European journal of pharmacology最新文献

FOXM1 is the "Achilles' heel" of cancers and hence the potential therapeutic target for anticancer drug discovery. In this work, we selected high affinity peptides against the protein of human DNA binding domain of FOXM1 (FOXM1-DBD) from the disulfide-constrained, phage displayed random cyclic heptapeptide library Ph.D.-C7C. We obtained a novel peptide, 9 R-CP29L, which was identified to be a potent anticancer peptide with IC₅₀ values of 9.0 and 11.1 μM at 24 h for HCCLM3 and MD-MBA-231 cells respectively. Molecular docking, CETSA, ITC and immunoblot assays demonstrated that 9 R-CP29L can potentially specifically bind to FOXM1-DBD with a K_d value of 1.25 μM and reduced the expression of FOXM1. In addition, Annexin V/PI flow cytometry, AO/EB staining, PI flow cytometry, clone formation and Transwell assays revealed that 9 R-CP29L also induced cell apoptosis and cell cycle arrest while inhibited the proliferation and migration of HCCLM3 cells. The findings were further supported by the results of qRT-PCR and immunoblot assays for the associated gene (CMYC, CDC25B, BAX, CASPASE3 and MMP2, etc) expression in HCCLM3 cells. Finally, in vivo experiment showed that 9 R-CP29 significantly reduced the tumor growth and downregulated the expression of FOXM1 in HCCLM3 xenograft nude mouse models. Taking together, our work provides a novel FOXM1 targeted peptide which has potential in both anticancer drug development and scientific researches.

Neuropathy is the most common complication of diabetes, leading to painful symptoms like hyperalgesia. Current treatments for diabetic painful neuropathy often prove inadequate, necessitating the exploration of new pharmacological approaches. Therefore, this study aimed to investigate the potential antinociceptive effect of aspirin-triggered lipoxin A4 (ATL), a specialized pro-resolving lipid mediator, when administered alone or in combination with cannabinoid agonists, to alleviate diabetic neuropathic pain. Mechanical hyperalgesia in the hindpaws of streptozotocin (STZ)-induced diabetic (DBT) rats was assessed using the electronic Von Frey test (VFT), before diabetes induction and for up to 32 days after STZ administration and intraperitoneal ATL (0.3, 1, 3, 10, or 30 ng/rat) treatment, alone or in combination with intrathecal CB1 or CB2 receptor agonists (ACEA or JWH-133, respectively; 10 or 30 μg/rat). The effect of ATL treatment on locomotor activity and anxious or depressive-like behaviors was also evaluated. In comparison to control normoglycemic rats, control DBT rats developed: 1) mechanical hyperalgesia; 2) increase in anxious and depressive-like behaviors. ATL treatment attenuated mechanical hyperalgesia in DBT rats both acutely (at 30 ng) and cumulatively (at doses of 1, 3, 10, or 30 ng), without compromising locomotor activity. The antinociceptive effect of ATL (at 1 or 3 ng) was augmented when combined with ACEA or JWH-133 treatments (only at a dose of 30 μg/rat). While ATL treatment alone reduced anxious-like behavior in DBT rats, it did not affect depressive-like behavior. These findings underscore the therapeutic potential of ATL, in diabetic complications, suggesting a possible interaction with the endocannabinoid system.

The IUPHAR Education Section's Pharmacology Education Project (PEP; www.pharmacologyeducation.org) provides an open-access, peer-reviewed platform to support pharmacology education globally. Launched in 2016, PEP offers a comprehensive range of freely accessible, peer-reviewed resources, including extensive topic summaries with links to videos, slide sets, and other media curated by pharmacologists and catering to diverse learners' needs. This paper provides an update on PEP's growth, providing analytics on user engagement and feedback. The platform averages 20,000 visits per month, with a peak of 50,000 during the COVID-19 pandemic. Engagement rates are approximately 40%, indicating robust interaction with the content. Feedback from 115 users spanning 31 countries praises the quality and quantity of PEP's resources and the ease of navigation through the website. Comparisons with traditional resources used in pharmacology education highlight PEP's advantages in accessibility and peer review. Examples of the use of PEP in education are provided, emphasizing active and self-directed learning methodologies. The discussion includes challenges in maintaining and expanding the platform, such as funding and content curation, and outlines strategies for sustainable development, including the role that artificial intelligence may play. PEP is a valuable resource in contemporary pharmacology education and plays a vital role in advancing the field globally.

Cerebrovascular diseases are major global health issues, responsible for significant morbidity and mortality. Basigin (additionally called CD147 or EMMPRIN) is a glycosylated transmembrane protein that facilitates intercellular communication. Recent research has highlighted the critical role of Basigin in inducing matrix metalloproteinases (MMPs), which contribute to the progression of cerebrovascular diseases. Consequently, Basigin has emerged as a promising therapeutic target for these conditions. However, inhibiting the pivotal role of Basigin in mediating cerebrovascular disease is an urgent area of investigation. In this review, we systematically examine the pathological mechanisms by which Basigin contributes to the development of cerebrovascular diseases. We present evidence demonstrating the protective effect of targeted inhibition of Basigin in these conditions and suggest future research directions.

