Frontiers in Pharmacology最新文献

Ethnopharmacological relevance: Eucommia ulmoides, recognized as a traditional Chinese medicinal herb, can tonify liver and kidney and strengthen bones and muscles. Modern pharmacological research has proved that E. ulmoides could prohibit the occurrence of osteoporosis and arthritis.

Aim: To investigate the effect and action mechanism of total flavonoids isolated from the leaves of E. ulmoides (TFEL) on bone loss in ovariectomized (OVX) rats, and to study its effect on intestinal flora.

Materials and methods: The 3-month-old female rats were randomly divided into six groups: sham operation group, OVX model group, estradiol group, TFEL low (TFEL-L) (50), mid (-M) (100) and high (-H) (200 mg/kg/d) dose groups. After 13 weeks of treatment, the rats were sacrificed to measure bone turnover markers, related tissue biochemical indices, microstructure parameters, and osteoclastogenesis promotor RANKL and inhibitor OPG expression levels. Additionally, fecal samples were obtained for high-throughput sequencing to analyze the intestinal flora.

Results: Oral administration of TFEL for 13 weeks increased the serum level of bone formation marker PINP and decreased the level of bone resorption marker NTX-I. The femoral microstructure parameters of the TFEL-M and TFEL-H groups were significantly improved compared with the OVX group, which were also confirmed by H&E histological staining. High-throughput sequencing indicated that TFEL may regulate the composition of intestinal flora and intestinal microecology.

Conclusion: TFEL can prevent osteoporosis in OVX rats and has no toxic side effects. Meanwhile, TFEL can increase the diversity and improve the composition of intestinal flora in OVX rats.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. Glycogen synthase kinase 3β (GSK-3β) plays a pivotal role in AD pathogenesis, particularly in tau protein hyperphosphorylation. Natural bioactive compounds have a wide range of sources, and medicinally valuable active compound can be extracted from plants, animals, and microorganisms. Currently, studies have found that various natural bioactive compounds from plants have the potential to improve AD symptoms, such as resveratrol and berberine. Therefore, this review examines the potential of natural bioactive compounds to modulate GSK-3β activity and inhibit the hyperphosphorylation of tau, offering a promising therapeutic strategy for AD. We summarize the current understanding of alkaloids, phenols, flavonoids, terpenoids and other natural compounds, highlighting their mechanisms of action and preclinical efficacy.

[This corrects the article DOI: 10.3389/fphar.2024.1440907.].

Purpose: Lappaol F (LAF), a lignan extracted from Fructus Arctii, has a wide spectrum of anti-tumor effects, including inhibition of TNBC cell growth. However, the pharmacological mechanism of LAF targeting epithelial-mesenchymal transition (EMT) to inhibit Triple-negative breast cancer (TNBC) growth remains poorly understood. The present study aimed to reveal the potential mechanism of LAF against TNBC by in vivo and in vitro experiments.

Methods: In situ, transplantation-induced MDA-MB-231 solid tumor model in NCG mice and cultured MDA-MB-231 and Hs-578T cells were used to evaluate the anti-TNBC effect of LAF. Flow cytometry, wound healing, transwell assay, western blot, RT-PCR, and immunofluorescence analysis were carried out to investigate the pharmacological mechanism of LAF against TNBC.

Results: LAF significantly inhibited the growth of MDA-MB-231 tumors, with downregulated tumor level of vimentin and upregulated level of ZO-1. In MDA-MB-231 and Hs-578T cells, LAF markedly suppressed cell proliferation, migration and invasion, and promoted apoptosis. Similarly, LAF increased the expression of ZO-1 and occludin proteins in MDA-MB-231 cells, and inhibited the expression of vimentin, snail and slug proteins in MDA-MB-231 and Hs-578T cells, as well as the expression of N-caderin in Hs-578T cells. Moreover, LAF also inhibited the phosphorylation of GSK-3β, thereby inhibited the downstream nuclear translocation of β-catenin and the expression of YAP. Furthermore, LAF significantly inhibited the expression of PI3K and AKT, and the phosphorylation of downstream mTOR.

