Propranolol can correct prolonged QT intervals in patients with cirrhosis.

Background: Prolonged QT intervals are extremely common in patients with cirrhosis and affect their treatment outcomes. Propranolol is often used to prevent gastroesophageal variceal hemorrhage in patients with cirrhosis; however, it is uncertain whether propranolol exerts a corrective effect on QT interval prolongation in patients with cirrhosis. Aim: The study aimed to investigate the therapeutic effects of propranolol on patients with cirrhosis and prolonged QT intervals. Methods: A retrospective cohort study approach was adopted. Patients with cirrhosis complicated by moderate-to-severe gastroesophageal varices, who were hospitalized at the Affiliated Hospital of Guangdong Medical University between 1 December 2020 and 31 November 2022, were included in the study. The patients were divided into the propranolol and control groups based on whether they had received propranolol. Upon admission, the patients underwent tests on liver and kidney functions, electrolytes, and coagulation function, as well as abdominal ultrasonography and electrocardiography. In addition to conventional treatment, the patients were followed up after the use or non-use of propranolol for treatment and subsequently underwent reexamination of the aforementioned tests. Results: The propranolol group (26 patients) had an average baseline corrected QT (QTc) interval of 450.23 ± 37.18 ms, of which 14 patients (53.8%) exhibited QTc interval prolongation. Follow-up was continued for a median duration of 7.00 days after the administration of propranolol and conventional treatment. Electrocardiographic reexamination revealed a decrease in the QTc interval to 431.04 ± 34.64 ms (p = 0.014), and the number of patients with QTc interval prolongation decreased to five (19.2%; p < 0.001). After treatment with propranolol and multimodal therapy, QTc interval normalization occurred in nine patients with QTc interval prolongation, leading to a normalization rate of 64.3% (9/14). The control group (n = 58) had an average baseline QTc interval of 453.74 ± 30.03 ms, of which 33 patients (56.9%) exhibited QTc interval prolongation. After follow-up for a median duration of 7.50 days, the QTc interval was 451.79 ± 34.56 ms (p = 0.482), and the number of patients with QTc interval prolongation decreased to 30 (51.7%; p = 0.457). The QTc interval normalization rate of patients in the control group with QTc interval prolongation was merely 10.0% (3/33), which was significantly lower than that in the propranolol group (p < 0.001). Conclusion: In patients with cirrhosis complicated by QT interval prolongation, the short-term use of propranolol aids in correction of a long QT interval and provides positive therapeutic value for cirrhotic cardiomyopathy.

Protection of p-Coumaric acid against chronic stress-induced neurobehavioral deficits in mice via activating the PKA-CREB-BDNF pathway.

There is a body of evidence to suggest that chronic stress modulates neurochemical homeostasis, alters neuronal structure, inhibits neurogenesis and contributes to development of mental disorders. Chronic stress-associated mental disorders present common symptoms of cognitive impairment and depression with complex disease mechanisms. P-coumaric acid (p-CA), a natural phenolic compound, is widely distributed in vegetables, cereals and fruits. p-CA exhibits a wide range of health-related effects, including anti-oxidative-stress, anti-mutagenesis, anti-inflammation and anti-cancer activities. The current study aims to evaluate the therapeutic potential of p-CA against stress-associated mental disorders. We assessed the effect of p-CA on cognitive deficits and depression-like behavior in mice exposed to chronic restraint stress (CRS); we used network pharmacology, biochemical and molecular biological approaches to elucidate the underlying molecular mechanisms. CRS exposure caused memory impairments and depression-like behavior in mice; p-CA administration attenuated these CRS-induced memory deficits and depression-like behavior. Network pharmacology analysis demonstrated that p-CA was possibly involved in multiple targets and a variety of signaling pathways. Among them, the protein kinase A (PKA) - cAMP-response element binding protein (CREB) - brain derived neurotrophic factor (BDNF) signaling pathway was predominant and further characterized. The levels of PKA, phosphorylated CREB (pCREB) and BDNF were significantly lowered in the hippocampus of CRS mice, suggesting disruption of the PKA-CREB-BDNF signaling pathway; p-CA treatment restored the signaling pathway. Furthermore, CRS upregulated expression of proinflammatory cytokines in hippocampus, while p-CA reversed the CRS-induced effects. Our findings suggest that p-CA will offer therapeutic benefit to patients with stress-associated mental disorders.

