Naunyn-Schmiedeberg's archives of pharmacology最新文献

Intracerebral hemorrhage (ICH) is an acute and potentially fatal brain disease that causes severe brain damage, resulting in hemiplegia, speech disorders, and even coma or death. Recently, oxidative stress and ferroptosis are claimed involved in the pathogenesis of ICH brain injury. Eupatilin (EUP) is a flavonoid component with promising anti-inflammatory and anti-oxidative stress properties. The present study aimed to explore the pharmacological activity and potential mechanisms of EUP in treating ICH brain injury from the respect of ferroptosis. The ICH model was established in mouse, followed by treating with 3 and 10 mg/kg EUP. Elevated mNSS score, increased brain water content, reduced Nissl bodies, and enhanced EB concentrations were observed in ICH mice, which were sharply alleviated by EUP treatments. Furthermore, increased ROS, MDA, and iNOS levels; declined SOD activities; and enhanced proinflammatory factors like interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1β (IL-1β) in ICH mice were remarkably reversed by EUP. In addition, increased iron⁺ cells and downregulated GPX4, FTH1, and SLC7A11, as well as reduced SOX2 levels, in ICH mice were rescued by EUP. SH-SY5Y cells were stimulated by hemin, followed by treating with EUP (25 and 50 μM). Enhanced ROS and MDA contents; decreased SOD activities; increased iron levels; and downregulated GPX4, FTH1, SLC7A11, and SOX2 were observed in hemin-stimulated SH-SY5Y cells, which were reversed by EUP. Moreover, silencing SOX2 abolished influences of EUP on oxidative stress and ferroptosis in hemin-stimulated SH-SY5Y cells. Collectively, EUP alleviated ICH-induced secondary brain injury by repressing SOX2/SLC7A11 axis-mediated ferroptosis, which provides potential treatment strategies for ICH in the clinic.

Bitter taste receptors belong to the class A of the GPCR superfamily of G protein-coupled receptors. Bitter taste receptors have different numbers and structures in different species, and an analysis of their structures facilitates the discovery and development of their agonists and inhibitors. In addition, bitter taste receptors differ in expression between species and tissues, which corresponds to the diversity and specificity of their mechanisms of action. At present, bitter taste receptors also have a wide range of effects on the treatment of diseases, including gastrointestinal, airway, heart, orthopedic, urinary disease, and cancer. Therefore, this article reviewed the structure, expression, function, and mechanism of bitter taste receptors, in order to develop more bitter taste receptors and bitter ligands for treatment, and provide some new ideas and goals for the clinical use of bitter drugs.

This work demonstrates the antiferroptotic and cytotoxic effects of 2-aminomethyl phenothiazine (PTZ-NH₂), and its alkyl derivative (PTZ-capryl) and mitochondria-targeted triphenylphosphonium conjugate (PTZ-TPP) on BT-474 cells, as well as their effects on isolated rat liver mitochondria. It was found that all studied compounds at 0.5 and 1 μM concentrations have a protective effect in the erastin-induced ferroptosis model. This effect of the tested compounds may be associated with the elimination of ROS overproduction in erastin-treated cells. The antioxidant effect of the compounds was also demonstrated on isolated rat liver mitochondria. At the same time, high concentrations of PTZ-NH₂ had a cytotoxic effect on BT-474 cells (IC₅₀=55 μM), and it was significantly enhanced in the case of PTZ-TPP (IC₅₀=15 μM), which is possibly due to the mitochondrial targeting of PTZ-TPP. In contrast, the alkyl derivative did not exhibit cytotoxic action up to a maximum concentration of 100 μM, which allows it to be recommended as a promising antiferroptotic agent with a wide therapeutic window. The current findings discuss the possible mechanisms of inhibitory action of the tested compounds on ferroptotic cell death.

