Association between dosing of spironolactone and outcomes in heart failure with preserved ejection fraction patients combined with chronic kidney disease------Balance of efficacy and risk.

Aims: Few studies have compared the association between dosing of spironolactone and outcomes in patients with heart failure with preserved ejection fraction (HFpEF), and whether spironolactone dose could significantly affect the prognosis of HFpEF patients combined with chronic kidney disease (CKD) remains unclear. Our aim was to directly compare 'high vs. low' doses of spironolactone in an attempt to find a benefit-risk-balanced point, and infer an adequate dose for HFpEF with CKD patients. Methods: Overall, 4,321 symptomatic heart failure inpatients were initially screened from January 2013 to December 2019, and all enrolled patients were followed-up for 36 months; After including patients who meet the diagnostic criteria of HFpEF and CKD with ejection fraction > 45% and estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2, a total of 387 patients was selected. Primary outcome was a composite of all-cause death, heart failure (HF) hospitalization and non-fatal stroke. The key safety outcome was hyperkalemia rates during the follow-up period. Results: The primary outcome event rates in patients with or without spironolactone were 12.74 and 21.45 per 100 person-years, respectively. Compared with patients not taking spironolactone, the adjusted hazard ratio (HR) [95% confidence interval (CI)] was 0.55 (0.38-0.79) with spironolactone group for primary outcomes. After grouped by the daily dose of spironolactone, low-dose group (≤ 40 mg) was associated with lower relative risk for the primary efficacy outcome [adjusted HR (95% CI) was 0.43 (0.23-0.81), 0.50 (0.33-0.76) and 0.74 (0.36-2.79) with < 40 mg, 40 mg and >40 mg, respectively]. During 3-year follow-up, the risk for hyperkalemia was amplified in the higher dose group (>40 mg) while showed no significant difference compared with low dose group (p = 0.425). Conclusion: HFpEF with CKD patients using spironolactone had lower risk of adverse cardiovascular outcomes. And the use of low-dose spironolactone (≤ 40 mg) showed the best efficacy and safety, therefore we may recommend ≤ 40 mg as the optimal initial dose for these patients. However, this was a relatively small sample size, retrospective study, and further adequately powered randomized trials are needed to verify these results.

Assembly of the FKBP51-PHLPP2-AKT signaling complex in cerebral ischemia/reperfusion injury in rats.

The imbalance of cell pro-death and pro-survival signaling pathways determines the neuronal fate during cerebral ischemia/reperfusion (I/R) injury. However, the biological mechanisms regulating the balance between activation of the pro-death or the pro-survival signaling pathways remain unclear. In this study, a rat model of I/R injury was established using four-vessel occlusion followed by different times of reperfusion. I/R injury did not affect the level of FK506 binding protein 51 (FKBP51), PH domain and leucine rich repeat protein phosphatases (PHLPP)-2, and AKT, but induced assembly of the FKBP51-PHLPP2-AKT signaling complex, as indicated by the enhancement of interactions among these compounds following reperfusion. Using an antisense oligonucleotide, PHLPP2 expression was effectively inhibited. Critically, the inhibition of PHLPP2 prohibited the interactions of FKBP51, PHLPP2 and AKT, reversed the decrease of p-AKT expression and increased the expression of p-JNKs and p-c-Jun elicited by I/R injury. In addition, PHLPP2 inhibition reversed I/R-injury-induced Caspase-3 cleavage and loss of pyramid neurons in the CA1 region of hippocampus. The results of the current study indicate that the assembly of the FKBP51-PHLPP2-AKT signaling complex plays a critical role in mediating cell death in I/R injury. The inhibition of PHLPP2 via antisense oligonucleotide treatment may be an effective method to prohibit the assembly of the FKBP51-PHLPP-AKT signaling complex, thus balancing the cell pro-survival and pro-death signaling pathways ultimately mitigating cell death in I/R injury.

EZH2 genetic variants affect risk of gastric cancer in the Chinese Han population.