Introduction: The Dutch National Pharmacotherapy Assessment (DNPA) was introduced in 2013 to improve clinical pharmacology and therapeutics (CPT) education. This study investigated final-year medical students' perceived motivation and level of preparation for the DNPA in different scenarios: mandatory vs. non-mandatory, and traditional high-stakes assessment programme vs. programmatic assessment programme.

Methods: In this survey study, students from four Dutch medical schools participated. In two medical schools the DNPA is a mandatory assessment in a programmatic assessment programme, and in two schools it is a mandatory, high-stakes assessment in a traditional assessment programme. The questionnaire included six 5-point Likert-type questions, and one open-ended question.

Results: A total of 142 final-year medical students completed the survey. Their overall satisfaction with and current preparation for the DNPA was good (both median scores were 4 out of 5), without differences between students with a traditional or programmatic assessment programme. The majority of the students said they would be more (or much more) motivated (62.7%) and prepared (59.2%) if the DNPA were a high-stakes assessment rather than a programmatic assessment; the non-mandatory or mandatory nature of the assessment would only modestly affect their motivation and preparation (62.7% of the students would be less or similar motivated, 74.6% less or similar prepared). Students opined that the DNPA should be given earlier in the curriculum, together with more dedicated CPT education.

Conclusion: While students expressed a greater motivation and preparation when having a high-stakes assessment, and almost a similar motivation and preparation for mandatory and non-mandatory assessments, there were no notable differences in their current perceived motivation and preparation across medical schools with different assessment programmes. This suggests that students appreciate the importance of the DNPA assessment, being almost similarly motivated to prepare for the assessment regardless of whether it is mandatory or non-mandatory or a programmatic or high-stakes assessment.

Diabetic cardiomyopathy, a heart disease resulting from diabetes mellitus, inflicts structural and functional damage to the heart. Recent studies have highlighted the potential role of luteolin, a flavonoid, in mitigating diabetic cardiovascular injuries. The Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) is implicated in exacerbating diabetes- and obesity-related complications. Interestingly, luteolin has been shown to inhibit protein tyrosine phosphatases, but it's unclear how SHP2 relates to luteolin's protective effects against diabetic heart disease. Here, we hypothesized that the inhibition of SHP2 signaling could play a role in luteolin's protective action against diabetic heart injury. Diabetes was induced in male Sprague-Dawley rats through a high-fat diet followed by a single intraperitoneal dose of streptozotocin (30 mg/kg). Five weeks post-diabetes induction, these rats were intraperitoneally injected with luteolin at varying doses (5, 10, 20 mg/kg) every other day for an additional 5 weeks. Then cardiac function was assessed, and hearts were isolated for further analysis. We found that luteolin notably improved cardiac function, inhibited cardiac hypertrophy and fibrosis, reduced levels of inflammatory factors and reactive oxygen species, and activated superoxide dismutase. Importantly, luteolin treatment also reduced the expression of SHP2 and phosphorylated signal transducer and activator of transcription 3 (STAT3) in a dose-dependent manner. These findings suggest that luteolin protects the diabetic heart against inflammation, oxidative stress, hypertrophy, and fibrosis, which may relate to down-regulating cardiac SHP2/STAT3 signaling.

Background: Depression is a leading chronic mental illness worldwide, characterized by anhedonia and pessimism. Connexin is a kind of widely distributed protein in the body. Connexin 43 (Cx43) plays an important role in the pathogenesis of depression. Growing evidence has indicated that inflammation is closely associated with neuropsychiatric diseases such as depression. Inflammation occurs in patients with mood disorders, and symptomatic relief after multiple treatments is often accompanied by proinflammatory restoration. In this study, we sought to determine the upstream and downstream relationship of Cx43 abnormalities and peripheral inflammation in inducing depression.

Methods and results: Gap27, as a Cx43 mimetic peptide, specifically blocks Cx43 gap junction channels in the brain. The mice were treated with injection of Gap27 into the prefrontal cortex (PFC), conditional knockout of Cx43 in the PFC, and lipopolysaccharide (LPS) intraperitoneal injection. Our results revealed that the treatments gave rise to the depressive-like behavior occurrence in mice, including reducing the sucrose preference and spontaneous activities, and increasing immobility time in the forced swimming test. Functional blockade of Cx43 induced abnormal expression of peripheral inflammatory cytokines including interleukin (IL)-1β, IL-6, tumor necrosis factor-α, IL-2, IL-10, and IL-18. Furthermore, depression associated with peripheral inflammation derived from LPS intraperitoneal injection significantly reduced the Cx43 expression and the diffusion distance of gap junction channel permeability dye in the PFC.

