreased the generation of ROS and the number of apoptotic cells in a dose‑dependent manner. Furthermore, GK markedly decreased the protein expression levels of p‑p38, p‑JNK, p‑p53, p‑c‑Jun and the expression levels of Bcl‑2, Bax, cleaved caspase‑9 and caspase‑3. In conclusion, GK demonstrated a neuroprotective effect on the simulated cerebral ischemia in vitro, and this effect was mediated through the inhibition of the mitochondria‑mediated apoptosis pathway triggered by ROS‑evoked p38 and JNK activation.