SIRT6 protects vascular smooth muscle cells from osteogenic transdifferentiation via Runx2 in chronic kidney disease.

Vascular calcification (VC) is regarded as an important pathological change lacking effective treatment and associated with high mortality. Sirtuin 6 (SIRT6) is a member of the Sirtuin family, a class III histone deacetylase and a key epigenetic regulator. SIRT6 has a protective role in patients with chronic kidney disease (CKD). However, the exact role and molecular mechanism of SIRT6 in VC in patients with CKD remain unclear. Here, we demonstrated that SIRT6 was markedly downregulated in peripheral blood mononuclear cells (PBMCs) and in the radial artery tissue of patients with CKD with VC. SIRT6-transgenic (SIRT6-Tg) mice showed alleviated VC, while vascular smooth muscle cell-specific (VSMC-specific) SIRT6 knocked-down mice showed severe VC in CKD. SIRT6 suppressed the osteogenic transdifferentiation of VSMCs via regulation of runt-related transcription factor 2 (Runx2). Coimmunoprecipitation (co-IP) and immunoprecipitation (IP) assays confirmed that SIRT6 bound to Runx2. Moreover, Runx2 was deacetylated by SIRT6 and further promoted nuclear export via exportin 1 (XPO1), which in turn caused degradation of Runx2 through the ubiquitin-proteasome system. These results demonstrated that SIRT6 prevented VC by suppressing the osteogenic transdifferentiation of VSMCs, and as such targeting SIRT6 may be an appealing therapeutic target for VC in CKD.

Dexamethasone is Associated With a Lower Risk of the Progression of Thoracic Aortic Calcification in Breast Cancer Survivors.

Background and Purpose: Breast cancer survivors have an increased cardiovascular risk, and vascular calcification is the pathological basis of cardiovascular disease. Some factors that affect the progression of thoracic aortic calcification (TAC) in survivors are unclear, and this study aims to explore the relationship between dexamethasone or radiotherapy and the progression of TAC in survivors. Materials and Methods: This study included 189 female patients with breast cancer, and they were divided into the progression and non-progression TAC groups. Radiation or dexamethasone doses, and related laboratory parameters were collected. Results: The cumulative dose of dexamethasone was higher [40 (10-180) mg versus 180 (80-270) mg, p < 0.001], and the cycle was longer [4 (1-6) cycles versus 6 (4-8) cycles, p < 0.001] in the non-progression TAC group. The cumulative dose (r = -0.303, p < 0.001) and cycle (r = -0.357, p < 0.001) of dexamethasone were negatively correlated with the level of increased TAC Agatston scores in survivors. Logistic regression analysis showed that dexamethasone was a protective factor for the progression of TAC (p = 0.029, odds ratio = 0.263, 95% confidence interval = 0.08-0.872). However, there wasn't significant relationship between radiotherapy, radiation dose, follow-up time and the progression of TAC (all p > 0.05). In addition, aorta volume was positively correlated with the level of increased TAC Agatston scores in intensity modulated radiation therapy (r = 0.460, p < 0.001). Conclusion: Dexamethasone is associated with a lower risk of the progression of TAC in breast cancer survivors, and there's no correlation between radiotherapy and progression of TAC, but the aorta volume may be a predictor of the severity of progression of TAC.

Inhibitory effect of D3 dopamine receptors on neuropeptide Y­induced migration in vascular smooth muscle cells.

Abnormal migration of vascular smooth muscle cells (VSMCs) serves an important role in hypertension, atherosclerosis and restenosis following angioplasty, which is regulated numerous hormonal and humoral factors, including neuropeptide Y (NPY) and dopamine. Dopamine and NPY are both sympathetic neurotransmitters, and a previous study reported that NPY increased VSMC proliferation, while dopamine receptor inhibited it. Therefore, the authors wondered whether or not there is an inhibitory effect of dopamine receptor on NPY­mediated VSMC migration. The present study demonstrated that stimulation with NPY dose­dependence (10­10­10­7M, 24 h) increased VSMC migration, the stimulatory effect of NPY was via the Y1 receptor. This is because, in the presence of the Y1 receptor antagonist, BIBP3226 (10­7 M), the stimulatory effect of NPY on VSMC migration was blocked. Activation of the D3 receptor by PD128907 dose­dependence (10­11­10­8 M) reduced the stimulatory effect of NPY on VSMC migration. The effect of PD128907 was via the D3 receptor, because the inhibitory effect of PD128907 on NPY­mediated migration was blocked by the D3 receptor antagonist, U99194. The authors' further study suggested that the inhibitory effect of the D3 receptor was via the PKA signaling pathway, in the presence of the PKA inhibitor, 14­22 (10­6 M), the inhibitory effect of PD128907 on VSMC migration was blocked. Moreover, the inhibitory effect of PD128907 was imitated by PKA activator, Sp­cAMP [S], in the presence of Sp­cAMP [S], the NPY­mediated stimulatory effect on VSMC migration was abolished. The present study indicated that activation of the D3 receptor inhibits NPY Y1­mediated migration on VSMCs, PKA is involved in the signaling pathway.

