Hypoxia inducible factor-1α (HIF-1α) plays an important role in angiogenesis-osteogenesis coupling during bone regeneration, which can enhance the bone healing capacity of mesenchymal stem cells (MSCs) by improving their osteogenic and angiogenic activities. Previous studies transduced the HIF-1α gene into MSCs with lentivirus vectors to improve their bone healing capacity. However, the risks due to lentivirus vectors, such as tumorigenesis, should be considered before clinical application. Dimethyloxaloylglycine (DMOG) is a cell-permeable prolyl-4-hydroxylase inhibitor, which can activate the expression of HIF-1α in cells at normal oxygen tension. Therefore, DMOG is expected to be an alternative strategy for enhancing HIF-1α expression in cells. In this study, we explored the osteogenic and angiogenic activities of adipose-derived stem cells (ASCs) treated with different concentrations of DMOG in vitro, and the bone healing capacity of DMOG-treated ASCs combined with hydrogels for treating critical-sized calvarial defects in rats. The results showed that DMOG had no obvious cytotoxic effects on ASCs and could inhibit the death of ASCs induced by serum deprivation. DMOG markedly increased vascular endothelial growth factor production in ASCs in a dose-dependent manner and improved the osteogenic differentiation potential of ASCs by activating the expression of HIF-1α. Rats with critical-sized calvarial defects treated with hydrogels containing DMOG-treated ASCs had more bone regeneration and new vessel formation than the other groups. Therefore, we believe that DMOG enhanced the angiogenic and osteogenic activity of ASCs by activating the expression of HIF-1α, thereby improving the bone healing capacity of ASCs in rat critical-sized calvarial defects.

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Intervertebral disc degeneration (IDD) is associated with the deterioration of nucleus pulposus (NP) cells due to hypertrophic differentiation and calcification. Emerging studies have shown that long noncoding RNAs (lncRNAs) play critical roles in the development of IDD. Using bioinformatics prediction, we hereby sought to identify the lncRNAs that regulate the expression of microRNA-146a-5p (miR-146a-5p), an IDD-related inflammatory factor. Our study demonstrated that lncRNA HCG18 acted as an endogenous sponge to down-regulate miR-146a-5p expression in the NP cells by directly binding to miR-146a-5p. In addition, HCG18 expression was up-regulated in the patients with IDD, bulging or herniated discs, and its level was positively correlated with the disc degeneration grade. In vitro, miR-146a-5p up-regulation HCG18 retarded the growth of NP cells by decreasing S phase of cell cycle, inducing cell apoptosis, recruitment of macrophages and hypercalcification. Conversely, down-regulation of miR-146a-5p exerted opposite effects. Furthermore, we elucidated that TRAF6, a target gene by miR-146a-5p, was modulated by HCG18 expression. Restore of TRAF6 expression by virus infection reserved the effect of HCG18 on the NP cells. Altogether, our data indicated that HCG18 suppressed the growth of NP cells and promoted the IDD development via the miR-146a-5p/TRAF6/NFκB axis.

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The quorum-sensing (QS) system is an intercellular cell-cell communication mechanism that controls the expression of genes involved in a variety of cellular processes and that plays critical roles in the adaption and survival of bacteria in their environment. The LuxS/AI-2 QS system, which uses AI-2 (autoinducer-2) as a signal molecule, has been identified in both Gram-negative and Gram-positive bacteria. As one of the important global regulatory networks in bacteria, it responds to fluctuations in the numbers of bacteria and regulates the expression of a number of genes, thus affecting cell behavior. We summarize here the known relationships between the LuxS/AI-2 system and drug resistance, discuss the inhibition of LuxS/AI-2 system as an approach to prevent bacterial resistance, and present new strategies for the treatment of drug-resistant pathogens.

Tubular cell necrosis is a key histological feature of acute kidney injury (AKI). Necroptosis is a type of programed necrosis, which is executed by mixed lineage kinase domain-like protein (MLKL) upon its binding to the plasma membrane. Emerging evidence indicates that necroptosis plays a critical role in the development of AKI. However, it is unclear whether renal tubular cells undergo necroptosis in vivo and how the necroptotic pathway is regulated during AKI. Repulsive guidance molecule (RGM)-b is a member of the RGM family. Our previous study demonstrated that RGMb is highly expressed in kidney tubular epithelial cells, but its biological role in the kidney has not been well characterized. In the present study, we found that RGMb reduced membrane-associated MLKL levels and inhibited necroptosis in cultured cells. During ischemia/reperfusion injury (IRI) or oxalate nephropathy, MLKL was induced to express on the apical membrane of proximal tubular (PT) cells. Specific knockout of Rgmb in tubular cells (Rgmb cKO) increased MLKL expression at the apical membrane of PT cells and induced more tubular cell death and more severe renal dysfunction compared with wild-type mice. Treatment with the necroptosis inhibitor Necrostatin-1 or GSK'963 reduced MLKL expression on the apical membrane of PT cells and ameliorated renal function impairment after IRI in both wild-type and Rgmb cKO mice. Taken together, our results suggest that proximal tubular cell necroptosis plays an important role in AKI, and that RGMb protects against AKI by inhibiting MLKL membrane association and necroptosis in proximal tubular cells.

Streptococcus suis 2 (SS2) is a zoonotic pathogen that can participate in biofilm formation to survive in hostile environments. In this study, virulent SS2 strains HA9801 and ZY05719 displayed increased biofilm formation compared with SS2 avirulent strain T15. In addition, a 58% reduction in adherence to HEp-2 cells was observed for HA9801 biofilm cells, compared with HA9801 planktonic cells. The 50% lethal dose (LD(50) ) of biofilm cells was 40-fold greater than that of planktonic cells. Quantification of expression levels of known virulence genes by real-time PCR revealed that the transcription levels of the gdh, cps2 and mrp genes in biofilm cells were downregulated, while the sly and gapdh genes were upregulated. HA9801 biofilm and planktonic vaccines provided 60% and 46% protection, respectively, when challenged with 50 times the LD(50) of the HA9801 strain. These results suggest a possible connection between virulence and the ability of biofilm formation; cell adhesion, transcription levels and virulence properties are different between biofilm cells and planktonic cells. Furthermore, this work offers a novel insight into bacterium infection mechanisms, which suggests that a virulent strain may be able to decrease its virulence by forming a biofilm so that it can achieve persistent infection in vivo.