Background: Multiple myeloma (MM) is the second most common hematological malignancy, which is still incurable and relapses inevitably, highlighting further understanding of the possible mechanisms. Side population (SP) cells are a group of enriched progenitor cells showing stem-like phenotypes with a distinct low-staining pattern with Hoechst 33342. Compared to main population (MP) cells, the underlying molecular characteristics of SP cells remain largely unclear. This bioinformatics analysis aimed to identify key genes and pathways in myeloma SP cells to provide novel biomarkers, predict MM prognosis and advance potential therapeutic targets. Methods: The gene expression profile GSE109651 was obtained from Gene Expression Omnibus database, and then differentially expressed genes (DEGs) with P-value <0.05 and |log2 fold-change (FC)| > 2 were selected by the comparison of myeloma light-chain (LC) restricted SP (LC/SP) cells and MP CD138 + cells. Subsequently, gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis, protein-protein interaction (PPI) network analysis were performed to identify the functional enrichment analysis of the DEGs and screen hub genes. Cox proportional hazards regression was used to select the potential prognostic DEGs in training dataset (GSE2658). The prognostic value of the potential prognostic genes was evaluated by Kaplan-Meier curve and validated in another external dataset (MMRF-CoMMpass cohort from TCGA). Results: Altogether, 403 up-regulated and 393 down-regulated DEGs were identified. GO analysis showed that the up-regulated DEGs were significantly enriched in innate immune response, inflammatory response, plasma membrane and integral component of membrane, while the down-regulated DEGs were mainly involved in protoporphyrinogen IX and heme biosynthetic process, hemoglobin complex and erythrocyte differentiation. KEGG pathway analysis suggested that the DEGs were significantly enriched in osteoclast differentiation, porphyrin and chlorophyll metabolism and cytokine-cytokine receptor interaction. The top 10 hub genes, identified by the plug-in cytoHubba of the Cytoscape software using maximal clique centrality (MCC) algorithm, were ITGAM, MMP9, ITGB2, FPR2, C3AR1, CXCL1, CYBB, LILRB2, HP and FCER1G. Modules and corresponding GO enrichment analysis indicated that myeloma LC/SP cells were significantly associated with immune system, immune response and cell cycle. The predictive value of the prognostic model including TFF3, EPDR1, MACROD1, ARHGEF12, AMMECR1, NFATC2, HES6, PLEK2 and SNCA was identified, and validated in another external dataset (MMRF-CoMMpass cohort from TCGA). Conclusions: In conclusion, this study provides reliable molecular biomarkers for screening, prognosis, as well as novel therapeutic targets for myeloma LC/SP cells.

Osteoarthritis (OA) is one of the most common musculoskeletal degenerative diseases and contributes to heavy socioeconomic burden. Current pharmacological and conventional non-pharmacological therapies aim at relieving the symptoms like pain and disability rather than modifying the underlying disease. Surgical treatment and ultimately joint replacement arthroplasty are indicated in advanced stages of OA. Since the underlying mechanisms of OA onset and progression have not been fully elucidated yet, the development of novel therapeutics to prevent, halt, or reverse the disease is laborious. Recently, small molecules of herbal origin have been reported to show potent anti-inflammatory, anti-catabolic, and anabolic effects, implying their potential for treatment of OA. Herein, the molecular mechanisms of these small molecules, their effect on physiological or pathological signaling pathways, the advancement of the extraction methods, and their potential clinical translation based on in vitro and in vivo evidence are comprehensively reviewed.

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Osteoarthritis (OA) is the most common degenerative joint disease without clear pathophysiological mechanism and effective drugs for treatment. Although various animal models exist, the translation of the outcome into clinics remains difficult due to species differences. In this study, an ex vivo inflammatory OA model was induced using different concentrations of interleukin one beta (IL-1β) and tumor necrosis factor α (TNF-α) on explants from the human femoral head. In the inflammatory OA groups, the gene expression levels of cartilage catabolism (matrix metalloproteinase 1 (MMP1), matrix metalloproteinase 3 (MMP3)), and inflammation (interleukin 6 (IL-6), interleukin 8 (IL-8)) markers were significantly upregulated, while the anabolic genes (collagen 2 (COL2), aggrecan (ACAN), and proteoglycan 4 (PRG4)) were downregulated compared to the control group. The release of cytokines (IL-6, IL-8) and nitric oxide (NO) in the conditioned medium was also upregulated in inflammatory OA groups. The Safranin O/Fast Green staining showed loss of proteoglycan in the superficial zone cartilage after cytokine treatment. The results indicated that an ex vivo inflammation and degeneration model was successfully established using osteochondral explants from the human femoral head. This model can be used to elucidate the in-depth mechanism of inflammatory OA and to screen new drugs for OA treatment.

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