European Journal of Pharmacology

Ginsenoside Rd, one of the main active components in ginseng, exerts various biological activities. However, its effectiveness on myocardial ischemia injury and its potential mechanism need further clarification. The model of isoproterenol (ISO)-induced myocardial ischemia injury (MI) mice and cobalt chloride (CoCl2 )-induced cardiomyocytes injury were performed. Ginsenoside Rd significantly alleviated MI injury, as evidenced by ameliorated cardiac pathological features and improved cardiac function. Simultaneously, ginsenoside Rd notably mitigated CoCl2 -induced cell injury, decreased the lactate dehydrogenase (LDH) release and reactive oxygen species (ROS) generation in vitro...

Myocardial ischemia-reperfusion (I/R) injury triggers several cell death types, including apoptosis, autophagy, and ferroptosis. Licochalcone A (LCA), a natural flavonoid compound isolated from the root of Glycyrrhiza glabra, has been demonstrated to exert potential pharmacological benefits, such as antioxidant, antitumor, and anti-inflammatory activities. The present study aimed to investigate the involvement of ferroptosis in the pathogenesis of I/R and determine whether LCA can inhibit ferroptosis to prevent the myocardial I/R injury in rats...

There is evidence that high daily intake of aluminum (Al) is associated with an increased risk of dementia or cognitive decline. We injected L-arginine into the dorsal hippocampus (DH) of an AlCl3-induced Alzheimer's model and studied memory deficit, β-amyloid (βA) accumulation, neurodegeneration, and molecular changes. Male Wistar rats were cannulated unilaterally in the DH under a stereotaxic apparatus and a dose of AlCl3 (1-200 μg/rat) was injected into the CA1. After recovery, L-arginine and L-NAME (0...

OBJECTIVE: To reveal the core mechanism of berberine (BBR) in the treatment of diabetic retinopathy (DR), by using Four-dimensional independent data acquisition (4D-DIA) proteomics combined bioinformatics analysis with experimental validation. METHODS: DR injury model was established by injecting streptozotocin intraperitoneally. At 8 weeks after BBR administration, optical coherence tomography (OTC) photos and Hematoxylin-eosin staining from retina in each group were performed, then the retinas was collected for 4D-DIA quantitative proteomics detection...

Most social animals self-organize into dominance hierarchies that strongly influence their behavior and health. The serotonin (5-HT) system is believed to play an important role in the formation of social hierarchy. 5-HT receptors are abundantly expressed in the amygdala, which is considered as the central node for the perception and learning of social hierarchy. In this study, we assessed the functions of various 5-HT receptor subtypes related to social rank determination in different subregions of the amygdala using the confrontation tube test in mice...

AIMS: (-)-2,5-dimethoxy-4-methylamphetamine (DOM) induces the head-twitch response (HTR) primarily by activating the serotonin 5-hydroxytryptamine 2A receptor (5-HT2A receptor) in mice. However, the mechanisms underlying 5-HT2A receptor activation and the HTR remain elusive. Gβγ subunits are a potential treatment target in numerous diseases. The present study investigated the mechanism whereby Gβγ subunits influence DOM-induced HTR. MAIN METHODS: The effects of the Gβγ inhibitor 3',4',5',6'-tetrahydroxyspiro[2-benzofuran-3,9'-xanthene]-1-one (gallein) and antagonistic peptide βARKct (β-adrenergic receptor kinase C-terminal fragment) on DOM-induced HTR were studied via an HTR test...

Prostate cancer (PCa) is the most frequently diagnosed cancer among men and the second leading cause of death in Western countries. Clinically, screening drugs and develop developing new therapeutics to treat PCa is of great significance. In this study, BML-275 was demonstrated to exert potent antitumor effects in PCa by antagonizing mTOR activity. In cultured PCa cells, BML-275 treatment reduced the expression levels of c-Myc and survivin, promoted the activation of p53, and thereby induced p21/cyclin D1/CDK4/6-dependent cell cycle G1/S arrest...

Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting mental ability and interrupts neurocognitive functions. Treating multifactorial conditions of AD with a single-target-directed drug is highly difficult. Thus, a multi-target-directed ligand (MTDL) development strategy has been developed as a promising approach for the treatment of AD. Herein, we have synthesized two novel thiosemicarbazones as MTDLs and reported their bioactivities against diverse neuropathological events involved in AD...

Voltage dependent anion channels (VDAC) in the outer mitochondrial membrane regulate the influx of metabolites that sustain mitochondrial metabolism and the efflux of ATP to the cytosol. Free tubulin and NADH close VDAC. The small molecules X1 and SC18 open VDAC and modulate mitochondrial metabolism. X1 antagonizes the inhibitory effect of tubulin on VDAC. SC18 occupies an NADH-binding pocket in the inner wall of all VDAC isoforms. Here, we hypothesized that X1 and SC18 have a synergistic effect with sorafenib, regorafenib or lenvatinib to arrest proliferation and induce death in hepatocarcinoma cells...

Preeclampsia (PE) harms a significant number of pregnant women and fetuses. However, because of its complex pathological mechanisms, there is no cure except for delivery. This study identified the impact and mechanisms of action of HOXB3 in PE. The behaviors of HTR-8/SVneo cells were analyzed using a cell counting kit-8, EdU, and transwell assays. The interaction between HOXB3 and Notch1 was assessed using a luciferase reporter and chromatin immunoprecipitation assays. Expression was measured by quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence assays...

