Naunyn-Schmiedeberg's archives of pharmacology最新文献

Trophinin-associated protein (TROAP), a cytoplasmic protein essential for spindle assembly and centrosome integrity during mitosis, has been reported to serve as an oncogene in various tumors. However, its role in endometrial cancer (EC) progression is still undefined. TROAP expression in EC was analyzed via GEPIA and HPA databases. The diagnostic and prognostic values of TROAP were examined by ROC curve analysis and Kaplan-Meier plotter, respectively. Cell proliferation was evaluated using CCK-8 and EdU incorporation assays. Apoptosis was assessed using TUNEL and flow cytometry assays. GSEA was performed to explore TROAP-related pathways in EC. Expression of TROAP, proliferating cell nuclear antigen (PCNA), Ki-67, cleaved-caspase-3 (cl-caspase-3), caspase-3, active β-catenin, and total β-catenin was detected using western blot analysis. TROAP was upregulated in EC. TROAP served as a potential diagnostic and prognostic marker in EC patients. TROAP silencing suppressed proliferation and enhanced apoptosis in EC cells. GSEA revealed that EC and Wnt signaling pathways were related to the expression of TROAP. We further demonstrated that TROAP knockout repressed the Wnt/β-catenin pathway in EC cells. Moreover, SKL2001, a Wnt/β-catenin activator, partially abrogated the effects of TROAP silencing on EC cell proliferation and apoptosis, while the signaling inhibitor XAV-939 had the opposite effect. In conclusion, TROAP knockout retarded proliferation and elicited apoptosis in EC cells by blocking the Wnt/β-catenin pathway.

Bruceines A-L are among the quassinoid representatives found in the medicinal plant Brucea javanica (L.). An overview of their pharmacological activities is still unknown. The given research deals with highlights in their pharmacological result, molecular mechanism of action, synthetic progress, and pharmacokinetics. From previous evidence, bruceine derivatives are potential agents for anticancer treatments, as well as they are appropriate to treat inflammation, diabetes, and parasitic infections, and protect the neurons, kidneys, and lungs. Cytokine inhibitions, oxidative stress responses, and various signaling pathways, such as MAPK (mitogen-activated protein kinase) and NF-κB (nuclear factor-kappa B), have been proposed as the underlying mechanisms of action. Synthetic approaches to synthesize new derivatives with enhancement activities are based on free hydroxyl group modifications. Bruceines seem to be promptly absorbed by both oral and intravenous administrations, but their bioavailability is not high (less than 6%). Pre-clinical and clinical studies to prove their anticancer potential and other activities are urgent. Structural modifications, nano-combinations, and synergistic effects are necessary.

Sodium-glucose transporter 2 (SGLT2) inhibitors such as empagliflozin are one of the main treatments for type 2 diabetes mellitus (DM2) and heart failure (HF). They have also demonstrated anti-arrhythmic effects in some preclinical and clinical studies. The purpose of this study was to assess the effects of empagliflozin on ventricular arrhythmias in HF patients with an implantable cardioverter-defibrillator (ICD). In a prospective double-blinded, randomized controlled trial of Iran County, Mashhad (72 patients 1:1), we compared the frequency and proportion of ventricular arrhythmias and ICD therapies during the 24 weeks to the prior 24 weeks. Results revealed that empagliflozin significantly reduced the frequency and proportion of ventricular tachycardia (VT)/fibrillation (VF) episodes (P = 0.019 and 0.039, respectively). Moreover, it tended to reduce the frequency and proportion of ICD therapies, including anti-tachycardia pacing (ATP) and shock. Subgroup analysis of patients with or without any antiarrhythmic drugs (digoxin, mexiletine, amiodarone, or sotalol) revealed that only patients who were previously on the antiarrhythmic drugs benefit from empagliflozin antiarrhythmic effects. In conclusion, empagliflozin exhibits anti-arrhythmic effects in HF patients with an ICD. Larger and long-term clinical studies are still needed to investigate and confirm all positive effects of SGLT2 inhibitors in this regard. Trial registration number: IRCT20120520009801N7 (Approval date: June 11, 2022).

