Zinc and p53 disrupt mitochondrial binding of HK2 by phosphorylating VDAC1.

Many cell death regulators physically or functionally interact with metabolic enzymes. These interactions provide insights into mechanisms of anticancer treatments from the perspective of tumor cell metabolism and apoptosis. Recent studies have shown that zinc and p53 not only induce tumor cell apoptosis, but also regulate tumor cell metabolism. However, the underlying mechanism is complex and remains unclear, making further research imperative to provide clues for future cancer treatments. In this study, we found that hexokinase 2 (HK2), which has dual metabolic and apoptotic functions, is downstream of zinc and p53 in both prostate cancer patient tissue and prostate cancer cell lines. Notably, the mitochondrial location of HK2 is crucial for its function. We demonstrate that zinc and p53 disrupt mitochondrial binding of HK2 in prostate cancer cells by phosphorylating VDAC1, which is mediated by protein kinase B (Akt) inhibition and glycogen synthase kinase 3ß (GSK3ß) activation. In addition, we found that zinc combined with p53 significantly inhibited tumor growth in a prostate cancer cell xenograft model. Therefore, interference of the mitochondrial localization of HK2 by zinc and p53 may provide a new treatment approach for cancer.

Zinc promotes prostate cancer cell chemosensitivity to paclitaxel by inhibiting epithelial-mesenchymal transition and inducing apoptosis.

BACKGROUND: Paclitaxel (PTX) is a first-line chemotherapeutic drug for the treatment of prostate cancer. However, most patients develop resistance and metastasis, and thus new therapeutic approaches are urgently required. Recent studies have identified widespread anti-tumor effects of zinc (Zn) in various tumor cell lines, especially prostate cancer cells. In this study, we examined the effects of Zn as an adjuvant to PTX in prostate cancer cells. METHODS: PC3 and DU145 cells were treated with different concentrations of Zn and/or PTX. MTT assay was used to detect cell viability. Real-time cell analysis (RTCA) and microscopy were used to observe morphological changes in cells. Western blotting was used to detect the expression of epithelial-mesenchymal transition (EMT)-related proteins. qPCR (reverse transcription-polymerase chain reaction) was used to examine changes in TWIST1 mRNA levels. Cell invasion and migration were detected by scratch and transwell assays. shRNA against TWIST1 was used to knockdown TWIST1. Colony formation assay was used to detect cell proliferation, while Annexin V and propidium iodide (PI) staining was used to detect cell apoptosis. RESULTS: Zn and PTX increased proliferation inhibition in a dose- and time-dependent manner in prostate cancer cells, while Zn increased prostate cancer cell chemosensitivity to PTX. Combined Zn and PTX inhibited prostate cancer cell invasion and migration by downregulating the expression of TWIST1. Furthermore, knockdown of TWIST1 increased the sensitivity of prostate cancer cells to PTX. In addition, Zn and PTX reduced cell proliferation and induced apoptosis in prostate cancer cells. CONCLUSIONS: Our results demonstrated that Zn and PTX combined therapy inhibits EMT by reducing the expression of TWIST1, which reduces the invasion and migration of prostate cancer cells. SiTWIST1 increased the sensitivity of prostate cancer cells to PTX. In addition, with prolonged treatment, Zn and PTX inhibited proliferation and led to prostate cancer cell apoptosis. Therefore, Zn may be a potential adjuvant of PTX in treating prostate cancer and combined treatment may offer a promising therapeutic strategy for prostate cancer.

Dysregulated MiR-3150a-3p Promotes Lumbar Intervertebral Disc Degeneration by Targeting Aggrecan.

