European journal of pharmacology最新文献

Pancreatic cancer (PCa) is one of the most devastating cancers with few clinical signs and no truly effective therapy. In recent years, our team has demonstrated that nucleolin antagonists such as N6L could be a therapeutic alternative for this disease. In order to study a possible clinic development of N6L (multivalent pseudopeptide), we undertook to study the effect of combination of N6L with chemotherapies classically used for PCa on the survival of pancreatic cancer cells. Thus, the combined effect of N6L with either gemcitabine, FOLFOX and paclitaxel (PTX) on the survival of PANC-1, Mia-PaCa-2 and BxPC3 was studied and shown additive effect. In addition, analysis of the data by Combenefit software indicates that there are synergistic effects between N6L and the 3 chemotherapy molecules tested with more sensitive effects with the N6L-PTX combination. This result was confirmed by associating N6L and paclitaxel on porous calcium carbonate particles loaded with cyclodextrin (CD) encapsulating PTX and carrying N6L at their surface. Porous calcium carbonate particles present highly benefits for biological purposes because of their large surface area and their high stability in neutral media. As for CD, it presents the advantage of owing hydrophilic exterior and a less polar cavity in the center. We have then combined the advantageous features of both porous and negatively charged surfaces of calcium carbonate (CaCO₃) particles and host molecules CD for developing carrier enabling all at once the loading of PTX (hydrophobic drug) and N6L (cationic drug). This association generates water-soluble particles capable of targeting via N6L and delivering paclitaxel to tumor cells.

Introduction: Alzheimer's disease (AD) is a leading cause of dementia, characterized by progressive neurodegeneration and cognitive dysfunction. The disease aetiology is closely associated with proteinopathies, mitochondrial abnormalities, and elevated ROS generation, which are some of the primary markers for AD brains.

Objectives: The current research was intended to elucidate the chemical interaction of β-pinene against potential targets and evaluate its neuroprotective potential in ICV-STZ-induced sAD.

Methodology: The potential binding interactions of β-pinene and galantamine were evaluated against the active sites of PP2A, SOD1, catalase-3, and AChE using AutoDock vina. Additionally, the β-pinene and galantamine were subjected to tests of their ADMET by employing the Swiss ADME and Protox-II web servers. To assess the neuroprotective potential, β-pinene (50, 100, and 200 mg/kg) and galantamine (2 mg/kg) was administered p.o in ICV-STZ-treated wistar rats for 21 days. Moreover, behavioral parameters (NOR & MWM), biochemical, AChE activities, and mitochondrial complexes were performed.

Results: Molecular docking study showed that β-pinene can interact with human PP2A, SOD1, Catalase-3, and AChE with better ligand efficiency as compared to galantamine. In-vivo data showed that β-pinene treatment (100, and 200 mg/kg) for 21 days exhibited significantly enhanced cognitive performance, as shown in behavioral studies. Additionally, β-pinene treatment significantly re-established antioxidant levels and mitochondrial capacities and attenuated altered AChE activity as compared to ICV-STZ-induced groups.

Conclusions: In-silico studies revealed that β-pinene shared the same binding pocket as galantamine, supporting its neuroprotective effects in the ICV-STZ-induced animal model by alleviating oxidative stress and mitochondrial dysfunction and reducing AChE activity.

Microbiota encompasses a diverse array of microorganisms inhabiting specific ecological niches. Gut microbiota significantly influences physiological processes, including gastrointestinal motor function, neuroendocrine signalling, and immune regulation. They play a crucial role in modulating the central nervous system and bolstering body defence mechanisms by influencing the proliferation and differentiation of innate and adaptive immune cells. Given the potential consequences of antibiotic therapy on gut microbiota equilibrium, there is a need for prudent antibiotic use to mitigate associated risks. Observational studies have linked increased antibiotic usage to various pathogenic conditions, including obesity, inflammatory bowel disease, anxiety-like effects, asthma, and pulmonary carcinogenesis. Addressing dysbiosis incidence requires proactive measures, including prophylactic use of β-lactamase drugs (SYN-004, SYN-006, and SYN-007), hydrolysing the β-lactam in the proximal GIT for maintaining intestinal flora homeostasis. Prebiotic and probiotic supplementations are crucial in restoring intestinal flora equilibrium by competing with pathogenic bacteria for nutritional resources and adhesion sites, reducing luminal pH, neutralising toxins, and producing antimicrobial agents. Faecal microbiota transplantation (FMT) shows promise in restoring gut microbiota composition. Rational antibiotic use is essential to preserve microflora and improve patient compliance with antibiotic regimens by mitigating associated side effects. Given the significant implications on gut microbiota composition, concerted intervention strategies must be pursued to rectify and reverse the occurrence of antibiotic-induced dysbiosis. Here, antibiotics-induced microbiota dysbiosis mechanisms and their systemic implications are reviewed. Moreover, proposed interventions to mitigate the impact on gut microflora are also discussed herein.