Chemotherapy resistance is a major obstacle in cancer therapy, and identifying novel druggable targets to reverse this phenomenon is essential. The exosome-mediated transmittance of drug resistance has been shown in various cancer models including ovarian and prostate cancer models. In this study, we aimed to investigate the role of exosomal miRNA transfer in chronic myeloid leukemia drug resistance. For this purpose, firstly exosomes were isolated from imatinib sensitive (K562S) and resistant (K562R) chronic myeloid leukemia (CML) cells and named as Sexo and Rexo, respectively. Then, miRNA microarray was used to compare miRNA profiles of K562S, K562R, Sexo, Rexo, and Rexo-treated K562S cells. According to our results, miR-125b-5p and miR-99a-5p exhibited increased expression in resistant cells, their exosomes, and Rexo-treated sensitive cells compared to their sensitive counterparts. On the other hand, miR-210-3p and miR-193b-3p were determined to be the two miRNAs which exhibited decreased expression profile in resistant cells and their exosomes compared to their sensitive counterparts. Gene targets, signaling pathways, and enrichment analysis were performed for these miRNAs by TargetScan, KEGG, and DAVID. Potential interactions between gene candidates at the protein level were analyzed via STRING and Cytoscape software. Our findings revealed CCR5, GRK2, EDN1, ARRB1, P2RY2, LAMC2, PAK3, PAK4, and GIT2 as novel gene targets that may play roles in exosomal imatinib resistance transfer as well as mTOR, STAT3, MCL1, LAMC1, and KRAS which are already linked to imatinib resistance. MDR1 mRNA exhibited higher expression in Rexo compared to Sexo as well as in K562S cells treated with Rexo compared to K562S cells which may suggest exosomal transfer of MDR1 mRNA.

Toxicology at the TUM is mainly associated with the Faculty of Medicine at the Klinikum rechts der Isar (MRI). The Department of Clinical Toxicology has been founded in 1963. Max von Clarmann, the head, focused his activities on the treatment of intoxications and the development of analytical methods and established a poison information center. His successors, Thomas Zielker and Florian Eyer, further developed this department to an internationally renown institution.In 1967, the MRI became the TUM faculty of medicine with its Institute of Pharmacology and Toxicology. The director Melchior Reiter, formerly Institute of Pharmacology of the Ludwig Maximilians University (LMU), in 1970 initiated the foundation of the Department of Toxicology at the Gesellschaft für Strahlen- und Umweltforschung (GSF) with the director Gerhard Lange. The research focused on the neurotoxic effects of heavy metals and the metabolism and hepatoxicity of persistent chemicals. After Lange's unexpected death in 1973, he was succeeded in 1975 by Helmut Greim from the University of Tübingen. The now Institute of Toxicology rapidly expanded developing and standardizing in vitro test methods, investigating the mechanism of carcinogens and mutagens and heavy metal toxicity. Training courses in the 15 major areas of toxicology have been organized at the GSF and competent centers in Germany. In 1987, Greim became the director of the newly founded Institute of Toxicology and Environmental Hygiene of the TUM, with expanded research and teaching activities, especially in toxicology at the faculties of Chemistry of the TUM and LMU, which thereafter became mandatory for students of chemistry at German universities.

Scientific fake papers, containing manipulated or completely fabricated data, are a problem that has reached dramatic dimensions. Companies known as paper mills (or more bluntly as "criminal science publishing gangs") produce and sell such fake papers on a large scale. The main drivers of the fake paper flood are the pressure in academic systems and (monetary) incentives to publish in respected scientific journals and sometimes the personal desire for increased "prestige." Published fake papers cause substantial scientific, economic, and social damage. There are numerous information sources that deal with this topic from different points of view. This review aims to provide an overview of these information sources until June 2024. Much more original research with larger datasets is needed, for example on the extent and impact of the fake paper problem and especially on how to detect them, as many findings are based more on small datasets, anecdotal evidence, and assumptions. A long-term solution would be to overcome the mantra of publication metrics for evaluating scientists in academia.

Pain management is a primary goal after oral surgeries, but little is known about sex differences in the sensitivity to analgesics. This study aimed to compare the efficacy of three drugs with analgesic potential on heat and mechanical hyperalgesia, spontaneous pain and locomotion on male and female rats subjected to a model of orofacial postoperative pain. Male and female Wistar rats were submitted to intraoral incision or sham surgery, and on postoperative day 3, the effect of the ibuprofen (30 and 100 mg/kg), acetaminophen (100 and 300 mg/kg) and codeine (3 and 10 mg/kg) was assessed on responses to heat and mechanical facial stimulation, facial grooming, and locomotion. Ibuprofen reduced heat and mechanical hyperalgesia and grooming behavior in male and female rats in a non-sedative dose; acetaminophen dose-dependently reduced the mechanical hyperalgesia and abolished the heat hyperalgesia and the grooming behavior but caused sedation in both sexes; codeine dose-dependently reduced the mechanical hyperalgesia in male and female rats, and reduced the heat hyperalgesia, but females were less sensitive than males. It reduced spontaneous facial grooming in both sexes, but induced hyperlocomotion in females. Ibuprofen presented the most favorable profile, since it reduced over 50% heat and mechanical hyperalgesia in male and female rats, and significantly reduced spontaneous pain, without causing sedation or affecting locomotion. The identification of sex differences in the sensitivity and safety profile of frequently used analgesics can help guide the choice of more effective individualized therapies for pain control.

