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Objective: Osteoarthritis (OA) is a degenerative joint disease. Excessive nitric oxide (NO) mediates the chondrocyte inflammatory response, apoptosis, and extracellular matrix (ECM) degradation during the occurrence and development of OA. NO in chondrocytes is mainly produced by inducible nitric oxide synthase (iNOS). The aim of this study was to design and synthesize an iNOS dimerization inhibitor and evaluate its effects on chondrocyte inflammation and articular cartilage injury in OA via in vitro and in vivo experiments.Design: The title compound 22o was designed, synthesized, and screened based on a previous study. The effects of different concentrations (5, 10, and 20 μM) of compound 22o on chondrocyte inflammatory response and ECM anabolism or catabolism were evaluated by Western blot and real-time quantitative reverse transcription-polymerase chain reaction using the rat chondrocyte model of IL-1β-induced OA. Furthermore, different doses (40 and 80 mg/kg) of compound 22o were administered by gavage to a rat OA model induced by anterior cruciate ligament transection (ACLT), and their protective effects on the articular cartilage were evaluated by histopathology and immunohistochemistry.Results: Compound 22o showed effective iNOS inhibitory activity by inhibiting the dimerization of iNOS. It inhibited the IL-1β-induced expression of cyclooxygenase-2 (COX-2) and matrix metalloproteinase 3 (MMP3) in the chondrocytes, decreased NO production, and significantly increased the expression levels of the ECM anabolic markers, aggrecan (ACAN), and collagen type II (COL2A1). Gavage with compound 22o was found to be effective in the rat OA model induced by ACLT, wherein it regulated the anabolism and catabolism and exerted a protective effect on the articular cartilage.Conclusions: Compound 22o inhibited the inflammatory response and catabolism of the chondrocytes and reduced articular cartilage injury in the rat OA model, indicating its potential as a disease-modifying OA drug.

Exosomes participate in many physiological and pathological processes by regulating cell-to-cell communication. This affects the etiology and development of diseases, such as osteoarthritis (OA). Although exosomes in the OA tissue microenvironment are involved in the progression of OA, exosomes derived from therapeutic cells represent a new therapeutic strategy for OA treatment. Recent studies have shown that exosomes participate in OA treatment by regulating the proliferation, apoptosis, inflammation, and extracellular matrix synthesis of chondrocytes. However, studies in this field are scant. This review summarizes the therapeutic properties of exosomes on chondrocytes in OA and their underlying molecular mechanisms. We also discuss the challenges and prospects of exosome-based OA treatment.

By adopting gradient analysis combining with the analysis of urban land use degree, this paper studied the spatial layout characteristics of residential and industrial lands in new Yinzhou Town, and explored the location characters of various urban land use by selecting public green land, public facilities, and road as the location advantage factors. Gradient analysis could effectively connect with the spatial layout of urban land use, and quantitatively depict the spatial character of urban land use. In the new town, there was a new urban spatial center mostly within the radius of 2 km, namely, the urban core area had obvious location advantage in the cross-shaft direction urban development. On the south of Yinzhou Avenue, the urban hinterland would be constructed soon. In the future land use of the new town, the focus would be the reasonable vicissitude of industrial land after the adjustment of industrial structure, the high-efficient intensive use of the commercial land restricted by the compulsive condition of urban core area, and the agricultural land protection in the southeastern urban-rural fringe. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study is to investigate the relationship between N-methylN'-nitro-N-nitrosoguanidine (MNNG)-induced lung adenocarcinoma mouse of different stages and the level of exosomes in serum. Methods: Fifty KM mice (4 weeks old, weighing 18-22 g, female) were selected for experiment. MNNG was applied to induce lung adenocarcinoma in mice for model establishment. HE staining method was used to observe pathological changes of lung tissues. Exosomes in serum were extracted, and observed under a Transmission Electron Microscopy (TEM). Western blot was employed to examine the protein levels of exosome markers TSG101 and CD63. Results: HE staining results suggested MNNG-induced lung adenocarcinoma model mice were successfully constructed. The morphology of exosomes in serum of mouse model was observed under an Electron Microscopy, showing clear membrane structures presenting as saucer or concave hemisphere. In addition, the protein level of exosome marker CD63 in advanced mouse model was significantly up-regulated relative to that in the control group. Meanwhile, the expression of exosome marker protein TSG101 was found to be markedly increased in mouse models by comparison with that in control cases. Conclusion: In lung adenocarcinoma model mice, the occurrence and development of lung adenocarcinoma are greatly correlated with the expression level of exosomes in serum, which provides theoretical basis for the diagnosis of pathological staging of lung adenocarcinoma by exosomes.

