Frontiers in Pharmacology最新文献

Introduction: Ulcerative colitis (UC) is an inflammatory bowel disease characterized by inflammation and ulceration of the digestive tract.

Methods: Photodynamic therapy (PDT) with a novel photosensitizer LD₄ was used to treat UC rat models to explore the therapeutic effect and mechanism of LD₄-PDT on UC. 16S ribosomal RNA was used to detect the composition of Gut microbiota.

Results: Our findings indicate that LD₄-PDT could protect the integrity of the colonic mucosa, alleviate the inflammatory response and promote the healing of colonic mucosa. Mechanism studies demonstrated that LD₄-PDT could inhibit the NF-κB signaling pathway, downregulated the expression of the inflammatory factors' tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and myeloperoxidase (MPO), increased the contents of glutathione (GSH) and superoxide dismutase (SOD) and decreased the content of malondialdehyde (MDA). Additionally, analysis of gut microbiota revealed that LD₄-PDT treatment could decrease the abundance of the Proteobacteria phylum in fecal samples, while no significant differences were observed in the Firmicutes, Bacteroidetes, or Actinobacteria phyla among the three groups using 16S rRNA analysis.

Discussion: In summary, our data suggested that LD₄-PDT could inhibit DSS-induced UC in rats via the NF-κB signaling pathway, indicating its potential as a novel photosensitizer for the treatment of UC.

Introduction: Deglycosylated azithromycin (Deg-AZM), a new transgelin agonist with positive therapeutic effects on slow transit constipation, has been approved for clinical trials in 2024. This work investigated the drug metabolism and transport of Deg-AZM to provide research data for further development of Deg-AZM.

Methods: A combination of UPLC-QTOF-MS was used to obtain metabolite spectra of Deg-AZM in plasma, urine, feces and bile. Caco-2 cells was used to investigate the permeability of Deg-AZM and whether it is a potential substrate of the efflux transporter P-glycoprotein. Human liver microsome phenotyping assays with chemical inhibition and recombinant CYPs phenotyping assays were used to investigate the CYP450 enzyme phenotype involved in Deg-AZM metabolism in vitro. A HLM inhibition reaction system was established to evaluate the inhibitory effect of Deg-AZM on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The mRNA expression of human primary hepatocytes incubated with Deg-AZM or not was evaluate the induction of Deg-AZM on CYP1A2, CYP2B6, and CYP3A4.

Results: 44 metabolites of Deg-AZM were identified in rat urine, feces, bile, and plasma, the metabolic pathways included demethylation, monohydroxylation, dihydroxylation, dehydroxidation, hydroreduction, hydrolysis, methylation, glucuronidation and the combination of different metabolic pathways. Deg-AZM was a low permeability drug in the intestine and a potential substrate of the efflux transporter P-glycoprotein. CYP3A4 was the major CYP isoform responsible for Deg-AZM metabolism. Deg-AZM showed moderate inhibition with CYP2B6 and CYP2D6. Data in three batches of human primary hepatocytes disclosed induction potential of Deg-AZM on CYP2B6 and CYP3A4.

Conclusion: The in vivo metabolic pathway of Deg-AZM and in vitro possibility of drug interaction for Deg-AZM with CYP enzymes and drug transporter were fully investigated. It was suggested that dose adjustments may be warranted depending on the potency of the corresponding modulators in clinical.

Introduction: The mortality rate for liver cancer is extremely high but clinical treatments have not made much progress, so it is necessary to develop anticancer agents with lower toxicities and more effective liver-targeting drug delivery systems (LTDDSs). At present, LTDDSs mediated by the asialoglycoprotein receptor (ASGPR) show excellent effects at improving the liver-targeting and antitumor effects of drugs. However, the galactosyl ligands are typically prepared by chemical synthesis and have some shortcomings. The present work endeavors to explore the influences of plant galactolipids as natural galactosyl ligands for LTDDSs.

Methods: Plant galactolipids were extracted from oat bran, and their characteristics were tested. Then, oat-galactolipid-modified curcumin-loaded liver-targeting vesicles (GCLTVs) and curcumin-loaded vesicles were prepared, which were used in a comparative study of the liver-targeting and liver anticancer effects in vitro and in vivo.