Conclusion: LAF showed anti-TNBC effect both in vitro and in vivo. Reversal of EMT by inhibiting GSK-3β/YAP/β-catenin signaling and PI3K/AKT/mTOR signaling contributes to the effect.

Introduction: Generalized Anxiety Disorder (GAD) is a mental health condition with a recent increase in prevalence. GAD is often underdiagnosed, leading to negative consequences for individuals, healthcare systems, and society. The economic burden and impaired quality of life associated with GAD underscores the need for effective treatment. Pregabalin has shown promise in reducing anxiety symptoms; however, further research is needed to evaluate its efficacy and compare it with other treatment options. This study aimed to assess the efficacy, safety, and optimal pregabalin dosage for the treatment of GAD.

Methods: This meta-analysis followed PRISMA guidelines. Pregabalin-treated patients comprised the intervention group, whereas the comparator group received benzodiazepines, SSRIs, SNRIs, or placebo. Efficacy and safety were evaluated using various scales and adverse events (AEs). Randomized clinical trials were included in the study. Four major databases were used for this study. Outcome measures included the Hamilton Anxiety Rating Scale (HAM-A), Clinical Global Impression Improvement Scale (CGI-I), discontinuation rates, costs, and quality-adjusted life-years (QALYs). Meta-analyses were conducted using Review Manager 5.4 software, employing odds ratios (ORs) and mean differences (MDs) with 95% confidence intervals (CIs). Subgroup and sensitivity analyses were performed based on follow-up and dosage.

Results: Fourteen studies involving 4,822 patients were analyzed. Pregabalin demonstrated superior efficacy in reducing HAM-A global scores at 2 weeks (MD -1.23, 95% CI -1.79 to -0.66), 4 weeks (MD -1.12, 95% CI -1.60 to -0.63), 8 weeks (MD -2.50, 95% CI -4.21 to -0.79), 12 weeks (MD 0.99, 95% CI 0.35-1.63), and 6 months to 1 year (MD -3.31, 95% CI -4.30 to -2.31). Pregabalin also showed a higher response rate to HAM-A (OR 1.51, 95% CI 1.31 1.75). CGI-I scores favored pregabalin (MD -0.25, 95% CI -0.38 to -0.12), with a higher response rate (OR 1.33, 95% CI 1.15-1.55). The discontinuation rates were lower with pregabalin (OR 0.80, 95% CI 0.70, 0.91). Adverse events favored pregabalin over SSRIs/SNRIs and benzodiazepines at different doses. Pregabalin was associated with higher cost-effectiveness (MD 0.02, 95% CI 0.01, 0.03).

Conclusion: Pregabalin is an effective and well-tolerated treatment for generalized anxiety disorder, showing superior efficacy and safety compared with first-line medications.

Systematic review registration: PROSPERO CRD42024556152.

Overview: Cannabinoids have gained increasing attention for their therapeutic potential in treating several neurological conditions, including neurodegenerative diseases, chronic pain, and epilepsy. This review aims to assess the current clinical trials investigating cannabinoids, primarily Tetrahydrocannabinol and Cannabidiol, for neurological disorders. This review will aim to highlight the efficacy, safety, and outcome measures used in these trials.

Methods: Clinical trials were identified using ClinicalTrials.gov, focusing on studies that examined the effects of cannabinoids in treating neurological conditions. All trials that fulfilled the following criteria were included: Phase 1-4, focused on cannabinoids as primary intervention, and measured relevant outcomes such as pain relief, cognitive function, or spasticity reduction. Data on conditions, interventions, primary and secondary outcomes, and trial phases were extracted and analysed.

