Frontiers in Pharmacology最新文献

Fuzi, a Chinese herb widely used in clinical settings, exhibits varying levels of toxicity depending on its geographical origin. Diester-type alkaloids are the primary contributors to the toxicity of Fuzi. This study aims to investigate regional differences and underlying mechanisms of Fuzi-induced neurotoxicity across China. Matrix-assisted laser desorption/Ionization mass spectrometry imaging (MALDI-MSI) method was employed to map the spatial distribution of six key diester-type alkaloids from Fuzi samples originating from five major regions. The results showed that the diester-type alkaloids were primarily distributed in the cuticle of Anguo- and Ludian-Fuzi, in the cuticle, cork, and pith of Butuo-Fuzi, in the phloem and pith tissues of Chenggu-Fuzi, and in the cuticle, cork, inner phloem, and pith of Jiangyou-Fuzi. When zebrafish were exposed to a Fuzi decoction for 24 h, it was observed that Jiangyou-Fuzi induced the most significant neurobehavioral abnormalities, lipid peroxidation damage, and aberrant neurotransmitters release. RNA sequencing analysis further indicated that the amino acid metabolism, ErbB, cGMP-PKG, and p53 signaling pathways-regulated by changes in the expression of Glub, Mao, GAB1, PRKG1B, PSEN2, and BAXα genes were disrupted to varying extents by Fuzi from different origins. In summary, the regional variability in the neurotoxicity of Fuzi can be attributed to differences in the distribution of its active compounds and underlying mechanisms. Among the samples tested, Jiangyou-Fuzi exhibited the highest neurotoxicity, followed by Anguo-, Chenggu-, Ludian-, and Butuo-Fuzi.

Background: Plant active substances are extensively utilized in treating rheumatoid arthritis (RA). Despite numerous experimental and clinical studies on plant active substances their efficacy remains largely unsubstantiated. The widespread use of these extracts as therapeutic measures for RA is problematic due to the lack of compelling evidence.

Objective: Our research aims to assess the impact of plant active substances on RA by conducting a network meta-analysis.

Methods: We systematically searched four electronic databases-PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and Web of Science-from their inception to August 2024. The main focus was on assessing primary outcomes, including the Visual Analogue Scale (VAS), inflammatory markers, Swollen Joint Count (SJC), Tender Joint Count (TJC), and Disease Activity Score on 28 joints (DAS28). We performed data analysis using StataMP 15.1 software and ranked the therapeutic effects based on the Surface Under the Cumulative Ranking Curve (SUCRA) probability values.

Results: Based on screening procedures, 18 eligible studies were incorporated into the analysis. These studies encompassed a total of 1,674 RA patients and investigated 10 different plant active substance therapies. Specifically, 10 studies included VAS indicators, 17 studies included inflammatory marker indicators, 14 studies included DAS28 indicators, 13 studies included SJC indicators, and 13 studies included TJC indicators. Based on SUCRA values, quercetin appeared to be the most effective treatment for decreasing serum VAS levels (67.3%). Furthermore, curcumin emerged as the most promising option for reducing inflammatory marker levels (72.3%), SJC (75.6%), and TJC (76.2%). Lastly, with respect to DAS28, resveratrol emerged as the optimal choice (74.3%).

Conclusion: According to the network meta-analysis (NMA), curcumin exhibited superior efficacy compared to placebo in decreasing SJC and TJC. Additionally, curcumin demonstrated greater effectiveness in reducing inflammatory markers. Quercetin was more effective in reducing VAS, and resveratrol was more effective in reducing DAS28. Patients with RA may benefit from these findings. Insightful information from this study is helpful for RA patients to consider using plant active substance therapies. For their efficacy and safety to be confirmed, more proof is needed.

Introduction: Colorectal cancer (CRC) represents the third most prevalent form of cancer worldwide, with liver metastasis representing a significant contributor to mortality. The interaction between tumor-associated macrophages (TAMs) and tumor cells plays a pivotal role in the development of colorectal cancer liver metastases (CRLM) and represents a promising avenue for therapeutic intervention. Stachydrine (STA), a compound derived from the Leonurus heterophyllus plant, has been shown to effectively inhibit tumor growth through a range of mechanisms.