Result: The experimental results show that the oat galactolipids and GCLTVs were prepared successfully. The hydrophilic-lipophilic balance, acid, ester, and saponification values of the oat galactolipids were 14.89, 47.22, 237.09, and 284.30, respectively. The morphology of the GCLTV was spherical, with an average particle size of 64.47 nm and average potential of -19.73 mV. The optimal proportion of galactolipids in the GCLTVs was selected as 30%. Compared with the curcumin-loaded vesicles, GCLTV uptakes were significantly higher at 1, 2, and 4 h; further, the galactolipid modification significantly improved the liver-targeting capability of the GCLTVs in vivo. The inhibitory effects of the GCLTVs on the proliferation of HepG2 cells were significantly higher than those of the curcumin-loaded vesicles after 24 and 48 h. The antitumor effects of GCLTVs in vivo based on H&E staining results on liver tissues were stronger than those of the curcumin-loaded vesicles, and the expressions of P53, Bcl-2, and Bax were correspondingly more significant.

Conclusion: The GCLTVs show excellent liver-targeting capabilities in vitro and in vivo. Compared to the curcumin-loaded vesicles, the cytotoxicity and anticancer effects of the GCLTVs were significantly higher in vitro and in vivo. Thus, oat galactolipids could be used as a type of natural ligand of the ASGPR and a membrane material that would be beneficial for liver-targeting nanopreparations.

Background: Statins, as an important class of lipid-lowering drugs, play a key role in the prevention and treatment of cardiovascular diseases. However, with their widespread use in clinical practice, some adverse events have gradually emerged. In particular, the hepatotoxicity associated with statins use has become one of the clinical concerns that require sufficient attention.

Methods: In this study, we conducted a comprehensive and detailed analysis of the hepatotoxicity of statins based on the data of the US Food and Drug Administration Adverse Event Reporting System database from the first quarter (Q1) of 2004 to the Q1 of 2024 and used Reporting Odds Ratios and Empirical Bayes Geometric Mean to mine the signal of adverse events.

Results: In this study, hepatic disorder related seven statins all exhibited positive signals. Through signal mining, we identified a total of 14,511 cases of adverse events associated with hepatic disorder caused by these statin drugs, with atorvastatin, simvastatin, and rosuvastatin occurring at a higher rate. A total of 148 positive signals related to adverse events of hepatic disorder were captured. Autoimmune hepatitis and drug-induced liver injury both presented positive signals across multiple statin drugs. Notably, atorvastatin had the most significant signal strength in cholestatic pruritus and bilirubin conjugation abnormal. Fluvastatin also showed notable signal strength in autoimmune hepatitis, while simvastatin had a relatively weaker signal strength for hepatic enzyme increased.

Conclusion: This study discovered specific adverse event signal values, revealing potential hepatotoxic risks associated with the use of statin drugs. The results provide an important reference for the safe clinical use of drugs, help to improve the understanding of the safety of statins, and also provide a scientific basis for clinicians to make more accurate and safe decisions when making treatment plans.

Background: Mitochondria, as the energy factories of cells, are involved in a wide range of vital activities, including cell differentiation, signal transduction, the cell cycle, and apoptosis, while also regulating cell growth. However, current pharmacological treatments for stroke are challenged by issues such as drug resistance and side effects, necessitating the exploration of new therapeutic strategies.

Objective: This review aims to summarize the regulatory effects of natural compounds targeting mitochondria on neuronal mitochondrial function and metabolism, providing new perspectives for stroke treatment.

Main findings: Numerous in vitro and in vivo studies have shown that natural products such as berberine, ginsenosides, and baicalein protect neuronal mitochondrial function and reduce stroke-induced damage through multiple mechanisms. These compounds reduce neuronal apoptosis by modulating the expression of mitochondrial-associated apoptotic proteins. They inhibit the activation of the mitochondrial permeability transition pore (mPTP), thereby decreasing ROS production and cytochrome C release, which helps preserve mitochondrial function. Additionally, they regulate ferroptosis, mitochondrial fission, and promote mitochondrial autophagy and trafficking, further enhancing neuronal protection.