Enhancer of zeste 2 (EZH2) gene encodes a histone methyltransferase that constitutes the catalytic component of the polycomb repressive complex-2 (PRC2) to initiate epigenetic silencing of genes. It is reported that the expression level of EZH2 in gastric cancer tissue was highly correlated with tumor progression, however, whether EZH2 genetic variants were associated with the risk of gastric cancer remains yet unknown. In this study, we conducted a genotyping analysis for EZH2 in 311 cases of gastric cancer and 425 controls from the Chinese Han population. We found five single nucleotide polymorphisms (SNP; rs12670401, rs6464926, rs2072407, rs734005, and rs734004) of EZH2 gene were significantly associated with the risk of gastric cancer. Of which, the rs12670401 with the minor allele C and rs6464926 with the minor allele T revealed strong associations with increased gastric cancer risk [P = 0.009, adjusted odds ratio (aOR) = 1.327, 95% CI = 1.075-1.683 and P = 0.012, aOR = 1.310, 95% CI = 1.059-1.619]. The other three SNPs, rs2072407, rs734005, and rs734004 contributed to significantly reduced risk of gastric cancer (P = 0.033, aOR = 0.787, 95% CI = 0.633-0.981, P = 0.045, aOR = 0.799, 95% CI = 0.642-0.995 and P = 0.048, aOR = 0.803, 95% CI = 0.645-0.999), respectively. We further found that rs12670401 and rs6464926 were in a strong LD while rs2072407, rs734005, and rs734004 were in another. Haplotype analysis of the five SNPs showed that haplotype CCTCT reduced the risk of gastric cancer (P = 0.031 and aOR = 0.784), while haplotype GTCTC significantly elevated the risk of gastric cancer (P = 0.011 and aOR = 1.310). We concluded that EZH2 variants were significantly associated with gastric cancer risk. Our results for the first time provided new insight into susceptibility factors of EZH2 gene variants in carcinogenesis of gastric cancer of the Chinese Han population.

TNIP1/ANXA6 and CSMD1 variants interacting with cigarette smoking, alcohol intake affect risk of psoriasis.

BACKGROUND: Psoriasis is a common multi-factorial skin disease, in which gene-gene and gene-environment interactions may affect the onset, manifestation and clinical course. OBJECTIVE: To investigate the underlying gene-environment interaction among several established susceptibility genes, cigarette smoking and alcohol intake. METHODS: Using a two-stage case-control design, we searched for pairwise interactions between cigarette smoking and alcohol intake respectively with 9 single nucleotide polymorphisms (SNPs) at ERAP1, PTTG1, CSMD1, GJB2, SERPINB8, ZNF816A and TNIP1/ANXA6 that have been associated with risk for psoriasis in 7,223 subjects. Multiple logistic regression analysis was used for data analysis. RESULTS: Significant interactions were found for alcohol intake with rs3762999 (p=0.0257) and rs999556 (p=0.0071) at TNIP/ANXA6; and for cigarette smoking with rs7007032 (p=0.0023) and rs10088247 (p=0.0023) at CSMD1. CONCLUSION: This study provides empirical evidence for the gene-environment interactions between TNIP1/ANXA6 and alcohol use, CSMD1 and cigarette smoking, highlighting the importance of gene-environment interactions in the pathogenesis of psoriasis.

[Effects of sodium aescinate on the apoptosis-related genes in lung injury induced by intestinal ischemia reperfusion in rats].

OBJECTIVE: To investigate the relationship between apoptosis-related genes and lung injury induced by intestinal ischemia reperfusion and to explore the effects and its possible mechanism of sodium aescinate. METHODS: Rat model of intestinal I/R injury was established with clamping of the superior mesenteric artery for 60 min and then clamping was relieved for 60 min. Twenty-four SD rats were randomly divided into three groups with eight rats in each: sham group, intestinal ischemia/reperfusion group (I/R group) and sodium aescinate group (SA + I/R group). Lung wet/dry weight ratio, lung coefficient and Superoxide dismutase (SOD), malondialdehyde (MDA) in plasma and lung tissue were measured, as well as the expression levels of Bcl-2 and Bax proteins in lung tissue were examined using immunohistochemical method. RESULTS: Compared with sham group, lung wet/dry weight ratio, lung coefficient and MDA in plasma and lung tissue were significantly increased, and while the activity of SOD in plasma and lung tissue were decreased significantly in I/R group. At the same time, the protein expression level of Bcl-2 and Bax were significantly increased. But Bax protein expression was much greater than that of Bcl-2, the ratio of Bcl-2 to Bax was decreased significantly in I/R group than that in sham group. Compared with I/R group, lung wet/dry weight ratio, lung coefficient and MDA in plasma and lung tissue were significantly decreased, and while the activity of SOD in serum and lung tissue were significantly increased in SA + I/R group. At the same time, Bax protein expression was significantly decreased, both Bcl-2 protein expression and the ratio of Bcl-2 to Bax were significantly increased in SA + I/R group than that in I/R group. CONCLUSION: Lung injury induced by intestinal ischemia reperfusion is correlated with abnormal expression levels of Bcl-2 and Bax protein which is caused by oxidative injury. Sodium aescinate can protect the lung injury induced by intestinal ischemia/reperfusion (I/R), which may be mediated by inhibiting lipid peroxidation, upregulating Bcl-2 gene protein expression, improving the ratio of Bcl-2/ Bax to inhibit lung apoptosis.