Adipose-derived Stem Cells Attenuates Diabetic Osteoarthritis via Inhibition of Glycation-mediated Inflammatory Cascade.

Diabetes mellitus (DM) is well-known to exert complications such as retinopathy, cardiomyopathy and neuropathy. However, in recent years, an elevated osteoarthritis (OA) complaints among diabetics have been observed, portending the risk of diabetic OA. Since formation of advanced glycation end products (AGE) is believed to be the etiology of various diseases under hyperglycemic conditions, we firstly established that streptozotocin-induced DM could potentiate the development of OA in C57BL/6J mouse model, and further explored the intra-articularly administered adipose-derived stem cell (ADSC) therapy focusing on underlying AGE-associated mechanism. Our results demonstrated that hyperglycemic mice exhibited OA-like structural impairments including a proteoglycan loss and articular cartilage fibrillations in knee joint. Highly expressed levels of carboxymethyl lysine (CML), an AGE and their receptors (RAGE), which are hallmarks of hyperglycemic microenvironment were manifested. The elevated oxidative stress in diabetic OA knee-joint was revealed through increased levels of malondialdehyde (MDA). Further, oxidative stress-activated nuclear factor kappa B (NF-κB), the marker of proinflammatory signalling pathway was also accrued; and levels of matrix metalloproteinase-1 and 13 were upregulated. However, ADSC treatment attenuated all OA-like changes by 4 weeks, and dampened levels of CML, RAGE, MDA, NF-κB, MMP-1 and 13. These results suggest that during repair and regeneration, ADSCs inhibited glycation-mediated inflammatory cascade and rejuvenated cartilaginous tissue, thereby promoting knee-joint integrity in diabetic milieu.

Tumor-Targeted Immunotherapy by Using Primary Adipose-Derived Stem Cells and an Antigen-Specific Protein Vaccine.

Cancer is a leading cause of mortality and a major public health problem worldwide. For biological therapy against cancer, we previously developed a unique immunotherapeutic platform by combining mesenchymal stem cells with an antigen-specific protein vaccine. However, this system possesses a few limitations, such as improperly immortalized mesenchymal stem cells (MSCs) along with transfected oncogenic antigens in them. To overcome the limitations of this platform for future clinical application, we freshly prepared primary adipose-derived stem cells (ADSCs) and modified the E7' antigen (E7') as a non-oncogenic protein. Either subcutaneously co-inoculated with cancer cells or systemically administered after tumor growth, ADSC labeled with enhanced green fluorescent protein (eGFP) and combined with modified E7' (ADSC-E7'-eGFP) cells showed significant antitumor activity when combined with the protein vaccine in both colon and lung cancer in mice. Specifically, this combined therapy inhibited tumor through inducing cell apoptosis. The significantly reduced endothelial cell markers, CD31 and vascular endothelial growth factor (VEGF), indicated strongly inhibited tumor angiogenesis. The activated immune system was demonstrated through the response of CD4+ T and natural killer (NK) cells, and a notable antitumor activity might be contributed by CD8+ T cells. Conclusively, these evidences imply that this promising immunotherapeutic platform might be a potential candidate for the future clinical application against cancer.

Correlation between Diabetes Mellitus and Knee Osteoarthritis: A Dry-To-Wet Lab Approach.

Recent years have witnessed an increased prevalence of knee osteoarthritis (KOA) among diabetes mellitus (DM) patients-conditions which might share common risk factors such as obesity and advanced aging. Therefore, we conducted dry-to-wet lab research approaches to assess the correlation of type 1 DM (T1DM) and type 2 DM (T2DM) with KOA among all age and genders of Taiwanese population. The strength of association (odds ratio: OR) was analyzed using a phenome-wide association study portal. Populations of 37,353 T1DM and 1,218,254 T2DM were included. We observed a significant association of KOA with T1DM (OR: 1.40 (1.33⁻1.47), p< 0.0001) and T2DM (OR: 2.75 (2.72⁻2.78), p< 0.0001). The association between T1DM and KOA among the obese (OR: 0.99 (0.54⁻1.67), p = 0.0477) was insignificant compared to the non-obese (OR: 1.40 (1.33⁻1.48), p < 0.0001). Interestingly, a higher association between T2DM and KOA among non-obese persons (OR: 2.75, (2.72⁻2.79), p < 0.0001) compared to the obese (OR: 1.71 (1.55⁻1.89), p < 0.0001) was noted. Further, histopathologic and Western blot studies of diabetic mice knee joints revealed enhanced carboxymethyl lysine (advanced glycation end product), matrix metalloproteinase-1, and reduced cartilage-specific proteins, including type II collagen (Col II), SOX9, and aggrecan (AGN), indicating deteriorated articular cartilage and proteoglycans. Results indicate that DM is strongly associated with KOA, and obesity may not be a confounding factor.

NSC 95397 Suppresses Proliferation and Induces Apoptosis in Colon Cancer Cells through MKP-1 and the ERK1/2 Pathway.

NSC 95397, a quinone-based small molecule compound, has been identified as an inhibitor for dual-specificity phosphatases, including mitogen-activated protein kinase phosphatase-1 (MKP-1). MKP-1 is known to inactivate mitogen-activated protein kinases by dephosphorylating both of their threonine and tyrosine residues. Moreover, owing to their participation in tumorigenesis and drug resistance in colon cancer cells, MKP-1 is an attractive therapeutic target for colon cancer treatment. We therefore investigated the inhibitory activity of NSC 95397 against three colon cancer cell lines including SW480, SW620, and DLD-1, and their underlying mechanisms. The results demonstrated that NSC 95397 reduced cell viability and anchorage-independent growth of all the three colon cancer cell lines through inhibited proliferation and induced apoptosis via regulating cell-cycle-related proteins, including p21, cyclin-dependent kinases, and caspases. Besides, by using mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor U0126, we provided mechanistic evidence that the antineoplastic effects of NSC 95397 were achieved via inhibiting MKP-1 activity followed by ERK1/2 phosphorylation. Conclusively, our results indicated that NSC 95397 might serve as an effective therapeutic intervention for colon cancer through regulating MKP-1 and ERK1/2 pathway.

Combating Osteoarthritis through Stem Cell Therapies by Rejuvenating Cartilage: A Review.

Knee osteoarthritis (OA) is a chronic degenerative disorder which could be distinguished by erosion of articular cartilage, pain, stiffness, and crepitus. Not only aging-associated alterations but also the metabolic factors such as hyperglycemia, dyslipidemia, and obesity affect articular tissues and may initiate or exacerbate the OA. The poor self-healing ability of articular cartilage due to limited regeneration in chondrocytes further adversely affects the osteoarthritic microenvironment. Traditional and current surgical treatment procedures for OA are limited and incapable to reverse the damage of articular cartilage. To overcome these limitations, cell-based therapies are currently being employed to repair and regenerate the structure and function of articular tissues. These therapies not only depend upon source and type of stem cells but also on environmental conditions, growth factors, and chemical and mechanical stimuli. Recently, the pluripotent and various multipotent mesenchymal stem cells have been employed for OA therapy, due to their differentiation potential towards chondrogenic lineage. Additionally, the stem cells have also been supplemented with growth factors to achieve higher healing response in osteoarthritic cartilage. In this review, we summarized the current status of stem cell therapies in OA pathophysiology and also highlighted the potential areas of further research needed in regenerative medicine.