Pulmonary arterial hypertension (PAH) is a life‑threatening disease induced by the excessive proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs). Formononetin (FMN) is a natural isoflavone with numerous cardioprotective properties, which can inhibit the proliferation and induce the apoptosis of tumor cells; however, whether FMN has a therapeutic effect on PAH remains unclear. In the present study, PAH was induced in rats with monocrotaline (MCT, 60 mg/kg); rats were then administered FMN (10, 30 or 60 mg/kg/day). At the end of the experiment, hemodynamic changes, right ventricular hypertrophy and lung morphological characteristics were evaluated. α‑smooth muscle actin (α‑SMA), proliferating cell nuclear antigen (PCNA), and TUNEL were detected by immunohistochemical staining. The expression of PCNA, Bcl‑2‑associated X protein (Bax), Bcl‑2 and, cleaved caspase‑3, and activation of AKT and ERK were examined by western blot analysis. The results demonstrated that FMN significantly ameliorated the right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling induced by MCT. FMN also attenuated MCT‑induced increased expression of α‑SMA and PCNA. The ratio of Bax/Bcl‑2 and cleaved caspase‑3 expression increased in rat lung tissue in response to FMN treatment. Furthermore, reduced phosphorylation of AKT and ERK was also observed in FMN‑treated rats. Therefore, FMN may provide protection against MCT‑induced PAH by preventing pulmonary vascular remodeling, potentially by suppressing the PI3K/AKT and ERK pathways in rats.

Elucidating the mechanisms for circadian expression of drug-metabolizing enzymes is essential for a better understanding of dosing time-dependent drug metabolism and pharmacokinetics. CYP2B6 (Cyp2b10 in mice) is an important enzyme responsible for metabolism and detoxification of approximately 10% of drugs. Here, we aimed to investigate a potential role of nuclear receptor co-repressor RIP140 in circadian regulation of Cyp2b10 in mice. We first uncovered diurnal rhythmicity in hepatic RIP140 mRNA and protein with peak values at ZT10 (ZT, zeitgeber time). RIP140 ablation up-regulated Cyp2b10 expression and blunted its rhythm in mice and in AML-12 cells. Consistent with a negative regulatory effect, overexpression of RIP140 inhibited Cyp2b10 promoter activity and reduced cellular Cyp2b10 expression. Furthermore, RIP140 suppressed Car- and Pxr-mediated transactivation of Cyp2b10, and the suppressive effects were attenuated when the RIP140 gene was silenced. Chromatin immunoprecipitation assays revealed that recruitment of RIP140 protein to the Cyp2b10 promoter was circadian time-dependent in wild-type mice. More extensive recruitment was observed at ZT10 than at ZT2 consistent with the rhythmic pattern of RIP140 protein. However, the time-dependency of RIP140 recruitment was lost in RIP140^-/- mice. Additionally, we identified a D-box and a RORE cis-element in RIP140 promoter. D-box- and RORE-acting clock components such as Dbp, E4bp4, Rev-erbα/β and Rorα transcriptionally regulated RIP140, potentially accounting for its rhythmic expression. In conclusion, RIP140 regulates diurnal expression of Cyp2b10 in mouse liver through periodical repression of Car- and Pxr-mediated transactivation. This co-regulator-driven mechanism represents a novel source of diurnal rhythmicity in drug-metabolizing enzymes.

Robot-Assisted Minimally Invasive Surgery (RAMIS), which introduced robot-actuated invasive tools to increase the dexterity and efficiency of traditional MIS, has become popular. Investigations on how to achieve autonomy in RAMIS have drawn vast intention recently, which urges further insights into the process of the surgical procedures. In this paper, the definition of critical actions, which discriminates the essential stages from regular surgical actions, is proposed to help decompose the complicated surgical processes. A critical intra-operative moment of the surgical workflow, which is called the keyframe, is introduced to indicate the beginning or ending moments of the critical actions. A keyframe detection method is proposed for critical action identification based on a new in-vivo dataset labeled by expert surgeons. Surgeons' criteria for critical actions are captured by the explainable features, which can be extracted from the raw laparoscopic images with a two-stage network. Motivated by the surgeon's decision process of keyframes, a hierarchical structure is designed for keyframe identification by checking the spatial-temporal characteristics of the explainable features. Experimental results show that the reliability of the proposed method for keyframe detection achieves unanimous agreement by expert surgeons.

Objective: This study aimed to investigate regulation of the cyclic adenosine monophosphate (cAMP) signaling pathway on connective tissue growth factor (CTGF) during myocardial fibrosis (MF) in mice after myocardial infarction (MI). Methods: An MI mouse model was established and cardiac function indices were detected by ultrasound. Quantitative reverse transcription polymerase chain reaction and western blotting were used to determine CTGF and transforming growth factor β1 (TGF-β1) cardiac expression. Mouse cardiac fibroblasts (MCFs) were used to study the mechanism of MF after MI. Results: Cardiac function indices were lower after MI. Cardiac function indices were better in the MI + meglumine adenosine cyclophosphate (MAC) group than in the MI group, and CTGF expression in the MI + MAC group was downregulated. TGF-β1 expression was not different among the MI groups. Forskolin increased intracellular cAMP levels and inhibited CTGF expression in MCFs. Expression of p44/42 mitogen-activated protein kinase (MAPK) was significantly lower in the TGF-β1 + forskolin group than in the TGF-β1 group, while protein kinase A was significantly upregulated. CTGF expression was significantly lower in the TGF-β1 + forskolin + PD98509 group than in the TGF-β1 + forskolin group. Conclusions: This study shows that cAMP upregulates protein kinase A expression through the p44/42MAPK signaling pathway and decreases p44/42MAPK phosphorylation levels, inhibiting CTGF expression.