Valproate is a first-line therapy for epilepsy. It enhances GABA-mediated inhibition by increasing GABA synthetase enzyme activity. However, it causes hepatotoxicity. Metformin, a biguanide derivative that lowers glucose, is given for type 2 diabetes. There have been reports of its potential to protect the liver. Recent studies show that metformin activates AMPK, which improves lithium- and pilocarpine-induced status epilepticus in rats. Hence, the present study investigated the anti-epileptic activity of valproate- and metformin-encapsulated solid lipid nanoformulation against pentylenetetrazole-induced epileptic rats. The valproate- and metformin-loaded solid lipid nanoparticles were prepared using the solvent evaporation method followed by the ultra-sonication method. Stearic acid and glyceryl monostearate concentrations (2-10%) were employed as solid lipids. The formulated valproate- and metformin-loaded solid lipid nanoparticles were evaluated for their antiepileptic activity using pentylenetetrazole-induced epileptic rats. The 6% stearic acid shows better entrapment efficacy, zeta potential, particle size, and surface morphology. So, the same formulation was evaluated for its antiepileptic activity against pentylenetetrazole-induced epileptic rats. The duration and severity of convulsions were significantly decreased in solid lipid nanoparticle-treated epileptic rats. Also, valproate- and metformin-loaded solid lipid nanoparticles treated in epileptic rats increased the GABA, and serotonin levels, and decreased glutamate levels. The current study shows that valproate and metformin do not protect rats against convulsions better than valproate alone. However, the nanoformulation with lower dosage enhances bioavailability and acts similarly to valproate, reducing dose-related toxicity.

Gastrointestinal (GI) malignancies, including esophageal cancer, gastric cancer, and colon cancer, are associated with high mortality rates worldwide. Thymoquinone is one of the main bioactive components of Nigella sativa, and it has been documented to have anticancer effects including GI cancer. Thymoquinone inhibits GI cancer progression by inducing cell cycle arrest, apoptosis, and oxidative stress and inhibiting inflammation, migration, invasion, metastasis, histone deacetylases, STAT3, PI3K/AKT/mTOR, and Wnt/β-catenin signaling pathways. Although the beneficial effects of thymoquinone have been documented, some limitations, including poor bioavailability and hydrophobicity, have hindered its clinical application. Nanotechnology approaches bypass these limitations. In this review article, we outline the different cellular and molecular pathways influenced by thymoquinone and its nanoformulations in GI cancer.

Breast cancer remains the most diagnosed cancer in females and one of its most challenging subtypes is Triple Negative Breast Cancer (TNBC). Treatment of TNBC presents challenges due to limited targeted therapies, inefficacy of chemotherapy, and severe side effects. Therefore, combination therapies are preferred to reduce toxicity and drug resistance. All-trans-retinoic acid (ATRA), a key player in cell growth, differentiation, and organogenesis, also exerts significant anti-cancer effects. NVP-BEZ235 is a dual PI3K and mTOR kinase inhibitor. In this study we investigated the anti-proliferative potential of NVP-BEZ235 and ATRA on TNBC cell line MDA-MB-231. The effective combination dosage was found to be 1 µM for NVP-BEZ235 and 5 µM for ATRA on MDA-MB-231 cells at 48 h. Combination treatment of NVP-BEZ235 and ATRA significantly reduced migration and colony formation compared to the control group. Co-treatment of NVP-BEZ235 and ATRA showed increase at G0/G1 phase in MDA-MB-231 cells. Treatment of NVP-BEZ235 and ATRA in MDA-MB-231 cells showed a significant increase in Caspase-3 genes, while a significant decrease in mTOR and BCL-2 genes were detected when compared to the untreated group. These results indicate that this combination therapy is a promising anti-cancer agent and has potential use in the treatment of TNBC.

Chronic muscle and joint pain affect many people. However, current treatment options harbor a considerable risk of adverse drug reactions, which is why the search for other treatment alternatives is constantly expanding. As a result, research is also focusing on plant-based products. These include devil's claw, a medicinal plant from the sesame family, which is native to the African continent and is used there as a traditional remedy. In this study, 16 different criteria were selected for a critical analysis of devil's claw products, which included aspects such as drug-drug interactions, adverse drug reactions, and recommended daily dose, and 88 products were analyzed with the help of these criteria. Furthermore, products classified as food supplements, dietary supplements, and herbal medicinal products were compared with each other. Our goal was to analyze how consumers are informed, with a focus on consumer safety. The primary objective was not to analyze the actual ingredients of the products or to compare them based on their composition. The results almost invariably show the pharmaceutical reliability of herbal medicinal products. In contrast, products marketed as food supplements and dietary supplements have questionable reliability, as most products in these categories allow manufacturers more freedom and impose fewer controls and requirements. Devil's claw products labeled as food or dietary supplement show significant gaps in consumer information compared to herbal medicinal products. Product naming and packaging are often suggestive, potentially misleading consumers. Our study shows that food supplements and dietary supplements are clearly pursuing financial interests, and that consumer protection is often neglected in the process. The study analysis also revealed a limited number of clinical studies, no long-term studies, and poor methodological quality, undermining their reliability.