BACKGROUND/AIMS: Low back pain has become one of the most common musculoskeletal diseases in the world. Studies have shown that intervertebral disc degeneration (IDD) is an important factor leading to low back pain, but the mechanisms underlying IDD remain largely unknown. Research over the past decade has suggested critical roles for microRNAs (miRNAs) in natural growth and disease progression. However, it remains poorly understood whether circular RNAs participate in IDD. METHODS: Clinical IDD samples were collected from 20 patients who underwent discectomy. Weighted gene co-expression network analysis was used to identify the co-expression miRNA network modules (highly co-expressed clusters of miRNAs) that were associated with IDD grade. RESULTS: miR-3150a-3p was the most significantly up-regulated miRNA in module "Blue." Notably, aggrecan (ACAN) was identified as a direct target gene of miR-3150a-3p and ACAN expression was regulated by miR-3150a-3p. Overexpression of miR-3150a-3p decreased ACAN expression in nucleus pulposus cells, whereas inhibition of miR-3150a-3p increased ACAN expression. In addition, ACAN expression was negatively correlated with IDD grade. CONCLUSION: Our study suggests that the reduction of ACAN expression induced by the upregulation of miR-3150a-3p might participate in the development of IDD.

Zinc cooperates with p53 to inhibit the activity of mitochondrial aconitase through reactive oxygen species accumulation.

Metabolic reprogramming is a central hallmark of cancer. Therefore, targeting metabolism may provide an effective strategy for identifying promising drug targets for cancer treatment. In prostate cancer, cells undergo metabolic transformation from zinc-accumulating, citrate-producing cells to citrate-oxidizing malignant cells with lower zinc levels and higher mitochondrial aconitase (ACO2) activity. ACO2 is a Krebs cycle enzyme that converts citrate to isocitrate and is sensitive to reactive oxygen species (ROS)-mediated damage. In this study, we found that the expression of ACO2 is positively correlated with the malignancy of prostate cancer. Both zinc and p53 can lead to an increase in ROS. ACO2 can be a target for remodeling metabolism by sensing changes in the ROS levels of prostate cancer. Our results indicate that targeting ACO2 through zinc and p53 can change prostate cancer metabolism, and thus provides a potential new therapeutic strategy for prostate cancer.

Circular RNA GRB10 as a competitive endogenous RNA regulating nucleus pulposus cells death in degenerative intervertebral disk.

Intervertebral disc degeneration (IDD) is an important factor leading to low back pain, but the underlying mechanisms remain poorly understood. Compared with normal nucleus pulposus (NP) tissues, the expression of circ-GRB10 was downregulated in IDD. Furthermore, overexpression of circ-GRB10 inhibited NP cell apoptosis. circ-GRB10 could sequester miR-328-5p, which could potentially lead to the upregulation of target genes related to cell proliferation via the ErbB pathway. In conclusion, the present study revealed that circ-GRB10/miR-328-5p/ERBB2 signaling pathway is involved in IDD development, suggesting that circ-GRB10 might be a novel therapeutic target for IDD.

Silencing Transmembrane Protein 45B (TNEM45B) Inhibits Proliferation, Invasion, and Tumorigenesis in Osteosarcoma Cells.

Transmembrane protein 45B (TMEM45B) is a member of the TMEM family of proteins and has been reported to be expressed abnormally in different kinds of human tumors. However, the biological function of TMEM45B in osteosarcoma remains unclear. The objective of this study was to investigate the role of TMEM45B in regulating the biological behavior of osteosarcoma cells. Our results demonstrated that the expression of TMEM45B at both the protein and mRNA levels was dramatically upregulated in human osteosarcoma cell lines. Knockdown of TMEM45B significantly suppressed the proliferation, migration, and invasion of U2OS cells in vitro. Mechanistically, knockdown of TMEM45B sharply downregulated the expression level of ß-catenin, cyclin D1, and c-Myc in U2OS cells. Finally, knockdown of TMEM45B attenuated tumor growth in transplanted U2OS-derived tumors in nude mice. Taken together, our results demonstrated that TMEM45B plays an important role in regulating the proliferation, migration, and invasion of osteosarcoma cells and that its effects on proliferation and invasion were mediated partially through the Wnt/ß-catenin signaling pathway. These observations support our belief that TMEM45B may serve as an oncogene in the development and progression of osteosarcoma.

