Frontiers in Pharmacology最新文献

Background: Migraine represents a chronic neurological disorder characterized by high prevalence, substantial disability rates, and significant economic burden. Its pathogenesis is complex, and there is currently no cure. The rapid progress in multi-omics technologies has provided new tools to uncover the intricate pathological mechanisms underlying migraine. This systematic review aims to synthesize the findings of multi-omics studies on migraine to further elucidate the complex mechanisms of disease onset, thereby laying a scientific foundation for identifying new therapeutic targets.

Methods: We conducted a comprehensive systematic review, specifically focusing on clinical observational studies that investigate various aspects of migraine through the integration of genomics, transcriptomics, proteomics, and metabolomics. Our search encompassed multiple databases including PubMed, EMBASE, the Web of Science Core Collection, the Cochrane Library, China National Knowledge Infrastructure, the Chinese Science and Technology Periodical Database, the Wanfang database, and the China Biology Medicine Database to cover studies from database inception until 20 March 2024., The scope of our review included various aspects of migraine such as ictal and interictal phases; episodic or chronic migraine; menstrual-related migraine; and migraine with or without aura (PROSPERO registration number: CRD42024470268).

Results: A total of 38 studies were ultimately included, highlighting a range of genetic variations, transcriptional abnormalities, protein function alterations, and disruptions in metabolic pathways associated with migraine.These multi-omics findings underscore the pivotal roles played by mitochondrial dysfunction, inflammatory responses, and oxidative stress in the pathophysiology of migraine.

Conclusion: Multi-omics approaches provide novel perspectives and tools for comprehending the intricate pathophysiology of migraine, facilitating the identification of potential biomarkers and therapeutic targets.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=470268, identifier CRD42024470268.

Objectives: To assess the pharmacokinetics and pharmacodynamics of imipenem in a retrospective cohort of hospitalized Chinese older patients.

Methods: A population pharmacokinetic (PPK) model was constructed utilizing a nonlinear mixed-effects modeling approach. The final model underwent evaluation through bootstrap resampling and visual predictive checks. Additionally, a population pharmacokinetic and pharmacodynamic analysis was conducted employing Monte Carlo simulations to investigate the impact of commonly used dosing regimens (0.25 g every 6 h, 0.5 g every 6 h, 0.5 g every 8 h, 1 g every 6 h, 1 g every 8 h, and 1 g every 12 h) on the likelihood of achieving the target therapeutic outcomes.

Results: A total of 370 observations available from 142 patients were incorporated in the PPK model. A two-compartment PPK model with linear elimination best predicted the imipenem plasma concentrations, with the creatinine clearance as a significant covariate of clearance. Typical estimates for clearance, inter-compartmental clearance, central and peripheral volume were 13.1 L·h^-1, 11.9 L·h^-1, 11.7 L, 29.3 L, respectively.

Conclusion: The pharmacokinetics of imipenem in elderly patients were effectively characterized by the established PPK model, which includes creatinine clearance as a key covariate. This research will enhance our understanding of imipenem elimination and support precision dosing in this patient demographic.

Endothelial cell dysfunction plays a crucial role in the early development of cerebral small vessel disease (CSVD). Arginase-1 (ARG1) is expressed in endothelial cells, and its deficiency may exacerbate cerebrovascular damage by increasing reactive oxygen species (ROS) production, thereby inducing endothelial cell apoptosis. Berbamine (BBM) has shown potential in neuroprotection and cardiovascular disease prevention. This study aimed to investigate the impact of ARG1 deficiency on human brain microvascular endothelial cells and the protective effects of BBM against ARG1 deficiency-induced damage. Human brain microvascular endothelial cells (HCMEC/D3) were cultured in vitro, and ARG1 knockdown or overexpression was achieved using plasmid transfection techniques. We examined the effects of ARG1 expression levels on HCMEC/D3 cell viability, migration, apoptosis, adhesion, and angiogenesis through cellular experiments. Additionally, we explored how ARG1 expression levels influenced arginine (Arg), nitric oxide (NO), and ROS levels in HCMEC/D3 cells. The results demonstrated that ARG1 deficiency inhibited HCMEC/D3 cell viability, migration, adhesion, and angiogenesis, while promoting apoptosis and elevating Arg, NO, and ROS levels in HCMEC/D3 cells. Next, the effect of different BBM concentrations on HCMEC/D3 cell viability was assessed using the CCK-8 assay, revealing that BBM at a concentration of 5 µM had no significant impact on cell viability. Subsequently, after successfully knocking down ARG1 in HCMEC/D3 cells, the cells were treated with BBM. The results showed that BBM effectively mitigated the negative effects of ARG1 deficiency on HCMEC/D3 cell viability, migration, apoptosis, adhesion, and angiogenesis, while also reducing Arg, NO, inducible nitric oxide synthase (iNOS), and ROS levels in HCMEC/D3 cells. In conclusion, this study suggests that ARG1 deficiency may damage HCMEC/D3 cells by increasing Arg levels, leading to elevated NO and ROS levels. BBM may provide protection to ARG1-deficient HCMEC/D3 cells by reducing Arg, NO, iNOS, and ROS levels. These findings deepen our understanding of the pathogenesis of CSVD and provide a theoretical basis for the clinical application of BBM.