Conclusion: These results showed that blockade of Cx43 in the PFC and peripheral inflammation are complicatedly intertwined, and reinforcing each other during the induction of depression.

Despite osteoarthritis (OA) being recognised for over a century as a debilitating disease that affects millions, there are huge gaps in our understanding of the underlying pathophysiology that drives this disease. Present day studies that focussed on ubiquitination (Ub) and ubiquitylation-like (Ubl) modification related mechanisms have brought light into the possibility of attenuating OA development by targeting these specific proteins in chondrocytes. In the present review, we discuss recent advances in studies involving Ub ligases and deubiquitinating enzymes (DUBs) which are of importance in the development of OA, and may offer potential therapeutic strategies for OA. Such targets may involve attenuating proteases such as matrix metalloproteinases (MMP) 1, 8, 13, 4 and several A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) that are well known for their roles in cartilage breakdown. Ligases such as ubiquitin-conjugating enzymes (E2) and ubiquitin-ligating enzymes (E3) that are involved in extracellular matrix (ECM) degradation in OA and of their pathogenesis would be discussed. In addition to catabolic and degenerative downstream effects of Ub and DUBs in OA, inflammatory mechanisms most notably involving nuclear factor-kappa B (NF-κB) signalling pathways regulated through Ub and using various targeting molecules would also be highlighted. Challenges, gaps and insights from clinical trials will provide valuable guidance for future investigations on targeting ubiquitin-proteosome system (UPS) as a therapeutic option for OA.

Dihydrotanshinone I (DHT) is an active ingredient derived from Salvia miltiorrhiza. Previous studies have demonstrated that DHT can improve cardiac function in rats with myocardial ischemia-reperfusion injury (IR). However, the mechanism by which DHT improves myocardial injury in rats still requires further research. Lymphangiogenesis can reduce myocardial edema, inflammation, and fibrosis after myocardial infarction in rats, and improve cardiac function. In this study, the changes in cardiac functions, collagen fiber deposition in the infarcted area and the level of relevant indicators of lymphangiogenesis were examined by echocardiography, Masson's trichrome staining, immunohistochemistry and Western blot, respectively. Human lymphatic endothelial cells (HLECs) were transfected with siVE-cadherin and siVEGFR-3, and the effects of DHT on HLEC cell viability, migration and tube formation were detected through CCK8, TUNEL, transwell, wound healing and tube formation assay. We found that in myocardial IR rats treated with DHT, the levels of LYVE-1, PROX1, VEGF-C, VEGFR-3, IGF-1, podoplanin and IGF-1R, which are associated with lymphangiogenesis, were increased, as well as the level of VE-cadherin, which maintains endothelial cell function. DHT reduced the levels of inflammatory factors and myocardial cell apoptosis, thereby improving cardiac function after I/R. To explore the mechanism of DHT promoting lymphangiogenesis, H₂O₂ and OGD/R injury models of HLECs were constructed to simulate the microenvironment of myocardial IR in vitro. The results proved that DHT could reduce the damage and apoptosis of HLECs. On the other hand, DHT enhanced the expression of VEGFR-3 and VE-cadherin in HLECs, promoted cell migration and tube formation. The effects of DHT on the tube formation and migration of HLECs were significantly decreased after knocking down VEGFR-3 or VE-cadherin. Our research proposed that DHT could improve the heart function after IR through the enhancement of lymphangiogenesis and contributed to the development of the treatment methods for myocardial IR.

Hyperlipidemia is a major risk factor for hypertension, coronary heart disease, diabetes and stroke, triggering an intensified research efforts into its prevention and treatment. Tetrahydroberberrubine (THBru) is a derivative of berberine (BBR) that has been shown to have higher bioavailability and lower toxicity compared to its parent compound. However, its impact on hyperlipidemia has not been fully explored. This study was aimed to investigate the effects and potential mechanisms of THBru on hyperlipidemia. Herein, we constructed the hyperlipidemia animal model in C57BL/6J mice through the administration of a 20-week high-fat diet (HFD). The liver damage and lipid metabolism disorders in hyperlipidemic mice were effectively alleviated by THBru (25 or 50 mg/kg) administration. Molecular docking and cellular thermal shift assay (CETSA) have revealed a direct interaction between THBru and the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). THBru was found to downregulate the expression of sterol regulatory element-binding protein 2 (SREBP2) and proprotein convertase subtilisin/kexin type 9 (PCSK9), while upregulate the expression of low-density lipoprotein cholesterol (LDL-C) in the liver of hyperlipidemic mice and lipid metabolism abnormalities cells. The application of AMPK inhibitor in HepG2 cells was able to effectively reverse the regulatory effect of THBru on the AMPK/SREBP2/PCSK9/LDL receptor signaling pathway. In summary, this study for the first time found that THBru is a potential agonist of AMPK, regulate the SREBP2/PCSK9/LDL receptor pathway to improve hyperlipidemia, providing new insights into the prevention and treatment of hyperlipidemia.