Characterization of circSEC11A as a novel regulator of Iodine-125 radioactive seed-induced anticancer effects in hepatocellular carcinoma via targeting ZHX2/GADD34 axis.

Iodine-125 (I-125) radioactive seed implantation is used for the local treatment of hepatocellular carcinoma (HCC), but the molecular mechanisms regulating its anticancer effects remain incompletely understood. In this study, we report that hsa_circ_0000647 (circSEC11A) is highly expressed after I-125 treatment in HCC cell lines and tissues and is a key regulator of I-125-induced anticancer effects. CircSEC11A acts as a competing endogenous RNA (ceRNA) to sponge miR-3529-3p, promoting the expression of zinc fingers and homeoboxes 2 (ZHX2) and enhancing I-125-induced anticancer effects. Dual-luciferase reporter assay, RNA pull-down, RNA immunoprecipitation, and fluorescence in situ hybridization were thereafter performed to verify the interaction among the molecules. Anticancer effects were detected using CCK-8, flow cytometry, TUNEL, EdU, transwell, and wound healing assays. Furthermore, ZHX2 transcriptionally inhibits GADD34, a negative regulator of endoplasmic reticulum stress (ERS), to enhance I-125- induced anticancer effects in vivo and in vitro. In conclusion, we characterized circSEC11A as a novel regulator of I-125-induced anticancer effects in HCC via miR-3529-3p/ZHX2/GADD34 axis-mediated ERS. Thus, circSEC11A may act as a potential therapeutic target for I-125 implantation in the clinic.

Chimney Technique and Single-Branched Stent Graft for the Left Subclavian Artery Preservation During Zone 2 Thoracic Endovascular Aortic Repair for Type B Acute Aortic Syndromes.

PURPOSE: The purpose of this study was to evaluate the efficacy and safety of zone 2 thoracic endovascular aortic repair assisted by the chimney technique or single-branched stent graft for the preservation of the left subclavian artery, and summarize our single-center experience with the techniques. MATERIALS AND METHODS: From February 2017 to June 2020, 137 patients who underwent left subclavian artery revascularization during zone 2 thoracic endovascular aortic repair were enrolled. Patients had acute type B aortic dissection and penetrating aortic ulcer associated with intramural hematoma. The chimney technique was performed in 68 patients (group A), and single-branched stent graft was deployed in 69 patients (group B). All procedures were performed during the acute phase. Primary technical success, immediate postoperative endoleak, neurologic complications (stroke or spinal cord ischemia), 30-day mortality, 1-year technical success, all-cause mortality, patency of the left subclavian artery, and reintervention were analyzed. Comparing the occurrence of the Bird-Beak Configuration, defined as a gap between the aortic wall and the sent graft with stent protrusion into the aortic lumen more than 5 mm, was also performed. RESULTS: Primary technique success was achieved in 66 and 67 patients in groups A and B, respectively. The incidence of immediate postoperative endoleak, neurologic complications (stroke or spinal cord ischemia), and 30-day mortality were 5.9%, 1.5%, and 4.4% in group A, and 2.9%, 2.9%, and 2.9% in group B, respectively. During follow-up, the 1-year technical success rate was similar in both groups. All-cause mortality was similar in both groups (3.1% in group A and 4.5% in group B). The patency of the left subclavian artery was not significantly different between the 2 groups with 2 and 3 occlusions in groups A and B, respectively. The rate of reintervention was higher in group B (3.1% vs 1.6%, p=0.536), with a non-significant difference. Bird-Beak Configuration was more prominent in group B with the incidence of 59.42%. CONCLUSIONS: Acting as minimally invasive alternatives, both techniques are feasible for left subclavian artery preservation during zone 2 thoracic endovascular aortic repair for type B acute aortic syndromes with encouraging mid-term outcomes. Long-term follow-up is required to confirm these findings.

Mechanism of calcitriol regulating parathyroid cells in secondary hyperparathyroidism.

