Sirtuin 6 promotes cell aging of myeloma cell line KM-HM_(31) by via Hippo signal pathway.

OBJECTIVE: Myeloma poses a serious risk for people's health and life quality. Molecular targeted treatment of myeloma emerges as a promising therapy. This study aimed to determine the effect of Sirtuin 6 on myeloma KM-HM_(31) cell aging and provide evidence for clinical treatment. MATERIALS AND METHODS: Myeloma KM-HM_(31) cell aging model induced by Carbamide peroxide (CP) was generated. Cells were transfected with Sirtuin 6 over-expression plasmid and specific siRNA. Western blot was used to study Sirtuin 6 expression, P53, P16, and Hippo in KM-HM_(31) cells. ß-galactosidase assay was applied to measure cell aging. Verteporfin inhibited Hippo signal pathway and measured aging of KM-HM_(31) cells. RESULTS: The levels of Sirtuin 6, aging protein P53, and P16 were remarkably elevated while Hippo expression was significantly inhibited in CP-induced KM-HM_(31) cells. Transfection of Sirtuin 6 over-expression plasmid enhanced Sirtuin 6 expression in KM-HM_(31) cells and potentiated cell aging with downregulation of Hippo protein. In contrast, a block of Sirtuin 6 resulted in the opposite effect. Moreover, Verteporfin inhibited Hippo signal pathway and enhanced CP-induced KM-HM_(31) cell aging, which contributed similar effect as Sirtuin 6 did. CONCLUSIONS: We showed that sirtuin 6 facilitates CP-induced myeloma cell KM-HM_(31) aging via suppressing Hippo.

[Mutations of vitamin D receptor gene found in patients with multiple myeloma].

Objective: To explore the mutations of vitamin D receptor (VDR) gene in patients with multiple myeloma (MM). Methods: Polymerase chain reaction (PCR) and direct DNA sequencing were used to detect the mutations of VDR gene(loci Fok Ⅰ, Bsm Ⅰ, Apa Ⅰ, Taq Ⅰ) in forty MM cases and 84 healthy control subjects. Results: A synonymous mutation (ATC→ATA , both encode isoleucine) at cDNA codon1421 of VDR gene was found in one MM patients, which correlated to a better therapeutic response. Rare Bsm Ⅰ AA genotype and Taq Ⅰ CC genotype were detected in a MM patient, which might be related to the relapsing and refracfory disease. Meanwhile, a rare allele(rs201747972, global MAF: A=0.0005/1), was found in another MM patient, which might be related to MM cell lines of two origins. rs11574113 G>C, rs2229829 C>A and rs201747972 C>T polymorphic loci(the same as Fok Ⅰ, Bsm Ⅰ, Apa Ⅰ and Taq Ⅰ) were found in a MM patient, which were associated with nonsense-mediated mRNA decay(NMD), contributing to the onset of MM. Conclusions: A new synonymous mutation, rare genotype, rare allele and new SNP are found in this study. These data enrich the genetic information of MM in China, and are helpful for the further research on MM pathogenesis.

Effects of perindopril, propranolol, and dihydrochlorothiazide on cardiovascular remodelling in spontaneously hypertensive rats.

AIM: To investigate the effects of perindopril, propranolol, and dihydrochlorothiazide on artery wall thickening, left ventricular hypertrophy, and cardiac fibrosis in spontaneously hypertensive rats (SHR). METHODS: After measurement of systolic blood pressure (SBP), 16-wk-old Male SHR were randomly divided into 3 groups (each n = 10), given perindopril (Per, 5 mg.kg-1.d-1), propranolol (Pro, 40 mg.kg-1.d-1), dihydrochlorothiazide (DCT, 100 mg.kg-1.d-1) respectively by gavage for 12 wk. Sex-, age-, and number-matched untreated SHR and normotensive Wistar Kyoto rats (WKY) served as controls. When the treatment finished, body weights (BW) and SBP were measured before decapitation of the rats. The heart was excised rapidly, the left ventricle was weighed and then subjected to collagen content analysis. Vascular wall and lumen ratio from aorta, renal arteries and branch III vessels of mesenteric arteries were determined morphometrically. RESULTS: Treated rats in 3 groups showed a lower SBP and the ratio of left ventricle weight to body weight (LVW/BW) compared with WKY. Artery wall thickening was similarly inhibited in the treated groups. Per and Pro inhibited cardiac fibrosis, but collagen concentration increased in DCT treated SHR [collagen volume fraction (CVF): 19 +/- 4 vs SHR 14 +/- 4, P < 0.05; perivascular collagen fraction(PVCF): 84 +/- 7 vs SHR 79 +/- 5, P < 0.05]. CONCLUSION: Per and Pro inhibited, but DCT promoted, cardiac fibrosis.

Inhibitory effects of captopril on c-myc expression during left ventricular hypertrophy.

AIM: To study the molecular mechanism of captopril (Cap) on the inhibition of left ventricular hypertrophy (LVH), disclose the expression and distribution of c-myc in different cell types in left ventricle (LV) in spontaneously hypertensive rats (SHR). METHODS: Cap 100 mg.kg-1.d-1 was given p.o. to SHR. Systolic blood pressure (SBP), left ventricular weight (LVW), and body weight (BW) were measured at 16-wk old. The level of angiotensin II (Ang II), c-myc mRNA, and oncoprotein were determined by immunohistochemical method, Northern blot, and Western blot, respectively. RESULTS: Cap reduced SBP, LVW/BW in SHR, with a decrease of Ang II and c-myc expression in LV. Local cardial Ang II mainly distributed in cardiomyocytes. Cap inhibited cardial Ang II production and c-myc expression (histochemical staining intensity index, 0.49 +/- 0.04 vs 0.83 +/- 0.24, P < 0.01). The c-myc oncoprotein was prevailingly located in cardiac fibroblasts. The c-myc oncoprotein in Cap treated SHR was lower than that of WKY. CONCLUSION: High expression of c-myc in fibroblasts played an important role in the development of LVH in SHR. Inhibitory effects of Cap on LVH was associated with a decreased myocardial Ang II and interstitial fibroblasts c-myc expression. The c-myc oncoprotein post-transcriptional translation was also interrupted by Cap.