A previous study has confirmed the upregulation of circ_0007142 expression in CC. Here, we aimed to investigate the effect and mechanism of circ_0007142 in CC progression. The expression of circ_0007142, microRNA-128-3p (miR-128-3p), S100 calcium-binding protein A14 (S100A14), and epithelial mesenchymal transition (EMT)-related markers was measured by qRT-PCR and Western blot. Cell proliferative, migratory, and invasion abilities were evaluated using cell counting Kit-8, cell colony formation, 5-ethynyl-2'-deoxyuridine, and transwell assays, respectively. The interaction among circ_0007142, miR-128-3p and S100A14 was identified by dual-luciferase reporter and RNA immunoprecipitation assays. In vivo experiment was implemented to investigate the effect of circ_0007142 on tumor growth. CC tissues and cells displayed high expression of circ_0007142 and S100A14, and low expression of miR-128-3p in comparison to the controls. Knockdown of circ_0007142 resulted in the inhibition of cell proliferation, migration invasion, and EMT in vitro. In support, circ_0007142 deficiency hindered tumor growth and EMT in vivo. In rescue experiments, downregulation of miR-128-3p relieved circ_0007142 absence-mediated anticancer impacts. MiR-128-3p overexpression-induced inhibitory effects on cell growth and metastasis were attenuated by S100A14 overexpression. Importantly, circ_0007142 regulated S100A14 expression by sponging miR-128-3p. Circ_0007142 knockdown suppressed CC cell malignant behaviors by miR-128-3p/S100A14 pathway, providing a possible circRNA-targeted therapy for CC.

The risk of adhesive capsulitis of shoulder in diabetic patients taking metformin has not been evaluated. We aimed for evaluating the relative risk of adhesive capsulitis of shoulder in diabetic patients taking metformin at the level of the whole country population. We conducted a retrospective cohort study using a national health insurance database in Taiwan from 2000 to2015. We used International Classification of Diseases, Ninth Revision, to categorise the medical condition for study group and comparison group. We used Cox proportional hazard regression analyses to determined adjusted hazard ratios (aHRs) of adhesive capsulitis of shoulder between study and comparison group after adjusting for sex, age, and comorbidities.Among 30,412 diabetic patients using metformin, 3020 patients were diagnosis with adhesive capsulitis of shoulder during follow up. Of the 121,648 patients without the use of metformin, 11,375 patients developed adhesive capsulitis of shoulder. Adhesive capsulitis of shoulder risk was elevated in patients taking metformin than in non-metformin group (adjusted hazard ratio [HR] 1.179, 95% confidence interval [95% CI] 1.022 to 1.268; p = 0.039). Risk of adhesive capsulitis of shoulder among the diabetic patients taking metformin was higher than those did not taking metformin.

Pulmonary fibrosis is a debilitating lung disease marked by excessive fibrotic tissue accumulation, which significantly impairs respiratory function. Given the limitations of current therapies, there is an increasing interest in exploring traditional herbal formulations like Jie Geng Tang (JGT) for treatment. This study examines the potential of JGT and its bioactive component, quercetin, in reversing bleomycin (BLM)-induced pulmonary fibrosis in mice. We employed a BLM-induced MLE-12 cell damage model for in vitro studies and a bleomycin-induced fibrosis model in C57BL/6 mice for in vivo experiments. In vitro assessments showed that JGT significantly enhanced cell viability and reduced apoptosis in MLE-12 cells treated with BLM. These findings underscore JGT's potential for cytoprotection against fibrotic agents. In vivo, JGT was effective in modulating the expression of E-cadherin and vimentin, key markers of the epithelial-mesenchymal transition (EMT) pathway, indicating its role in mitigating EMT-associated fibrotic changes in lung tissue. Quercetin, identified through network pharmacology analysis as a potential key bioactive component of JGT, was highlighted for its role in the regulatory mechanisms underlying fibrosis progression, particularly through the modulation of the IL-17 pathway and Il6 expression. By targeting inflammatory pathways and key processes like EMT, JGT and quercetin offer a potent alternative to conventional therapies, meriting further clinical exploration to harness their full therapeutic potential in fibrotic diseases.