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Circular RNAs (circRNAs) participate in the pathogenesis of various diseases by sponging microRNAs (miRs). However, the roles of circRNAs remain unreported in glomerular diseases. We previously reported that miR-150 positively correlated with renal chronicity index in patients with lupus nephritis (LN). We aimed to investigate renal circRNA profiling and the interaction between circRNAs and miR-150 in LN patients. Six renal biopsies from untreated female patients with LN class IV and five normal kidney tissues from urology patients were used for circRNA sequencing. 171 circRNAs with 2-fold differential expression were identified in LN compared with normal control. Ten selected circRNAs were validated by real-time qPCR, and seven circRNAs showed the same significant increases as the sequencing results. circHLA-C positively correlated with proteinuria (R = 0.92, p < 0.01), serum creatinine (R = 0.76, p = 0.08), renal activity index (R = 0.88, p < 0.05), and crescentic glomeruli (R = 0.93, p < 0.01). Renal circHLA-C increased 2.72-fold, and miR-150 decreased 66% in LN compared with normal control (p < 0.05). Bio-informatic analysis predicted miR-150 was regulated by circHLA-C and displayed one perfect match seed between circHLA-C and miR-150. The renal miR-150 showed a tendency of negative correlation with circHLA-C in LN patients. In conclusion, circHLA-C may play an important role in the pathogenesis of lupus nephritis by sponging miR-150.

Accumulating evidence indicates that ectopic expression of non‐coding RNAs are responsible for breast cancer progression. Increased non‐coding RNA PVT1, the host gene of microRNA‐1207‐5p (miR‐1207‐5p), has been associated with breast cancer proliferation. However, how PVT1 functions in breast cancer is still not clear. In this study, we show a PVT1‐derived microRNA, miR‐1207‐5p, that promotes the proliferation of breast cancer cells by directly regulating STAT6. We first confirm the positive correlated expression pattern between PVT1 and miR‐1207‐5p by observing consistent induced expression by estrogen, and overexpression in breast cancer cell lines and breast cancer patient specimens. Moreover, silence of PVT1 also decreased miR‐1207‐5p expression. Furthermore, increased miR‐1207‐5p expression promoted, while decreased miR‐1207‐5p expression suppressed, cell proliferation, colony formation, and cell cycle progression in breast cancer cell lines. Mechanistically, a novel target of miR‐1207‐5p,STAT6, was identified by a luciferase reporter assay. Overexpression of miR‐1207‐5p decreased the levels of STAT6, which activated CDKN1A and CDKN1B to regulate the cell cycle. We also confirmed the reverse correlation of miR‐1207‐5p and STAT6 expression levels in breast cancer samples. Therefore, our findings reveal that PVT1‐derived miR‐1207‐5p promotes the proliferation of breast cancer cells by targeting STAT6, which in turn controls CDKN1A and CDKN1B expression. These findings suggest miR‐1207‐5p might be a potential target for breast cancer therapy.

BackgroundIntracavitary electrocardiogram (IC ECG) guidance emerges as a new technique for peripherally inserted central catheters (PICCs) placement and demonstrates many potential advantages in recent observational studies.AimsTo determine whether IC ECG-guided PICCs provide more accurate positioning of catheter tips compared to conventional anatomical landmarks in patients with cancer undergoing chemotherapy.MethodsIn this multicenter, open-label, randomized controlled study (ClinicalTrials.gov number, NCT02409589), a total of 1,007 adult patients were assigned to receive either IC ECG guidance (n = 500) or anatomical landmark guidance (n = 507) for PICC positioning. The confirmative catheter tip positioning x-ray data were centrally interpreted by independent radiologists. All reported analyses in the overall population were performed on an intention-to-treat basis. Analyses of pre-specified subgroups and a selected large subpopulation were conducted to explore consistency and accuracy.ResultsIn the IC ECG-guided group, the first-attempt success rate was 89.2% (95% confidence interval [CI], 86.5% to 91.9%), which was significantly higher than 77.4% (95% CI, 73.7% to 81.0%) in the anatomical landmark group (P < 0.0001). This trend of superiority of IC ECG guidance was consistently noted in almost all prespecified patient subgroups and two selected large subpopulations, even when using optimal target rates for measurement. In contrast, the superiority nearly disappeared when PICCs were used via the left instead of right arms (interaction P-value = 0.021). No catheter-related adverse events were reported during the PICC intra-procedures in either group.ConclusionsOur findings indicated that the IC ECG-guided method had a more favorable positioning accuracy versus traditional anatomical landmarks for PICC placement in adult patients with cancer undergoing chemotherapy. Furthermore, there were no significant safety concerns reported for catheterization using the two techniques.

Cardamonin (CD), a naturally occurring chalcone isolated from large black cardamom, was previously reported to suppress the proliferation of breast cancer cells. However, its precise molecular anti‐tumor mechanisms have not been well elucidated. In this study, we found that CD markedly inhibited the proliferation of MDA‐MB 231 and MCF‐7 breast cancer cells through the induction of G2/M arrest and apoptosis. Reactive oxygen species (ROS) plays a pivotal role in the inhibition of CD‐induced cell proliferation. Treatment with N‐acetyl‐cysteine (NAC), an ROS scavenger, blocked CD‐induced G2/M arrest and apoptosis in this study. Quenching of ROS by overexpression of catalase also blocked CD‐induced cell cycle arrest and apoptosis. We showed that CD enhanced the expression and nuclear translocation of Forkhead box O3 (FOXO3a) via upstream c‐Jun N‐terminal kinase, inducing the expression of FOXO3a and its target genes, including p21, p27, and Bim. This process led to the reduction of cyclin D1 and enhancement of activated caspase‐3 expression. The addition of NAC markedly reversed these effects, knockdown of FOXO3a using small interfering RNA also decreased CD‐induced G2/M arrest and apoptosis. In vivo, CD efficiently suppressed the growth of MDA‐MB 231 breast cancer xenograft tumors. Taken together, our data provide a molecular mechanistic rationale for CD‐induced cell cycle arrest and apoptosis in breast cancer cells.

