Frontiers in Pharmacology最新文献

Copper is an essential micronutrient involved in various physiological processes in various cell types. Consequently, dysregulation of copper homeostasis-either excessive or deficient-can lead to pathological changes, such as heart failure (HF). Recently, a new type of copper-dependent cell death known as cuproptosis has drawn increasing attention to the impact of copper dyshomeostasis on HF. Notably, copper dyshomeostasis was associated with the occurrence of HF. Hence, this review aimed to investigate the biological processes involved in copper uptake, transport, excretion, and storage at both the cellular and systemic levels in terms of cuproptosis and HF, along with the underlying mechanisms of action. Additionally, the role of cuproptosis and its related mitochondrial dysfunction in HF pathogenesis was analyzed. Finally, we reviewed the therapeutic potential of current drugs that target copper metabolism for treating HF. Overall, the conclusions of this review revealed the therapeutic potential of copper-based therapies that target cuproptosis for the development of strategies for the treatment of HF.

Objective: Single inhaler triple therapy is widely used in Chronic Obstructive Pulmonary Disease (COPD) and asthma. This research aimed to analyze adverse events (AEs) associated with Budesonide/Glycopyrronium/Formoterol Fumarate (BUD/GLY/FOR) and Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI).

Methods: This is a cross-sectional study. BUD/GLY/FOR (2020Q3-2024Q3) and FF/UMEC/VI (2018Q1-2024Q3) report files were downloaded from the U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) database. We use reporting odds ratio (ROR), proportional reporting ratio (PRR), and Bayesian confidence propagation neural network (BCPNN) for disproportionality analysis. The aim was to explore associations between drugs and preferred term (PT) and system organ classification (SOC) levels. We focused on exploring the top 10 PTs of each drug's BCPNN (IC) effect value and the PT of pneumonia.

Results: 16,355 AEs in BUD/GLY/FOR and 39,110 AEs in FF/UMEC/VI were extracted. Device use issues, oropharyngeal and vocal problems, pneumonia, candida infections, and urinary retention were the standard PTs present in drug leaflets. The risk of device use issues was higher in BUD/GLY/FOR, whereas the risk of pneumonia and candida infection in FF/UMEC/ VI had higher risk. Outside of the drug leaflets, both drugs were associated with a higher risk of AEs in vascular disorders. BUD/GLY/FOR group had a higher risk of AEs in body height decreased and hypoacusis. Notably, this study found an association between the above PTs and drugs, and the causal relationship needs to be verified by further longitudinal studies.

Conclusion: Our study provides a preliminary exploration of the safety of clinical use of BUD/GLY/FOR and FF/UMEC/VI, and clinicians should be alert to potential adverse effects.

Background: Compound schizonepeta fumigation lotion is a type of Chinese patent medicine for external use. It has the effect of dispelling wind, eliminating dampness, reducing swelling, and relieving pain. Clinically, it is used for anal fumigation and treatment of external hemorrhoids, anal fissures, and other diseases. Aconitum species are widely used in the field of traditional Chinese medicine. However, improper use and overdose can easily cause acute poisoning, leading to malignant arrhythmias, cardiogenic shock, and even death.

Methods: This study retrospectively analyzed the clinical data of eight patients who were treated in our hospital from June 2023 to February 2024 after taking compound schizonepeta fumigation lotion by mistake.

Case presentation: We report 8 cases of patients who took compound schizonepeta fumigation lotion by mistake. Most patients were illiterate and older, and poisoning was attributed to the misuse of an external drug. The affected patients exhibited different degrees of arrhythmia, with 2 receiving tracheal intubation, assisted ventilation, and hemoperfusion. Finally, all patients were clinically cured and subsequently discharged.

Conclusion: A considerable number of accidental aconitine poisoning cases were reported over a short period, alerting clinicians to their growing incidence. Meanwhile, when prescribing medications, clinicians must provide clear instructions on proper usage and ensure that patients strictly adhere to the dosage and administration guidelines outlined in the drug instructions. Additionally, patients should be informed that any errors in medication administration require urgent medical attention. Health professionals should aim to improve public understanding of safe medication practices, promote health literacy.

