Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie最新文献

Background: Acute myocardial ischemia/reperfusion injury (MIRI) with complicated mechanisms contributes to a high risk of ventricular arrhythmia, high lethality, and even sudden death. In vitro, Fraxinellone (FRA) exhibits an array of biologic activities and may possess cardioprotective effects. However, no relevant studies have examined FRA's protective potential against MIRI and related ventricular arrhythmias. The present study was undertaken to determine the effectiveness of FRA on MIRI and ventricular fibrillation (VF) susceptibility in rats and to elucidate the underlying mechanisms.

Methods: 48 healthy male Sprague-Dawley (SD) rats were randomly divided into the following four groups: Sham+vehicle(n=12), Sham+FRA(n=12), I/R+vehicle(n=12) and I/R+FRA(n=12). Histopathology, electrophysiological examination, HRV analysis in combination with molecular biology were used to investigate the therapeutic benefits of FRA on cardiac injury and VF susceptibility during myocardial IR. Finally, the potential mechanism by which FRA protects myocardium from MIRI was explored.

Results: Pretreatment with FRA ameliorated myocardial fibrosis after MIRI in vivo, alleviated myocardial injury, inflammation, oxidative stress and apoptosis in vivo and in vitro, thereby protecting myocardium from MIRI injury. In addition, FRA administration could improve HRV, prolong ventricular effective refractory period (ERP) and action potential duration (APD), attenuate VF induction rate, and contribute to improving ventricular sympathetic nerve remodeling and ion channel remodeling. Mechanistically, FRA may reduce MIRI via the PI3K/AKT pathway.

Conclusion: FRA may exert cardioprotective effects during MIRI by inhibiting myocardial inflammation, oxidative stress and apoptosis, and decrease VF susceptibility by improving sympathetic remodeling and ion channel remodeling, which might represent a potential therapeutic strategy for attenuation of MIRI.

This study aimed to evaluate the effects of liposome-encapsulated eugenol-based thiazolic derivatives against efflux pump-carrying bacteria. The Minimum Inhibitory Concentration (MIC) was determined to evaluate the antibacterial activity and antibiotic potentiation against Pseudomonas aeruginosa and Staphylococcus aureus, as well as to analyze the inhibition of efflux pumps in S. aureus strains 1199B and K2068 in the ethidium bromide assay. The direct antibacterial activity analysis showed no clinically relevant results since the compounds presented MICs ≥1024 µg/mL. Regarding the analysis of antibiotic potentiation against multidrug-resistant (MDR) strains of S. aureus, compound LF16 reduced norfloxacin MIC from 128 µg/mL to 64 µg/mL. All associated with gentamicin caused a significant antibiotic MIC reduction. None of the compounds could potentate the activity of norfloxacin against P. aeruginosa. However, all of them potentiated the activity of gentamicin against the same strain. Only the LF 26 caused a significant MIC reduction in the ethidium bromide assay, suggesting efflux inhibition in the S. aureus 1199B strain. Similar results were observed with the K2068 strain. Observing antibiotic MIC reduction S. aureus strains carrying the NorA and MepA proteins brought additional evidence of efflux pump inhibition. Our results indicate that while eugenol-based thiazoles didn't exhibit direct activity, they can potentiate the antibiotics activity against MDR strains of P. aeruginosa and S. aureus. Among them, compound LF 26 potentiated the inhibitory effects of ethidium bromide and antibiotics against S. aureus strains carrying the NorA and MepA proteins, indicating a potential role of this class of compounds as efflux pump inhibitors.

Background: Imbalances in Th1/Th2 and Th17/Treg immune axes, coupled with disruptions in the gut microbiota (GM), play a pivotal role in the pathogenesis of inflammatory bowel disease (IBD). Cordycepin, a natural anti-inflammatory compound, holds promise in mitigating IBD by rebalancing these immune axes in conjunction with modulating the GM. The aim of this experiment is to investigate the potential of cordycepin in mitigating enteritis and elucidate the underlying mechanisms associated with its ameliorative effects on enteritis.

Methods: On the day of inducing experimental colitis with Dextran Sulfate Sodium (DSS), mice in the DSS + Cordycepin and Cordycepin groups received 50 mg/kg/day Cordycepin via intra-gastric administration (i.g.) for seven consecutive days, respectively. Mice in the DSS and control groups were treated with equal volumes of saline. On day 8, all mice were euthanized under pentobarbital sodium anesthesia.