Boosting Anti-tumour Immunity Using Adjuvant Apigenin.

The interactions and secretions within the tumour have a pivotal role in tumour growth and therapy. Immunosuppressive cells such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumour-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs) secrete some substances, which can result in the exhaustion of anti-tumour immunity. To stimulate anti-tumour immunity, suppression of the secretion and interactions of immunosuppressive cells, on the other hand, stimulation of proliferation and activation of natural killer (NK) cells and CD8+ T lymphocytes are required. Apigenin is a flavone with anticancer properties. Emerging evidence shows that not only does apigenin modulate cell death pathways in cancer cells but it also can stimulate anti-tumour immune cells to release death signals and suppress the release of tumour-promoting molecules. In this review, we discuss the interactions between apigenin and various cells within the tumour microenvironment (TME). These interactions may enhance anti-tumour immunity to improve the efficiency of anticancer remedies such as immunotherapy.

P-Coumaric Acid Reverses Depression-Like Behavior and Memory Deficit Via Inhibiting AGE-RAGE-Mediated Neuroinflammation.

Depression, a mood disorder, affects one in fifteen adults, has multiple risk factors and is associated with complicated underlying pathological mechanisms. P-coumaric acid (p-CA), a phenolic acid, is widely distributed in vegetables, fruits and mushrooms. P-CA has demonstrated a protective role against oxidative stress and inflammation in various diseases, including cardiovascular disease, diabetes and cancer. In the current study, we investigated the protection of p-CA against depression and memory impairment in a corticosterone (CORT)-induced chronic depressive mouse model. CORT administration resulted in depression-like behaviors and memory impairment. P-CA treatment alleviated CORT-induced depression-related behaviors and memory impairment. Network pharmacology predicted that p-CA had multiple targets and mediated various signaling pathways, of which inflammation-associated targets and signaling pathways are predominant. Western blotting showed CORT-induced activation of the advanced glycation end product (AGE)-receptor of AGE (RAGE) (AGE-RAGE) signaling and increased expression of the proinflammatory cytokines interleukin-1 beta (IL-1ß) and tumor necrosis factor-alpha (TNFα) in the hippocampus, while p-CA treatment inactivated AGE-RAGE signaling and decreased the levels of IL-1ß and TNFα, suggesting that protection against depression and memory impairment by p-CA is mediated by the inhibition of inflammation, mainly via the AGE-RAGE signaling pathway. Our data suggest that p-CA treatment will benefit patients with depression.

Propofol attenuates mast cell degranulation via inhibiting the miR-221/PI3K/Akt/Ca2+ pathway.

The aim of the present study was to investigate the effect of propofol on immunoglobulin (Ig)E-activated mast cell degranulation and explore the underlying mechanisms responsible. RBL-2H3 cells were treated with propofol for at a variety of concentrations and different amounts of time. Cell viability was assessed using an MTT assay and microRNA (miR)-221 expression was quantified using reverse transcription-quantitative polymerase chain reaction. RBL-2H3 cells were transfected with miR-221 mimic or a negative control and degranulation, including the release of ß-hexosaminidase and histamine, was evaluated using an ELISA kit. The effect of miR-221 overexpression on the phosphorylation of protein kinase B (Akt) was detected using western blotting and extracellular Ca2+ influx was measured via afura-2 assay. The phosphoinositide 3-kinase(PI3K) inhibitor LY294002 was used to investigate the association between PI3K/Akt signaling and Ca2+ influx in the presence of propofol. The results demonstrated that propofol treatment suppressed RBL-2H3 cell proliferation in a dose- and time-dependent manner. Propofol inhibited miR-221 expression in a dose-dependent manner compared with the control group; however, the inhibitive effect was significantly abrogated following transfection with miR-221 mimics. Furthermore, ß-hexosaminidase and histamine release, PI3K/Akt signaling and Ca2+ influx were decreased following propofol application. miR-221 overexpression markedly ameliorated the suppressive effect of propofol. Treatment with LY294002 reversed the propofol-induced decrement of Ca2+ influx on IgE-mediated RBL-2H3 cells, suggesting an association between PI3K/Akt signaling and Ca2+ influx. In conclusion, the results of the present study suggest that propofol treatment attenuates mast cell degranulation via inhibiting the miR-221/PI3K/Akt/Ca2+ pathway. These results indicate that propofol may have a potential therapeutic effect as a treatment for allergic diseases.