A common consequence of chronic renal disease is secondary hyperparathyroidism (SHPT) and is closely related to the mortality and morbidity of uremia patients. Secondary hyperparathyroidism (SHPT) is caused by excessive PTH production and release, as well as parathyroid enlargement. At present, the mechanism of cell proliferation in secondary hyperparathyroidism (SHPT) is not completely clear. Decreased expression of the vitamin D receptor (VDR) and calcium-sensing receptor (CaSR), and 1,25(OH)2D3 insufficiency all lead to a decrease in cell proliferation suppression, and activation of multiple pathways is also involved in cell proliferation in renal hyperparathyroidism. The interaction between the parathormone (PTH) and parathyroid hyperplasia and 1,25(OH)2D3 has received considerable attention. 1,25(OH)2D3 is commonly applied in the therapy of renal hyperparathyroidism. It regulates the production of parathormone (PTH) and parathyroid cell proliferation through transcription and post-transcription mechanisms. This article reviews the role of 1,25(OH)2D3 in parathyroid cells in secondary hyperparathyroidism and its current understanding and potential molecular mechanism.

Pro- and anti-fibrotic effects of vascular endothelial growth factor in chronic kidney diseases.

Renal fibrosis is the inevitable common end-point of all progressive chronic kidney diseases. The underlying mechanisms of renal fibrosis are complex, and currently there is no effective therapy against renal fibrosis. Renal microvascular rarefaction contributes to the progression of renal fibrosis; however, an imbalance between proangiogenic and antiangiogenic factors leads to the loss of renal microvasculature. Vascular endothelial growth factor (VEGF) is the most important pro-angiogenic factor. Recent studies have unraveled the involvement of VEGF in the regulation of renal microvascular rarefaction and fibrosis via various mechanisms; however, it is not clear whether it has anti-fibrotic or pro-fibrotic effect. This paper reviews the available evidence pertaining to the function of VEGF in the fibrotic process and explores the associated underlying mechanisms. Our synthesis will help identify the future research priorities for developing specialized treatments for alleviating or preventing renal fibrosis. Abbreviation: VEGF: vascular endothelial growth factor; CKD: chronic kidney disease; ESKD: end-stage kidney disease; ER: endoplasmic reticulum; VEGFR: vascular endothelial growth factor receptor; AKI: acute kidney injury; EMT: epithelial-to-mesenchymal transition; HIF: hypoxia-inducible factor; α-SMA: α smooth muscle actin; UUO: unilateral ureteral obstruction; TGF-ß: transforming growth factor-ß; PMT: pericyte-myofibroblast transition; NO: nitric oxide; NOS: nitric oxide synthase; nNOS: neuronal nitric oxide synthase; iNOS: inducible nitric oxide synthase; eNOS: endothelial nitric oxide synthase; sGC: soluble guanylate cyclase; PKG: soluble guanylate cyclase dependent protein kinases; UP R: unfolded protein response.

Magnesium in renal fibrosis.

PURPOSE: Renal fibrosis (RF) is the main pathological feature of chronic kidney disease (CKD). The main focus of research on treatment for CKD is to develop strategies that delay or prevent RF from progressing to end-stage renal disease (ESRD). Inflammation and oxidative stress occur during all stages of CKD. The magnesium cation (Mg2+) can reduce inflammation and oxidative stress, regulate apoptosis, and improve RF, and magnesium-based therapies are promising new treatments that can prevent RF. We reviewed the current evidence on the effects of magnesium in RF and examined the possible mechanism of magnesium in delaying RF. METHODS: We searched PubMed, Web of Science, and EMBASE for articles on magnesium and fibrosis, with a focus on magnesium and RF. RESULTS: Inflammation, oxidative stress, and apoptosis are related to the occurrence of CKD. Previous research showed that Mg2+ inhibits the differentiation of inflammatory cells, down-regulates the production of inflammatory cytokines, reduces inflammation, and reduces the production of reactive oxygen species (ROS) and oxidative stress. In addition, Mg2+ also regulates apoptosis and protects renal tubular function. Magnesium may also regulate TRPM6/7, promote the secretion of klotho protein and improve renal fibrosis. Therefore, Mg2+ can protect the kidney from damage and slow down the progression of RF through many molecular and cellular effects. Some of the anti-fibrotic effects of Mg2+ may be related to its antagonism of intracellular Ca2+. CONCLUSION: Magnesium may prevent the progression of renal fibrosis and delay CKD by reducing renal inflammation and oxidative stress, and by regulating fibrosis-related signaling pathways and cytokines.