Results: A total of 47 clinical trials were identified, including different neurological conditions. The most frequently studied conditions were Multiple Sclerosis, Fibromyalgia, and Parkinson's Disease. Most trials were in Phase 2, with the primary outcome measures focused on pain management, spasticity, and cognitive function. Secondary outcomes included safety and tolerability measures.

Conclusion: The review highlights the broad therapeutic potential of cannabinoids in neurology, with promising results in symptom management for conditions like Multiple Sclerosis and Fibromyalgia. However, the lack of standardized study protocols, dosing, and outcome measures presents challenges for broader clinical implementation.

Systematic review registration: clinicatrials.gov.

Background: With the improvement of living standards, an increasing number of patients are presenting with mixed hyperlipidemia. In addition to cholesterol reduction, it is imperative to lower triglyceride levels. The combination of statin and fibrate for reducing lipid levels has commonly been applied in clinical therapy. However, the combination of drugs also increases the risk of adverse events (AEs). In this study, we analyzed the safety signals of rosuvastatin-fenofibrate combination by assessing the publicly available US Food and Drug Administration Adverse Event Reporting System (FAERS), so as to provide a reference for rational clinical use of rosuvastatin and fenofibrate, and reduce the occurrence of related AEs.

Methods: Reports to the FAERS from 1 January 2004 to 19 March 2020 were analyzed. The proportional report ratio (PRR), reporting odds ratio (ROR), and Bayesian Confidence Propagation Neural Network (BCPNN) analysis were used to extract data from FAERS for suspected signals referring to the combination of rosuvastatin and fenofibrate.

Results: A total of 68 safety signals were detected from the top 250 AEs in 3,587 reports, of which 28 signals were not included in the drug labels. All the detected AEs were associated with 12 System Organ Classes (SOC), such as gastrointestinal, musculoskeletal and connective tissue, general diseases, investigations and nervous system. The most frequent AEs were analyzed, and it was found that women generally have a higher susceptibility to experiencing AEs, including pain, nausea, fatigue, myalgia, diarrhea, dyspnea, headache, weakness, and dizziness.

Conclusion: Clinicians should pay more attention to the AEs of gastrointestinal and muscular system during combination therapy, and it is recommended to strengthen pharmaceutical care during clinical application.

Introduction: Conflict reports exist on the impact of pyrethroid insecticides on immune function and the probable underlying mechanisms.

Methods: This study evaluated the effect of an extensively used pyrethroid insecticide, fenpropathrin (FTN) (15 mg/kg b.wt), on the innate and humoral immune components, blood cells, splenic oxidative status, and mRNA expression of CD3, CD20, CD56, CD8, CD4, IL-6, TNF-α, and Caspase3 in a 60-day trial in rats. Besides, the possible defensive effect of curcumin-loaded chitosan nanoparticle (CML-CNP) (50 mg/kg b.wt) was evaluated.

Results: FTN exposure resulted in hypochromic normocytic anemia, thrombocytosis, leukocytosis, and lymphopenia. Besides, a significant reduction in IgG, not IgM, but increased C3 serum levels was evident in the FTN-exposed rats. Moreover, their splenic tissues displayed a substantial increase in the ROS, MDA, IL-6, and IL-1β content, altered splenic histology, and reduced GPX, GSH, and GSH/GSSG. Furthermore, a substantial upregulation of mRNA expression of splenic CD20, CD56, CD8, CD4, CD3, IL-6, and TNF-α, but downregulation of CD8 was detected in FTN-exposed rats. FTN exposure significantly upregulated splenic Caspase-3 and increased its immunohistochemical expression, along with elevated TNF-α immunoexpression. However, the alterations in immune function, splenic antioxidant status, blood cell populations, and immune-related gene expression were notably restored in the FTN + CML-CNP-treated group.

Conclusion: The findings of this study highlighted the immunosuppressive effects of FTN and suggested the involvement of many CD cell markers as a potential underlying mechanism. Additionally, the results demonstrated the effectiveness of CML-CNP in mitigating pollutant-induced immune disorders.