European journal of pharmacology最新文献

Prostate cancer is a prevalent malignancy that is frequently managed with radiotherapy. However, resistance to radiotherapy remains a significant challenge in controlling this disease. Early radiotherapy is employed for locally confined prostate cancer (PCa), while recurrent disease post-surgery and metastatic castration-resistant prostate cancer (mCRPC) are treated with late-stage radiotherapy, including radium-223. Combination therapies to integrate radiotherapy and chemotherapy have demonstrated enhanced treatment efficacy. Nonetheless, both modalities can induce severe local and systemic toxicities. Consequently, selectively sensitizing prostate tumors to radiotherapy could improve therapeutic outcomes while minimizing systemic side effects. The mechanisms underlying radioresistance in prostate cancer are multifaceted, including DNA damage repair (DDR) pathways, hypoxia, angiogenesis, androgen receptor (AR) signaling, and immune evasion. The advent of 177Lu-PSMA-617, which was approved in 2022, has shown promise in targeting prostate-specific membrane antigen (PSMA) in advanced prostate cancer. Experimental and clinical studies have yielded promising results in suppressing prostate tumors by targeting these pathways. This paper reviews potential targets for sensitizing prostate tumors to radiotherapy. We discuss cellular and molecular mechanisms contributing to therapy resistance and examine findings from experimental and clinical trials on promising targets and drugs that can be used in combination with radiotherapy.

RAF kinases, particularly the BRAF isoform, play a crucial role in the MAPK/ERK signaling pathway, regulating key cellular processes such as proliferation, differentiation, and survival. Dysregulation of this pathway often caused by mutations in the BRAF gene or alterations in upstream regulators like Ras and receptor tyrosine kinases contributes significantly to cancer development. Mutations, such as BRAF-V600E, are present in a variety of malignancies, with the highest prevalence in melanoma. Targeted therapies against RAF kinases have achieved substantial success, especially in BRAF-V600E-mutant melanomas, where inhibitors like vemurafenib and dabrafenib have demonstrated remarkable efficacy, leading to improved patient outcomes. These inhibitors have also shown clinical benefits in cancers such as thyroid and colorectal carcinoma, although to a lesser extent. Despite these successes, therapeutic resistance remains a major hurdle. Resistance mechanisms, including RAF dimerization, feedback reactivation of the MAPK pathway, and paradoxical activation of ERK signaling, often lead to diminished efficacy over time, resulting in disease progression or even secondary malignancies. In response, current research is focusing on novel therapeutic strategies, including combination therapies that target multiple components of the pathway simultaneously, such as MEK inhibitors used in tandem with RAF inhibitors. Additionally, next-generation RAF inhibitors are being developed to address resistance and enhance therapeutic specificity. This review discusses the clinical advancements in RAF-targeted therapies, with a focus on ongoing efforts to overcome therapeutic resistance and enhance outcomes for cancer patients. It also underscores the persistent challenges in effectively targeting RAF kinase in oncology.

Background: Abdominal aortic aneurysm (AAA), albeit usually asymptomatic, is highly lethal if ruptured. The 28-member transient receptor potential (TRP) ion channel superfamily, most of which are present in the aortic cells, is understudied in AAA. We aim to identify single TRP channel that could represent a novel therapeutic target, and dissect dysfunctional ionic signaling that drives AAA.

Methods: AAA was developed in mice by perfusing porcine pancreatic elastase into the infrarenal abdominal aorta. AAA was assessed by measurement of external diameter with digital caliper, or internal diameter with ultrasonography. Aortic pathohistology was evaluated via histological and immunohistochemical staining. The TRP channel family was analyzed in the GSE17901 dataset. TRPC6, TRPC1/4/5 and TRPC3 channels were blocked in aneurysmal mice by BI749327, Pico145 and Pyr3, respectively. Endothelial cell-selective Trpv4 knockout mice were generated and leveraged for AAA analysis. TRPV4 channel was activated indirectly by TPPU or directly opened by GSK1016790A.

Results: RNA-seq data mining revealed altered expression profiles of Trpc3/Trpc6, Trpv4. Pharmacological block of TRPC6, TRPC1/4/5 or TRPC3 did not influence AAA, whereas selective deletion of endothelial TRPV4 protected against AAA in endothelial cell-selective Trpv4 knockout mice. Indirect activation of TRPV4 by TPPU exacerbated AAA, but TRPV4-mediated nitric oxide signaling contributed minimally to AAA. TRPV4 activation promoted endothelial cell apoptosis in a Ca²⁺-dependent manner, a relevant mechanism underlying AAA.

Conclusions: Our data underscore the pathogenic importance of Ca²⁺ perturbation in AAA and illuminate that endothelial TRPV4 cation channel could be harnessed for AAA treatment.

Background: Empagliflozin (EMPA) attenuates inflammation-induced ROS generation in static endothelial cells through inhibition of sodium hydrogen exchanger 1 (NHE1) and modulation of ion homeostasis. We hypothesize that EMPA will alleviate TNF-α stimulated endothelial dysfunction under flow conditions, and that this might be mediated by NHE1 and intracellular Ca²⁺.