Platelet-derived growth factor alpha (PDGFRA) plays a significant role in various malignant tumors. PDGFRA expression boosts thyroid cancer cell proliferation and metastasis. Radiorefractory thyroid cancer is poorly differentiated, very aggressive, and resistant to radioiodine therapy. Thus, novel anticancer drugs that inhibit its metastasis are urgently required. In this context, we proposed the PDGFRA inhibitors by an optimized structure-based drug design approach. We performed a virtual screening of metabolites derived from anticancer medicinal plants (Swertia chirayita, Myristica fragrans, and Datura metel) and successfully identified seven hits, namely cis-Grossamide K, Daturafoliside O, N-cis-feruloyltyramine, Maceneolignan H, Erythro-2-(4-allyl-2, 6-dimethoxyphenoxy)-1-(3, 4, 5-trimethoxyphenyl) propan-1, 3-diol, Myrifralignan C, and stigmasteryl-3-O-β-glucoside as potential PDGFRA inhibitors. Not only the top 7 hits exhibited higher docking scores in docking simulation but also optimal drug-likeness and non-toxic profiles in pharmacokinetics analysis among 119 compounds. Our top hits are non-mutagenic, can cross the blood-brain barrier, and inhibit p-glycoprotein, while the N-cis-feruloyltyramine has the potential to become a lead compound. The protein-ligand stability of the top 3 hits, namely cis-Grossamide K, Daturafoliside O, and N-cis-feruloyltyramine, and their interactions at the potential binding site of target protein were confirmed through molecular dynamic simulations. We also analyzed pharmacophoric features for stable binding in the PDGFRA active site. These drug candidates were further characterized to predict their biological activity spectra in the human body and medicinal characteristics to know their extensive behavior in laboratory testing. This study necessitates the in-vitro and in-vivo studies to confirm the potential of our hits for the discovery of novel therapeutics against the thyroid cancer.

Recent research has demonstrated the efficacy of traditional Chinese medicine (TCM) and its active compounds in combating cancer, leading to an increasing utilization of TCM as adjunctive therapy in clinical oncology. However, the optimal dosage of TCM remains unclear, and excessive use may result in cardiotoxicity, which poses a significant health concern for patients undergoing systemic treatment. Therefore, elucidating the underlying mechanisms of cytotoxicity induced by TCM can provide valuable insights for clinical management. In this study, we employed a comprehensive bioinformatics analysis to present sequencing data obtained from AC16 myocardial cells treated with two bioactive derived from botanical drugs: Matrine and Evodiamine. We aim to investigate the dysregulated signaling pathways associated with cardiotoxicity induced by these compounds. Based on our sequencing results, we observed consistent patterns of gene expression and epitranscriptome regulation (m6A and A-to-I modifications) across various drugs-treated AC16 cells when analyzed using KEGG pathway enrichment and gene ontology analyses. Furthermore, m6A writers VIRMA and A-to-I writers ADARB1 is consistent target of Evodiamine and Matrine. In general, our findings suggest that different Chinese botanical drugs induced cardiotoxicity may share common therapeutic strategies.

Introduction: TNFα inhibitor (TNFi) immunogenicity in rheumatoid arthritis (RA) is a major obstacle to its therapeutic effectiveness. Although methotrexate (MTX) can mitigate TNFi immunogenicity, its adverse effects necessitate alternative strategies. Targeting nuclear factor of activated T cells (NFAT) transcription factors may protect against biologic immunogenicity. Therefore, developing a potent NFAT inhibitor to suppress this immunogenicity may offer an alternative to MTX.

Methods: We performed a structure-based virtual screen of the NFATC2 crystal structure to identify potential small molecules that could interact with NFATC2. For validation, we investigated the effect of the identified compound on NFAT transcriptional activity, nuclear localization, and binding to the NFAT consensus sequence. In vivo studies assessed the ability of the compound to protect against TNFi immunogenicity, while ex vivo studies evaluated its effect on CD4⁺ T cell proliferation and B cell antibody secretion.

