5-ARI induces autophagy of prostate epithelial cells through suppressing IGF-1 expression in prostate fibroblasts.

OBJECTIVES: 5α-reductase inhibitor (5-ARI) is a commonly used medicine in the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Our study mainly focuses on the mechanism of BPH development after 5ARI treatment. MATERIALS AND METHODS: Prostate specimens from patients were collected. Insulin-like growth factor 1 (IGF-1), Beclin-1, LC3 levels, was analysed by immunohistochemistry. The role IGF-1 on autophagic flux in prostate epithelial cells was studied. Additionally, effect of autophagy on recombinant grafts consisting of prostate stromal and epithelial cells in nude mice was investigated. RESULTS: We demonstrated that IGF-1 expression is down-regulated in prostate fibroblasts after long-term 5-ARI application. A decrease in IGF-1 levels was found to activate autophagic flux through the mTOR pathway in prostate epithelial cells, while the inhibition of IGF-1 receptor function induced autophagy in prostate epithelial cells. In addition, we revealed that blocking autophagic flux initiation can reduce the volume of recombinant grafts in vivo. Finally, our findings suggest that long-term 5-ARI application reduces IGF-1 secretion by prostatic stromal cells, thereby inducing autophagy of prostatic epithelial cells, which is one of the mechanisms underlying BPH pathogenesis and progression. CONCLUSIONS: Focusing on the autophagy induced by low levels of IGF-1 in prostatic epithelial cells, after elucidating AR signalling impairment of prostate stromal cells, might provide a novel strategy for the treatment and prevention of BPH development.

Porous Se@SiO2 nanosphere-coated catheter accelerates prostatic urethra wound healing by modulating macrophage polarization through reactive oxygen species-NF-κB pathway inhibition.

Benign prostatic hyperplasia (BPH) patients experience complications after surgery. We studied oxidative stress scavenging by porous Se@SiO2 nanospheres in prostatic urethra wound healing after transurethral resection of the prostate (TURP). Beagle dogs were randomly distributed into two groups after establishing TURP models. Wound recovery and oxidative stress levels were evaluated. Re-epithelialization and the macrophage distribution at the wound site were assessed by histology. The mechanism by which porous Se@SiO2 nanospheres regulated macrophage polarization was investigated by qRT-PCR, western blotting, flow cytometry, immunofluorescence and dual luciferase reporter gene assays. Our results demonstrated that Porous Se@SiO2 nanosphere-coated catheters advance re-epithelization of the prostatic urethra, accelerating wound healing in beagle dogs after TURP, and improve the antioxidant capacity to inhibit oxidative stress and induced an M2 phenotype transition of macrophages at the wound. By restraining the function of reactive oxygen species (ROS), porous Se@SiO2 nanospheres downregulated Ikk, IκB and p65 phosphorylation to block the downstream NF-κB pathway in macrophages in vitro. Since activation of NF-κB signaling cascades drives macrophage polarization, porous Se@SiO2 nanospheres promoted macrophage phenotype conversion from M1 to M2. Our findings suggest that porous Se@SiO2 nanosphere-coated catheters promote postoperative wound recovery in the prostatic urethra by promoting macrophage polarization toward the M2 phenotype through suppression of the ROS-NF-κB pathway, attenuating the inflammatory response. STATEMENT OF SIGNIFICANCE: The inability to effectively control post-operative inflammatory responses after surgical treatment of benign prostatic hyperplasia (BPH) remains a challenge to researchers and surgeons, as it can lead to indirect cell death and ultimately delay wound healing. Macrophages at the wound site work as pivotal regulators of local inflammatory response. Here, we designed and produced a new type of catheter with a coating of porous Se@SiO2 nanosphere and demonstrated its role in promoting prostatic urethra wound repair by shifting macrophage polarization toward the anti-inflammatory M2 phenotype via suppressing ROS-NF-κB pathway. These results indicate that the use of porous Se@SiO2 nanosphere-coated catheter may provide a therapeutic strategy for postoperative complications during prostatic urethra wound healing to improve patient quality of life.

microRNA-193a stimulates pancreatic cancer cell repopulation and metastasis through modulating TGF-ß2/TGF-ßRIII signalings.

BACKGROUND: Pancreatic cancer characterizes high recurrence and poor prognosis. In clinical practice, radiotherapy is widely used for pancreatic cancer treatment. However, the outcome remains undesirable due to tumor repopulation and following recurrence and metastasis after radiation. So, it is highly needed to explore the underlying molecular mechanisms and accordingly develop therapeutic strategies. Our previous studies revealed that dying cells from chemoradiation could stimulate repopulation of surviving pancreatic cancer cells. However, we still knew little how dying cells provoke pancreatic cancer cell repopulation. We herein would explore the significance of TGF-ß2 changes and investigate the modulation of microRNA-193a (miR-193a), and identify their contributions to pancreatic cancer repopulation and metastasis. METHODS: In vitro and in vivo repopulation models were established to mimic the biological processes of pancreatic cancer after radiation. Western blot, real-time PCR and dual-luciferase reporter assays were accordingly used to detect miR-193a and TGF-ß2/TGF-ßRIII signalings at the level of molecular, cellular and experimental animal model, respectively. Flow cytometry analysis, wound healing and transwell assay, vascular endothelial cell penetration experiment, and bioluminescence imaging were employed to assessthe biological behaviors of pancreatic cancer after different treatments. Patient-derived tumor xenograft (PDX) mice models were established to evaluate the therapeutic potential of miR-193a antagonist on pancreatic cancer repopulation and metastasis after radiation. RESULTS: miR-193a was highly expressed in the irradiated pancreatic cancer dying cells, accordingly elevated the level of miR-193a in surviving cells, and further promoted pancreatic cancer repopulation and metastasis in vitro and in vivo. miR-193a accelerated pancreatic cancer cell cycle and stimulated cell proliferation and repopulation through inhibiting TGF-ß2/TGF-ßRIII/SMADs/E2F6/c-Myc signaling, and even destroyed normal intercellular junctions and promoted metastasis via repressing TGF-ß2/TGF-ßRIII/ARHGEF15/ABL2 pathway. Knockdown of miR-193a or restoration of TGF-ß2/TGF-ßRIII signaling in pancreatic cancer cells was found to block pancreatic cancer repopulation and metastasis after radiation. In PDX models, the treatment in combination with miR-193a antagonist and radiation was found to dramatically inhibit pancreatic cancer cell repopulation and metastasis, and further improved the survival after radiation. CONCLUSIONS: Our findings demonstrated that miR-193a stimulated pancreatic cancer cell repopulation and metastasis through modulating TGF-ß2/TGF-ßRIII signalings, and miR-193a might be a potential therapeutic target for pancreatic cancer repopulation and metastasis.

