Frontiers in Pharmacology最新文献

Background: Adherence to Highly Active Antiretroviral Therapy (HAART) medication is the major predictor of HIV/AIDS treatment success. Poor adherence to HAART creates the risk of transmitting HIV, deteriorating health conditions, treatment failure, increased occurrences of drug-resistant HIV, morbidity and mortality. The objective of the study was to explore and describe factors influencing HAART adherence among HIV-positive women in Southern Ethiopia.

Methods: A hospital-based descriptive cross-sectional survey was used among 220 randomly selected respondents. Data was collected with a structured interview guide after each respondent had given consent to take part in the study. The collected data was entered into and analyzed by using the Statistical Package for Social Sciences (SPSS) software program version 27.

Results: The level of self-reported adherence (measured by dose) to HAART in the past 30 days was found to be 82.7%. In multivariate analysis, the divorced/separated HIV-positive women had poor adherence to their HAART medication as compared to those who were married [AOR: 2.94, 95% CI: (1.02-8.44)]. Respondents who used reminders in their medication were 75% less likely to be poorly adherent to their HAART medication than those who did not use reminders [AOR: 0.25, 95% CI: (0.06-0.97)]. Those who self-reported depression, perceived stigma, and low perceived susceptibility had poor adherence to their HAART than those who did not report depression, perceived stigma, and low perceived susceptibility [AOR:2.34, 95% CI: (1.01-5.42)], [AOR:2.37, 95% CI: (1.06-5.34)], and [AOR: 4.1, 95% CI: (1.53-11.1)] respectively. HIV-positive women who self-reported low perceived severity were poorly adherent to HAART than those who self-reported high perceived severity [AOR: 2.92, 95% CI: (1.14-7.47)].

Conclusion: Factors including being divorced/separated, not using reminders, depression, perceived stigma, perceived susceptibility, and perceived severity negatively impact HIV-positive women's adherence to HAART.

Background: Inhibition of indolamine-2,3-dioxygenase 1 (IDO1) has been proposed as a promising strategy for cancer immunotherapy; however, it has failed in clinical trials. Macrophages in the tumor microenvironment (TME) contribute to immune escape and serve as potential therapeutic targets. This study investigated the expression pattern of IDO1 in TME and its impact on prognosis and therapeutic response of patients with esophageal squamous cell carcinoma (ESCC).

Methods: RNA sequencing data from 95 patients with ESCC from The Cancer Genome Atlas (TCGA) database were used to explore the prognostic value of IDO1. Bioinformatics tools were used to estimate scores for stromal and immune cells in tumour tissues, abundance of eight immune cell types in TME, and sensitivity of chemotherapeutic drugs and immune checkpoint (IC) blockage. The results were validated using digitalized immunohistochemistry and multiplexed immunofluorescence in ESCC tissue samples obtained from our clinical center.

Results: TCGA and validation data suggested that high expression of IDO1 was associated with poor patient survival, and IDO1 was an independent prognostic factor. IDO1 expression positively correlated with macrophages in TME and PDCD1 within diverse IC genes. Single-cell RNA sequencing data analysis and multiplexed immunofluorescence verified the coexpression of IDO1 and PD-1 in tumor-associated macrophages (TAMs). Patients with high IDO1 expression showed increased sensitivity to various chemotherapeutic drugs, while were more likely to resist IC blockage.

Conclusion: This study identifies IDO1 as an independent prognostic indicator of OS in patients with ESCC, reveals a compelling connection of IDO1, PD-1, and TAMs, and explores the sensitivity of patients with high IDO1 expression to chemotherapeutic drugs and their resistance to IC blockade. These findings open new avenues for potential targets in ESCC immunotherapy.

Background: Currently, there remains substantial controversy in research regarding whether the concomitant use of colchicine and statins increases the occurrence of rhabdomyolysis, warranting further substantiation.

Objective: This study aimed to identify the likelihood drug-drug interactions (DDIs) for the co-administration of colchicine and statins resulting in rhabdomyolysis.

Methods: A disproportionality analysis was conducted by using data sourced from the US Food and Drug Administration Adverse Event Reporting System (FAERS) to detect rhabdomyolysis signals associated with the combined use of colchicine and statins. The association between (colchicine/statins/colchicine and statins) and rhabdomyolysis were evaluated using information component (IC). DDI signals were calculated based on the Ω shrinkage measure and Bayesian confidence propagation neural network (BCPNN) method. Furthermore, stratification was performed based on colchicine and individual statins agents.

Results: In total, 11,119 reports of rhabdomyolysis were identified in the FAERS database, 255 (2.29%) involved both colchicine and statins. Our analysis showed potential DDI signals of rhabdomyolysis (Ω₀₂₅ = 1.17) among individuals concurrent use of colchicine and statins. Moreover, further drug-specific analysis suggests DDI signals in the colchicine-atorvastatin pair (Ω₀₂₅ = 1.12), and colchicine-rosuvastatin pair (Ω₀₂₅ = 1.05), along with a higher proportion of rhabdomyolysis (IC₀₂₅ = 5.20) and (IC₀₂₅ = 4.26), respectively.

Conclusion: The findings suggest that concomitant use of colchicine and statins may increase the risk of rhabdomyolysis, particularly when combined with atorvastatin or rosuvastatin. Therefore, healthcare professionals should pay special attention to life-threatening AE such as rhabdomyolysis, when co-prescribing colchicine statins.

Background: Overexpression of monopolar spindle 1 (MPS1) and histone deacetylase 8 (HDAC8) is associated with the proliferation of liver cancer cells, so simultaneous inhibition of both MPS1 and HDAC8 could offer a promising therapeutic approach for the treatment of liver cancer. Dual-targeted MPS1/HDAC8 inhibitors have not been reported.

Methods: A combined approach of pharmacophore modeling and molecular docking was used to identify potent dual-target inhibitors of MPS1 and HDAC8. Enzyme inhibition assays were performed to evaluate the optimal compound with the strongest inhibitory activity against MPS1 and HDAC8. The selectivity of MPH-5 for MPS1 and HDAC8 was assessed on a panel of 68 kinases and other histone deacetylases. Subsequently, molecular dynamics (MD) simulation verified the binding stability of the optimal compound to MPS1 and HDAC8. Ultimately, in vitro cellular assays and in vivo antitumor assays evaluated the antitumor efficacy of the most promising compound for the treatment of hepatocellular carcinoma.

Results: Six dual-target compounds (MPHs 1-6) of both MPS1 and HDAC8 were identified from the database using a combined virtual screening protocol. Notably, MPH-5 showed nanomolar inhibitory effect on both MPS1 (IC₅₀ = 4.52 ± 0.21 nM) and HDAC8 (IC₅₀ = 6.07 ± 0.37 nM). MD simulation indicated that MPH-5 stably binds to both MPS1 and HDAC8. Importantly, cellular assays revealed that MPH-5 exhibited significant antiproliferative activity against human liver cancer cells, especially HepG2 cells. Moreover, MPH-5 exhibited low toxicity and high efficacy against tumor cells, and it overcomes drug resistance to some extent. In addition, MPH-5 may exert its antitumor effects by downregulating MPS1-driven phosphorylation of histone H3 and upregulating HDAC8-mediated K62 acetylation of PKM2. Furthermore, MPH-5 showed potent inhibition of HepG2 xenograft tumor growth in mice with no apparent toxicity and presented favorable pharmacokinetics.

Conclusion: The study suggests that MPH-5 is a potent, selective, high-efficacy, and low-toxicity antitumor candidate for the treatment of hepatocellular carcinoma.