Ticagrelor or Clopidogrel as Antiplatelet Agents in Patients with Chronic Kidney Disease and Cardiovascular Disease: A Meta-analysis.

INTRODUCTION: The worldwide prevalence of chronic kidney disease (CKD) has significantly increased in the past decades. Scientific reports have shown CKD to be an enhancing risk factor for the development of cardiovascular disease (CVD), which is the leading cause of premature death in patients with CKD. Clinical practice guidelines are ambiguous in view of the use of antiplatelet drugs in patients with CKD because patients with moderate-to-severe CKD were often excluded from clinical trials evaluating the efficacy and safety of anticoagulants and antiplatelet agents. In this analysis, we aimed to systematically assess the adverse cardiovascular and bleeding outcomes that were observed with ticagrelor versus clopidogrel use in patients with CKD and cardiovascular disease. METHODS: Electronic databases including Web of Science, Google Scholar, http://www. CLINICALTRIALS: gov , Cochrane database, EMBASE, and MEDLINE were carefully searched for English-based articles comparing ticagrelor with clopidogrel in patients with CKD. Adverse cardiovascular outcomes and bleeding events were the endpoints in this study. The latest version of the RevMan software (version 5.4) was used to analyze the data. Risk ratios (RR) with 95% confidence intervals (CI) were used to represent the data post analysis. RESULTS: A total of 15,664 participants were included in this analysis, whereby 2456 CKD participants were assigned to ticagrelor and 13,208 CKD participants were assigned to clopidogrel. Our current analysis showed that major adverse cardiac events (MACEs) (RR: 0.85, 95% CI: 0.71-1.03; P = 0.09), all-cause mortality (RR: 0.82, 95% CI: 0.57- 1.18; P = 0.29), cardiovascular death (RR: 0.83, 95% CI: 0.56-1.23; P = 0.35), myocardial infarction (RR: 0.87, 95% CI: 0.70-1.07; P = 0.19), ischemic stroke (RR: 0.80, 95% CI: 0.58-1.11; P = 0.18), and hemorrhagic stroke (RR: 1.06, 95% CI: 0.38-2.99; P = 0.91) were not significantly different in CKD patients who were treated with ticagrelor versus clopidogrel. Thrombolysis in myocardial infarction (TIMI)-defined minor (RR: 0.89, 95% CI: 0.52-1.53; P = 0.68) and TIMI major bleeding (RR: 1.10, 95% CI: 0.69-1.76; P = 0.67) were also not significantly different. However, bleeding defined according to the academic research consortium (BARC) bleeding type 1 or 2 (RR: 1.95, 95% CI: 1.13-3.37; P = 0.02) and BARC bleeding type 3 or 5 (RR: 1.70, 95% CI: 1.17-2.48; P = 0.006) were significantly higher with ticagrelor. CONCLUSIONS: When compared with clopidogrel, even though ticagrelor was not associated with higher risk of adverse cardiovascular outcomes in these patients with CKD, it was associated with significantly higher BARC bleeding. Therefore, the safety outcomes of ticagrelor still require further evaluation in patients with CKD. Nevertheless, this hypothesis should only be confirmed with more powerful results that could usually only be achieved using large-scale randomized trials.

Protective effect of panaxydol against repeated administration of aristolochic acid on renal function and lipid peroxidation products via activating Keap1-Nrf2/ARE pathway in rat kidney.

Panaxydol (PX), a polyacetylenic compound isolated from the roots of Panax notoginseng, is found to possess various biological functions. However, its protective effects against aristolochic acid (AA)-induced renal injury have not been elucidated yet. The present study was undertaken to elucidate the renoprotective effect of PX on Wistar male rats via activating Keap1-Nrf2/ARE pathway. Experimental animals were randomized into four groups, such as control group, I/R group, AA (5 mg/kg/d; ip for 10 days), and AA-induced rats treated with PX (10 and 20 mg/kg/d; po for 20 days). At the end of the experimental period, the rats were killed, and the biochemical parameters denoting renal functions were evaluated; histological analysis displaying the renal tissue architecture, real-time quantitative reverse-transcription polymerase chain reaction, and immunohistochemistry (IHC) analysis of Keap1-Nrf2/ARE genes were elucidated. The results demonstrated that the rats administered with AA displayed a significant increase in the blood urea nitrogen level with an increased urine creatinine and protein excretion. Also, the serum levels of urea, uric acid, and albumin levels were increased. Furthermore, the histological evaluation denoted the cellular degeneration with increased tissue lipid peroxidation levels. In contrast, rats administered with PX significantly prevented the tissue degeneration with improved antioxidant levels. Conversely, PX treatment increased the messenger RNA expression of Nrf2, NQO1, HO-1 with an attenuated expression of 4HNE and NOX-4 levels in IHC analysis. Thus, the results of the present study suggest that PX could suppress AA-induced renal failure by suppressing oxidative stress through the activation of Keap1-Nrf2 signaling pathway.