Case of Langerhans Cell Histiocytosis That Mimics Meningioma in CT and MRI.

Langerhans cell histiocytosis (LCH) is a rare disorder histologically characterized by the proliferation of Langerhans cells. Here we present the case of a 13-year-old girl with LCH wherein CT and MRI results led us to an initially incorrect diagnosis of meningioma. The diagnosis was corrected to LCH based on pathology findings. An intracranial mass was found mainly in the dura mater, with thickening of the surrounding dura. It appeared to be growing downward from the calvaria, pressing on underlying brain tissue, and had infiltrated the inner skull, causing a bone defect. The lesion was calcified with the typical dural tail sign. The dural origin of the lesion was verified upon surgical dissection. There are no previous reports in the literature describing LCH of dural origin presenting in young patients with typical dural tail signs and meningioma-like imaging findings. The current case report underscores the need for thorough histological and immunocytochemical examinations in LCH differential diagnosis.

[Changes of osteocalcin in bone and bone marrow in tail suspended rats].

OBJECTIVE: To study osteocalcin [correction of osteocakin] (OC) changes in bone and marrow and calcium deposition in bone and cartilage under simulated weightlessness. METHOD: Twenty SD rats were randomly divided into 14 d and 28 d tail suspension group and 2 corresponding control groups. Histological samples were in situ hybridized and trichrome stained. RESULT: OC expression of bone and marrow of rats were lower in tail suspended rats than that in the control (P<0.05). OC expression in 14 d tail suspended rats were higher than that in 28 d tail suspended group (P<0.05). Mineralization was inhibited, and demineralization of femur [correction of furmer] and cartilage mineralized matrix was prominent. Demineralization was more prominent in 28 d group. CONCLUSION: OC levels in bone and marrow of rats were lower after tail suspension. Calcium deposition was inhibited in bone and cartilage. Demineralization was prominent after long term hindlimb unloading.

Coronary CT angiography incorporating Doppler-guided prospective ECG gating in patients with high heart rate: comparison with results of traditional prospective ECG gating.

PURPOSE: As Doppler ultrasound has been proven to be an effective tool to predict and compress the optimal pulsing windows, we evaluated the effective dose and diagnostic accuracy of coronary CT angiography (CTA) incorporating Doppler-guided prospective electrocardiograph (ECG) gating, which presets pulsing windows according to Doppler analysis, in patients with a heart rate >65 bpm. MATERIALS AND METHODS: 119 patients with a heart rate >65 bpm who were scheduled for invasive coronary angiography were prospectively studied, and patients were randomly divided into traditional prospective (n = 61) and Doppler-guided prospective (n = 58) ECG gating groups. The exposure window of traditional prospective ECG gating was set at 30%-80% of the cardiac cycle. For the Doppler group, the length of diastasis was analyzed by Doppler. For lengths greater than 90 ms, the pulsing window was preset during diastole (during 60%-80%); otherwise, the optimal pulsing intervals were moved from diastole to systole (during 30%-50%). RESULTS: The mean heart rates of the traditional ECG and the Doppler-guided group during CT scanning were 75.0±7.7 bpm (range, 66-96 bpm) and 76.5±5.4 bpm (range: 66-105 bpm), respectively. The results indicated that whereas the image quality showed no significant difference between the traditional and Doppler groups (P = 0.42), the radiation dose of the Doppler group was significantly lower than that of the traditional group (5.2±3.4 mSv vs. 9.3±4.5 mSv, P<0.001). The sensitivities of CTA applying traditional and Doppler-guided prospective ECG gating to diagnose stenosis on a segment level were 95.5% and 94.3%, respectively; specificities 98.0% and 97.1%, respectively; positive predictive values 90.7% and 88.2%, respectively; negative predictive values 99.0% and 98.7%, respectively. There was no statistical difference in concordance between the traditional and Doppler groups (P = 0.22). CONCLUSION: Doppler-guided prospective ECG gating represents an improved method in patients with a high heart rate to reduce effective radiation doses, while maintaining high diagnostic accuracy.

