European Journal of Pharmacology

The formation of the microenvironment preceding liver metastasis is intricately linked to the intestinal tract. In recent years, mounting evidence has revealed the significant involvement of neutrophil extracellular traps (NETs) in tumor metastasis, particularly in liver metastasis. Disruption of the intestinal barrier can lead to the translocation of bacteria and their metabolites, such as lipopolysaccharide, into the liver. As the primary defense against pathogens, NETs help eliminate gut-derived toxins and shape the liver's inflammatory and immunosuppressive environment...

Clinical studies documented that cenobamate (CNB) has a marked efficacy compared to other antiseizure medications (ASMs) in reducing focal seizures. To date, different aspects of CNB need to be clarified, including its efficacy against generalized seizures. Similarly, the pattern of drug-drug interactions between CNB and other ASMs also compels further investigation. This study aimed to detect the role of CNB on generalized seizures using the DBA/2 mouse model. We have also studied the effects of an adjunctive CNB treatment on the antiseizure properties of some ASMs against reflex seizures...

BACKGROUND: Anticancer angiogenesis inhibitors cause hypertension and renal injury. Previously we observed in rats that high-dose aspirin (capable of blocking cyclooxygenase (COX)-1 and-2) was superior to low-dose aspirin (blocking COX-1 only) to prevent these side-effects during treatment with the angiogenesis inhibitor sunitinib, suggesting a role for COX-2. High-dose aspirin additionally prevented the rise in COX-derived prostacyclin (PGI2 ). Therefore, we studied the preventive effects of selective COX-2 inhibition and the hypothesized contributing role of PGI2 during angiogenesis inhibition...

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common chronic liver disease, but there are few specific medications for it. Lusianthridin, a major phenanthrene component that originates from Dendrobium Sonia, has various in vitro biological functions. In this study, we aimed to evaluate the therapeutic effects of lusianthridin on high-fat diet (HFD)-induced MAFLD as well as to examine the mechanism of its effects. We fed male mice high-fat-diet for 12 weeks to induce MAFLD and then continued to feed them, either with or without lusianthridin, for another six weeks...

Sepsis-associated acute kidney injury (SA-AKI) has a high mortality rate and lacks effective targeted treatment. We applied lipopolysaccharides-induced injury models in human and mouse renal tubular epithelial cells, and at the same time, we selected a commonly used sedative drug, dexmedetomidine, to investigate its potential for renal protection. We found a significant increase in the expression level of HSP90, and the interaction with glutathione peroxidase 4 (GPX4) led to autophagic degradation of GPX4, triggering ferroptosis...

The current study investigated the effect of chlorogenic acid, a polyphenolic compound found in numerous plant products, on a kainic acid-induced seizure rat model and its potential mechanism. Rats were administered chlorogenic acid (10 and 50 mg/kg) intraperitoneally for 30 min before kainic acid (15 mg/kg) intraperitoneal administration. Pretreatment with chlorogenic acid decreased the seizure score, increased the latency to onset of the first seizure, and decreased the mortality rate...

One of the cost-effective alternative methods to find new inhibitors has been the repositioning approach of existing drugs. The advantage of computational drug repositioning method is saving time and cost to remove the pre-clinical step and accelerate the drug discovery process. Hence, an ensemble computational-experimental approach, consisting of three different steps, a machine learning model, simulation of drug-target interaction and experimental characterization, was developed. The machine learning type used here was different tree classification method, which is one of the best randomize machine learning model to identify potential inhibitors from weak inhibitors...

Phosphodiesterase 4 (PDE4) inhibitors are expected to exhibit efficacy against inflammatory diseases due to their broad pharmacological activity. The launched PDE4 inhibitors apremilast, crisaborole, and roflumilast have not exhibited sufficient inhibitory potential due to poor margins of effectiveness and tolerability. In this report, we describe the non-clinical efficacy, brain translocation, and vomit-inducing effects of ME3183 compared with apremilast. ME3183 showed extensive cytokine suppression in vitro studies using human peripheral blood mononuclear cells and T cells...

Our previous study reported that the heterodimer of Angiotensin II Type I Receptor (AT1R) and Mu-Opioid Receptor 1 (MOR1) involves Nitric Oxide (NO) reduction which leads to elevation of blood pressure. Secondly, we showed that Toll-like Receptor 4 (TLR4) may be involved in the heterodimerization of AT1R and MOR1 in the brainstem Nucleus Tractus Solitarii (NTS), which regulates systemic blood pressure and gastric nitric oxide through the insulin pathway. Here, we investigated the role of microglial activation and TLR4 in the heterodimerization of AT1R and MOR1...

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve various symptoms such as headache, arthralgia, and dental pain. While the primary mechanism of NSAID-based pain relief is the inhibition of cyclooxygenase-2, several NSAIDs also modulate other molecular targets related to nociceptive transmission such as voltage-gated Na+ channels. In the present study, we examined the effects of NSAIDs on persistent Na+ current (INaP ) mediated by tetrodotoxin-resistant (TTX-R) Na+ channels in small-to medium-sized trigeminal ganglion neurons using a whole-cell patch-clamp technique...