Cervical radiculopathy represents aberrant mechanical hypersensitivity. Primary sensory neuron’s ability to sense mechanical force forms mechanotransduction. However, whether this property undergoes activity-dependent plastic changes and underlies mechanical hypersensitivity associated with cervical radiculopathic pain (CRP) is not clear. Here we show a new CRP model producing stable mechanical compression of dorsal root ganglion (DRG), which induces dramatic behavioral mechanical hypersensitivity. Amongst nociceptive DRG neurons, a mechanically sensitive neuron, isolectin B4 negative Aδ-type (IB4− Aδ) DRG neuron displays spontaneous activity with hyperexcitability after chronic compression of cervical DRGs. Focal mechanical stimulation on somata of IB4- Aδ neuron induces abnormal hypersensitivity. Upregulated HCN1 and HCN3 channels and increased Ih current on this subset of primary nociceptors underlies the spontaneous activity together with neuronal mechanical hypersensitivity, which further contributes to the behavioral mechanical hypersensitivity associated with CRP. This study sheds new light on the functional plasticity of a specific subset of nociceptive DRG neurons to mechanical stimulation and reveals a novel mechanism that could underlie the mechanical hypersensitivity associated with cervical radiculopathy.

BackgroundThe prevalence of lupus nephritis (LN) remains high despite various emerging monoclonal antibodies against with targeting systemic lupus erythematosus (SLE). Renal fibrosis is the main feature of late stage LN, and novel therapeutic agents are still needed. We previously reported that microRNA (miR)-150 increases in renal biopsies of American LN patients and that miR-150 agonist promotes fibrosis in cultured kidney cells. Presently, we aim to verify whether locked nucleic acid (LNA)-anti-miR-150 can ameliorate LN in mice and to investigate its corresponding mechanisms.MethodsWe first observed natural history and renal miR-150 expression in female Fcgr2b−/− mice of a spontaneously developed LN model. We then verified miR-150 renal absorption and determined the dose of the suppressed miR-150 by subcutaneous injection of LNA-anti-miR-150 (2 and 4 mg/kg). Thirdly, we investigated the therapeutic effects of LNA-anti-miR-150 (2 mg/kg for 8 weeks) on LN mice and the corresponding mechanisms by studying fibrosis-related genes, cytokines, and kidney resident macrophages. Lastly, we detected the expression of renal miR-150 and the mechanism-associated factors in renal biopsies from new onset untreated LN patients.ResultsFcgr2b−/− mice developed SLE indicated by positive serum autoantibodies at age 19 weeks and LN demonstrated by proteinuria at age 32 weeks. Renal miR-150 was overexpressed in LN mice compared to wild type mice. FAM-labeled LNA-anti-miR-150 was absorbed by both glomeruli and renal tubules. LNA-anti-miR-150 suppressed the elevated renal miR-150 levels in LN mice compared to the scrambled LNA without systemic toxicity. Meanwhile, serum double strand-DNA antibody, proteinuria, and kidney injury were ameliorated. Importantly, the elevated renal pro-fibrotic genes (transforming growth factor-β1, α-smooth muscle antibody, and fibronectin) and decreased anti-fibrotic gene suppressor of cytokine signal 1 were both reversed. Renal pro-inflammatory cytokines (interferon-γ, interleukin-6, and tumor necrosis factor-α) and macrophages were also decreased. In addition, the changes of renal miR-150 and associated proteins shown in LN mice were also seen in human subjects.ConclusionsLNA-anti-miR-150 may be a promising novel therapeutic agent for LN in addition to the current emerging monoclonal antibodies, and its renal protective mechanism may be mediated by anti-fibrosis and anti-inflammation as well as reduction of the infiltrated kidney resident macrophages.

Highlights The cationic waterborne polyurethanes microspheres with Diels-Alder bonds were synthesized for the first time. The electrostatic attraction not only endows the composite with segregated structure to gain high electromagnetic-interference shielding effectiveness, but also greatly enhances mechanical properties. Efficient healing property was realized under heating environment. Abstract It is still challenging for conductive polymer composite-based electromagnetic interference (EMI) shielding materials to achieve long-term stability while maintaining high EMI shielding effectiveness (EMI SE), especially undergoing external mechanical stimuli, such as scratches or large deformations. Herein, an electrostatic assembly strategy is adopted to design a healable and segregated carbon nanotube (CNT)/graphene oxide (GO)/polyurethane (PU) composite with excellent and reliable EMI SE, even bearing complex mechanical condition. The negatively charged CNT/GO hybrid is facilely adsorbed on the surface of positively charged PU microsphere to motivate formation of segregated conductive networks in CNT/GO/PU composite, establishing a high EMI SE of 52.7 dB at only 10 wt% CNT/GO loading. The Diels–Alder bonds in PU microsphere endow the CNT/GO/PU composite suffering three cutting/healing cycles with EMI SE retention up to 90%. Additionally, the electrostatic attraction between CNT/GO hybrid and PU microsphere helps to strong interfacial bonding in the composite, resulting in high tensile strength of 43.1 MPa and elongation at break of 626%. The healing efficiency of elongation at break achieves 95% when the composite endured three cutting/healing cycles. This work demonstrates a novel strategy for developing segregated EMI shielding composite with healable features and excellent mechanical performance and shows great potential in the durable and high precision electrical instruments.