Methods: Human coronary artery endothelial cells were pre-treated with EMPA or vehicle before starting flow with or without TNF-α. Intracellular Ca²⁺ was recorded for 5 min at the start of flow. ROS generation and NO bioavailability, Piezo-1, cytokines, adhesion molecules, VE-cadherin and eNOS were detected after 6 h. BAPTA-AM was applied to chelate intracellular Ca²⁺ and NHE1 was knocked down with specific siRNA.

Results: Under flow conditions, EMPA inhibited ROS production and [Ca²⁺] increase in cells exposed to TNF-α (P<0.05). BAPTA-AM and NHE1 knockdown both reduced ROS generation (P<0.05), and genetical inhibition of NHE1 led to reduction of intracellular [Ca²⁺] in HCAECs receiving TNF-α (P<0.05). Yet, EMPA showed no effect on the increased cytokine production, adhesion molecule expression and phosphorylation of eNOS in endothelial cells exposed to TNF-α.

Conclusion: EMPA mitigates increased ROS production and impaired NO bioavailability in TNF-α stimulated cells under flow. The anti-oxidative effect of EMPA is mediated by the decreased intracellular [Ca²⁺] following NHE1 inhibition.

An endogenous time-keeping system found in all kingdoms of life, the endogenous circadian clock, is the source of the essential cyclic change mechanism known as the circadian rhythm. The primary circadian clock that synchronizes peripheral circadian clocks to the proper phase is housed in the anterior hypothalamus's suprachiasmatic nuclei (SCN), which functions as a central pacemaker. According to many epidemiological studies, many cancer types, especially brain tumors, have shown evidence of dysregulated clock gene expression, and the connection between clock and brain tumors is highly specific. In some studies, it is reported that the treatment administered in the morning has been linked to prolonged survival for brain cancer patients, and drug sensitivity and gene expression in gliomas follow daily rhythms. These results suggest a relationship between the circadian rhythm and the onset and spread of brain tumors, while further accumulation of research evidence will be needed to establish definitely these positive outcomes as well as to determine the mechanism underlying them. Chronotherapy provides a means of harnessing current medicines to prolong patients' lifespans and improve their quality of life, indicating the significance of circadian rhythm in enhancing the design of future patient care and clinical trials. Moreover, it is implicated that chronobiological therapy target may provide a significant challenge that warrants extensive effort to achieve. This review examines evidence of the relationship of circadian rhythm with glioma molecular pathogenesis and summarizes the mechanisms and drugs implicated in this disease.

Lung cancer is one of the most commonly diagnosed cancers worldwide, with non-small cell lung cancer (NSCLC) accounting for 80-85% of cases. To clarify the mechanisms underlying its onset and development, and to identify small molecule compounds that target related pathways effectively inhibiting tumor development and transformation. Small molecular compounds with a β-carboline nucleus exhibit a range of biological activities, with significant anti-tumor effects. A series of small molecule β-carboline compounds were synthesized and the dominant structure 1- (3-chlorophenyl) - 9H -pyridino - [3,4-b] indole - 3 -carboxylic acid methyl ester (10830733) was initially screened out. However, the effect of 10830733 on NSCLC is unclear. In this study, we investigated the anti-NSCLC activity of 10830733 and explored its potential mechanisms of action. First, we found that 10830733 decreased proliferation and invasion and promoted apoptosis, as well as S and G2 phase cell cycle arrest in NSCLC cells. Furthermore, network pharmacological analysis and Western blot confirmed that 10830733 inhibits the PI3K/Akt/GSK 3β pathway, and that the PI3K inhibitor LY294002 enhances the effects of 10830733 on proliferation, invasion, apoptosis, S and G2 phase arrest, and the expression of PI3K/Akt/GSK 3β related proteins. In conclusion, our data demonstrate that 10830733 reduces proliferation and invasion, promotes S and G2 phase arrest and apoptotic cell death in NSCLC cells by suppressing the PI3K/Akt/GSK 3β signaling pathway, suggesting that 10830733 could be a promising new candidate for NSCLC therapy.

In an era of rapid scientific advancement, gene therapy has emerged as a groundbreaking approach with the potential to revolutionize the treatment of a myriad of diseases and medical conditions. The trend of current clinical trials suggests that there is growing interest and investment in exploring gene therapy as a viable treatment option. In 2023, a significant milestone was achieved with the approval of seven gene therapies by the Food and Drug Administration (FDA). Projections indicate that between 10 and 20 gene therapies could receive annual FDA approval by 2025. In this review, we conducted a comprehensive analysis of registered clinical trials on Clinicaltrials.gov to determine the progression status of gene therapies. Upon extraction of the data, we conducted a comprehensive analysis of the 2809 included studies. This involved a systematic approach, commencing with an overview, followed by a detailed examination of gene therapy strategies employed in various malignant and non-malignant disorders. Additionally, the study will cover the types of vectors utilized in current trials. Lastly, a meticulous review of 105 phase III-IV clinical trials was conducted to identify potential therapies demonstrating promise. We trust that the comprehensive overview provided will serve as a solid foundation for forthcoming research and study designs, ultimately contributing to the progression of gene therapy and its practical application within healthcare settings. Also, we anticipate that such inquiries will bolster the formulation of practical policies and guidelines for pharmaceutical companies engaged in gene therapy research and development.