Background: Some cancer patients derive limited benefit from anti-angiogenic therapy or discontinuation due to adverse reactions. Vascular endothelial growth factor receptor 2 (VEGFR2) plays an important role in regulating angiogenesis in tumors. This study aims to evaluate the association of VEGFR2 polymorphisms with clinical outcomes of anti-angiogenic drugs (AADs) in cancer patients.

Methods: PubMed, Embase, Web of Science, and the Cochrane Library were searched from inception to Dec 26, 2023. Studies accessing the association of VEGFR2 polymorphisms with efficacy and/or safety of AADs in patients with solid tumor were included.

Results: A total of 32 studies encompassing 7075 patients were identified. The T allele of rs2305948 (C > T) was significantly associated with worse progression-free survival and overall survival, especially in Asians, patients with the dominant model (CT/TT vs. CC), bevacizumab-treated patients, colorectal cancer patients, and non-small cell lung cancer patients. The C allele of rs2071559 (T > C) was markedly associated with worse PFS and OS, specifically in the dominant model (CC/CT vs. TT), apatinib-treated patients, and non-small cell lung cancer patients. The A allele of rs1870377 (T > A) was significantly associated with improved PFS, particularly in patients with renal cell carcinoma. However, this A allele also significantly increased the risk of hypertension. No significant associations were observed for rs2305948 (G > A), rs11133360 (T > C), and rs12505758 (T > C) with the clinical outcomes of AADs.

Conclusion: Among VEGFR2 polymorphisms, rs2305948 (C > T) and rs2071559 (T > C) were associated with a high risk of disease progression and death, rs1870377 (T > A) was associated with improved PFS but an increased risk of hypertension.

Epilepsy is characterized by neuronal discharges that occur as a result of disruption of the excitatory and inhibitory balance of the brain due to functional and structural changes. It has been shown in the literature that this neurological disorder may be related to the expression of ion channels. Any defect in the function or expression mechanism of these channels can lead to various neuronal disorders such as epilepsy. Epileptic seizures occur as a result of the accumulation of biological disorders in the circulatory, respiratory and nervous systems. In this study, we aimed to examine the changes in the expression of inward-directing potassium channels (Kir 3.1 and 6.2) in lung tissue and respiratory functions, considering that it will contribute to the elucidation of the mechanisms of sudden deaths thought to be caused by cardiorespiratory complications in epilepsy. In the study, 48 adult male Wistar albino rats weighing 250-300 g were used in the study. During the research process, respiratory function tests were performed on epileptic rats induced with pentylenetetrazol (PTZ) firing model, and then histopathological changes in lung and hippocampus tissues, and expression levels of the Kir (3.1 and 6.2) channels were evaluated by immunohistochemistry, qRT-PCR and Western blot analysis. Memantine and tertiapin-Q have been shown to protect epileptic groups from histopathological harm induced by PTZ application and also reduce HIF-1α, Kir 3.1 and Kir 6.2 expression. The findings imply that memantine and tertiapin-Q would be suitable options for treating epilepsy patients.

ITFG2 is an intracellular protein known to modulate the immune response of T-cells. Our previous investigation revealed that ITFG2 specifically targets ATP5b to regulate ATP energy metabolism and maintain mitochondrial function, thereby protecting the heart from ischemic injury. However, the role of ITFG2 in ischemic ventricular arrhythmias and its underlying mechanisms have not been previously reported. In this study, we found ITFG2 overexpression, induced by an adeno-associated virus serotype 9 vector, partially reduced the incidence of ischemic ventricular arrhythmias and shortened the duration of ventricular arrhythmias in mice after myocardial infarction. Conversely, shRNA-mediated knockdown of endogenous ITFG2 aggravated ischemic ventricular arrhythmias. ITFG2 overexpression also shortened the prolonged QRS complex and increased the epicardial conduction velocity in MI mice. Additionally, the hearts from ITFG2 overexpression mice exhibited a higher maximal upstroke velocity at phase 0 of transmembrane action potential compared to MI mice. Patch-clamp analyses demonstrated a 50% increase in the peak current of voltage-dependent Na⁺ channel by ITFG2 overexpression in isolated ventricular cardiomyocytes post MI. In cultured neonatal mouse cardiomyocytes under hypoxic conditions, ITFG2 up-regulated Nav1.5 protein expression by inhibiting its ubiquitination. Co-immunoprecipitation experiments showed that ITFG2 reduces the binding affinity between NEDD4-2 and Nav1.5, thereby inhibiting Nav1.5 ubiquitination. Taken together, our data highlight the critical role of ITFG2 in reducing susceptibility to ischemic ventricular arrhythmias by down-regulating Nav1.5 ubiquitination. These findings suggest that ITFG2 may serve as a novel target for treating ischemic ventricular arrhythmias.