Conclusion: As multi-target chemical agents, natural products offer high efficacy with fewer side effects and present promising potential for innovative stroke therapies. Future research should further investigate the effectiveness and safety of these natural products in clinical applications, advancing their development as a new therapeutic strategy for stroke.

Background: Oxyberberine (OBB) is a naturally occurring isoquinoline alkaloid that is believed to possess various health-promoting properties, including anti-fungus, hepatoprotection, anti-inflammation, and anti-intestinal mucositis effects. Despite several studies reporting the health benefits of OBB in treating ulcerative colitis (UC), its specific mechanism of action has yet to be fully elucidated.

Purpose: This investigation is designed to explore the potential protective efficacy of OBB and the latent mechanism using an in vitro model of UC-like inflammatory intestinal cells.

Methods: Caco-2 cells were pretreated with OBB and subsequently exposed to lipopolysaccharide (LPS). The transepithelial electrical resistance (TEER), paracellular permeability, and the distribution and expression of tight- and adherent junction proteins were determined to assess barrier integrity. The levels of proinflammatory cytokines, reactive oxygen species (ROS), Nrf2, and NF-κB signaling cascade were analyzed via ELISA, qRT-PCR, immunofluorescence, or Western blotting.

Results: OBB was found to mitigate the effects of LPS on Caco-2 cell monolayers, as evidenced by the improvement in TEER and the decrease in FITC-dextran flux. Moreover, OBB ameliorated the LPS-induced decrease in the distribution and expression of several tight junction markers, including ZO-1, occludin, and E-cadherin. In addition, OBB treatment effectively inhibited LPS-induced increases in ROS, apoptosis, and Keap1 and decreases in Nrf2 and HO-1. LPS-induced elevations in nuclear NF-κB p65 and p-IκBα were suppressed by OBB. In addition, ML385, an antagonist of Nrf2, abolished the protective role of OBB.

Conclusion: OBB has a pronounced beneficial effect on LPS-induced damage to enteral barrier function, and the regulation of the Nrf2/NF-κB pathway is an important mechanism responsible for the protection afforded by OBB.

The epithelial-mesenchymal transition (EMT) is a biological process in which epithelial cells change into mesenchymal cells with fibroblast-like characteristics. EMT plays a crucial role in the progression of fibrosis. Classical inducers associated with the maintenance of EMT, such as TGF-β1, have become targets of several anti-EMT therapeutic strategies. Natural products from the pentacyclic triterpene class have emerged as promising elements in inhibiting EMT. Uvaol is a pentacyclic triterpene found in olive trees (Olea europaea L.) known for its anti-inflammatory, antioxidant, and antiproliferative properties. Yet, its effect on the TGF-β1-induced EMT in alveolar epithelial cells is unknown. The present study aimed to investigate the impact of uvaol upon TGF-β1-induced EMT in a cultured A549 human alveolar epithelial cell line, a classic in vitro model for studies of EMT. Changes in cell shape were measured using phase-contrast and confocal microscopy, whereas protein expression levels were measured using immunofluorescence, flow cytometry, and Western blotting. We also performed wound scratch experiments to explore its effects on cell migration. Uvaol had no significant cytotoxic effects on A549 cells. By contrast, the changes in the cell morphology consistent with TGF-β1-induced EMT were largely suppressed by treatment with uvaol. In addition, increased contents of mesenchymal markers, namely, vimentin, N-cadherin, and fibronectin in TGF-β1-induced A549 cells, were downregulated by uvaol treatment. Furthermore, the TGF-β1-induced migration of A549 cells was significantly suppressed by uvaol. Mechanistically, uvaol prevented the nuclear translocation of β-catenin and reduced the TGF-β1-induced levels of ZEB1 in A549 cells. These results provide compelling evidence that uvaol inhibits EMT by regulating proteins related to the mesenchymal profile in human alveolar epithelial cells, likely by modulating β-catenin and ZEB1 levels.

Objective: This study analysed the characteristics of new drugs listed under the pharmaco-economic evaluation exemption (PEE) system from 2015 to 2022 in South Korea and examined the factors influencing the pricing decisions under this system.