Mixed linked leukemia 4 (MLL4) is a specific methyltransferase of histone 3 position lysine 4 (H3K4). It is also one of the important members of COMPASS/Set1-like protein complex. Both MLL4 protein itself and its mediated H3K4 methylation modification can cause changes in chromatin structure and function, thus regulating gene transcription and expression. With the studies of MLL4 protein in recent years, the roles of MLL4 gene, MLL4 protein and protein complex in the development of tissues and organs, tumor diseases and other physiological and pathophysiological processes have been gradually revealed. In this paper, the research progress of MLL4 gene, MLL4 protein characteristics, biological function and its effect on disease were reviewed, in order to further understand the effect of histone methyltransferase on gene expression regulation, as well as its non-enzyme dependent function. This paper may provide new ideas for the prevention, diagnosis and treatment of related diseases.

In situ administration of 5-fluorouracil (5FU) "thermosensitive" gel effectively reduced systemic side effects in treating colon rectal cancer; however, the penetration efficacy of the formulation was considerably low due to the poor lipid solubility of 5FU. The aim of this study was to develop thermosensitive gel-mediated 5FU water-in-oil microemulsion (TG-5FU-ME) for improving the infiltration of 5FU. An in vitro release test showed that TG-5FU-ME sustained the drug's release up to 10 hours. TG-5FU-ME exhibited good stability, and the microemulsion entrapped did not show any change in morphology and 5FU content during the 4-month storage. Transportation test in the Caco-2 cell monolayer showed that TG-5FU-ME had a permeability 6.3 times higher than that of 5FU thermosensitive gel, and the intracellular uptake of 5FU increased by 5.4-fold compared to that of 5FU thermosensitive gel. In vivo tissue distribution analysis exhibited that the TG-5FU-ME group had drug levels in rectal tissue and mesenteric lymph nodes, which were significantly higher than those of 5FU thermosensitive gel group, with very low blood levels of 5FU in both groups. Furthermore, TG-5FU-ME was not associated with detectable morphological damage to the rectal tissue. Conclusively, TG-5FU-ME might be an efficient rectal delivery system to treat colorectal cancer.

Background/aims: This study aims to identify the optimal mini-invasive treatment for extrahepatic bile duct stones., Methodology: One hundred and seventy eight patients with EHBD stones were randomized into 4 groups: laparoscopic cholecystectomy (LC) and laparoscopic common bile duct exploration (LCBDE) plus T-tube drainage (group LT), LC and LCBDE with endonasobiliary drainage (ENBD) tube (group LE), and endoscopic sphincterotomy with ENBD followed by LC (group EE) and T-tube drainage of open CBDE (group OT). Demographic data, perioperative findings, postoperative outcomes, hospital expense, gastrointestinal quality of life index (GIQLI) scores and cost per quality-adjusted life year (QALY) were analyzed., Results: The operating time was longest in group EE. There was less bleeding in group OT and EE. Group LE and EE had shorter hospital stay and recovery time of intestinal motility. The postoperative white blood cell count and serum C-reaction protein level were higher in group LT and OT. Postoperatively, the mean GIQLI scores in group LE and EE were higher. Mean cost were highest in group EE. Patients in group LE had lowest cost per QALY., Conclusions: The modified laparoscopic procedure, LC combined with LCBDE followed by a primary closure over the ENBD tubes, appears to be the best option for patients with EHBD stones.