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Background and Purpose: Inhibition of PDE5 improves synaptic plasticity and memory via enhancing cGMP expression, thus activating the cGMP/cAMP response element binding protein (CREB) signalling pathway. This study investigated the effects of a PDE5 inhibitor on scopolamine-induced cognitive dysfunction, using memory-related behavioural tests and biochemical assays.Experimental Approach: In mice were pretreated with PDE5 inhibitor, amnesia was induced by scopolamine. The learning and memory abilities of mice were tested using the Morris water maze test, the Y-maze test, the passive avoidance test and the novel object recognition test in sequence. Expression of memory-related bio-molecules and oxidative stress parameters in brain tissue were measured using Western blot and spectrophotometry respectively.Key Results: KJH-1002, a novel and potent inhibitor of PDE5 (IC50 0.059 ± 0.04 nmol·L-1 ), was synthesized. In the behavioural tests, it markedly improved the memory performance impaired by scopolamine, indicating a restoration of cognitive function in the mice. Moreover, KJH-1002 increased cGMP levels in the cortex and the scopolamine-reduced expression of phosphorylated CREB, Levels of ERK 1/2, Akt and brain-derived neurotrophic factor in the cortex and hippocampus were restored by KJH-1002 treatment. In addition, KJH-1002 administration increased the activities of SOD, glutathione peroxidase and glutathione reductase, and decreased the level of malondialdehyde.Conclusion and Implications: KJH-1002 restored cognitive function in scopolamine-induced amnesia mice by activating the cGMP/CREB signalling pathway and attenuating oxidative stress. The beneficial effects of KJH-1002 on cognition indicate its potential as a therapeutic candidate for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Objective. Oxidative stress has been proven to be essential in the pathogenesis of ulcerative colitis (UC). Therefore, this study was designed to investigate the effect of Gegen Qinlian decoction (GQ) on the Nrf2 pathway in the treatment of UC and explore the potential mechanism. Methods. The UC rat model was induced by 5% dextran sodium sulfate (DSS) aqueous solution, and UC rats were treated with GQ orally. The effect of GQ on UC rats was recorded. Human clonal colon adenocarcinoma cells (Caco-2) stimulated by tumor necrosis factor-α (TNF-α) were employed in this study. After being stimulated with TNF-α for 2 hours, Caco-2 cells were cultured with GQ or its major components (puerarin, baicalin, berberine, and liquiritin) for 22 hours. In addition, the Nrf2 gene of Caco-2 cells was silenced and then cultured with GQ for 22 hours. The contents of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and malondialdehyde (MDA) in colonic tissues and Caco-2 cells were detected by assay kits. Reactive oxygen species (ROS) in Caco-2 cells were analyzed by flow cytometry. Quantitative real-time PCR and western blot were employed to detect the mRNA and protein expression of Nrf2 and its related target genes in colon tissues and Caco-2 cells. Results. GQ alleviated the injured colonic mucosa and activated the expression of Nrf2 in UC rats. In TNF-α stimulated Caco-2 cells and Nrf2 silenced Caco-2 cells, GQ also reversed the inhibitory effect of Nrf2. Furthermore, the major components of GQ could activate Nrf2 signaling in TNF-α stimulated cells as well. Moreover, the contents of SOD, GSH, MDA, and ROS were restored to normal after treatment with GQ or its major components. Among these components, puerarin, berberine, and liquiritin appear to have a better effect on activating Nrf2 in vitro. Overall, GQ can alleviate UC by increasing the activity of Nrf2/ARE signaling and enhancing the effect of antioxidant stress. [ABSTRACT FROM AUTHOR]

Background/Aims: Daphnetin (7,8-dihydroxycoumarin, DAP) exhibits various bioactivities, such as anti-inflammatory and antioxidant activities. However, the role of DAP in myocardial ischaemia/reperfusion (I/R) injury and I/R-related arrhythmia is still uncertain. This study aimed to investigate the mechanisms underlying the effects of DAP on myocardial I/R injury and electrophysiological properties in vivo and in vitro. Methods: Myocardial infarct size was measured by triphenyltetrazolium chloride staining. Cardiac function was assessed by echocardiographic and haemodynamic analyses. The levels of creatine kinase-MB, lactate dehydrogenase, malondialdehyde, superoxide dismutase, interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-α) were detected using commercial kits. Apoptosis was measured by terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labelling staining and flow cytometry. The viability of H9c2 cells was determined by the Cell Counting Kit-8 assay. In vitro, the levels of IL-6 and TNF-α were measured by quantitative PCR. The expression levels of proteins associated with apoptosis, inflammation, and the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor kappa B (TLR4/MyD88/NF-κB) signalling pathway were detected by Western blot analysis. The RR, PR, QRS, and QTc intervals were assessed by surface ECG. The 90% action potential duration (APD90), threshold of APD alternans, and ventricular tachycardia inducibility were measured by the Langendorff perfusion technique. Results: DAP preconditioning decreased myocardial I/R injury and hypoxia/reoxygenation (H/R) injury in cells. DAP preconditioning improved cardiac function after myocardial I/R injury. DAP preconditioning also suppressed apoptosis, attenuated oxidative stress, and inhibited inflammatory responses in vivo and in vitro. Furthermore, DAP preconditioning decreased the susceptibility to ventricular arrhythmia after myocardial I/R. Finally, DAP preconditioning inhibited the expression of TLR4, MyD88, and phosphorylated NF-κB (p-NF-κB)/P65 in mice subjected to I/R and cells subjected to H/R. Conclusions: DAP preconditioning protected against myocardial I/R injury and decreased susceptibility to ventricular arrhythmia by inhibiting the TLR4/MyD88/NF-κB signalling pathway. [ABSTRACT FROM AUTHOR]