Methods: A mixed-methods statistical approach was used to comprehensively evaluate the factors influencing drug pricing under PEE system. Descriptive statistics provide an overview of the dataset, while inferential statistics, including t-tests and Pearson's correlation analyses, are used to explore variable associations. Multiple and hierarchical regression models identify and quantify the key determinants of drug prices, controlling for multicollinearity among the variables.

Results: From 2015 to 2022, 30 new drugs were listed under the PEE system. The average annual number of new drugs was four, but this figure significantly increased to eight in 2022. The "KOR/A7 lowest" variable exhibited a strong negative correlation with the budget impact variable (coefficient: 0.838, P < 0.001), indicating that drugs with higher budget impact tend to have lower prices compared to the A7 countrie's lowest price.

Conclusion: Since the introduction of the PEE system in South Korea, patient access to new drugs has significantly improved. However, the rising expenditure on pharmaceuticals has made budget impact a significant consideration in pricing decisions, highlighting the need for ongoing monitoring of drug expenditure by payers. As the system evolves, enhanced oversight and policy adjustments will be crucial for balancing cost containment with equitable patient access. Developing tiered RSA models based on drug classification or therapeutic impact could be a viable approach to achieving this balance.

Objective: The combination of pembrolizumab and chemotherapy has demonstrated notable clinical advantages in improving overall survival than chemotherapy alone for patients with untreated advanced pleural mesothelioma. The purpose of this study was to assess its cost-effectiveness.

Materials and methods: A Markov state-transition model was constructed using data from the IND227 phase 3 randomized clinical trial. Utility values for health states were taken from the IND227 trial, and direct medical costs were from the pertinent literature and local pricing data. Outcomes measured included quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER), incremental net health benefit (INHB), and incremental net monetary benefit (INMB). To manage the uncertainty in the model, both probabilistic sensitivity analysis (PSA) and one-way sensitivity analysis (OWSA) were used.

Results: In the base-case analysis, pembrolizumab plus chemotherapy resulted in an incremental gain of 0.23 QALYs at an additional cost of $18,199.63, resulting in an ICER of $80,557.23/QALY. This was not favorable compared to China's willingness-to-pay (WTP) threshold of $38,042.49/QALY, with an INHB of -0.25 QALYs and an INMB of $-9,605.00. Subgroup analyses showed ICERs for pembrolizumab plus chemotherapy versus chemotherapy of $33,917.61 and $99,536.73 in non-epithelioid and epithelioid patients, respectively. PSA indicated probabilities of cost-effectiveness for pembrolizumab plus chemotherapy at 0.55%, 69.41%, and 0.14% for the entire population and the non-epithelioid and epithelioid subgroups, respectively.

Conclusion: In the Chinese healthcare system, the combination of pembrolizumab and chemotherapy did not prove to be more cost-effective than chemotherapy alone as an initial treatment for untreated advanced pleural mesothelioma, with the exception of patients who have non-epithelioid histology.

Atherosclerotic cardiovascular disease (ASCVD) causes significant morbidity and mortality globally. Most of the chemicals specifically target certain pathways and minimally impact other diseases associated with ASCVD. Moreover, interactions of these drugs can cause toxic reactions. Consequently, the exploration of multi-targeted and safe medications for treating and preventing ASCVD has become an increasingly popular trend. Gallic acid (GA), a natural secondary metabolite found in various fruits, plants, and nuts, has demonstrated potentials in preventing and treating ASCVD, in addition to its known antioxidant and anti-inflammatory effects. It alleviates the entire process of atherosclerosis (AS) by reducing oxidative stress, improving endothelial dysfunction, and inhibiting platelet activation and aggregation. Additionally, GA can treat ASCVD-related diseases, such as coronary heart disease (CHD) and cerebral ischemia. However, the pharmacological actions of GA in the prevention and treatment of ASCVD have not been comprehensively reviewed, which limits its clinical development. This review primarily summarizes the in vitro and in vivo pharmacological actions of GA on the related risk factors of ASCVD, AS, and ASCVD. Additionally, it provides a comprehensive overview of the toxicity, extraction, synthesis, pharmacokinetics, and pharmaceutics of GA,aimed to enhance understanding of its clinical applications and further research and development.