Retracted Article: PVT1 knockdown alleviates vancomycin-induced acute kidney injury by targeting miR-124 via inactivation of NF-κB signaling

Acute kidney injury (AKI) is a serious threat for human health and life. High dose of vancomycin (VAN) can give rise to AKI. The roles and molecular basis of long noncoding RNA plasmacytoma variant translocation 1 (PVT1) in VAN-induced AKI have been poorly defined till now. Protein levels of p65, phosphorylated p65 (p-p65), NF-κB inhibitor alpha (IκBα), phosphorylated IκBα (p-IκBα), Bcl-2 and Bax were measured by western blot assay. RNA levels of PVT1 and microRNA-124 (miR-124) were determined by RT-qPCR assay. HK-2 cell apoptosis was detected by an Annexin V-FITC apoptosis detection assay. Kidney functions were assessed by blood urea nitrogen (BUN) level, serum creatinine (Scr) level, histopathologic analysis, and TUNEL assay. Bioinformatical analysis, luciferase reporter assay, RIP and RNA pull down assays were performed to explore whether PVT1 could interact with miR-124. PVT1 was highly expressed in VAN-induced AKI models. Functional analysis revealed that PVT1 knockdown ameliorated VAN-induced AKI in vivo. Further exploration manifested that PVT1 directly interacted with miR-124. Moreover, the silencing of PVT1 abated VAN-induced HK-2 cell apoptosis in vitro, while this effect was reversed by the miR-124 inhibitor. Also, VAN treatment resulted in the reduction of miR-124 expression and the activation of NF-κB signaling in HK-2 cells. The inhibition of NF-κB alleviated VAN-induced HK-2 cell apoptosis. PVT1 activated NF-κB signaling by targeting miR-124 in VAN-induced HK-2 cells. PVT1 knockdown lessened VAN-induced AKI by targeting miR-124 via inactivating the NF-κB signaling, elucidating the critical roles and molecular basis of PVT1 in VAN-induced AKI and highlighting the diagnostic and therapeutic values of PVT1 in AKI.

PVT1 was highly expressed in the kidneys of VAN-induced AKI mice.     

Discovery and preliminary SAR of 14-aryloxy-andrographolide derivatives as antibacterial agents with immunosuppressant activity

Antibacterials (which restore gut flora balance) and immunosuppressants (which correct immune defects) are two important and effective therapeutic agents for the treatment of inflammatory bowel disease (IBD) in clinical use today. Since the structural skeleton of andrographolide, isolated from Andrographis paniculata, has become known as a natural antibiotic with anti-inflammation and heat-clearing and detoxifying properties, 14-aryloxy andrographolide derivatives have been designed, synthesized, and tested for their antibacterial effects on E. coli, S. aureus, and E. faecalis, which are related to IBD. It has been discovered in this study that the andrographolide skeleton is more selective against E. faecalis, the 14-aryloxy group with basicity is important for antibacterial functions, and the 14-(8′-quinolinyloxy) group is a good pharmacophore with antibacterial activity. In addition, we found that 7b1 and 8b1 are good and selective inhibitors of E. faecalis; two 14β-(8′-quinolinyloxy) andrographolide derivatives, 6b17 and 9b, exhibit good activity against E. coli, S. aureus, and E. faecalis. Likewise and importantly, further exploration of immunosuppressant activity for IBD shows that compound 7b1 is a selective inhibitor of the TNF-α/NF-κB signaling pathway, whereas 8b1 is selectively active against the TLR4/NF-κB signaling pathway; moreover, the compounds 6b17 and 9b are active in inhibiting the IL-6/STAT3, TLR4/NF-κB, and TNF-α/NF-κB signaling pathways. Based on these results, we have further focused on the development of dual function inhibitors of IBD as antibacterial and immunosuppressant agents by structural modification of andrographolide.

6b17 and 9b are active against 3 tested bacteria while they block IL-6/STAT3, TLR4/NF-κB and TNF-α/NF-κB pathways. 7b1 and 8b1 are selectively active against E. faecalis but 7b1 selectively blocks TNF-α/NF-κB pathway and 8b1 selectively blocks TLR4/NF-κB pathway.     

Immunomodulatory mechanism of α-d-(1→6)-glucan isolated from banana

Banana is a delicious fruit with potent immunomodulatory function. In this study, α-d-(1→6)-glucan was purified from banana pulp. It could significantly promote pinocytic activity and production of nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). The mRNA expression of nitric oxide synthase (iNOS), IL-6 and TNF-α was increased in RAW264.7 macrophages. α-d-(1→6)-glucan could not only increase the expression levels of p-p65 and p-IκBα, but also induce the translocation of nuclear factor-kappa B (NF-κB) p65 into the nucleus. Moreover, mitogen-activated protein kinases (MAPKs), including p-ERK, p-JNK and p-p38, were upregulated. These results suggested that NF-κB and MAPK signaling pathways were involved in the immunomodulatory mechanisms of α-d-(1→6)-glucan. The results revealed that α-d-(1→6)-glucan might be the critical component responsible for the health benefits of banana.

Banana is a delicious fruit with potent immunomodulatory function.     

TGF-β induces miR-182 to sustain NF-κB activation in glioma subsets

The strength and duration of NF-κB signaling are tightly controlled by multiple negative feedback mechanisms. However, in cancer cells, these feedback loops are overridden through unclear mechanisms to sustain oncogenic activation of NF-κB signaling. Previously, we demonstrated that overexpression of miR-30e* directly represses IκBα expression and leads to hyperactivation of NF-κB. Here, we report that miR-182 was overexpressed in a different set of gliomas with relatively lower miR-30e* expression and that miR-182 directly suppressed cylindromatosis (CYLD), an NF-κB negative regulator. This suppression of CYLD promoted ubiquitin conjugation of NF-κB signaling pathway components and induction of an aggressive phenotype of glioma cells both in vitro and in vivo. Furthermore, we found that TGF-β induced miR-182 expression, leading to prolonged NF-κB activation. Importantly, the results of these experiments were consistent with an identified significant correlation between miR-182 levels with TGF-β hyperactivation and activated NF-κB in a cohort of human glioma specimens. These findings uncover a plausible mechanism for sustained NF-κB activation in malignant gliomas and may suggest a new target for clinical intervention in human cancer.