Results: In a DSS-induced colitis mouse model, Cordycepin treatment led to a significant reduction in the disease activity index (DAI), splenic weight, and colonic pathological injury while simultaneously improving body weight and colonic length. Furthermore, it positively impacted GM composition, resulting in decreased Th1 and Th17 cells, alongside an increase in Th2 and Treg cells. The contents of the mouse colon were extracted for microbial community analysis. Mouse blood was prepared into a single-cell suspension, and flow cytometry was used to assess the expressio of Treg, Th17, Th1, and Th2 immune cells.

Conclusions: These results underscored the effective intervention of cordycepin in ameliorating DSS-induced colitis by harmonizing the interplay between GM and immune homeostasis.

Pancreatic cancer, characterized by a dismal prognosis and limited treatment options, persists as a formidable challenge in oncology. Trophoblast cell surface antigen 2 (TROP2)-directed antibody-drug conjugates have achieved great success in solid tumors such as breast cancer and uroepithelial carcinoma. However, their efficacy against pancreatic cancer was insufficient in clinical trials, necessitating an imperative exploration of underlying mechanisms and new therapeutic strategies. In this study, we indicated that αTROP2-MMAE, an antibody-drug conjugate targeting TROP2, induced apoptosis through the caspase-9/PARP pathway and exerted potent antitumor effects against TROP2-positive pancreatic cancer. Simultaneously, RNA sequencing suggested significant changes in autophagy after αTROP2-MMAE treatment. The formation of autophagosomes and activation of autophagic flux were markedly induced through mechanisms associated with suppressing the activation of the Akt/mTOR pathway. The addition of pharmacological inhibitors of autophagy enhanced the cytotoxicity and apoptosis caused by αTROP2-MMAE, revealing the cytoprotective role of autophagy in TROP2-positive pancreatic cancer. In the subcutaneous xenograft model using BxPC3 cells, the combined administration of αTROP2-MMAE and an autophagy inhibitor elevated the tumor inhibition rate of αTROP2-MMAE from 71.6 % to 99.0 %, resulting in the eradication of tumors in half of the mice. Collectively, our research demonstrated for the first time the cytoprotective role of autophagy in TROP2-targeted antibody-drug conjugate therapy for pancreatic cancer, providing new perspectives for mechanistic exploration and therapeutic strategies in the treatment of pancreatic cancer.

The effective treatment regimens of triple-negative breast cancer (TNBC), a specific subtype of breast cancer (BC) with proneness to relapse and poor prognosis, are still lacking. Simeprevir (SIM), approved for hepatitis C infection treatment, has been proved to be a competitive drug for the treatment of various solid tumors recently. However, the anti-tumor mechanisms of SIM and therapeutic effects on TNBC are uncertain. In this study, we suggested that SIM effectively restrained the growth of MDA-MB-231 and BT-549 cells, two cell lines from TNBC. The RNA sequencing revealed that ferroptosis signaling was activated in SIM-treated TNBC cells. SIM induced ferroptosis in TNBC cells through reduced glutathione (GSH) levels, increased iron levels, ROS and lipid peroxidation. Mechanistically, SIM promoted the expression of β-TrCP to inhibit the Nrf2/GPX4 axis in TNBC cells, leading to ferroptosis. Moreover, SIM administration into the xenografts formed by MDA-MB-231 dramatically suppressed the tumor progression by inducing ferroptosis in vivo. Collectively, this finding reveals that SIM may serve as a competitive therapeutic strategy to inhibit TNBC.

Background: 5-Fluorouracil (5-FU) is a cornerstone in colorectal cancer therapy, but resistance has compromised its efficacy, necessitating detailed research into resistance mechanisms. Traditional methods for developing 5-FU-resistant cell lines are lengthy, unstable, and often unrepresentative of clinical scenarios.

Methods: We devised a rapid approach to create 5-FU-resistant colorectal cancer cells using an integrated in vivo/in vitro methodology. HCT116 cells were pretreated with 5-FU, then implanted into nude mice. Tumor growth was monitored, and cells from the tumors were cultured to establish the HCT116-Tumor cell line. Cells from 5-FU-exposed tumors received increasing 5-FU doses to induce resistance, creating the tumor-derived resistant (TR) cell line. Cells cultured without 5-FU were termed tumor-derived parental (TP) cells. An in vitro 5-FU resistance model, CR, served as a benchmark. Resistance metrics were evaluated using CCK-8 assays, Western Blotting, flow cytometry, and in vivo studies. Proteomics identified resistance-related differentially expressed proteins (DEPs).

Results: Low-dose 5-FU pretreatment accelerated tumor growth. Combining in vivo and in vitro methods, we developed 5-FU-resistant TR cells within two and a half months, faster than the ten-month conventional protocol. TR cells showed stronger and more durable 5-FU resistance than CR cells, with inhibited apoptosis, autophagy, and ferroptosis, and activation of MDR1. Proteomic analysis indicated more DEPs in TR cells, suggesting unique resistance mechanisms. Animal studies confirmed enhanced drug resistance in TR cells.