microRNA-7 impairs autophagy-derived pools of glucose to suppress pancreatic cancer progression.

Pancreatic cancer commonly addicts to aerobic glycolysis, and abnormally activates autophagy to adapt the stringent metabolic microenvironment. microRNA-7 (miR-7) was supposed to modulate various gastrointestinal cancer progression. We wonder whether miR-7 could destroy the reprogrammed metabolic homeostasis in pancreatic cancer via modulating the level of autophagy, and further affect tumor proliferation and survival. Herein, we first reported that pancreatic cancer could take advantage of autophagy as a survival strategy to provide essential glucose required for glycolysis metabolism. Of note, under the stressful tumor microenvironment, miR-7 could repress autophagy through up-regulation of LKB1-AMPK-mTOR signaling, and directly targeting the stages of autophagy induction and vesicle elongation to reduce the supply of intracellular glucose to glycolysis metabolism. Furthermore, miR-7 inhibited pancreatic cancer cell proliferation and metastasis in vitro and in vivo. Consistently, lentivirus-mediated miR-7 effectively reduced the growth of patient-derived xenograft by interfering glycolysis via inhibition of autophagy. Together, these data suggested miR-7 might function as an important regulator to impair autophagy-derived pools of glucose to suppress pancreatic cancer progress. Hence, miR-7 might be a potential therapeutic target in pancreatic cancer.

The J-curve relationship between diastolic pressure and coronary collateral circulation in patients with single chronic total occlusion.

BACKGROUND: In our previous study, we had shown that high diastolic blood pressure (DBP) was positively related to well-developed coronary collateral circulation (CCC). This study sought to find out the more precise relationship between DBP and CCC. METHODS AND RESULTS: To investigate this, we conducted a study of 671 patients with single chronic total occlusion of coronary artery. The DBP of the patients was divided into six groups: ≤ 65 mmHg, >65-≤ 75 mmHg, >75-≤ 85 mmHg, >85-≤ 95 mmHg, >95-≤ 105 mmHg, >105 mmHg). The extent of CCC was graded as poorly-developed or well-developed collaterals according to Rentrop classification. There was a J-curve relationship between the level of DBP and the incidence of poorly-developed collaterals. CONCLUSION: The relationship between DBP and CCC is similar to the J-curve relationship between DBP and cardiovascular risk. The influence of DBP on the development of CCC may be one of the pathophysiologic mechanisms of the J-curve phenomenon relating DBP to cardiovascular risk.

The relationship between diastolic pressure and coronary collateral circulation in patients with stable angina pectoris and chronic total occlusion.

BACKGROUND: The most important biomechanical source of activation of the coronary collateral circulation (CCC) is increased tangential fluid shear stress at the arterial endothelial surface. The coronary circulation is unique in that most coronary blood flow occurs in diastole. Consequently, the diastolic blood pressure (DBP) may influence the tangential fluid shear stress on the arterial endothelial surface in diastole, therebyaffecting development of the CCC. METHODS: To investigate this, we conducted a study of 222 patients with stable angina pectoris and chronic total occlusion of coronary arteries. All of the patients had no history of coronary artery interventional therapy, coronary artery bypass surgery, cardiomyopathy, or congenital heart disease. The extent of the collateral vasculature of the area perfused by the artery affected by chronic total occlusion was graded as poor or well-developed according to Rentrop's classification. RESULTS: Univariate analysis showed a significant difference between the study subgroup with poorly developed collaterals and that with well-developed collaterals in terms of high diastolic blood pressure (DBP) and mean DBP. Multivariate analysis revealed high DBP as the only independent positive predictor of a well-developed collateral circulation. CONCLUSIONS: High DBP is positively related to a well-developed CCC. Differences in development of the CCC may be one of the pathophysiologic mechanisms responsible for the J-curve phenomenon in the relationship between DBP and cardiovascular risk.

Comparing the biological characteristics of adipose tissue-derived stem cells of different persons.

Scientists have found that cell sex is a variable that considerably influences the regeneration abilities of muscle-derived stem cells' in mice. We try to find out whether the cell sex or cell age (the age of donor) will influence the biological characteristics of human adipose tissue-derived stem cells (H-ADSCs). The results indicate that cell sex influences the proliferation, differentiation, paracrine, and anti-apoptosis abilities of the H-ADSCs, and cell age may also affect the H-ADSCs' differentiation and anti-apoptosis abilities.