Obesity and diabetes constitute significant global health issues associated with one another. In contrast to diabetes, which is characterised by oxidative stress that enhances cellular damage and the following complications. Obesity dynamics involve chronic inflammation that promotes insulin resistance and metabolic disruptions. Anti-inflammatory and antioxidant agents, therefore, hold promise for synergistic effects, addressing inflammation and oxidative stress, key factors in managing obesity and diabetes...

Osteogenic differentiation, proliferation, and/or apoptosis of bone marrow mesenchymal stem cells (BMSCs) are involved in the progression of postmenopausal osteoporosis (PMO). However, circular RNA (circRNA)-mediated changes in the cellular function of BMSCs in PMO are still unclear. This study revealed the excellent ability of circ-Plod2 to promote osteogenic differentiation of BMSCs and its molecular mechanisms. In this study, ovariectomized (OVX) rats and control (Sham) rats were used to simulate PMO. Initially, we found that the expression of circ-Plod2 in OVX BMSCs is down-regulated and the expression of the Mpo gene is up-regulated by sequencing and verification...

BACKGROUND: Renal ischemia-reperfusion (I/R) is one of the main causes of acute kidney injury (AKI), for which there is currently no effective treatment. Recently, the interaction between endoplasmic reticulum (ER) stress and pyroptosis during AKI has been investigated. AIM: The purpose of this study was to investigate the protective effects of Gypenoside XVII (GP-17) against I/R-induced renal injury. METHODS: In this study, mice were divided into 6 groups, sham group, I/R group, GP-17 low-, medium-, high-dose group, and positive control 4-PBA group...

Multiple sclerosis (MS) is an inflammatory demyelinating disease in the central nervous system caused by T cell activation mediated by peripheral macrophages, resulting in severe neurological deficits and disability. Due to the currently limited and expensive treatments for MS, we here introduce an economic Chinese medicine extract, (5R)-5-Hydroxytriptolide (LLDT-8), which shows low toxicity and high immunosuppressive activity. We used the widely accepted mouse model of MS, experimental autoimmune encephalomyelitis (EAE), to examine the immunosuppressive effect of LLDT-8 in vivo...

Bile acid (BA)-induced apoptosis is a common pathologic feature of cholestatic liver injury. Glycyrrhetinic acid (GA) is the hepatoprotective constituent of licorice. In the present study, the anti-apoptotic potential of GA was investigated in wild type and macrophage-depleted C57BL/6 mice challenged with alpha-naphthyl isothiocyanate (ANIT), and hepatocytes stimulated with Taurocholic acid (TCA) or Tumor necrosis factor alpha (TNF-α). Apoptosis was determined by TUNEL positive cells and expression of executioner caspases...

BACKGROUND: Many drugs have been explored for their role in improving skin flap survival. 1-deamino-8-D-arginine vasopressin (DDAVP or desmopressin) is a synthesized form of anti-diuretic hormone (ADH) and a selective agonist for vasopressin type-2 receptors (V2 receptors). Desmopressin has been shown to improve endothelial function, induce vasodilation, and reduce inflammation. We aimed to evaluate its efficacy in enhancing flap survival and assess the role of vasopressin receptors in this process...

Age-related cataract (ARC) is a common eye disease, the main cause of which is oxidative stress-mediated apoptosis of lens epithelial cells (LECs). Epigallocatechin gallate (EGCG) is the most potent antioxidant in green tea. Our results demonstrated that EGCG could effectively reduce apoptosis of LECs and retard lens clouding in aged mice. By comparing transcriptome sequencing results of three groups of mice (young control, untreated aged, and EGCG-treated) and screening using GO and KEGG analyses, we selected RASSF2 as the effector gene of EGCG for mechanistic exploration...

Glucagon-like peptide-1 (GLP-1) has gained much attention in the last decade for the treatment of type 2 diabetes. Accumulating evidence indicates that some metabolites of GLP-1 have biological activities that might contribute to the pleiotropic effects of GLP-1 independent of the GLP-1 receptor. The hypoglycemic and weight-reducing effects of the reported metabolites and modifications still need to be confirmed. In this study, we started from the C-terminal nonapeptide GLP-1(28-36) amide and developed a series of GLP-1(28-36) amide-derived hybrid peptides...

The pathogenesis of immunoglobulin A nephropathy (IgAN) is closely related to immunity and inflammation. The clinical process of IgAN varies greatly, making the assessment of prognosis challenging and limiting progress on effective treatment measures. Autophagy is an important pathway for the development of IgAN. However, the role of autophagy in IgAN is complex, and the consequences of autophagy may change during disease progression. In the present study, we evaluated the dynamic changes in autophagy during IgAN...

Septic encephalopathy (SE) is a critical mental status allied with potential long-term cognitive deficits and higher mortality rates in ICU patients. The shortfall in comprehending its pathophysiology limits effective treatment options, however, GLP-1 agonists opened an entry point for future neurodegenerative disease management. This work aims to validate mTORC1 prospective role in the pathogenesis of SE using rapamycin (RAPA) and investigate the involvement of this complex in exendin-4 (EX4) neurotherapeutic potential using cecal ligation and puncturing (CLP)-induced SE model, focusing on necroptosis as a novel intervention besides necrosis and apoptosis...