Methods: The study employed imaging and histopathology to evaluate the efficacy of STA monotherapy in preventing CRLM. The inhibition of M2 macrophage polarization by STA was confirmed through the use of flow cytometry and immunofluorescence. Subsequently, a series of assays, including quantitative reverse transcription polymerase chain reaction (qRT-PCR), flow cytometry, scratch, invasion, and tube formation assays, were conducted to confirm STA's capacity to impede tumor cell migration, invasion, and angiogenesis in vitro. Western blotting and flow cytometry were employed to elucidate the mechanisms through which STA exerts its effects on tumor metastasis.

Results: In our research, STA has been shown to attenuate liver metastasis in CRC mouse models by inhibiting the polarization of macrophages to the M2 phenotype. This anti-metastatic effect is dependent on the presence of macrophages. In vitro, STA has been found to impede tumor cell migration, invasion, and angiogenesis by preventing TAMs from polarizing to the M2 phenotype via the JAK2/STAT3 signaling pathway. Moreover, the combination of STA with anti-PD-1 therapy has been observed to restore immune infiltration within the tumor microenvironment and inhibit tumor progression.

Conclusion: The findings of this study demonstrate that STA exerts an inhibitory effect on colorectal cancer liver metastasis by targeting macrophages and impeding their M2 polarization via the JAK2/STAT3 pathway. Furthermore, the combination of STA with anti-PD-1 therapy has been observed to enhance the effectiveness of immune checkpoint blockade and reduce tumor spread, indicating the potential of STA to improve the efficacy of immunotherapy for liver metastases.

Diabetic retinopathy is the main microvascular complication of diabetes and the first blinding eye disease in the working-age population. Oxidative stress is an important pathogenesis of diabetic retinopathy. Plant metabolites can be divided into two types: primary metabolites and secondary metabolites, secondary metabolites are the main active components and important sources for developing new drugs. It has unique effect in the treatment of diabetic retinopathy. However, the research on the intervention mechanism of plant metabolites in diabetic retinopathy are still relatively shallow, which limit the application of plant metabolites. With the deepening of research, more and more plant metabolites have been reported to play a role in treating diabetic retinopathy through anti-oxidative stress, including polyphenols, polysaccharides, saponins, alkaloids, etc. Therefore, this article reviewed the potential of plant metabolites in the treatment of diabetic retinopathy in the last 10 years and elucidated their mechanism of action. We hope to provide some references for the application of plant metabolites and provide valuable resources for the research and development of new drugs for diabetic retinopathy.

Background: Interstitial pneumonia is a group of pathologies affecting the pulmonary interstitium, characterized by interstitial fibrosis and extensive alveolar consolidation. This disease can extend to the surrounding blood vessels and pulmonary interstitium, sometimes affecting the entire lung, resulting in functional limitations, including restrictive ventilatory defect, impaired gas exchange, and hypoxemia. Severe interstitial pneumonia can lead to death. Antitumor drugs can induce interstitial pneumonia. Sintilimab is an immune checkpoint inhibitor, a recombinant fully human immunoglobulin G-type programmed death protein-1 monoclonal antibody inhibitor. S-1 is a compound preparation consisting of gimeracil, oteracil potassium, and ftorafur. There have been cases of interstitial pneumonia caused by treatment with sintilimab or S-1 in clinical settings, but no cases of interstitial pneumonia caused by treatment with a combination of sintilimab and S-1 have been reported.

Case report: A patient diagnosed with gastric cancer underwent nine courses of treatment using a chemotherapy regimen of combined oxaliplatin S-1., Due to severe bone marrow suppression and gastrointestinal adverse reactions, the treatment was switched to sintilimab in combination with S-1therapy., This change resulted in the development of interstitial pneumonia, as revealed by non-contrast chest Computed Tomography scans. Following a review of blood test results and a multidisciplinary consultation, we suspect that the interstitial pneumonia may have been caused either by Sintilimab alone or by the combined effects of sintilimab and S-1. The treatment was discontinued, and after receiving adequate glucocorticoid therapy, the pulmonary lesions showed slight improvement.