Inhibitory effect of D1-like dopamine receptors on neuropeptide Y-induced proliferation in vascular smooth muscle cells.

Proliferation of vascular smooth muscle cells (VSMCs) is thought to have a key role in the development of atherosclerotic lesions. Neuropeptide Y (NPY), norepinephrine and dopamine are sympathetic neurotransmitters. NPY has been particularly shown to stimulate proliferation of VSMCs. NPY, norepinephrine and dopamine are all sympathetic transmitters. In our previous study, we found that in the presence of the dopamine receptor, the α1-adrenergic receptor-mediated VSMC proliferation is reduced. We hypothesize that the activation of the D1-like receptor might inhibit the NPY-mediated VSMC proliferation. In our present study, we found that NPY, mainly via the Y1 receptor, increased VSMC proliferation. This was determined by [(3)H]-thymidine incorporation, in a concentration (10(-11) to 10(-8) M)-dependent manner. In the presence of the D1-like receptor agonist, fenoldopam (10(-12) to 10(-5) M), the stimulatory effect of NPY on VSMC proliferation was reduced. The involvement of the D1-like receptor was confirmed when the inhibitory effect of fenoldopam was reversed in the presence of the D1-like receptor antagonist SCH-23390 (10(-8) M). Moreover, the inhibitory effect of fenoldopam on NPY-mediated VSMC proliferation was also blocked in the presence of the PKA inhibitor 14-22 (10(-6) M). Protein kinase A activator 8-(4-chlorophenylthio) adenosine-3,5-cyclic monophosphorothioate, Sp-isomer sodium salt (10(-6) M) could simulate the stimulatory effect of fenoldopam. It indicated that the inhibitory effect of D1-like receptors on NPY-mediated VSMC proliferation may have an important role in the regulation of blood pressure or prevention of atherosclerosis.

[Clinical study of laparoscopic rectal surgery without abdominal scar].

OBJECTIVE: To assess the feasibility and safety of laparoscopic rectal surgery without abdominal scar. METHODS: A total of 23 patients of rectal cancer were operated by laparoscopy with the assistance of PPH (procedure for prolapse and hemorrhoids) anal expander and TEM (transanal endoscopic microsurgery) outer-shell according to the principle of TME (total mesorectal excision). RESULTS: All operations were successfully accomplished laparoscopically. There was no conversion into an open procedure. The average operative duration was 129 (105 - 211) minutes. The intra-operative blood loss volume was 152 (85 - 420) ml. No immediate or delayed injury of urinary duct and other intra-operative severe complications, such as massive hemorrhage of presacral venous plexus, occurred. There was no pelvic infection or anastomotic stoma fistula during the post-operative period. The average follow-up period was 13.4 months. Neither anastomotic stoma recurrence nor Trocar implantation occurred. CONCLUSION: The laparoscopic technique of hybrid NOTES (Natural Orifice Transluminal Endoscopic Surgery), plus PPH/TEM is both feasible and convenient for selective rectal cancer surgery. There is no need for extra abdominal incision. It is recommended for laparoscopic rectal surgery.

[Clinical application of mastoscopic axillary sentinel lymph node biopsy].

OBJECTIVE: To evaluate the technique and significance of mastoscopic axillary sentinel lymph node biopsy. METHODS: Sixty-two patients with breast cancer use methylene blue to test axillary sentinel lymph node. Sentinel lymph node was moved with endoscopy, and endoscopic axillary lymph nod dissection was performed. Pathological examination of sentinel lymph node and axillary lymph node was made with HE. To evaluate detection rate and false negative rate in sentinel lymph node. RESULTS: Among the 62 patients, 61 were confirmed by endoscopic axillary sentinel lymph nod biopsy. Detection rate was 98.4%. Thirty-five cases were no metastasis, 27 cases were metastasis, false negative rate was 0. CONCLUSIONS: Mastoscopic axillary sentinel lymph node biopsy has a high detection rate, good efficiency of cosmetic and lower complications. It has higher sensitivity than traditional axillary lymph nod dissection and provide accurate lymph node stages.