Conclusions: Our integrated approach rapidly develops colorectal cancer cells with robust 5-FU resistance, offering a potent model for exploring multiple resistance pathways and counter-resistance strategies.

The high metabolic requirements of cancer cells result in excess accumulation of H⁺ in the tumor microenvironment. Therefore, the extracellular pH of solid tumors is acidic, whereas the pH of normal tissues is more alkaline. The acidic tumor environment is correlated with tumor metastasis, immune escape, and chemoresistance, but the underlying mechanisms remain elusive. Herein, we demonstrate that sodium bicarbonate, a weakly alkaline compound, induces cytotoxicity in ovarian cancer cells and hinders cancer migration and invasion in vitro. The anti-cancer efficacy of Olaparib can be significantly augmented when combined with sodium bicarbonate. In vivo experiments suggest that the combinatorial treatment of sodium bicarbonate and Olaparib is biocompatible and more effective at inhibiting ovarian cancer growth than either treatment alone. Additionally, RNA-sequencing results reveal that the differentially expressed genes are enriched in pathways related to reactive oxygen species (ROS) generation, such as the cGMP/PKG pathway. The combined treatment increases M1 macrophage composition in tumors and reduces the accumulation of excessive ROS. These findings strongly suggest that sodium bicarbonate holds great potential as an adjuvant treatment by scavenging ROS accumulation and promoting M1 macrophage composition, thereby enhancing Olaparib's anti-cancer activity.

Selectivity profiling is key for assessing the pharmacological properties of multi-target drugs. We have developed a cell-based and barcoded assay encompassing ten druggable targets, including G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs), nuclear receptors, a protease as well as their key downstream pathways and profiled 17 drugs in living cells for efficacy, potency, and side effects. Notably, this multiplex assay, termed safetyProfiler assay, enabled the simultaneous assessment of multiple target and pathway activities, shedding light on the polypharmacological profile of compounds. For example, the neuroleptics clozapine, paliperidone, and risperidone potently inhibited primary targets DRD2 and HTR2A as well as cAMP and calcium pathways. However, while paliperidone and risperidone also potently inhibited the secondary target ADRA1A and mitogen-activated protein kinase (MAPK) downstream pathways, clozapine only exhibited mild antagonistic effects on ADRA1A and lacked MAPK inhibition downstream of DRD2 and HTR2A. Furthermore, we present data on the selectivity for bazedoxifene, an estrogen receptor antagonist currently undergoing clinical phase 2 trials for breast cancer, on MAPK signaling. Additionally, precise potency data for LY2452473, an androgen receptor antagonist, that completed a phase 2 clinical trial for prostate cancer, are presented. The non-selective kinase inhibitor staurosporine was observed to potently inactivate the two RTKs EGFR and ERBB4 as well as MAPK signaling, while eliciting stress-related cAMP responses. Our findings underscore the value of comprehensive profiling in elucidating the pharmacological properties of established and novel therapeutics, thereby facilitating the development of novel multi-target drugs with enhanced efficacy and selectivity.

Chemotherapy treatment faces a major obstacle with the emergence of multidrug resistance (MDR), often attributed to the elevated expression of ATP-binding cassette (ABC) transporters such as ABCG2 and ABCB1 in cancer cells. These transporters hinder the efficacy of cytotoxic drugs via ATP hydrolysis-dependent efflux, leading to diminished intracellular drug levels. The scarcity of approved treatments for multidrug resistant cancers necessitates exploration of alternative strategies, including drug repositioning of molecular targeted agents to counteract ABCG2-mediated MDR in multidrug-resistant cancer cells. This study investigates the potential of edicotinib, a selective colony-stimulating factor-1 receptor (CSF-1R) tyrosine kinase inhibitor that is currently undergoing clinical trials for various diseases, to reverse MDR in ABCG2-overexpressing cancer cells. Our findings reveal that by attenuating the drug-efflux function of ABCG2 without altering its expression, edicotinib improves drug-induced apoptosis and reverses MDR in ABCG2-overexpressing multidrug-resistant cancer cells at non-toxic concentrations. Through ATPase activity analysis and molecular docking, potential interaction sites for edicotinib on ABCG2 were identified. These results underscore an additional pharmacological benefit of edicotinib against ABCG2 activity, suggesting its potential incorporation into combination therapies for patients with ABCG2-overexpressing tumors. Further research is warranted to validate these findings and explore their clinical implications.