Objective: This study aims to analyze the adverse drug events (ADEs) associated with tolvaptan in the Food and Drug Administration Adverse Event Reporting System database from the fourth quarter of 2009 to the second quarter of 2024.

Methods: After standardizing the data, various signal detection techniques, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network, and Multi-Item Gamma Poisson Shrinker, were employed for analysis.

Results: Among the 7,486 ADE reports where tolvaptan was the primary suspected drug, a total of 196 preferred terms were identified, spanning 24 different system organ classes. Specifically, hepatobiliary disorders, renal and urinary disorders, and metabolic and nutritional disorders were found to be characteristic adverse reactions associated with tolvaptan. Additionally, uncommon but notable ADE signals were observed, such as renal cyst rupture, renal cyst infection, polycystic liver disease, and renal cyst hemorrhage. These several ADEs have not been referred to in the previous literature. Notably, strong ADE signals were detected for decreased urine osmolality [n = 5, ROR 149.74, PRR 149.7, IC (Information Component) 7.13, EBGM (Empirical Bayes Geometric Mean) 139.79], osmotic demyelination syndrome (n = 38, ROR 128.47, PRR 128.25, IC 6.92, EBGM 120.91), and pulmonary-related tumors such as bronchial metastatic carcinoma, bronchial carcinoma, metastatic small cell lung carcinoma, and small cell lung carcinoma. In the concomitant medication analysis of 7,486 suspected adverse drug reaction reports related to tolvaptan, the top three drugs most commonly used in combination with tolvaptan were furosemide, spironolactone, and amlodipine.

Conclusion: While tolvaptan provides therapeutic benefits, it poses a risk of significant adverse reactions. Clinicians should closely monitor the occurrence of events related to hepatobiliary disorders, renal and urinary disorders, metabolic and nutritional disorders, as well as benign, malignant, and indeterminate tumors during its clinical use.

Background: Phytolacca acinosa is an herbaceous herb belonging to the Phytolaccaceae family. The plant has a long history of usage in traditional medicine for treating a variety of ailments including infectious diseases, edema, inflammation, gastric, and abdominal distress. The traditional use, phytochemistry, and pharmacological properties of Phytolacca acinosa are outlined in this article.

Main text: To date, few bioactive molecules have been identified and isolated from the plant, such as phytolacacinoside A, esculentoside H, jaligonic acid and esculentoside B, phytolaccanol and epiacetyl aleuritolic acid, esculentoside A, esculentoside C, esculentoside D, esculentoside T, esculentoside S, sitosterol. The literature related some of the reported ethnomedicinal uses of the plant to these compounds found in different parts of the plant.

Conclusion: The in-depth knowledge about the significance of Phytolacca acinosa presented in this review may open up opportunities for research development in drug discovery and a better comprehension of the therapeutic advantages of the plant.

Objective: In addition to its antiplatelet and anti-inflammatory properties, aspirin inhibits bacterial proliferation directly. The potential benefits of aspirin may enhance the prognosis for sepsis patients. However, little is known about the effects of early aspirin administration. This study aimed to examine the correlation between the administration of aspirin at an early stage and the 90-day mortality rate among sepsis patients.

