Gut microbiota dysbiosis has been studied under the pathological conditions of osteoarthritis (OA). However, the effect of antibiotic-induced gut flora dysbiosis on OA remains incompletely understood at present. Herein, we used a mouse (8 weeks) OA model of destabilization of the medial meniscus (DMM) and gut microbiome dysbiosis induced by antibiotic treatment with ampicillin and neomycin for 8 weeks. The results show that antibiotic-induced intestinal microbiota dysbiosis reduced the serum level of lipopolysaccharide (LPS) and the inflammatory response, such as suppression of the levels of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which can lead to decreased matrix metalloprotease-13 (MMP-13) expression and improvement of OA after joint injury. In addition, trabecular thickness (Tb.Th) and osteophyte scores were increased significantly in antibiotic-induced male mice compared with female mice. We further used network correlation analysis to verify the effect of gut microbiota dysbiosis on OA. Therefore, this study contributes to our understanding of the gut-joint axis in OA and reveals the relationship between the inflammatory response, sex and gut microbiota, which may provide new strategies to prevent the symptoms and long-term sequelae of OA.
Due to frequent phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway dysregulation, AKT is typically accepted as a promising anticancer therapeutic target. mTOR, in particular, represents a suitable therapeutic target for hepatocellular carcinoma, whilst suppressor with morphogenetic effect on genitalia family member-1 (SMG-1) is believed to serve a potential tumor suppressor role in human cancer. Despite SMG-1 and mTOR belonging to the same PI3K-related kinase family, the interactions between them are not yet fully understood. In the present study, a novel pyrrolopyrimidine-derived compound, AZD5363, was observed to suppress proliferation in liver cancer Hep-G2 and Huh-7 cells by inhibiting the phosphorylation of downstream molecules in the AKT signal pathway, in a dose- and time-dependent manner. AZD5363 activated the phosphorylation of mTOR, dependent on the liver cancer cell type, as it may have differing effects in various liver cancer cell lines. Additionally, AZD5363 also activated SMG-1 within the same liver cancer cells types, which subsequently activated the phosphorylation of mTOR. In conclusion, the present study indicates that AZD5363 inhibited phosphorylation of AKT downstream molecules, and activated phosphorylation of mTOR and SMG-1, dependent on the liver cancer type.
osteonecrosis of the femoral head (onFH) is a common osteological disease. Treatment of onFH prior to the collapse of the femoral head is critical for increasing therapeutic efficiency. Tissue engineering therapy using bone mesenchymal stem cells (BMSCs) combined with a scaffold is a promising strategy. However, it is currently unclear how to improve the efficiency of BMSC recruitment under such conditions. In the present study, a specific cyclic peptide for Sprague-Dawley rat BMSCs, CTTNPFSLC (known as C7), was used, which was identified via phage display technology. Its high affinity for BMSCs was demonstrated using flow cytometry and fluorescence staining. Subsequently, the cyclic peptide was placed on β-tricalcium phosphate (β-TcP) scaffolds using absorption and freeze-drying processes. Adhesion, expansion and proliferation of BMSCs was investigated in vitro on the c7-treated β-TcP scaffolds and compared with pure β-TCP scaffolds. The results revealed that C7 had a promoting effect on the adhesion, expansion and proliferation of BMSCs on β-TCP scaffolds. Therefore, C7 may be effective in future tissue engineering therapy for ONFH.
Background: Osteonecrosis of the femoral head (ONFH) is a disabling disease. Early treatment is crucial to the prognosis of the disease. Core decompression (CD) is one of the most commonly used methods for the treatment of early ONFH. But it could not prevent the collapse of the necrotic femoral head. How to improve the therapeutic effect of early ONFH on the basis of CD has become an area of focused research. Methods: Functional β-tricalcium phosphate (β-TCP) scaffolds modified by DPIYALSWSGMA (DPI) peptide, a bone marrow-derived mesenchymal stem cell (BMSC) affinity peptide, were constructed using an adsorption/freeze-drying strategy. The affinity of DPI peptide towards rabbit BMSCs was investigated using flow cytometry and fluorescence cytochemistry. In vitro cell adhesion assay was performed to study the adherent ability of rabbit BMSCs on functional β-TCP scaffolds. After the rabbit model of early ONFH was established, DPI peptide-modified and pure β-TCP scaffolds were transplanted into the remaining cavity after CD. Meanwhile, rabbits treated with pure CD were used as blank control. Twelve weeks after surgery, histological analysis was performed to show the therapeutic effect of three methods on early ONFH. Results: The result of ImageXpress Micro Confocal indicated that fabricated DPI peptide-modified functional β-TCP scaffolds exhibited green fluorescence. In flow cytometry, the average fluorescence intensity for rabbit BMSCs incubated with FITC-DPI was significantly higher than that of FITC-LSP (P = 2.733 × 10 −8). In fluorescence cytochemistry, strong fluorescent signals were observed in rabbit BMSCs incubated with FITC-DPI and FITC-RGD, whereas no fluorescent signals in cells incubated with FITC-LSP. In cell adhesion assay, the number of adherent cells to β-TCP-DPI scaffolds was more than that of pure β-TCP scaffolds (P = 0.033). The CD + β-TCP-DPI group expressed the lowest vacant bone lacunae percentage compared to CD group (P = 2.350 × 10 −4) and CD + β-TCP group (P = 0.020). The expression content of COL1 in CD + β-TCP-DPI group was much higher than CD group (P = 1.262 × 10 −7) and CD + β-TCP group (P = 1.666 × 10 −7) according to the integrated optical density (IOD) analyses. Conclusion: Functional β-TCP scaffolds modified by DPI peptide were successfully synthesized using an adsorption/ freeze-drying strategy. DPI peptide has good affinity towards rabbit BMSCs. The adhesion of rabbit BMSCs on DPI peptide-modified β-TCP scaffolds was apparently enhanced. CD followed by implantation of DPI peptide-modified β-TCP scaffolds can apparently improve the treatment of early ONFH compared with pure CD and CD followed by implantation of unmodified β-TCP scaffolds. Our current study provides an improved method for the treatment of early ONFH.
Osteonecrosis of the femoral head (ONFH) is a refractory disease present worldwide. In the development of therapies for this disease, mesenchymal stem cells (MSC) are a promising candidate cell source in tissue engineering (TE) and regenerative medicine. MSCs harvested from bone marrow (BM) are the gold standard. A significant barrier for BMMSC-based therapies is the inability and decreased number of BMMSCs in the tissues of interest. The ability to recruit BMMSCs efficiently to defective or injured sites in tissues or organs, for example the necrotic area of the femoral head in vivo, has been a major concern. In the present study, a peptide sequence (CDNVAQSVC), termed D7, was identified through phage display technology using C57BL/6 mouse BMMSCs. Subsequent analysis suggested that the identified loop-constrained heptapeptide exhibited a high specific affinity for mouse BMMSCs. Due to this specific affinity for BMMSCs, the present study provides a selective method to improve MSC-based TE strategies for the treatment of ONFH.
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