Stem cell therapy may provide a safe and promising treatment for retinal diseases. Wet age-related macular degeneration (wet-AMD) is a leading cause of blindness in China. We developed a clinical-grade human embryonic stem cell (hESC) line, Q-CTS-hESC-2, under xeno-free conditions that differentiated into retinal pigment epithelial cells (Q-CTS-hESC-2-RPE). A clinical trial with three wet-AMD patients was initiated in order to study the safety and tolerance to Q-CTS-hESC-2-RPE cell transplants. The choroidal neovascularization membrane was removed and then a suspension of 1 × 106 Q-CTS-hESC-2-RPE cells were injected into a subfoveal pocket. The patients were followed for 12 months during which no adverse effects resulting from the transplant were observed. Anatomical evidence suggested the existence of new RPE-like cell layer in the previously damaged area. Visual and physiological testing indicated limited functional improvement, albeit to different degrees between patients. This study provides some promising early results concerning the use of transplanted hESC-RPE cells to alleviate wet-AMD.

cIAP1 is an important member of the inhibitor of apoptosis family of proteins and is involved in the regulation of the NF-jBsignalling pathway downstream of the TNF receptor. We report here that UV irradiation leads to downregulation of cIAP1 expression because of enhanced cIAP1 mRNA destabilization. An AU-rich element located within the 3 0 untranslated region of cIAP1 mRNA is sufficient to mediate cIAP1 mRNA instability. Furthermore, we have identified hnRNP A1 as a cIAP1 3 0 UTR-binding protein. hnRNP A1 is a primarily nuclear protein, but accumulates in the cytoplasm after exposure of cells to UV irradiation. Indeed, we find that hnRNP A1 enhances the destabilization of cIAP1 mRNA during UV irradiation. Moreover, siRNAmediated knockdown of hnRNP A1 restores cIAP1 levels and prevents UV irradiation-induced activation of the NF-jB signal transduction pathway, suggesting that hnRNP A1 is an essential post-transcriptional modulator of cIAP1 expression, and thus cIAP1 activity. The inhibitor of apoptosis (IAP) family of proteins are key regulators of programmed cell death. 1 The IAP family comprises eight distinct members that participate in diverse cellular processes including cell cycle, signal transduction, ubiquitylation, and caspase inhibition. 2 Although it was initially believed that all IAPs are capable of inhibiting distinct caspases, the recent data suggest that only XIAP is a bona fide caspase inhibitor. 3 cIAP1 and cIAP2 were identified through an interaction with the TNF-receptor complex proteins TRAF1 and TRAF2, which regulate NF-kB signalling through the TNF receptor. 4 The C-terminal RING finger domain of cIAP1 possesses an ubiquitin E3 ligase activity and may sensitize cells to apoptosis by direct ubiquitylation and removal of TRAF2 following activation of the TNF receptor, resulting in the inhibition of NF-kB pathways. 5 Indeed, cIAP1 degradation induced by Smac mimetics leads to activation of both the canonical and non-canonical NF-kB pathways, strengthening the importance of IAPs in the regulation of NF-kB signalling. [6][7][8] Although cIAP1 and cIAP2 perform similar functions within the cell, their expression is regulated differently. The expression of cIAP2 is controlled primarily at the level of transcription in an NF-kB-dependent manner. 9 Also, the protein turnover of cIAP2 is regulated by the ubiquitin ligase activity of cIAP1. 10 In contrast, cIAP1 levels are controlled at the level of protein synthesis. The 5 0 untranslated region (UTR) of cIAP1 contains an upstream open reading frame that reduces the basal translation of cIAP1. 11 The 5 0 UTR of cIAP1 also harbours an internal ribosome entry site (IRES) element that mediates translational induction of cIAP1 in response to stress. 12,13 This complex regulatory network reflects the distinct spatial and temporal requirement for cIAP1 and cIAP2 proteins in response to various physiological conditions.Here, we describe an additional regulatory mechanism that governs the expression of cIAP1. We find that following UV irradiation the levels...

To maintain brain homeostasis, a unique interface known as the blood-brain barrier (BBB) is formed between the blood circulation and the central nervous system (CNS). Major facilitator superfamily domain-containing 2a (Mfsd2a) is a specific marker of the BBB. However, the mechanism by which Mfsd2a influences the BBB is poorly understood. In this study, we demonstrated that Mfsd2a is essential for sphingosine-1-phosphate (S1P) export from endothelial cells in the brain. We found that Mfsd2a and Spinster homolog 2 (Spns2) form a protein complex to ensure the efficient transport of S1P. Furthermore, the S1P-rich microenvironment in the extracellular matrix (ECM) in the vascular endothelium dominates the formation and maintenance of the BBB. We demonstrated that different concentrations of S1P have different effects on BBB integrity. These findings help to unravel the mechanism by which S1P regulates BBB and also provide previously unidentified insights into the delivery of neurological drugs in the CNS.

The increasing aging of the world population is accompanied by a rise in the incidence of knee osteoarthritis (KOA). There has been a growing interest in shockwave treatment for orthopedic diseases, including KOA. In previous trials, extracorporeal shockwave therapy (ESWT) was compared to physical therapy or placebo in the treatment of KOA. However, the efficacy and safety of ESWT for KOA remains disputed. The present meta-analysis assessed the effects of ESWT in KOA. The PubMed, Medline, Embase, Web of Science, Research Gate and the Cochrane Library were searched to identify comparative studies involving ESWT for patients with KOA. The outcome indicators included the visual analog scale (VAS) score, range of motion (ROM), the Lequesne index (LI) and the Western Ontario and McMaster Universities osteoarthritis index (WOMAC). In the comparison of the ESWT vs. placebo groups, the primary outcomes included the VAS score and ROM, while the LI was the secondary outcome. In the comparison of the ESWT vs. physical therapy groups, the primary outcomes included the pain score and ROM, while the secondary outcome was the WOMAC index. Relevant data were analyzed using RevMan v5.3. The ESWT group had a lower VAS core, larger ROM and a better LI than the placebo group after 1 month of therapy (P<0.05). Furthermore, at 1 month post-therapy, the ESWT group had a lower VAS score, larger ROM and a better WOMAC than the physical therapy group (P<0.05). The outcomes regarding pain, ROM, LI and WOMAC were significantly different between the two different groups (P<0.05). The present meta-analysis suggested that ESWT may achieve a better therapeutic effect for patients with KOA as compared to physical therapy. However, high-quality trials with large sample sizes are essential to substantiate these results.