The ventral tegmental area (VTA), located in the midbrain, plays a pivotal role in the regulation of many important behaviors, such as reward, addiction, aversion, memory, learning, and sleep-wakefulness cycles. The majority of VTA neurons are dopaminergic neurons, although there is a significant proportion of GABAergic neurons and few glutamatergic neurons. These neuronal types project to different brain regions, thus mediating various biological functions. Therefore, the diverse roles of the VTA might depend on its heterogeneous neuronal types and projecting circuits. General anesthesia and sleep-wakefulness cycles share the feature of reversible loss of consciousness, and several common neural mechanisms underlie these two conditions. In addition to the well-known regulatory role of VTA in sleep-wakefulness, emerging evidence has demonstrated that VTA activity is also associated with promoting emergence from general anesthesia. Herein, we reviewed the literature and summarized the evidence regarding the modulation of the VTA by general anesthesia in rodents, which will improve the understanding of the modulatory mechanism of the VTA in general anesthesia.

Background: While metformin has shown promise in treating septic myocardial injury (SMI), its underlying mechanisms and impact on metabolic disturbances remain poorly understood.

Methods: This study employed an integrated approach of metabolomics and network pharmacology to identify key targets and pathways through which metformin may act against SMI. Findings were validated using a lipopolysaccharide (LPS)-induced mouse model.

Results: Metformin was found to counter myocardial metabolic disruptions, indicated by the reversal of 49 metabolites primarily involved in purine metabolism, pantothenate and CoA biosynthesis, and histidine metabolism. In vivo, metformin significantly improved survival rates and cardiac function, reduced cardiomyocyte apoptosis, and inhibited inflammation and oxidative stress in LPS-induced mice. Integrated analyses identified 27 potential targets for metformin in SMI treatment. KEGG pathway analysis revealed significant enrichment in TNF, HIF-1, IL-17, and PI3K/AKT signaling pathways, while protein-protein interaction analysis pinpointed ten core targets, including IL6, IL1B, CCL2, CASP3, MMP9, HIF1A, IGF1, NOS3, MMP2, and LEP. Molecular docking and dynamics simulations demonstrated metformin's high affinity for these core targets. Further, RT-qPCR and western blot analyses confirmed that metformin modulates core target expression to mitigate SMI. Notably, our data underscore the importance of PI3K/AKT and MMP2/MMP9 signaling pathways in SMI therapy.

Conclusion: This study elucidates the metabolic and molecular mechanisms of metformin in SMI treatment, supporting its potential repurposing for SMI.

Background: Preeclampsia is prevalent in women with diabetes, but the mechanism is unclear. We previously found that oxidized, glycated lipoproteins robustly upregulated soluble fms-like tyrosine kinase-1 (sFlt1), a key mediator of preeclampsia. Here, we determined the role of protein kinase C (PKC) and its subtypes in sFlt1 regulation in placental trophoblasts, and whether this mechanism might mediate the effect of modified lipoproteins.

Methods: Cultured human HTR8/SVneo and BeWo trophoblasts were treated with the PKC activator phorbol-12-myristate-13-acetate (PMA) for 24h, ± PKC inhibitors GF109203X (general), Ro31-8220 (PKCα-selective), LY333531 (PKCβ-selective) and rottlerin (PKCδ-selective). The effect of 'heavily oxidized, glycated' low-density lipoproteins (HOG-LDL) vs. native LDL (N-LDL), ± high glucose (30 mM), was evaluated in HTR8/SVneo cells. sFlt1 secretion (ELISA), mRNA expression (RT-qPCR), and cellular PKC activity were measured.

Results: PMA stimulated robust sFlt1 release and mRNA expression in both cell lines; these effects were inhibited by GF109203X, Ro31-8220 and LY333531 in a concentration-dependent manner. Rottlerin inhibited sFlt1 in BeWo, but modestly enhanced it in HTR8/SVneo cells. HOG-LDL enhanced PKC activity vs. N-LDL in HTR8/SVneo cells. Also, HOG-LDL, but not high glucose, significantly increased sFlt1 secretion and mRNA expression; this response was inhibited by GF109203X, Ro31-8220 and LY333531 at concentrations comparable to those that blocked PMA induction of sFlt1.

Conclusion: Modified lipoproteins upregulate sFlt1 in trophoblasts via a PKC-mediated mechanism, involving at least α and β isoforms. The data suggest potential therapeutic targets to reduce the risk of preeclampsia in women with diabetes.