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Purpose: Bone marrow (BM) is frequently used as a source of mesenchymal stem cells (MSCs) because they have a high potential for differentiation. However, it is unclear whether BM-derived MSCs lead to better clinical and magnetic resonance imaging (MRI) outcomes postoperatively. Materials and Methods: This meta-analysis compared the clinical and MRI outcomes in patients with knee osteoarthritis (OA) treated with BMderived MSCs. Eight studies comparing the clinical and MRI outcomes assessed with various measurement tools in patients with knee OA treated with BM-derived MSCs were included. Results: The range of motion (95% confidence interval [CI], -13.05 to 4.24; p=0.32) and MRI outcomes (95% CI, -0.16 to 1.40; p=0.12) did not differ significantly between the baseline and final follow-up. In contrast, pain (95% CI, 0.89 to 1.87; p<0.001) and functional outcomes (95% CI, 0.70 to 2.07; p<0.001) were significantly improved at the final follow-up when compared to the baseline. Conclusions: This meta-analysis found no significant difference in the tested range of motion and MRI outcomes between the baseline and the final follow-up in patients treated with BM-derived MSCs, whereas significant functional improvement and pain relief were noted when compared with the baseline. Thus, BM-derived MSCs appear to be a viable alternative for patients with knee OA, although long-term and high-quality randomized controlled trials are needed to confirm the clinical benefits. [ABSTRACT FROM AUTHOR]

Background: Limited data are available for advanced colorectal neoplasm in asymptomatic individuals aged 40-49 years. We aimed to identify risk factors and develop a simple prediction model for advanced colorectal neoplasm in these persons.Methods: Clinical data were collected on 2781 asymptomatic subjects aged 40-49 years who underwent colonoscopy for routine health examination. Subjects were randomly allocated to a development or validation set. Logistic regression analysis was used to determine predictors of advanced colorectal neoplasm.Results: The prevalence of overall and advanced colorectal neoplasm was 20.2 and 2.5% respectively. Older age (45-49 years), male sex, positive serology of Helicobacter pylori, and high triglyceride and low high-density lipoprotein (HDL) levels were independently associated with an increased risk of advanced colorectal neoplasm. BMI (body mass index) was not significant in multivariable analysis. We developed a simple scoring model for advanced colorectal neoplasm (range 0-9). A cutoff of ≥4 defined 43% of subjects as high risk for advanced colorectal neoplasm (sensitivity, 79%; specificity, 58%; area under the receiver operating curve = 0.72) in the validation datasets.Conclusion: Older age (45-49 years), male sex, positive serology of H. pylori, high triglyceride level, and low HDL level were identified as independent risk factors for advanced colorectal neoplasm. [ABSTRACT FROM AUTHOR]

Background: β-Lapachone (β-LAP) is a natural naphthoquinone compound isolated from the lapacho tree (Tabebuia sp.), and it has been used for treatment of rheumatoid arthritis, infection, and cancer. In the present study, we investigated whether β-LAP has anti-inflammatory effects under in vitro and in vivo neuroinflammatory conditions. Methods: The effects of β-LAP on the expression of inducible nitric oxide synthase (iNOS), cytokines, and matrix metalloproteinases (MMPs) were examined in lipopolysaccharide (LPS)-stimulated BV2 microglial cells and rat primary microglia by ELISA, reverse transcription polymerase chain reaction (RT-PCR), and Western blot analysis. Microglial activation and the expression levels of proinflammatory molecules were measured in the LPS-injected mouse brain by immunohistochemistry and RT-PCR analysis. The detailed molecular mechanism underlying the anti-inflammatory effects of β-LAP was analyzed by electrophoretic mobility shift assay, reporter gene assay, Western blot, and RT-PCR analysis. Results: β-LAP inhibited the expression of iNOS, proinflammatory cytokines, and MMPs (MMP-3, MMP-8, MMP-9) at mRNA and protein levels in LPS-stimulated microglia. On the other hand, β-LAP upregulated the expressions of antiinflammatory molecules such as IL-10, heme oxygenase-1 (HO-1), and the tissue inhibitor of metalloproteinase-2 (TIMP-2). The anti-inflammatory effect of β-LAP was confirmed in an LPS-induced systemic inflammation mouse model. Thus, β-LAP inhibited microglial activation and the expressions of iNOS, proinflammatory cytokines, and MMPs in the LPS-injected mouse brain. Further mechanistic studies revealed that β-LAP exerts anti-inflammatory effects by inhibiting MAPKs, PI3K/AKT, and NF-κB/AP-1 signaling pathways in LPS-stimulated microglia. β-LAP also inhibited reactive oxygen species (ROS) production by suppressing the expression and/or phosphorylation of NADPH oxidase subunit proteins, such as p47phox and gp91phox. The anti-oxidant effects of β-LAP appeared to be related with the increase of HO-1 and NQO1 via the Nrf2/anti-oxidant response element (ARE) pathway and/or the PKA pathway. Conclusions: The strong anti-inflammatory/anti-oxidant effects of β-LAP may provide preventive therapeutic potential for various neuroinflammatory disorders. [ABSTRACT FROM AUTHOR]

Background Tissue inhibitors of metalloproteinases (TIMPs) are known to be endogenous inhibitors of matrix metalloproteinases (MMPs). Our preliminary study showed that TIMP-2 is constitutively expressed in microglia but significantly inhibited by lipopolysaccharide (LPS) treatment. The current study was undertaken to investigate the role of TIMP-2 in microglia. Methods The expression of TIMP-2 was evaluated in the BV2 mouse microglial cell line and rat primary cultured microglia. To investigate the role of TIMP-2, a TIMP-2 expression plasmid or small interfering RNA (siRNA) was introduced into BV2 cells by transient transfection, and their effects on LPS-induced inflammatory reactions were examined. We further analyzed the molecular mechanism underlying the anti-inflammatory effects of TIMP-2 by electrophoretic mobility shift assay (EMSA), a reporter gene assay and Western blot analysis. Results Overexpression of TIMP-2 significantly inhibited the production of nitric oxide (NO), TNF- α, IL-1β, and reactive oxygen species (ROS), while increasing anti-inflammatory IL-10 production. On the other hand, knockdown of TIMP-2 augmented the production of proinflammatory molecules and downregulated IL-10 in LPS-stimulated BV2 cells. The results suggest that endogenously expressed TIMP-2 plays an anti-inflammatory role. Further mechanistic studies revealed that overexpression of TIMP-2 suppresses microglial activation via inhibition of the activity of mitogen-activated protein kinases (MAPKs) and NF-κB with enhancement of the activity of anti-inflammatory Nrf2 and cAMP-response element binding protein (CREB) transcription factors. TIMP-2 also inhibited the activity and expression of LPS-induced MMP-3, -8, and -9. Finally, we demonstrated that TIMP-2 exerts a neuroprotective effect via the inhibition of microglial activation. Conclusions Enhancement of TIMP-2 expression may be a potential therapeutic target for neuroinflammatory disorders. [ABSTRACT FROM AUTHOR]