ABSTRACT
BACKGROUND: Patients with chronic heart failure (CHF) frequently develop hyperuricemia, an elevated serum uric acid level, associated with adverse outcomes. Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, demonstrates reduction in cardiovascular mortality and hospitalization in patients with CHF and ejection fraction (HFrEF), irrespective of diabetes. However, dapagliflozin's effect on the uric acid levels in patients with CHF and hyperuricemia remain unclear. AIM: To investigate the effects of dapagliflozin on uric acid levels in CHF patients with hyperuricemia. METHODS: We conducted a randomized, double-blind, placebo-controlled trial in 200 patients with CHF and hyperuricemia, with HFrEF and serum uric acid levels ≥ 7 mg/dL (≥ 416 µmol/L). The participants were randomly assigned to receive a daily dose of 10 mg dapagliflozin or placebo for 24 months. The primary endpoint was the change in serum uric acid level from baseline to 24 months. Secondary endpoints included changes in left ventricular ejection fraction (LVEF), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and quality of life (QoL) scores, as well as the incidence of cardiovascular death and hospitalization for heart failure. RESULTS: At 24 months, dapagliflozin significantly reduced serum uric acid levels by 1.2 mg/dL (71 µmol/L) compared with placebo (95%CI: -1.5 to -0.9; P < 0.001). Dapagliflozin also significantly improved LVEF by 3.5% (95%CI: 2.1-4.9; P < 0.001), NT-proBNP by 25% (95%CI: 18-32; P < 0.001), and QoL scores by 10 points (95%CI: 7-13; P < 0.001) and reduced the risk of cardiovascular death and hospitalization for heart failure by 35% (95%CI: 15-50; P = 0.002) compared with the placebo. Adverse events were similar between the two groups, except for a higher rate of genital infections in the dapagliflozin group (10% vs 2%, P = 0.01). CONCLUSION: Dapagliflozin significantly lowered serum uric acid levels and improved the clinical outcomes in patients with CHF and hyperuricemia. Therefore, dapagliflozin may be a useful therapeutic option for this high-risk population.
ABSTRACT
Akirin is a nuclear protein that controls development in vertebrates and invertebrates. The function of Akirin has not been assessed in any Coleopteran insects. We found that high levels of akirin transcripts in Henosepilachna vigintioctopunctata, a serious Coleopteran potato defoliator (hereafter Hvakirin), were present at prepupal, pupal and adult stages, especially in larval foregut and fat body. RNA interference (RNAi) targeting Hvakirin impaired larval development. The Hvakirin RNAi larvae arrested development at the final larval instar stage. They remained as stunted larvae, gradually blackened and finally died. Moreover, the remodelling of gut and fat body was inhibited in the Hvakirin depleted larvae. Two layers of cuticles, old and newly formed, were noted in the dsegfp-injected animals. In contrast, only a layer of cuticle was found in the dsakirin-injected beetles, indicating the arrest of larval development. Furthermore, the expression of three transforming growth factor-ß cascade genes (Hvsmox, Hvmyo and Hvbabo), a 20-hydroxyecdysone (20E) receptor gene (HvEcR) and six 20E response genes (HvHR3, HvHR4, HvE75, HvBrC, HvE93 and Hvftz-f1) was significantly repressed, consistent with decreased 20E signalling. Conversely, the transcription of a juvenile hormone (JH) biosynthesis gene (Hvjhamt), a JH receptor gene (HvMet) and two JH response genes (HvKr-h1 and HvHairy) was greatly enhanced. Our findings suggest a critical role of Akirin in larval development in H. vigintioctopunctata.
ABSTRACT
Although muscle development has been widely studied in Drosophila melanogaster, it was a great challenge to apply to developmental processes of other insect muscles. This study was focused on the functional characterization of a basic helix-loop-helix transcription factor gene twist in an herbivorous ladybird Henosepilachna vigintioctopunctata. Its transcript (Hvtwist) levels were detected in all developmental stages. RNA interference (RNAi)-aided knockdown of Hvtwist at the penultimate larval instar stage impaired pupation, and caused a deformed adult in the legs. The tarsi were malformed and did not support the bodies in an upright position. The climbing ability was impaired. Moreover, around 50% of the impaired adults had a malformed elytrum. In addition, they consumed less foliage and did not lay eggs. A hematoxylin-eosin staining of the leg demonstrated that the tibial extensor (TE) and the tibial flexor (TF) muscles were originated from the femurs while levator and depressor muscles of the tarsus (TL and TD) were located in the tibia in the control adults, in which tarsal segments were devoid of muscles. RNAi treatment specific to Hvtwist expression markedly impaired TE and TF muscles in the femurs, and prevented the development of TL and TD muscles in the tibia. Therefore, our findings demonstrate Twist plays a vital role in the myogenesis in H. vigintioctopunctata adult legs.
Subject(s)
Coleoptera , Drosophila melanogaster , Animals , Coleoptera/genetics , Larva/genetics , RNA Interference , Muscle DevelopmentABSTRACT
Objective: To observe the effect of Yishen Tonglong Decoction (YTD) on the epithelial-mesenchymal transition (EMT) and Ras/ERK signaling pathway in human PCa DU-145 cells and explore its action mechanism. METHODS: We treated human PCa DU-145 cells with normal plasma (the blank control) or plasma containing 5% (low-dose), 10% (medium-dose) and 15% (high-dose) YTD. After intervention, we examined the proliferation of the DU-145 cells in different groups with CCK-8 and their apoptosis by Annexin V/PI double staining. We detected the cell cycle by PI assay, the invasion and migration of the cells using the Transwell chamber and scratch test, and the expressions of the proteins and genes related to the EMT and Ras/ERK signaling pathways in the cells by Western blot and RT-PCR. RESULTS: Compared with the blank control group, high-, medium- and low-dose YTD significantly inhibited the proliferation of the PCa DU-145 cells, decreased their adherence and growth (P < 0.05, P < 0.01), promoted their apoptosis (P < 0.01), regulated their cell cycles (P < 0.05, P < 0.01), and reduced their in vitro invasion and migration abilities (P < 0.05), all in a dose-dependent manner. The results of Western blot and RT-PCR revealed down-regulated protein and mRNA expressions of N-cadherin, zinc finger transcription factor (Snail), Ras, p-ERK1/2 and ERK1/2, but up-regulated protein and mRNA expressions of E-cadherin in the PCa DU-145 cells treated with YTD (P < 0.05, P < 0.01). CONCLUSIONS: Yishen Tonglong Decoction can effectively inhibit the proliferation, promote the apoptosis, regulate the cell cycle and suppress the invasion and migration abilities and EMT process of human PCa DU-145 cells. The mechanism of Yishen Tonglong Decoction acting on PCa may be associated with its inhibitory effect on the EMT process and expression of the Ras/ERK signaling pathway in PCa cells./.