Planktonic pathogens pose a significant threat to the global community, especially as they develop into microbial biofilms. Pseudomonas aeruginosa, a gram-negative bacillus, is notorious for causing nosocomial infections and can easily transform into a multidrug-resistant form, particularly within biofilms. This transformation leads to chronic infections in immunocompromised individuals, increasing morbidity and mortality rates worldwide. P. aeruginosa uses biofilms to survive, becoming robust and evading the host's immune protection system. Biofilms also shield microorganisms from antibiotics, rendering them drug-resistant and causing treatment failures. P. aeruginosa biofilms are often associated with device-related infections, as indwelling medical devices (IMDs) serve as breeding grounds for microbial biofilm growth. The ubiquitous presence of P. aeruginosa on both living and abiotic surfaces makes it an excellent model for studying biofilms. The virulence factors of P. aeruginosa, such as lipopolysaccharides, pili, flagella, adhesins, and exopolysaccharides, facilitate disease progression and contribute to biofilm development and maturation. This review focuses on analyzing the characteristics of P. aeruginosa biofilms, including antimicrobial resistance and gene regulation. Methods for detecting biofilms are also briefly described. Additionally, this review provides a comprehensive exploration of the most effective methods for preventing and controlling microbial biofilms, particularly those formed by P. aeruginosa. This study aims to inspire future research and the development of innovative technologies to resist microbial adherence, colonization, and biofilm formation.

One of the most common cancers among women worldwide is breast cancer (BC). Many BC patients express estrogen receptors (ER), and estrogens are critical for their survival, development, and invasion. Therefore, the ability to produce and respond to estrogen, known as endocrine function, represents a potential drug treatment for ER-positive BC. Tamoxifen (TAM), a selective ER modulator, is widely used in hormone-based therapy. However, the emergence of TAM resistance is a significant clinical challenge that often leads to recurrence, progression, and metastasis. Despite its importance, there are currently no reliable biomarkers to predict patient response to hormone-based therapies. MicroRNAs (miRNAs), small non-coding RNAs, have emerged as key regulators in various physiological and pathological processes, including BC initiation, progression, and resistance to therapy. Recent studies highlight the potential of specific miRNAs as predictive biomarkers for TAM resistance. Notably, miR-382-3p and miR-93 are significantly upregulated in TAM-resistant patients, while miR-182-3p is increased in TAM-sensitive patients. Other studies have also shown that circulating miR-221/222 expression can predict recurrence and resistance to tamoxifen treatment in BC patients. Therefore, testing miR-221/222 expression in patients with ductal BC undergoing tamoxifen treatment is recommended to rapidly identify the risk of tamoxifen resistance and enhance treatment efficacy. These findings emphasize the diagnostic and prognostic potential of miRNAs in BC, especially in identifying patients at risk of developing resistance to hormone-based therapies, and provide insights that could enhance personalized treatment strategies and improve treatment outcomes for BC patients.

Huntington's disease is a brain-related hereditary condition characterized by a gradual loss of mental, physical, and emotional function. Quinolinic acid is a toxic substance that is formed because of the breakdown of tryptophan, a compound involved in the metabolism of the amino acid. Diacerein is an anthraquinone which shows anti-inflammatory effects. The binding capacity of diacerein on GSK-3β is screened via Auto Dock. The purpose of the study is to check neuroprotective and anti-inflammatory properties of diacerein on QA-induced HD in adult zebra fish. In this study, 14 fish in each group were used, QA was administered by i.c.v. route as a toxin on the day 0, and diacerein (25 and 50 mg/kg) as treatment and tetrabenazine as standard were used for 14 days. We have performed three neurobehavioral parameters such as open-field (for locomotion), T-maze (for memory), and novel diving test (for anxiety), followed by biochemical parameters such as total protein estimation, LPO, GSH, nitrite, AChEs, and catalase, neurotransmitters (GABA and glutamate) along with inflammatory markers (IL-1β, TNF-α, and IL-17), and histopathological evaluation at the end. Diacerein enhances motor function, modulates neurotransmitter levels, diminishes oxidative stress markers, controls the generation of inflammatory cytokines, and inhibits GSK-3β activity. Furthermore, diacerein improves the neurotoxicity and neurobehavioral impairments in adult zebra fish with Huntington's disease-like symptoms caused by quinolinic acid.