Aspirin Reduces Cardiac Interstitial Fibrosis by Inhibiting Erk1/2-Serpine2 and P-Akt Signalling Pathways.

BACKGROUND/AIMS: Cardiac interstitial fibrosis is an abnormality of various cardiovascular diseases, including myocardial infarction, hypertrophy, and atrial fibrillation, and it can ultimately lead to heart failure. However, there is a lack of practical therapeutic approaches to treat fibrosis and reverse the damage to the heart. The purpose of this study was to investigate the effect of long-term aspirin administration on pressure overload-induced cardiac fibrosis in mice and reveal the underlying mechanisms of aspirin treatment. METHODS: C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with 10 mg·kg-1·day-1 of aspirin for 4 weeks. Masson staining and a collagen content assay were used to detect the effects of aspirin on cardiac fibrosis in vivo and in vitro. Western blot and qRT-PCR were applied to examine the impact of aspirin on extracellular signal-regulated kinases (Erks), p-Akt/ß-catenin, SerpinE2, collagen I, and collagen III levels in the mice heart. RESULTS: Aspirin significantly suppressed the expression of α-smooth muscle actin (α-SMA; 1.19±0.19-fold) and collagen I (0.95±0.09-fold) in TAC mice. Aspirin, at doses of 100 and 1000 µM, also significantly suppressed angiotensin II-induced α-SMA and collagen I in cultured CFs. The enhanced phosphorylation of Erk1/2 caused by TAC (p-Erk1, 1.49±0.19-fold; p-Erk2, 1.96±0.68-fold) was suppressed by aspirin (p-Erk1, 1.04±0.15-fold; p-Erk2, 0.87±0.06-fold). SerpinE2 levels were suppressed via the Erk1/2 signalling pathway following treatment with aspirin (1.36±0.12-fold for TAC; 1.06±0.07-fold for aspirin+TAC). The p-Akt and ß-catenin levels were also significantly inhibited in vivo and in vitro. CONCLUSIONS: Our study reveals a novel mechanism by which aspirin alleviates pressure overload-induced cardiac interstitial fibrosis in TAC mice by suppressing the p-Erk1/2 and p-Akt/ß-catenin signalling pathways.

Molecular editing of NSC-666719 enabling discovery of benzodithiazinedioxide-guanidines as anticancer agents.

DNA polymerase ß (Polß) is crucial for the base excision repair (BER) pathway of DNA damage repair and is an attractive target for suppressing tumorigenesis as well as chemotherapeutic intervention of cancer. In this study, a unique strategy of scaffold-hopping-based molecular editing of a bioactive agent NSC-666719 was investigated, which led to the development of new molecular motifs with Polß inhibitory activity. NSC compound and its analogs (two series) were prepared, focusing on pharmacophore-based molecular diversity. Most compounds showed higher activities than the parent NSC-666719 and exhibited effects on apoptosis. The inhibitory activity of Polß was evaluated in both in vitro reconstituted and in vivo intact cell systems. Compound 10e demonstrated significant Polß interaction and inhibition characteristics, including direct, non-covalent, reversible, and comparable binding affinity. The investigated approach is useful, and the discovered novel analogs have a high potential for developing as anticancer therapeutics.

Voluntary Assist-as-Needed Controller for an Ankle Power-Assist Rehabilitation Robot.

OBJECTIVE: Although existing assist-as-needed (AAN) controllers have been designed to adapt the robotic assistance to patients' movement performance, they ignore patient's active participation. This study proposed a voluntary AAN (VAAN) controller considering both movement performance and active participation for an ankle rehabilitation robot. METHODS: According to the trajectory tracking error of the human-robot cooperation movement, the controller can switch among four working modes, including robot-resist, free, robot-assist, and robot-dominant mode. In order to reflect patients' active participation, the voluntary torque of the ankle joint was estimated by an EMG-driven musculoskeletal model. The control torque in robot-resist, free, and robot-assist mode was determined by the voluntary torque of ankle joint multiplied by an assistance ratio to encourage subjects' active participation, and a stiff torque was provided in robot-dominant mode. The controller was evaluated with 2 healthy subjects and 5 stroke patients on an ankle rehabilitation robot to investigate the clinical impact on the stroke patients. RESULTS: The experiment results showed that as patients' disability level increased, the trajectory tracking error increased and the proportion of human-dominant time and the voluntary torque of ankle joint decreased. Moreover, the results showed that the proposed VAAN controller achieved higher human contribution ratio than that of previous studies. CONCLUSION: The proposed VAAN controller can adapt the working mode to the movement performance and promote the subjects to participate actively. SIGNIFICANCE: Based on its performance, the proposed VAAN controller has potential for use in robot-assisted rehabilitation.