Evaluation of anterior ethmoidal artery by 320-slice CT angiography with comparison to three-dimensional spin digital subtraction angiography: initial experiences.

OBJECTIVE: To explore the usefulness of 320-slice CT angiography (CTA) for evaluating the course of the anterior ethmoidal artery (AEA) and its relationship with adjacent structures by using three-dimensional (3D) spin digital subtraction angiography (DSA) as standard reference. MATERIALS AND METHODS: From December 2008 to December 2010, 32 patients with cerebrovascular disease, who underwent both cranial 3D spin DSA and 320-slice CTA within a 30 day period from each other, were retrospectively reviewed. AEA course in ethmoid was analyzed in DSA and CTA. In addition, adjacent bony landmarks (bony notch in medial orbital wall, anterior ethmoidal canal, and anterior ethmoidal sulcus) were evaluated with CTA using the MPR technique oriented along the axial, coronal and oblique coronal planes in all patients. The dose length product (DLP) for CTA and the dose-area product (DAP) for 3D spin DSA were recorded. Effective dose (ED) was calculated. RESULTS: The entire course of the AEA was seen in all 32 cases (100%) with 3D spine DSA and in 29 of 32 cases (90.1%) with 320-slice CTA, with no significant difference (p = 0.24). In three cases where AEA was not visualized on 320-slice CTA, two were due to the dominant posterior ethmoidal artery, while the remaining case was due to diminutive AEA. On MPR images of 320-slice CT, a bony notch in the orbital medial walls was detected in all cases (100%, 64 of 64); anterior ethmoidal canal was seen in 28 of 64 cases (43.8%), and the anterior ethmoidal sulcus was seen in 63 of 64 cases (98.4%). The mean effective dose in CTA was 0.6 ± 0.25 mSv, which was significantly lower than for 3D spin DSA (1.3 ± 0.01 mSv) (p < 0.001). CONCLUSION: 320-slice CTA has a similar detection rate for AEA to that of 3D spin DSA; however, it is noninvasive, and may be preferentially used for the evaluation of AEA and its adjacent bony variations and pathologic changes in preoperative patients with paranasal sinus diseases.

[Accumulation of soil arsenic by Panax notoginseng and its associated health risk].

Panax notoginseng is a valued traditional Chinese medical herb. In this study, the arsenic (As) contamination of soil in P. notoginseng plantation area in Wenshan (Yunnan, China) was investigated; the absorption and accumulation of soil As by the P. notoginseng was revealed; and the associated health risk was evaluated. The results revealed that the soil As concentrations ranged between 6.9-242.0 mg x kg(-1). Arsenic concentrations in 48% of the total soil samples were > 40 mg x kg(-1). The As concentrations in 24% of main root samples, 81% of fibrous root samples, 14% of stem samples, 57% of leaf samples, and 44% of flower/fruit samples were greater than the regulation concentration of 2.0 mg x kg(-1). Arsenic accumulation in the main root increased with the soil As concentration at soil As concentrations < 100 mg x kg(-1), but sharply decreased with the soil As concentration at soil As concentrations > 100 mg x kg(-1). With increasing soil As concentration, the total biomass of P. notoginseng and the main root biomass decreased. Calculating with the As concentration in different parts of Sanqi P. notoginseng plants, percent of the average ingestion rates of As with ADI regulated by FAO/WHO showed fibrous root > leave > flower/fruit > main root > stem. Based on the As concentration in the main root, the daily As intake accounted for a mean fraction of 12.83% (maximum 45.87%) of the acceptable daily intake specified by FAO/WHO,and the ratio increased with the increasing of soil As concentration. Arsenic contamination of soil and P. notoginseng at the plantation area of Wenshan should not be neglected, and effective strategies should be adopt to reduce As accumulation in the plant and human health risk.