ABSTRACT
Osteoarthritis, as a common joint disease among middle-aged and elderly people, has many problems, such as diverse pathogenesis, poor prognosis and high recurrence rate, which seriously affects patients' physical and mental health and reduces their quality of life. At present, the pathogenesis of osteoarthritis is not completely clear, and the treatment plan is mainly to relieve symptoms and ensure basic quality of life. Therefore, it is particularly urgent to explore the pathogenesis of osteoarthritis. Protein, as organic macromolecule which plays a major role in life activities, plays an important role in the development of disease. Through protein omics, this study found that with the increase of age, excessive sulfur oxidation occurred in endoplasmic reticulum of chondrocytes, which then drove the occurrence of inflammatory reaction, and provided a direction for the follow-up molecular targeted.
ABSTRACT
Ursolic acid (UA), found widely in nature, exerts effective anti-tumoral activity against various malignant tumors. However, the low water solubility and poor bioavailability of UA have greatly hindered its translation to the clinic. To overcome these drawbacks, a simple redox-sensitive UA polymeric prodrug was synthesized by conjugating UA to polyethylene glycol using a disulfide bond. This formulation can self-assemble into micelles (U-SS-M) in aqueous solutions to produce small size micelles (â¼62.5 nm in diameter) with high drug loading efficiency (â¼16.7%) that exhibit pH and reduction dual-sensitivity. The cell and animal studies performed using the osteosarcoma MG-63 cell line and MG-63 cancer xenograft mice as the model systems consistently confirmed that the U-SS-M formulation could significantly prolong the circulation in blood and favor accumulation in tumor tissue. Targeted accumulation allows the U-SS-M to be effectively internalized by cancer cells, where the rapid release of UA is favored by a glutathione-rich and acidic intracellular environment, and ultimately achieves potent antitumor efficacy.
Subject(s)
Antineoplastic Agents, Phytogenic/chemistry , Osteosarcoma/drug therapy , Polyethylene Glycols/chemistry , Polymers/chemistry , Prodrugs , Triterpenes/chemistry , Animals , Antineoplastic Agents, Phytogenic/administration & dosage , Bone Neoplasms , Cell Line, Tumor , Drug Delivery Systems , Humans , Mice , Micelles , Oxidation-Reduction , Polymers/administration & dosage , Stimuli Responsive Polymers , Triterpenes/administration & dosage , Xenograft Model Antitumor Assays , Ursolic AcidABSTRACT
Shikonin has previously been shown to have antitumor, anti-inflammatory, antiviral and extensive pharmacological effects. The aim of the present study was to explore whether the protective effect of shikonin is mediated via the inhibition of inflammation and chondrocyte apoptosis, and to elucidate the potential molecular mechanisms in a rat model of osteoarthritis. A model of osteoarthritis was established in healthy male Sprague-Dawley rats and 10 mg/kg/day shikonin was administered intraperitoneally for 4 days. It was found that shikonin treatment significantly inhibited inflammatory reactions in the rats with osteoarthritis. Osteoarthritis was found to significantly increase interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS) levels compared with those in the sham group. However, shikonin treatment significantly inhibited the increases in IL-1ß, TNF-α and iNOS levels in the rats with osteoarthritis. Furthermore, caspase-3 activity and cyclooxygenase (COX)-2 protein expression were significantly increased and phosphorylated Akt protein expression was greatly suppressed in rats with osteoarthritis when compared with the sham group. Shikonin administration attenuated the changes in caspase-3 activity and COX-2 expression and Akt phosphorylation in rats with osteoarthritis. These results indicate that shikonin inhibits inflammation and chondrocyte apoptosis by regulating the phosphoinositide 3-kinase/Akt signaling pathway in a rat model of osteoarthritis.