Conclusion: This case provides a clinical reference, indicating that prior touse of sintilimab in combination with S-1 antitumor regimen, a comprehensive baseline assessment should be conducted, including blood routine examination, enzyme tests, and pulmonary imaging examination, with close monitoring of the patient's pulmonary condition. If drug-induced lung injury is suspected, the medication should be discontinued immediately, and appropriate treatment should be initiated promptly.

Background: Antiparkinsonian medication has significantly evolved over the last 2 decades, offering various pharmacologic approaches. The aim of this study was to explore the trends and to determine the statistical significance of the observed changes in the antiparkinsonian medication utilization in Romania during 1998-2022.

Methods: This antiparkinsonian drug utilization study used data provided by CEGEDIM Romania, originating from the Pharma and Hospital Report. Quantitative data for each ATC N04 antiparkinsonian medication were converted to total defined daily doses (DDDs) and to DDD/1000inhabitants/day (DDD/TID). The autoregressive integrated moving average (ARIMA) model was employed to determine the statistical significance of the observed changes in the trends of antiparkinsonian drug use.

Results: The utilization of antiparkinsonian medication increased considerably (6-folds) in Romania during the 25 years, from 1.03 DDD/TID in 1998 to 6.22 DDD/TID in 2022. Starting 2005, dopamine precursor (levodopa) became the most used antiparkinsonian drug and remained on this position until the end of the study (13-fold increase from 0.17 in 1998 to 2.30 DDD/TID in 2022). MAO-B inhibitors represented the second most used antiparkinsonian drug class for the majority of the years. Selegiline was the most used until 2017 (0.82 DDD/TID), when a decrease in use was observed and continued until 2022 (0.49 DDD/TID). Utilization of dopamine agonists started in 1999, with less than 0.01 DDD/TID, and increased to 1.47 DDD/TID in 2022. Ropinirole was the most used dopamine agonist (0.56 DDD/TID in 2022). Anticholinergic agents represented the most used antiparkinsonian drugs until 2005. Trihexyphenidyl was the main anticholinergic prescribed with a maximum utilization of 0.82 DDD/TID in 2000 followed by a slight decrease until 2022 (0.56 DDD/TID). Amantadine utilization was mainly constant throughout the 25 years, with 0.32 DDD/TID prescribed in 2022. ARIMA analysis showed that the changes in antiparkinsonian drugs consumption were not statistically significant and overall, the trend for antiparkinsonian drug use demonstrates an upward trajectory.

Conclusion: Antiparkinsonian medication showed an increasing utilization trend in Romania during 1998-2022. Levodopa was the most used antiparkinsonian medicine after 2005, replacing anticholinergic agents. MAO-inhibitors utilization came in second and was followed by dopamine agonists. Observing the trend in antiparkinsonian medication utilization over time is essential for providing insights into their real-world use and uptake in a large population.

Background: Tubulin alpha 1b (TUBA1B) is a key microtubule protein essential for maintaining cellular structure and function. This protein contributes significantly to cytoskeletal formation and is implicated in various diseases. Despite its fundamental roles, TUBA1B's impact on tumor prognosis and the tumor immune microenvironment across cancer types remains inadequately understood. Methods To elucidate TUBA1B's role in cancer prognosis and immune response, we conducted a comprehensive analysis, integrating data from established databases such as The Cancer Genome Atlas, Genotype Tissue Expression, Cancer Cell Lineage Encyclopedia, Human Protein Atlas, Kaplan-Meier Plotter, cBioPortal, TIMER, and ImmuCellAI, along with a large-scale clinical study and immunotherapy cohort. We also conducted in vitro functional assays to assess TUBA1B's functional role in tumor cells, allowing for a detailed examination of its relationship with cancer prognosis and immune modulation. Results: Our findings indicate that TUBA1B expression is dysregulated across multiple cancers, correlating strongly with poor survival outcomes and advanced pathological stages. Functional enrichment analyses further revealed that TUBA1B regulates key cell cycle processes, driving tumor proliferation, migration, and invasion. It also influences immune functions within both the innate and adaptive immune systems, affecting immune-related signaling pathways. These insights underscore TUBA1B's multifaceted role in cancer progression and immune response. Conclusion: This study highlights TUBA1B's potential as a human oncogene with substantial roles in tumorigenesis and immune regulation. Elevated TUBA1B levels are associated with an immunosuppressive tumor microenvironment, impacting cancer progression and treatment outcomes. Targeting TUBA1B may offer promising therapeutic avenues for enhancing cancer treatment, offering new perspectives for innovative anti-tumor strategies with high clinical impact.

