Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Matrine induces apoptosis in human acute myeloid leukemia cells via the mitochondrial pathway and Akt inactivation.

Acute myeloid leukemia (AML) is a hematological malignancy characterized by a rapid increase in the number of immature myeloid cells in bone marrow. Despite recent advances in the treatment, AML remains an incurable disease. Matrine, a major component extracted from Sophora flavescens Ait, has been demonstrated to exert anticancer effects on various cancer cell lines. However, the effects of matrine on AML remain largely unknown. Here we investigated its anticancer effects and underlying mechanisms on human AML cells in vitro and in vivo. The results showed that matrine inhibited cell viability and induced cell apoptosis in AML cell lines as well as primary AML cells from patients with AML in a dose- and time-dependent manner. Matrine induced apoptosis by collapsing the mitochondrial membrane potential, inducing cytochrome c release from mitochondria, reducing the ratio of Bcl-2/Bax, increasing activation of caspase-3, and decreasing the levels of p-Akt and p-ERK1/2. The apoptotic effects of matrine on AML cells were partially blocked by a caspase-3 inhibitor Z-DEVD-FMK and a PI3K/Akt activator IGF-1, respectively. Matrine potently inhibited in vivo tumor growth following subcutaneous inoculation of HL-60 cells in SCID mice. These findings indicate that matrine can inhibit cell proliferation and induce apoptosis of AML cells and may be a novel effective candidate as chemotherapeutic agent against AML

Effects of matrine on proliferation of AML cells, leukemic CD34⁺lin⁻ cells and normal CD34⁺lin⁻ cells.

<p>AML cell lines (HL-60, NB4, and U937), primary AML cells (BMMNCs), leukemic CD34⁺lin⁻ cells, and normal CD34⁺lin⁻ cells were treated with various concentrations of matrine for 12 h, 24 h and 48 h. Cell viability was assessed by MTT assay, and data were presented as the mean of at least three independent experiments. <b>A.</b> HL-60 cells. <b>B.</b> NB4 cells. <b>C.</b> U937 cells. <b>D.</b> BMMNCs. <b>E.</b> Leukemic CD34⁺lin⁻ cells. <b>F.</b> Normal CD34⁺lin⁻ cells.^*<i>P</i><0.05 vs the respective control.</p

Matrine induced apoptosis in AML cells.

<p><b>A.</b> AML cells, leukemic CD34⁺lin⁻ cells, and normal CD34⁺lin⁻ cells were treated with 1.5 g/L matrine for 24 h. The Annexin V-FITC binding and PI staining method was used to assess apoptosis, and representatives were shown. Both annexin V- and PI- negative (lower - left quadrant), annexin V- positive and PI- negative (lower - right quadrant), and both annexin V- and PI- positive (upper - right quadrant) cells were considered as the viable, early-phase apoptotic, late-phase apoptotic/necrotic cells, respectively. The percentage (%) of cells was described in each quadrant. <b>B.</b> AML cells were treated with various concentrations of matrine (0∼2 g/L) for 24 h. <b>C.</b> AML cells were treated by 1.5 g/L matrine for 12 h, 24 h and 48 h. The values represent the mean ± SD of at least three independent experiments. ^*<i>P</i><0.05 vs the respective control.</p

Effects of matrine on Bcl-2/Bax ratio in AML cells for 24 h. A.

<p>The expression of Bcl-2 and Bax were detected by FCM, and representatives were shown in AML cells treated by 1.5 g/L matrine for 24 h. <b>B.</b> AML cells were treated by various concentrations of matrine for 24 h. The values represent the mean ± SD of at least three independent experiments.^*<i>P</i><0.05 vs the respective control.</p

Matrine induced apoptosis through Akt and ERK1/2 inactivation in AML cells. A.

<p>AML cell lines (HL-60, NB4, and U937) and primary AML cells were exposed to 1.5 g/L matrine for 24 h, after which cell lysates were extracted and subjected to western blot analysis to monitor expression of Akt, p-Akt, ERK1/2, and p-ERK1/2. Representatives were shown. <b>B.</b> The optical densities of the bands were measured using Scion image analysis and data were presented as the mean ± SD of at least three independent experiments. <b>C.</b> Effects of IGF-1 on matrine-induced apoptosis detected by annexin V-FITC binding and PI staining method. Apoptotic cells were determined after treatment with matrine (1.5 g/L) in the presence (+) or absence (−) of IGF-1 (100 ng/ml ) for 24 h. The values represent the mean ± SD of at least three independent experiments.^*<i>P</i><0.05 vs the respective control, ^#<i>P</i><0.05 vs the matrine only group.</p

Toxicological Profiling of Highly Purified Single‐Walled Carbon Nanotubes with Different Lengths in the Rodent Lung and Escherichia Coli

Carbon nanotubes (CNTs) exhibit a number of physicochemical properties that contribute to adverse biological outcomes. However, it is difficult to define the independent contribution of individual properties without purified materials. A library of highly purified single-walled carbon nanotubes (SWCNTs) of different lengths is prepared from the same base material by density gradient ultracentrifugation, designated as short (318 nm), medium (789 nm), and long (1215 nm) SWCNTs. In vitro screening shows length-dependent interleukin-1β (IL-1β) production, in order of long &gt; medium &gt; short. However, there are no differences in transforming growth factor-β1 production in BEAS-2B cells. Oropharyngeal aspiration shows that all the SWCNTs induce profibrogenic effects in mouse lung at 21 d postexposure, but there are no differences between tube lengths. In contrast, these SWCNTs demonstrate length-dependent antibacterial effects on Escherichia coli, with the long SWCNT exerting stronger effects than the medium or short tubes. These effects are reduced by Pluronic F108 coating or supplementing with glucose. The data show length-dependent effects on proinflammatory response in macrophage cell line and antibacterial effects, but not on collagen deposition in the lung. These data demonstrate that over the length scale tested, the biological response to highly purified SWCNTs is dependent on the complexity of the nano/bio interface