Journal of molecular medicine : official organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
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Understanding the underlying molecular mechanisms in burn wound progression is crucial to providing appropriate diagnoses and designing therapeutic regimens for burn patients. When inflammation becomes unregulated, recurrent, or excessive, it interferes with burn wound healing. Autophagy, which is a homeostatic and catabolic degradation process, was found to protect against ischemic injury, inflammatory diseases, and apoptosis in some cases. In the present study, we investigated whether far-infrared (FIR) could ameliorate burn wound progression and promote wound healing both in vitro and in a rat model of deep second-degree burn. We found that FIR induced autophagy in differentiated THP-1 cells (human monocytic cells differentiated to macrophages). Furthermore, FIR inhibited both the NLRP3 inflammasome and the production of IL-1β in lipopolysaccharide-activated THP-1 macrophages. In addition, FIR induced the ubiquitination of ASC, which is the adaptor protein of the inflammasome, by increasing tumor necrosis factor receptor-associated factor 6 (TRAF6), which is a ubiquitin E3 ligase. Furthermore, the exposure to FIR then promoted the delivery of inflammasome to autophagosomes for degradation. In a rat burn model, FIR ameliorated burn-induced epidermal thickening, inflammatory cell infiltration, and loss of distinct collagen fibers. Moreover, FIR enhanced autophagy and suppressed the activity of the NLRP3 inflammasome in the rat skin tissue of the burn model. Based on these results, we suggest that FIR-regulated autophagy and inflammasomes will be important for the discovery of novel therapeutics to promote the healing of burn wounds. ⋯ Far-infrared (FIR) induced autophagy in THP-1 macrophages. FIR suppressed the NLRP3 inflammasome through the activation of autophagy. FIR induced the ubiquitination of ASC by increasing TRAF6. FIR ameliorated burn wound progression and promoted wound healing in a rat burn model.
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Accumulating evidence suggests that microRNAs (miRNAs) play an important role in intervertebral disc degeneration (IDD), but the precise role of specific miRNAs involved in this disease remains elusive. The purpose of this study was to identify IDD-specific miRNAs, followed by functional validation of results. MiRNA expression profile was determined in nucleus pulposus (NP) tissues from patients with IDD and controls, employing Solexa sequencing and quantitative real-time PCR (qRT-PCR). Biological functions of differential expression miRNAs were further investigated in vitro and in vivo. Luciferase reporter assays and Western blotting were performed to determine miRNA targets. We identified 28 miRNAs that were differentially expressed in patients compared with controls. Following qRT-PCR confirmation, miR-193a-3p was significantly down-regulated in degenerative NP tissues. Moreover, its level was correlated with grade of disc degeneration. Through gain- and loss-of-function studies, miR-193a-3p was demonstrated to significantly promote type II collagen expression in NP cells. Knockdown of MMP14 induced effects on NP cells similar to those induced by miR-193a-3p. Bioinformatics target prediction identified MMP14 as a putative target of miR-193a-3p. Furthermore, luciferase reporter assays and Western blotting demonstrated that miR-193a-3p directly targets MMP14. MiR-193a-3p inhibited IDD in vitro and in vivo. The downregulation of miR-193a-3p induces the expression of MMP14, which promotes loss of type II collagen and thereby contributes to the development of human IDD. Our findings extend the role of miR-193a-3p in the pathogenesis of IDD and provide a potential novel therapeutic target for degenerative disc disease. ⋯ Intervertebral disc degeneration (ICC)-specific miRNA profile generated by next generation sequencing. Downregulation of miR-193a-3p promoted loss of type II collagen by directly targeting MMP14 in IDD. miR-193a-3p inhibited IDD in vitro and in vivo. miR-193a-3p may be a promising candidate for prevention of degenerative disc disease.
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K-Ras proteins are major drivers of human cancers, playing a direct causal role in about one million cancer cases/year. In cancers driven by mutant K-Ras, the protein is locked in the active, GTP-bound state constitutively, through a defect in the off-switch mechanism. As such, the mutant protein resembles the normal K-Ras protein from a structural perspective, making therapeutic attack extremely challenging. ⋯ Furthermore, Ras proteins lack pockets to which small molecules can bind with high affinity, with a few interesting exceptions. However, new insights into the structure and function of K-Ras proteins reveal opportunities for intervention that were not appreciated many years ago, when efforts were launched to develop K-Ras therapies. Furthermore, K-Ras undergoes post-translational modification and interactions with cellular signaling proteins that present additional therapeutic opportunities, such as specific binding to calmodulin and regulation of non-canonical Wnt signaling.
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Multiple myeloma is a plasma cell skeletal malignancy. While therapeutic agents such as bortezomib and lenalidomide have significantly improved overall survival, the disease is currently incurable with the emergence of drug resistance limiting the efficacy of chemotherapeutic strategies. ⋯ Defining the interactions between myeloma cells and the more genetically stable hematopoietic and mesenchymal components of the bone microenvironment is critical for the development of new therapeutic targets. In this review, we discuss recent advances in our understanding of how microenvironmental elements contribute to myeloma progression and, therapeutically, how those elements can or are currently being targeted in a bid to eradicate the disease.
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Interleukin (IL)-6 plays important roles in autoimmunity and inflammation and is essential for T helper (Th) 2 and Th17 differentiation. However, whether it is involved in the development and function of dendritic cells (DCs) during allergen-induced airway inflammation and airway hyper-reactivity (AHR) remains undefined. In this study, Dermatophagoides pteronyssinus (Der p)-induced airway inflammation and AHR were studied in IL-6 knockout (KO) mice. Der p-loaded bone marrow-derived DCs (BMDCs) from IL-6 KO mice were used to assaying their ability to induce airway inflammation in naïve wild-type mice. Our results showed that IL-6 KO mice showed reduced AHR, significant decreases in inflammatory cell recruitment and Th2 and Th17 cytokine production in the airways, and lowered Der p-specific immunoglobulin G1 after Der p exposure. Further exploration of BMDCs from IL-6 KO mice revealed decreased activity of phagocytosis and reduced expression of MHC class II and CD86 after Der p stimulation. Adoptive transfer of Der p-loaded BMDCs from IL-6 KO mice also showed a functional defect in their inability to induce Th2 and Th17 immune responses and trigger airway inflammation and AHR in recipient mice. Finally, in allergic asthmatics, DCs that differentiated from monocytes treated with anti-IL-6 receptor antibody (tocilizumab) had poor capacity for eliciting Th2 polarization as compared to DCs generated from monocytes without antibody treatment. In conclusion, IL-6 signaling in DCs is essential for their uptake of allergens, maturation, and initiation of Th2/Th17-mediated airway inflammation and AHR in asthma, thus providing a new potential target for treating allergic asthma. ⋯ IL-6 signaling is important for DCs to take up allergens and to initiate Th2/Th17-mediated airway inflammation. DCs from allergic asthmatics treated with anti-IL-6 receptor antibody had poor capacity for eliciting Th2 polarization. Anti-IL-6 treatment may provide a new potential target for treating allergic asthma.