Results: We identified duvelisib (DV) as a novel NFATC2 and NFATC1 inhibitor that attenuates NFAT transcriptional activity without inhibiting calcineurin or NFAT nuclear localization. Our results suggest that DV inhibits NFAT independently of PI3K by interfering with nuclear NFAT binding to the NFAT consensus promoter sequence. DV significantly protected mice from adalimumab immunogenicity and attenuated ex vivo CD4⁺ T cell proliferation and B cell antibody secretion.

Discussion: DV is a promising NFAT inhibitor that can protect against TNFi immunogenicity without inhibiting calcineurin phosphatase activity. Our results suggest that the future development of DV analogs may be of interest as agents to attenuate unwanted immune responses.

Background: The natural killer (NK) activity of peripheral blood mononuclear cells (PBMCs) is a crucial defense against the onset and spread of cancer. Studies have shown that patients with reduced NK activity are more susceptible to cancer, and NK activity tends to decrease due to cancer-induced immune suppression. Enhancing the natural cytotoxicity of PBMCs remains a significant task in cancer research.

Methods: This study investigates the potential of urolithin A, a polyphenolic metabolite produced by the gut microbiota, to enhance the natural cytotoxicity of PBMCs in prostate cancer patients and healthy subjects. We investigated the possible role of aryl hydrocarbon receptor (AhR) in this capability of urolithin A. We analyzed the ability of PBMCs preincubated with urolithin A, AhR agonist or antagonist to kill K562 (human chronic myelogenous leukemia) target cells.

Results: Our results demonstrate that urolithin A enhances the natural cytotoxicity of PBMCs in a dose-dependent manner. Specifically, at a concentration of 10 μM, urolithin A increased the NK activity of PBMCs from prostate cancer patients by an average of 23% (95% CI, 7%-38%). In addition, urolithin A modulates the level of cytokine production by PBMCs, decreasing the level of fractalkine, IL-8, and MCP-3. An AhR antagonist (CH223191, 1 μM) also increased NK activity, while an AhR agonist (β-naphthoflavone, 10 μM) did not increase NK activity and partially inhibited the urolithin A-induced enhancement.

Conclusion: Urolithin A increases the NK activity of PBMCs from patients with prostate cancer and healthy subjects, and the AhR may be involved in this capability of urolithin A.

Background: Pancreatic cancer remains one of the deadliest malignancies, largely due to its late diagnosis and lack of effective therapeutic targets.

Materials and methods: Using traditional machine learning methods, including random-effects meta-analysis and forward-search optimization, we developed a robust signature validated across 14 publicly available datasets, achieving a summary AUC of 0.99 in training datasets and 0.89 in external validation datasets. To further validate its clinical relevance, we analyzed 55 peripheral blood samples from pancreatic cancer patients and healthy controls using qPCR.

Results: This study identifies and validates a novel five-gene transcriptomic signature (LAMC2, TSPAN1, MYO1E, MYOF, and SULF1) as both diagnostic biomarkers and potential drug targets for pancreatic cancer. The differential expression of these genes was confirmed, demonstrating their utility in distinguishing cancer from normal conditions with an AUC of 0.83. These findings establish the five-gene signature as a promising tool for both early, non-invasive diagnostics and the identification of actionable drug targets.

Conclusion: A five-gene signature is established robustly and has utility in diagnostics and therapeutic targeting. These findings lay a foundation for developing diagnostic tests and targeted therapies, potentially offering a pathway toward improved outcomes in pancreatic cancer management.