Methods: In order to distinguish between septic patients who received early aspirin treatment and those who did not, queries were conducted on the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. The principal metric utilized was 90-day mortality. We determined the association between early aspirin use and 90-day mortality using multivariate Cox regression, and propensity score matching (PSM) was utilized to validate our findings. The analyses of the subgroups have been completed.

Results: Our analysis comprised 28,425 septic patients, of whom 7,568 (26.6%) received aspirin within 24 h of intensive care unit (ICU) admission. The aspirin users group had a lower 90-day mortality than the aspirin nonusers group [1,624 (21.8%) vs. 2,035 (27.3%), P < 0.001]. The logistic regression showed that early aspirin use was associated with a lower 90-day mortality (OR, 0.74, 95% CI, 0.69-0.80, P < 0.001). K-M curve analysis showed that the 90-day mortality of the aspirin users group was significantly lower than that of the aspirin nonusers group (P < 0.001). Subgroup analysis revealed comparable relationships between early aspirin use and 90-day mortality among individuals.

Conclusion: In conclusion, early aspirin use was associated with decreased in-hospital and 90-day mortality in septic patients, emphasizing the significance of early aspirin use administration in the ICU.

Background: Prostate cancer was the fourth most diagnosed cancer worldwide in 2022. Radical treatments and androgen deprivation therapy benefit newly diagnosed patients but impact quality of life, often leading to castration-resistant prostate cancer. Short-term dietary changes significantly affect the gut microbiota, which differs markedly between prostate cancer patients and healthy individuals, impacting both cancer progression and treatment response. A high-choline diet increases the risk of fatal prostate cancer, potentially mediated by the conversion of choline to the trimethylamine N-oxide (TMAO) by the gut microbiota.

Methods: The CCK8 assay was employed to investigate whether TMAO affects the proliferation ability of prostate cancer cells and to determine the appropriate drug concentration. Subsequently, CCK8 time gradients, colony formation assays, and EdU assays measured TMAO's influence on cell proliferation. Wound healing and transwell migration assays evaluated TMAO's effect on cell migration. RNA-seq analysis was performed to explore the mechanisms by which TMAO influences the proliferation and migration of prostate cancer cells. qPCR and Western blotting were utilized to validate the expression of related mRNA or proteins. Finally, we performed in vivo experiments to evaluate the effect of a high choline diet on the growth of subcutaneous tumors and lung metastases in mice.

Results: Our study found that TMAO enhances the proliferation and migration of prostate cancer cells by upregulating HMOX1 via activation of the MAPK signaling pathway, specifically p38 MAPK. In mouse subcutaneous tumor and lung metastatic tumor experiments, the high-choline diet increased prostate cancer cell proliferation and migration, resulting in significantly greater tumor volume and number of metastases than controls.

Conclusion: This study is the first to demonstrate the role of the gut microbiota-derived metabolite TMAO in prostate cancer. TMAO promotes the proliferation and migration of prostate cancer cells by activating the p38 pathway and increasing HMOX1 expression. Reducing choline intake through dietary intervention may delay the onset and progression of prostate cancer, presenting significant clinical application value.

Objective: This research investigated the possible shielding properties of BB (Berberrubine) against the harmful auditory effects of cisplatin, preliminarily delving into the underlying mechanisms responsible for this protection.

Methods: HEI-OC1 cell viability was determined using a Cell Counting Kit-8 (CCK-8). The impact of BB on cochlear hair cells was studied through in vitro cochlear explants culture. Apoptosis levels were measured through Annexin V-PI, Cleaved Caspase-3, and TUNEL staining. The level of ROS (reactive oxygen species) was measured through the application of DCFH-DA, MitoSOX, and JC-1 fluorescent dyes for staining. Immunofluorescence analysis of cochlear samples from mice was conducted to quantify the hair cell count, and concurrently, ABR (Auditory Brainstem Response) testing was utilized to evaluate auditory function. The mechanism of action of BB was explored using RNA-Seq and qRT-PCR analysis.

