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.

Ca2+ participates in the regulation of microalgae triacylglycerol metabolism under heat stress.

Microalgae are the largest CO2 fixer and O2 producer on the earth and occupy an increasingly important position in human life and production. Various environmental factors have a significant impact on the growth and metabolism of microalgae. As global warming intensifies, heat stress has become a crucial factor affecting the microalgae industry. However, till now, it has not been clear how microalgae sensed the temperature stress, transmitted stress signals and adjusted in intracellular metabolic pathways. In this study, the growth of microalgae Auxenochlorella protothecoides UTEX2341 was inhibited at 32 °C, but the single cell dry weight increased. The cell component analyses showed that both the carbohydrate and total protein content decreased significantly, while the lipid content increased by 158%. Meanwhile, the intracellular Ca2+ concentration increased continuously, with a maximum increase of 1.65 times. According to the transcriptome analyses, the up-regulation of Ca2+ influx channel protein mid1-complementing activity 1 (MCA1) gene and the down-regulation of efflux channel protein cation exchanger 1(CAX) and autoinhibited Ca2+-ATPase 1 (ACA1) genes in cytoplasmic membrane jointly facilitated the increase of Ca2+ in the cytoplasm. Coexpression network analysis indicated that the fluctuation of Ca2+ in the cytoplasm could activate the expression of transcription factors MYB3 and AP2-4 through calmodulin (CAM) and calcium-dependent protein kinase (CDPK), and then regulate glycerol-3-phosphate acyltransferases (GPAT) at the beginning of TAG synthesis and diacylglycerol acyltransferase (DGAT)/phospholipid: diacylglycerol acyltransferase (PDAT) in the last step of TAG synthesis. Furthermore, the addition of Ca2+ specific chelator BAPTA-AM inhibited the expression of GPAT, which was consistent with the decrease in microalgae lipid content. The results proved that Ca2+ participated in the regulation of microalgae TAG synthesis under heat stress, which provided a new view for the understanding of the microalgae lipid accumulation mechanism.

Human umbilical vein endothelial cells-derived microRNA-203-containing extracellular vesicles alleviate non-small-cell lung cancer progression through modulating the DTL/p21 axis.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and is characterized by extensive metastasis and poor prognosis. Extracellular vesicles (EVs) derived from endothelial cells carrying microRNAs (miRNAs/miRs) have diagnostic and therapeutic potential for NSCLC. We herein investigate the potential of EVs derived from human umbilical vein endothelial cells (HUVECs) to transfer miR-203 to affect the progression of NSCLC. miR-203 and p21 were poorly expressed while DTL was highly expressed both in NSCLC tissues and cell lines. We employed CCK-8 proliferation, colony formation, and Transwell migration and invasion assays to evaluate the effects of miR-203 on NSCLC cell behaviors using loss- and gain-function approaches. EVs were isolated from HUVECs and then co-cultured with the A549 cells transfected with mimic-NC or miR-203 inhibitor. miR-203 targeted DTL and downregulated its expression, subsequently leading to increased stability of p21 which is a tumor suppressor. EV-enriched miR-203 from HUVECs suppressed malignant phenotypes of NSCLC cells and delayed tumor growth. In conclusion, miR-203 from HUVEC-derived EVs exerts inhibitory effects on the progression of NSCLC by targeting DTL and promoting p21 protein stability.

Level of phosphate diets effect on fibroblast growth factor-23 levels in chronic kidney disease subjects: A meta-analysis.

BACKGROUND: High fibroblast growth factor-23 levels increase cardiovascular disease risk in chronic kidney disease subjects. The effects of dietary phosphate levels on fibroblast growth factor-23 in chronic kidney disease subjects have conflicting results. This meta-analysis was performed to evaluate this relationship. METHODS: A systematic-literature search up to July 2020 was performed and 7 studies were detected with 548 chronic kidney disease subjects at the baseline of the studies; a total of 170 of them were with lower dietary phosphate levels and 175 were higher dietary phosphate levels. They reported relationships between dietary phosphate levels and fibroblast growth factor-23 level in chronic kidney disease subjects. Mean differences (MD) with 95% confidence intervals (CIs) were calculated comparing the lower versus higher phosphate levels effect on urinary phosphate levels and fibroblast growth factor-23 level in chronic kidney disease subjects using the contentious methods with a random or fixed-effect model. RESULTS: Lower dietary phosphate levels had significantly lower 24-hour urinary phosphate excretion (MD, -41.23; 95% CI, -59.95 to 22.52, P < .001), and lower intact fibroblast growth factor-23 level (MD, -25.68; 95% CI, -39.85 to -11.51, P < .001) compared with higher dietary phosphate levels in chronic kidney disease subjects. However, no significant difference was found between low and high dietary phosphate levels in C-terminal fibroblast growth factor-23 level in chronic kidney disease subjects (MD, -7.10; 95% CI, -14.29 to 0.10, P = .05). CONCLUSIONS: Lower dietary phosphate levels had significantly lower 24-hour urinary phosphate excretion, intact fibroblast growth factor-23 level compared with higher dietary phosphate levels in chronic kidney disease subjects. This relationship forces us to recommend low dietary phosphate levels in chronic kidney disease subjects to decrease fibroblast growth factor-23 level to avoid any possible cardiovascular disease risk in such a subject.

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.

Oxidative Stress and TGF-ß1/Smads Signaling Are Involved in Rosa roxburghii Fruit Extract Alleviating Renal Fibrosis.

Fibrosis is involved in the pathogenesis of kidney diseases. We previously discovered that Rosa roxburghii fruit (Cili) possesses antifibrosis property in chronic renal disease, but the mechanisms are unknown. We hypothesized that Cili might prevent fibrosis development through mediating TGF-ß/Smads signaling, which is known to be involved in renal fibrosis. This study aimed to confirm the effects of freeze-dried Cili powder in a rat model of unilateral ureteral obstruction (UUO) and examine TGF-ß/Smads signaling. Rats were randomized to (n=12/group): sham operation, UUO, UUO with losartan, UUO with moderate Cili dose (3 g/kg/d), and UUO with high Cili dose (6 g/kg/d). The rats were sacrificed after 14 days of treatment. Collagen deposition was tested using Masson's staining. TGF-ß/Smads signaling was examined by qRT-PCR, western blot, and immunohistochemistry. Rats in the UUO group showed excessive deposition of collagen in kidney interstitium, accompanied with high levels of renal 8-hydroxy-2'-deoxyguanosine, renal malondialdehyde, blood urea nitrogen (BUN), serum creatinine (Scr), and proteinuria (all P<0.05). Cili powder efficiently alleviated the pathological changes and oxidative stress in the kidneys of UUO rats, and decreased BUN, Scr and proteinuria (all P<0.05). Cili powder also inhibited the upregulation of TGFB1, TGFBR1, TGFBR2, SMAD2, and SMAD3 and reversed the downregulation of SMAD7 in obstructed kidneys (mRNA and protein) (all P<0.05). In summary, the results suggest that Cili freeze-dried powder effectively prevents renal fibrosis and impairment in UUO rats, which is associated with the inhibition of oxidative stress and TGF-ß1/Smads signaling.

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.