The current investigation aimed to explore the potential of etoricoxib nanostructured lipid carriers (ET-NLCs) as an anti-inflammatory drug in radiation-exposed rats, with a focus on assessing its efficacy in reducing inflammation while minimizing cardiac toxicity compared to conventional etoricoxib (ET) treatment. The ET-NLCs were prepared by the low-temperature melt emulsification solidification technique. Various techniques were employed to characterize the NLCs. Rats were exposed to gamma-irradiation (6 Gy) to induce cardiac inflammation and injury, followed by oral administration of ET or ET-NLCs (10 mg/kg b...

Chronic kidney disease (CKD) with anxiety disorder is of a great concern due to its high morbidity and mortality. Urea, as an important toxin in CKD, is not only a pathological factor for complications in patients with CKD, but also is accumulated in the brain of aging and neurodegenerative diseases. However, the pathological role and underlying regulatory mechanism of urea in CKD related mood disorders have not been well established. We previously reported a depression phenotype in mice with abnormal urea metabolism...

Neonatal hypoxic-ischemic brain damage (HIBD) is a prominent contributor to both immediate mortality and long-term impairment in newborns. The elusive nature of the underlying mechanisms responsible for neonatal HIBD presents a significant obstacle in the effective clinical application of numerous pharmaceutical interventions. This comprehensive review aims to concentrate on the potential neuroprotective agents that have demonstrated efficacy in addressing various pathogenic factors associated with neonatal HIBD, encompassing oxidative stress, calcium overload, mitochondrial dysfunction, endoplasmic reticulum stress, inflammatory response, and apoptosis...

Allyl-isothiocyanate (AITC) is a common Isothiocyanates (ITC) and its chemo-preventive and anti-tumor effects are believed to be related to the activation of NF-E2 p45-related Factor 2 (Nrf2). However, its anti-tumor effects on colorectal cancer (CRC) are not well elucidated. Here, we investigated the therapeutic in vitro and/or in vivo effects and mechanisms of action (MOA) for AITC on CRC cell line HCT116 (human) and MC38 (mouse). AITC treatment in a low concentration range (1 mg/kg in vivo) significantly inhibited the tumor cell growth and increased the expression of p21 and Nrf2...

In decompensated cirrhosis, the severity of portal hypertension (PHT) is associated with increased hepatic endothelial nitric oxide synthase (eNOS) trafficking inducer (Nostrin), but the mechanism remains unclear. AIM: To investigate: (1) Whether in cirrhosis-PHT models, ± superimposed inflammation to mimic acute-on-chronic liver failure (ACLF) modulates hepatic nitric oxide synthase trafficking inducer (NOSTRIN) expression, nitric oxide (NO) synthesis, and/or endothelial dysfunction (ED); and (2) Whether the "angiotensin II type 1 receptor blocker" candesartan cilexetil (CC) affects this pathway...

Acute kidney injury (AKI) is a clinically serious disorder associated with high mortality rates and an increased risk of progression to end-stage renal disease. As an essential supportive treatment for patients with respiratory failure, mechanical ventilation not only save many critically ill patients, but also affect glomerular filtration function by changing renal hemodynamics, neurohumoral and positive end-expiratory pressure, eventually leading to AKI. AMP-activated protein kinase (AMPK), a crucial energy homeostasis regulator, could enhance macrophage phagocytic ability and inhibit inflammation, but whether it can engulf neutrophil extracellular traps (NETs) and alleviate mechanical ventilation-associated AKI is still unclear...

Non-alcoholic fatty liver disease (NAFLD) is a common condition that can progress to the more severe conditions like non-alcoholic steatohepatitis (NASH) for which limited effective therapeutic options are available. In this study, we set out to evaluate the novel glucocorticoid receptor modulator CORT125385, an analogue of the previously studied miricorilant but without mineralocorticoid receptor binding activity. Male and female mice that received high-fat diet and fructose water were treated with either vehicle, CORT125385 or mifepristone...

The proteasome is the main complex responsible for maintaining intracellular protein homeostasis, impairment of which is associated with cardiac ischaemia/reperfusion (I/R) injury. The small molecule TCH-165 has been found to activate the 20S proteasome to remove disordered proteins in multiple myeloma and glioblastoma. However, the preventive effect of TCH-165 against I/R-mediated cardiac impairment in mice remains largely unknown. Here, a cardiac I/R model was established in mice. Heart function was assessed with echocardiography...

Conventional chemotherapy, one of the most widely used cancer treatment methods, has serious side effects, and usually results in cancer treatment failure. Drug resistance is one of the primary reasons for this failure. The most significant drawbacks of systemic chemotherapy are rapid clearance from the circulation, the drug's low concentration in the tumor site, and considerable adverse effects outside the tumor. Several ways have been developed to boost neoplasm treatment efficacy and overcome medication resistance...

Small molecule drugs are of significant importance in the treatment of non-small cell lung cancer (NSCLC). Here, we explored biological effects of the PI3K/mTOR inhibitor VS-5584 on NSCLC. Our findings indicated that VS-5584 administration resulted in a dose-dependent inhibition of NSCLC cell proliferation, as well as the induction of apoptosis and cycle arrest. Additionally, we observed a significant increase in intracellular reactive oxygen species (ROS) levels following VS-5584 treatment. The use of the ROS inhibitor N-acetylcysteine (NAC) effectively reduced ROS levels and decreased the proportion of apoptotic cells...