Background: In recent years, the incidence of alcoholic liver disease (ALD) has rapidly increased worldwide, becoming a significant health issue. Silibinin capsules have shown potential in treating ALD, but clinical evidence is still insufficient. This meta-analysis aimed to evaluate the efficacy and safety of Silibinin capsules in the treatment of ALD.

Methods: The study was registered with PROSPERO (CRD42024509676). Randomized controlled trials (RCTs) were included from six databases, covering the period from database inception to 30 December 2023. Primary outcomes included liver function indicators such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), total bilirubin (TBIL), lipid indicators including triglycerides (TG) and total cholesterol (TC), coagulation indicators including prothrombin time (PT), liver fibrosis indicator (PC-III), and Effective Rate. Analysis was performed using Review Manager 5.4.1 and STATA 14.0.

Results: In 15 RCTs involving 1,221 patients, compared to the non-Silibinin group, Silibinin capsules showed significant efficacy in terms of liver function, lipid levels, and effective rate in patients with ALD. Detailed parameters were as follows: ALT [SMD = -1.16, 95% CI (-1.84, -0.47)], AST [SMD = -1.56, 95% CI (-2.18, -0.95)], GGT [SMD = -1.48, 95% CI (-2.09, -0.87)], TBIL [SMD = -1.14, 95% CI (-2.16, -0.13)], TG [SMD = -1.29, 95% CI (-1.93, -0.66)], TC [SMD = -1.11, 95% CI (-1.61, -0.61)], PT [SMD = -0.01, 95% CI (-0.29, 0.26)], PC-III [SMD = -1.94, 95% CI (-3.04, -0.84)], and Effective Rate [OR = 3.60, 95% CI (2.28, 5.70)]. Importantly, Silibinin capsules exhibited a favorable safety profile, with only mild gastrointestinal reactions and reports of insomnia as adverse events.

Conclusion: This review reveals the clinical efficacy and safety of Silibinin capsules in the treatment of ALD, and confirms that the drug is an effective adjuvant therapy to alleviate ALD. At present, the mechanism of action of this drug for ALD is still unclear, and we expect more experimental studies to prove the clinical value of Silibinin capsules.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=509676.

Leptomeningeal disease (LMD) is a particular mode of central metastasis in malignant tumors. It occurs when tumor cells infiltrate the subarachnoid space and cerebrospinal fluid (CSF), spreading throughout the central nervous system (CNS). LMD is a rare but devastating complication of malignant tumors. It can occur in various types of cancers, with lung and breast cancer being the most frequently associated. The treatment approach for LMD includes a combination of supportive care, surgery, chemotherapy, radiotherapy, targeted therapy, immunotherapy, and intrathecal (IT) therapy, among other modalities. Despite the challenges in determining the optimal treatment for LMD, IT therapy remains one of the primary therapeutic strategies. This therapy can directly circumvent the blood-brain barrier. Moreover, a low-dose medication can achieve a higher drug concentration in the CSF, resulting in better cytotoxic effects. Chemotherapy drugs such as methotrexate, cytarabine, and thiotepa have been widely studied as traditional IT therapies. In recent years, the advent of novel anti-tumor drugs has led to a growing number of agents being employed for IT administration in the treatment of malignant tumors with LMD. This article presents a comprehensive review of the current advancements in IT administration of chemotherapy, targeted, and immunotherapy drugs for the treatment of LMD in solid tumors. In addition, we also discuss the safety issues associated with IT therapy, summarize the advantages of IT administration of different types of anti-tumor drugs, and put forward some suggestions for reducing adverse reactions. It is hoped that future research will focus on exploring more potentially effective anti-tumor drugs for IT treatment, conducting in-depth pharmacokinetic studies, and developing long-acting and low-toxic IT administration regimens for the treatment of meningeal metastases.