Intensity- and Duration-Adaptive Functional Electrical Stimulation Using Fuzzy Logic Control and a Linear Model for Dropfoot Correction.

Functional electrical stimulation (FES) is important in gait rehabilitation for patients with dropfoot. Since there are time-varying velocities during FES-assisted walking, it is difficult to achieve a good movement performance during walking. To account for the time-varying walking velocities, seven poststroke subjects were recruited and fuzzy logic control and a linear model were applied in FES-assisted walking to enable intensity- and duration-adaptive stimulation (IDAS) for poststroke subjects with dropfoot. In this study, the performance of IDAS was evaluated using kinematic data, and was compared with the performance under no stimulation (NS), FES-assisted walking triggered by heel-off stimulation (HOS), and speed-adaptive stimulation. A larger maximum ankle dorsiflexion angle in the IDAS condition than those in other conditions was observed. The ankle plantar flexion angle in the IDAS condition was similar to that of normal walking. Improvement in the maximum ankle dorsiflexion and plantar flexion angles in the IDAS condition could be attributed to having the appropriate stimulation intensity and duration. In summary, the intensity- and duration-adaptive controller can attain better movement performance and may have great potential in future clinical applications.

Enterolactone has stronger effects than enterodiol on ovarian cancer.

BACKGROUND: Ovarian cancer is one of the three leading gynecological malignancies, characterized by insidious growth, highly frequent metastasis, and quick development of drug resistance. As a result, this disease has low 5-year survival rates. Estrogen receptor inhibitors were commonly used for the treatment, but only 7% to 18% of patients respond to anti-estrogen therapies. Therefore, more effective therapies to inhibit estrogen-related tumors are urgently needed. Recently, phytoestrogens, such as lignans with estrogen-like biological activities, have attracted attention for their potential effects in the prevention or treatment of estrogen-related diseases. Enterodiol (END) and enterolactone (ENL) are mammalian lignans, which can reduce the risk of various cancers. However, the effects of END and ENL on ovarian cancer are not adequately documented. METHODS: We used in vitro assays on the ES-2 cell line to evaluate the inhibiting effects of END and ENL on ovarian cancer cell proliferation, invasion and migration ability and in vivo xenograft experiments on nude mice to validate the anticancer effects of END and ENL. RESULTS: The in vitro assays demonstrated that high-dose END and ENL could obviously inhibit ovarian malignant properties, including cancerous proliferation, invasion, and metastasis. Compared to END, ENL behaved in a better time-dose dependent manner on the cancer cells. The in vivo experiments showed that END (1 mg/kg), ENL (1 mg/kg) and ENL (0.1 mg/kg) suppressed tumor markedly, and there were statistically significant differences between the experimental and control groups in tumor weight and volume. Compared to END, which have serious side effects to the animals at high concentration such as 1 mg/kg, ENL had higher anticancer activities and less side effects in the animals than END at the same concentrations, so it would be a better candidate for drug development. CONCLUSION: END and ENL both have potent inhibitory effects on ovarian cancer but ENL possesses a more effective anti-cancer capability and less side effects than END. Findings in this work provide novel insights into ovarian cancer therapeutics with phytoestrogens and encourage their clinical applications.

Main components of pomegranate, ellagic acid and luteolin, inhibit metastasis of ovarian cancer by down-regulating MMP2 and MMP9.

Ovarian cancer is the third most common cancer in the female reproductive organs and epithelial ovarian cancer has the highest lethality of all gynecological cancers. Pomegranate fruit juice (PFJ) has been shown to inhibit the growth of several types of cancer other than ovarian cancer. In this study, we exposed the ovarian cancer cell line A2780 to PFJ and two of its components (ellagic acid and luteolin). MTT and wound healing assays demonstrated that all three treatments suppressed the proliferation and migration of the ovarian cancer cells. In addition, western blotting and ELISA assays showed that the expression levels of MMP2 and MMP9 gradually decreased after treatment with increasing concentrations of ellagic acid and luteolin. To confirm our findings in the in vitro experiments, we used another ovarian cancer cell line, ES-2, in nude mice experiments. All three treatments inhibited tumor growth without obvious side-effects. Furthermore, compared with the control group, the expression levels of MMP2 and MMP9 were depressed. Ellagic acid induced a greater effect than luteolin, suggesting that ellagic acid might be a promising candidate for further preclinical testing for treatment of human ovarian cancer.