Objective: The expanding field of hematopoietic cell transplantation (HCT) for non-malignant diseases, including those amenable to gene therapy or gene editing, faces challenges due to limited donor availability and the toxicity associated with cell collection methods. Umbilical cord blood (CB) represents a readily accessible source of hematopoietic stem and progenitor cells (HSPCs); however, the cell dose obtainable from a single cord blood unit is frequently insufficient. This limitation can be addressed by enhancing the potency of HSPCs, specifically their capacity to reconstitute hematopoiesis. In our study, we investigated the combined effects of treprostinil, a prostaglandin analog, and cinacalcet, a calcium-sensing receptor modulator, on the reconstitution of hematopoiesis.

Methods: A Lineage Cell Depletion Kit was employed to isolate lineage-negative (lin^-) HSPCs from mouse bone marrow. A Human CB CD34 Positive Selection Kit was utilized to isolate CD34⁺ cells from the CB of healthy donors. In vitro, the effects of treprostinil, cinacalcet, and their combination on the migration, adhesion, and differentiation of HSPCs were assessed. In vivo, homing and engraftment were examined. Eight-week-old female and male C57BL/6J, BALB/c, or female NSG mice served as recipient models.

Results: When administered concomitantly, treprostinil and cinacalcet exhibited mutual antagonism: the survival of recipient animals was lower when both drugs were administered together compared to either agent alone. Conversely, a sequential regimen involving priming with treprostinil/forskolin followed by cinacalcet treatment in vivo enhanced survival, irrespective of whether hematopoiesis was reconstituted by human or murine HSPCs. In vitro assays demonstrated enhanced migration and adhesion in response to the presence of treprostinil and cinacalcet, suggesting potential synergistic effects. Colony formation confirmed synergism.

Conclusion: Augmenting the bone marrow reconstitution potential of HSPCs with treprostinil and cinacalcet shows promise for rescuing patients undergoing HCT. This approach is particularly beneficial for those patients at high risk of transplant failure due to limited numbers of available HSPCs. Furthermore, enhancing the potency of HSPCs has the potential to alleviate the burden and risks associated with HSPC donation, as it would reduce the number of cells needed for collection.

Background: Fatty Liver Disease (FLD) progresses from steatosis to steatohepatitis and, if left untreated, can lead to irreversible conditions such as cirrhosis and hepatocarcinoma. The etiology of FLD remains unclear, but factors such as overconsumption, poor diet, obesity, and diabetes contribute to its development. Palmitic acid (PA) plays a significant role in FLD progression by inducing apoptosis, inflammation, oxidative stress, and endoplasmic reticulum (ER) stress in hepatocytes. Cordyceps militaris (CM), a fungus with various biological activities, including antioxidant properties is examined both in vitro and in vivo to assess its effectiveness in mitigating PA-induced hepatocyte apoptosis and preventing FLD progression.

Purpose: This study aims to investigate the potential and mechanism of CM in combating FLD, particularly in inhibiting hepatocyte apoptosis.

Methods: In vitro studies utilized Clone9 hepatocytes treated with PA to simulate FLD conditions. The effects of CM ethyl acetate extract (EAECM) on apoptosis, mitochondrial function, ER stress, inflammation, and oxidative stress were evaluated. In vivo experiments involved FVB mice fed a NASH diet containing high levels of PA to induce FLD, with powdered CM administered orally to assess its impact on body weight, fasting blood glucose level, liver health, fibrosis, and markers of ER stress, inflammation, and oxidative stress.

Results: EAECM demonstrated protective effects against PA-induced apoptosis, mitochondrial dysfunction, ER stress, inflammation, and oxidative stress in vitro. In vivo, powdered CM supplementation attenuated body weight gain, improved fasting blood glucose level, prevented hepatomegaly, reduced serum triglycerides, and inhibited liver fibrosis. Furthermore, powdered CM treatment mitigated ER stress, inflammation, and oxidative stress in the liver of mice receiving a NASH diet.

Conclusion: C. militaris holds promise as a therapeutic agent for FLD, as evidenced by its ability to alleviate PA-induced hepatocytes damage and hinder FLD progression in mice. Further research is warranted to identify the active compounds responsible for its beneficial effects and to explore its potential clinical applications in treating FLD.