IcarisideII facilitates the differentiation of ADSCs to SCs via let-7i/STAT3 axis to preserve erectile function.

BACKGROUND: IcarisideII (ICAII) could promote the differentiation of adipose tissue-derived stem cells (ADSCs) to Schwann cells (SCs), leading to improvement of erectile function (EF) and providing a realistic therapeutic option for the treatment of erectile dysfunction (ED). However, the underlying molecular mechanisms of ADSCs and ICAII in this process remain largely unclear. METHODS: ADSCs were treated with different concentrations of ICAII. Cell proliferation was determined by MTT assay. qRT-PCR and western blot were performed to detect expressions of SCs markers, signal transducer and activator of transcription-3 (STAT3), and microRNA-let-7i (let-7i). Luciferase reporter assay was conducted to verify the regulatory relationship between let-7i and STAT3. The detection of intracavernosal pressure (ICP) and the ratio of ICP/mean arterial pressure (MAP) were used to evaluate the EF in bilateral cavernous nerve injury (BCNI) rat models. RESULTS: ICAII promoted cell proliferation of ADSCs in a dose-dependent manner. The mRNA and protein levels of SCs markers were increased by ICAII treatment in a dose-dependent manner in ADSCs. Moreover, let-7i was significantly decreased in ICAII-treated ADSCs and upregulation of let-7i attenuated ICAII-induced promotion of SCs markers. In addition, STAT3 was a direct target of let-7i and upregulated in ICAII-treated ADSCs. Interestingly, overexpression of STAT3 abated the let-7i-mediated inhibition effect on differentiation of ADSCs to SCs and rescued the ICAII-mediated promotion effect on it. Besides, combination treatment of ADSCs and ICAII preserved the EF of BCNI rat models, which was undermined by let-7i overexpression. CONCLUSION: ICAII was effective for preserving EF by promoting the differentiation of ADSCs to SCs via modulating let-7i/STAT3 pathway.

IcarisideII facilitates the differentiation of ADSCs to SCs via let-7i/STAT3 axis to preserve erectile function

BACKGROUND: IcarisideII (ICAII) could promote the differentiation of adipose tissue-derived stem cells (ADSCs) to Schwann cells (SCs), leading to improvement of erectile function (EF) and providing a realistic therapeutic option for the treatment of erectile dysfunction (ED). However, the underlying molecular mechanisms of ADSCs and ICAII in this process remain largely unclear. METHODS: ADSCs were treated with different concentrations of ICAII. Cell proliferation was determined by MTT assay. qRT-PCR and western blot were performed to detect expressions of SCs markers, signal transducer and activator of transcription-3 (STAT3), and microRNA-let-7i (let-7i). Luciferase reporter assay was conducted to verify the regulatory relationship between let-7i and STAT3. The detection of intracavernosal pressure (ICP) and the ratio of ICP/mean arterial pressure (MAP) were used to evaluate the EF in bilateral cavernous nerve injury (BCNI) rat models. RESULTS: ICAII promoted cell proliferation of ADSCs in a dose-dependent manner. The mRNA and protein levels of SCs markers were increased by ICAII treatment in a dose-dependent manner in ADSCs. Moreover, let-7i was significantly decreased in ICAII-treated ADSCs and upregulation of let-7i attenuated ICAII-induced promotion of SCs markers. In addition, STAT3 was a direct target of let-7i and upregulated in ICAII-treated ADSCs. Interestingly, overexpression of STAT3 abated the let-7i-mediated inhibition effect on differentiation of ADSCs to SCs and rescued the ICAII-mediated promotion effect on it. Besides, combination treatment of ADSCs and ICAII preserved the EF of BCNI rat models, which was undermined by let-7i overexpression. CONCLUSION: ICAII was effective for preserving EF by promoting the differentiation of ADSCs to SCs via modulating let-7i/STAT3 pathway.