Cellular senescence precipitates a decline in physiological activities and metabolic functions, often accompanied by heightened inflammatory responses, diminished immune function, and impaired tissue and organ performance. Despite extensive research, the mechanisms underpinning cellular senescence remain incompletely elucidated. Emerging evidence implicates circadian rhythm and hypoxia as pivotal factors in cellular senescence. Circadian proteins are central to the molecular mechanism governing circadian rhythm, which regulates homeostasis throughout the body. These proteins mediate responses to hypoxic stress and influence the progression of cellular senescence, with protein Brain and muscle arnt-like 1 (BMAL1 or Arntl) playing a prominent role. Hypoxia-inducible factor-1α (HIF-1α), a key regulator of oxygen homeostasis within the cellular microenvironment, orchestrates the transcription of genes involved in various physiological processes. HIF-1α not only impacts normal circadian rhythm functions but also can induce or inhibit cellular senescence. Notably, HIF-1α may aberrantly interact with BMAL1, forming the HIF-1α-BMAL1 heterodimer, which can instigate multiple physiological dysfunctions. This heterodimer is hypothesized to modulate cellular senescence by affecting the molecular mechanism of circadian rhythm and hypoxia signaling pathways. In this review, we elucidate the intricate relationships among circadian rhythm, hypoxia, and cellular senescence. We synthesize diverse evidence to discuss their underlying mechanisms and identify novel therapeutic targets to address cellular senescence. Additionally, we discuss current challenges and suggest potential directions for future research. This work aims to deepen our understanding of the interplay between circadian rhythm, hypoxia, and cellular senescence, ultimately facilitating the development of therapeutic strategies for aging and related diseases.

Manzamine A, a natural compound derived from various sponge genera, features a β-carboline structure and exhibits a range of biological activities, including anti-inflammatory and antimalarial effects. Its potential as an anticancer agent has been explored in several tumor models, both in vitro and in vivo, showing effects through mechanisms such as cytotoxicity, regulation of the cell cycle, inhibition of cell migration, epithelial-to-mesenchymal transition (EMT), autophagy, and apoptosis through multi-target interactions of E2F transcriptional factors, ribosomal S6 kinases, androgen receptor (AR), SIX1, GSK-3β, v-ATPase, and p53/p21/p27 cascades. This systematic review evaluates existing literature on the potential application of this marine alkaloid as a novel cancer therapy, highlighting its promising ability to inhibit cancer cell growth while causing minimal side effects.

Background: Myocarditis tends to lead to a poor prognosis, but there are no satisfactory preventive or therapeutic strategies. Erianin, a natural benzene compound, has been found to have antioxidant and anti-inflammatory effects. However, the effects of erianin on myocarditis remain unclear. This study aimed to investigate the effects of erianin on myocarditis and the involved mechanisms.

Methods: We developed a mouse model of experimental autoimmune myocarditis (EAM) and assessed the effects of erianin using echocardiography and pathological staining. In vitro experiments, flow cytometry, immunofluorescence and western blotting were performed to determine whether erianin inhibits macrophage activation.

Results: Erianin ameliorated cardiac fibrosis and cardiac dysfunction and reduced the percentage of M1-type macrophages and the secretion of inflammatory factors. Mechanistically, erianin inhibits the activation of the NLRP3 inflammasome by inhibiting the NF-κB pathway.

Conclusion: Erianin could be a natural therapeutic drug for EAM by inhibiting NLRP3 activation and M1 macrophage-mediated inflammation through the IκBα/NF-κB pathway.

Colorectal cancer (CRC) remains a significant global health challenge, demanding continuous advancements in treatment strategies. This review explores the complexities of targeting colorectal cancer stem cells (CSCs) and the mechanisms contributing to resistance to 5-fluorouracil (5-FU). The efficacy of 5-FU is enhanced by combination therapies such as FOLFOXIRI and targeted treatments like bevacizumab, cetuximab, and panitumumab, particularly in KRAS wild-type tumors, despite associated toxicity. Biomarkers like thymidylate synthase (TYMS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD) are crucial for predicting 5-FU efficacy and resistance. Targeting CRC-CSCs remains challenging due to their inherent resistance to conventional therapies, marker variability, and the protective influence of the tumor microenvironment which promotes stemness and survival. Personalized treatment strategies are increasingly essential to address CRC's genetic and phenotypic diversity. Advances in immunotherapy, including immune checkpoint inhibitors and cancer vaccines, along with nanomedicine-based therapies, offer promising targeted drug delivery systems that enhance specificity, reduce toxicity, and provide novel approaches for overcoming resistance mechanisms. Integrating these innovative strategies with traditional therapies may enhance the effectiveness of CRC therapy by addressing the underlying causes of 5-FU resistance in CSCs.