The role of bile acid subtypes in the diagnosis of cholangiocarcinoma.

OBJECTIVES: To find the potential biomarkers of cholangiocarcinoma, form a biomarker package, evaluate its efficiency, and validate it. METHODS: R software was used to analyze the differential expression of mRNAs between cholangiocarcinoma and adjacent nontumorous tissues, obtained from The Cancer Genome Atlas (TCGA), and enrich the KEGG pathway. Metabo-Profile Inc. performed the comprehensive bile acid profiling and quantitation. The training set concluded 20 cholangiocarcinoma and 20 nontumorous volunteers. Receiver operating characteristic (ROC) curve and accompanying area under the curve (AUC) was calculated. The top four bile acids formed a new biomarker package. The validation set included 15 cholangiocarcinoma and 15 nontumorous, and the sensitivity and specificity of the new biomarker package were tested. RESULTS: Gene expression of 36 cholangiocarcinoma and nine adjacent nontumorous tissues was obtained in January 2020. Totally 9887 differential genes were eligible (logFC ≥ 1 or ≤ -1, P < 0.05, and adjust P < 0.01). GO analysis showed that 20 KEGG pathways were enriched, including primary bile acid biosynthesis and bile secretion. Comprehensive bile acid profiling and quantitation showed 15 differential bile acid types, and the ROC-AUC was between 0.953 and 0.750. HDCA, isoLCA, bCDCA, and DCA were selected to form a biomarker package. The Logit (p = cholangiocarcinoma) = 7.898 - 3.70*(1isoLCA) - 0.444*(bCDCA) + 0.415*(HDCA) + 0.041*DCA. Its ROC-AUC was 0.944. In the validation set, the sensitivity was 0.933 and the specificity was 0.867. CONCLUSION: Bile acid types package was efficient to distinguish nontumorous population and cholangiocarcinoma. The difference might be associated to the downregulation of primary bile acid biosynthesis and bile secretion pathway of cholangiocarcinoma.

Scutellarin improves the radiosensitivity of non-small cell lung cancer cells to iodine-125 seeds via downregulating the AKT/mTOR pathway.

BACKGROUND: In our previous study, we indicated that scutellarin (SCU) induced an anticancer effect in A549 cells. However, whether SCU regulates the radiosensitivity of non-small cell lung cancer (NSCLC) and its related mechanism is still unclear. METHODS: In this study, we explored the anticancer effect induced by iodine-125 (125 I) and SCU at a sensitizing concentration in A549 and H1975 cells. Cellular apoptosis and proliferation were detected by flow cytometry, Bcl-2/Bax expression level, cell cycle, CCK-8, and EdU staining. A tumor model using nude mice was also carried out to investigate the combined effect of 125 I and SCU in vivo. In addition, the expression level of AKT/mTOR pathway was detected to investigate whether it is linked to the anticancer effect of 125 I and SCU. RESULTS: SCU at a sensitizing concentration promoted the 125 I-induced apoptosis and antiproliferative effect in A549 and H1975 cells. Moreover, the same results were obtained in vivo. Based on our findings, the AKT/mTOR pathway was significantly downregulated after combined treatment with 125 I and SCU. CONCLUSIONS: The results of our study suggested that SCU promotes the anticancer effects induced by 125 I in NSCLC cells by downregulating the AKT/mTOR pathway and lays a foundation for future application of this combined treatment.