Fibrinogen-like protein 2 (FGL2) is highly expressed in various tumour tissues and plays a vital role in tumour initiation and progression. This study evaluated the clinical significance of FGL2 in patients with clear cell renal cell carcinoma (ccRCC). FGL2 expression in fresh and 170 archived paraffin-embedded ccRCC tissues was measured by quantitative RT-PCR, western blotting, and immunohistochemitry. FGL2 expression was significantly upregulated in ccRCC. Statistical analyses by using Kaplan–Meier method showed that high FGL2 expression was associated with poor overall survival (OS) and recurrence-free survival (RFS) of patients with ccRCC. Multivariate analyses indicated that FGL2 was as an independent prognostic factor of survivaland that tumoural FGL2 levels could significantly predict the prognosis of patients with early-stage ccRCC. Nomogram systems, which integrated FGL2 expression and other clinical parameters, were established and were found to be better than TNM staging in predicting the OS and RFS of patients with ccRCC. FGL2 silencing led to a significant reduction in cells viability and increase in cells apoptosis, accompanied with a reduced ERK1/2 and p38 MAPK activation, in ccRCC cells. Thus, our results suggest that high FGL2 expression is a novel, independent, and an adverse prognostic factor of clinical outcomes in patients with ccRCC.

Renal fibrosis is the final manifestation of various chronic kidney diseases, and no effective therapy is available to prevent or reverse it. Celastrol, a triterpene that derived from traditional Chinese medicine, is a known potent anti-fibrotic agent. However, the underlying mechanisms of action of celastrol on renal fibrosis remain unknown. In this study, we found that celastrol treatment remarkably attenuated unilateral ureteral obstruction (UUO)-induced mouse renal fibrosis. This was evidenced by the significant reduction in tubular injury; collagen deposition; accumulation of fibronectin, collagen I, and α-smooth muscle actin; and the expression levels of pro-fibrotic factors Vim, Cola1, and TGF-β1 mRNA, as well as inflammatory responses. Celastrol showed similar effects in a folic acid-induced mouse renal fibrosis model. Furthermore, celastrol potentiated the expression of the anti-fibrotic factor cannabinoid receptor 2 (CB2R) in established mouse fibrotic kidney tissues and transforming growth factor β1 (TGF-β1)-stimulated human kidney 2 (HK-2) cells. In addition, the CB2R antagonist (SR144528) abolished celastrol-mediated beneficial effects on renal fibrosis. Moreover, UUO- or TGF-β1-induced activation of the pro-fibrotic factor SMAD family member 3 (Smad3) was markedly inhibited by celastrol. Inhibition of Smad3 activation by an inhibitor (SIS3) markedly reduced TGF-β1-induced downregulation of CB2R expression. In conclusion, our study provides the first direct evidence that celastrol significantly alleviated renal fibrosis, by contributing to the upregulation of CB2R expression through inhibiting Smad3 signaling pathway activation. Therefore, celastrol could be a potential drug for treating patients with renal fibrosis.

Psoriasis is one of the most common chronic inflammatory skin diseases, affecting ~2% of the population. The lack of characterization of the pathogenesis of psoriasis has hindered efficient clinical treatment of the disease. In our study, we observed that expression of complement component 5a receptor 1(C5aR1) was significantly increased in skin lesions of both imiquimod (IMQ) and IL23-induced psoriatic mice and patients with psoriasis. C5aR1 deficiency or treatment with C5a receptor 1 antagonist (C5aR1a) in mice significantly attenuated psoriasis-like skin lesions and expression of inflammatory cytokines and chemokines. Moreover, C5aR1 deficiency significantly decreased IMQ-induced infiltration of plasmacytoid dendritic cells (pDCs), monocytes and neutrophils in psoriatic skin lesions and functions of pDCs, evidenced by the remarkable reduction in the IMQ-induced production of interferon-α (IFN-α) and tumor necrosis factor α (TNF-α), and FMS-like tyrosine kinase 3 ligand (FLT3L)-dependent pDCs differentiation. Accordingly, in vitro treatment with recombinant C5a accelerated pDCs migration and the differentiation of bone marrow cells into pDCs. Furthermore, biopsies of psoriatic patients showed a dramatic increase of C5aR1 + pDCs infiltration in psoriatic skin lesions, compared to healthy subjects. Our results provide direct evidence that C5a/C5aR1 signaling plays a critical role in the pathogenesis of psoriasis. Inhibition of C5a/C5aR1 pathway is expected to be beneficial in the treatment of patients with psoriasis.

TNF-α and IFN-γ are the major pro-inflammatory cytokines in the β-cell destruction. However, the underlying mechanism remains unclear. The present study used a murine insulinoma cell line MIN6 for further investigation of the effect of Caspase-3 on the cytokines-induced pancreatic β-cell apoptosis and analyzed the mechanisms involved in the activation of Caspase-3. It was showed that the combination of IFN-γ and TNF-α significantly reduced the viability of MIN6 cells and the observed cells growth inhibition was due to cell apoptosis as judged by the morphological changes under a confocal laser scanning microscopy and FACS assay of Annexin-V/7-AAD double staining. Accompanying with NF-κB activation and Bcl-2 downregulation, both the cleaved Caspase-3 and PARP, a known substrate of Caspase-3 in vivo, were observed at 24 and 12 h, respectively, after cells exposure to IFN-γ and TNF-α treatment. Pretreatment of Caspase-3 inhibitors remarkably attenuated IFN-γ- and TNF-α-induced cells apoptosis. Inhibition of NF-κB activation led to the increase in Bcl-2 expression, a significant attenuation in Caspase-3 activity, and an obvious amelioration in cells viability in IFN-γ- and TNF-α-treated MIN6 cells. Taken together, our results indicate that Caspase-3 is critical for the induction of MIN6 cells apoptosis and it's activation is further confirmed to be related to the NF-κB-mediated Bcl-2 downregulation, which may be the underlying mechanism of IFN-γ- and TNF-α-mediated MIN6 cells apoptosis.

Sepsis is a life-threatening syndrome caused by a dysregulated host response to infection. 1,2 Sepsis most commonly results in multiorgan dysfunction, especially kidney dysfunction, namely sepsis-associated acute kidney injury (SA-AKI). It constitutes almost 50% of cases diagnosed with acute kidney injury in intensive care units (ICU). 3-7 Furthermore, SA-AKI increases the risk of chronic kidney disease and is a leading independent cause of high mortality. 2 Unlike any other phenotype of acute kidney injury (AKI), SA-AKI