Results: BB significantly improved cell survival rates under cisplatin treatment, reduced levels of apoptotic markers (TUNEL, Cleaved Caspase-3, Annexin V-PI), decreased ROS and MitoSOX levels, and improved JC-1 signals in both HEI-OC1 cells and cochlear hair cells in cochlear explants culture. Animal studies demonstrated that treatment with BB enhanced the survival of cochlear hair cells, reduced hearing impairment caused by cisplatin in mice. RNA-seq and qRT-PCR analysis revealed that BB influenced the expression levels of multiple genes (Ccnd2, Reln, Pgf, Mylk3, Ppplr12c, Thbsl), by promoting folate biosynthesis for hearing protection.

Conclusion: Our findings suggest that BB protects against cisplatin-induced hearing damage by enhancing folate biosynthesis, decreasing intracellular ROS levels, and inhibiting apoptosis.

Background: Polydatin (3,4',5-trihydroxy-3-β-d-glucopyranoside, PD) is known for its antioxidant and anti-inflammatory properties. Oxaliplatin (OXA)-based chemotherapy is the first-line treatment for metastatic and recurrent colorectal cancer (CRC). However, the lack of selectivity for normal cells often results in side effects. Consequently, the search for anti-cancer components with high efficacy and low cytotoxicity has become a significant focus in recent years.

Methods: The anti-tumor effects of PD, OXA or their combination were assessed by cell viability, colony formation, and wound-healing assays. Reactive oxygen species (ROS) generation was measured by flow cytometry and DNA damage was assessed by immunofluorescence assay. The relative gene and protein expressions were analyzed by quantitative real time-PCR (qRT-PCR) and Western blot assays. Molecular docking analysis predicted the interaction between PD and potential targets.

Results: We found that PD exerted anti-CRC activity by promoting Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase 5 (NOX5)-mediated ROS production, activating the endoplasmic reticulum (ER) stress, and inducing DNA damage. Knocking down NOX5 attenuated the inhibition of proliferation and colony forming ability induced by PD in colon cancer cells and reversed the expression of C/EBP-homologous protein (CHOP) and activating transcription factor 4 (ATF4) proteins. In addition, combination of PD and OXA synergistically exerted anti-CRC activities by promoting DNA damage and activating ER stress signaling pathway.

Conclusion: The combination of PD and OXA could be an effective treatment strategy for certain patients with CRC.

Background: Dabigatran etexilate (DABE), a prodrug of dabigatran (DAB), is a direct thrombin inhibitor used to prevent ischemic stroke and thromboembolism during atrial fibrillation. The effect of genetic polymorphisms on its metabolism, particularly UGT2B15, has not been extensively explored in humans. This study aimed to investigate the effects of UGT2B15, ABCB1, and CES1 polymorphisms on the pharmacokinetics of DAB and its acylglucuronide metabolites in healthy subjects.

Methods: A total of 124 healthy males were genotyped for UGT2B15, ABCB1, and CES1 polymorphisms. After a single 150 mg dose of DABE, plasma concentrations of total and free DAB, as well as dabigatran acylglucuronide (DABG) were measured using LC-MS/MS. Pharmacokinetic parameters were analyzed using non-compartmental methods, and statistical comparisons were conducted between the genotype groups.

Results: UGT2B15 c.253G>T significantly affected free DAB pharmacokinetics, with a lower T_max and oral clearance in TT genotype (n = 28, p < 0.05). For DABG, C_max was significantly higher in GG genotypes (n = 32, 42.3 ± 16.3 ng/mL) compared to that in GT (n = 64, 32.4 ± 20.5 ng/mL) and TT (29.7 ± 17.1 ng/mL) genotypes. Similarly, the AUC_all of DABG was highest in GG genotypes (327 ± 148.3 ng h·mL^-1), followed by GT (238.7 ± 166.5 ng h·mL^-1) and TT (223.3 ± 165.4 ng h·mL^-1) genotypes (p < 0.05). The metabolite-to-parent ratios (m/p ratios) for C_max and AUC_all were significantly higher in GG and GT genotypes than that in TT genotype. ABCB1 and CES1 polymorphisms had no significant impact on the pharmacokinetics of DAB or DABG.

Conclusion: UGT2B15 polymorphisms were associated with difference in DAB glucuronidation and pharmacokinetics in healthy male participants.