Frontiers in Pharmacology最新文献

Imidazolines are sympathomimetic drugs used to treat a range of conditions including nasal congestion, ocular disorders, and hypertension. Imidazolines were discovered over 150 years ago. However, it was research from the 1940s onwards which established the therapeutic benefits of imidazolines. Although there is extensive literature describing imidazolines, the history and timeline of their development is not well documented. This review focuses on the evolution of imidazoline pharmacology particularly those used in nasal decongestants, naphazoline, tetrahydrozoline, xylometazoline and oxymetazoline. These derivatives activate the α₁-and α₂-adrenergic receptors with varying degrees of selectivity, to provide decongestive relief through vasoconstriction. This reduces swelling of the nasal mucosa, delivering both subjective and objective relief from congestion. Each new imidazoline derivative has improved onset and duration of action, resulting in treatments with enhanced efficacy, tolerability, and safety. Although these advancements allow for less frequent dosing with comparable effects, the importance of correct usage for optimal benefit cannot be overstated. These nasal decongestants are considered safe when used as recommended however, rhinitis medicamentosa, characterized by chronic nasal congestion, can occur with excessive use. Imidazolines are an important class of compounds which have shown improvements in efficacy and safety over time. However, further improvements could be made with more advances in understanding their pharmacology.

Prediabetes is a significant risk factor for type 2 diabetes mellitus (T2DM). Emerging evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may modulate the gut microbiota and improve dysglycemia in T2DM. In this study, we investigated the effects of liraglutide on dysglycemia and gut microbiota in prediabetic mice. KKay mice were fed a high-fat diet to establish prediabetes. The prediabetic mice were then treated with a daily intraperitoneal injection of liraglutide for 12 weeks. 16S rDNA sequencing was employed to investigate alterations in the gut microbiota in prediabetic mice and liraglutide-treated prediabetic mice. The gut bacterial metabolites in the ileal contents of prediabetic mice were measured via a liquid chromatography‒mass spectrometry (LC‒MS) system. Prediabetic mice presented significantly increased body weights, blood glucose levels, and inflammatory factor levels and decreased GLP-1 levels. Liraglutide treatment improved dysglycemia and insulin secretion and inhibited systematic and tissue inflammation in prediabetic mice. Prediabetic mice presented pronounced increases in the abundance of f_Ruminococcaceae, g_Anaerotruncus, s_Anaerotruncus_sp_G3_2012, s_Ligilactobacillus_murinus, s_Desulfovibrio_fairfieldensis, g_Ligilactobacillus, g_Parabacteroides, g_Butyricimonas, and g_unclassified_Ruminococcaceae. Liraglutide treatment changed the intestinal microbiota composition and related signaling pathways. Our preliminary results demonstrate that GLP-1RA liraglutide exerts beneficial effects by improving dysglycemia and body weight, inhibiting inflammation, and modulating gut microbiota in prediabetic mice, potentially contributing to delaying or preventing the progression from prediabetes to overt diabetes.

Introduction: The widespread use of organophosphorus pesticides (OPs) in Chinese herbal medicines cultivation raises urgent concerns about residue contamination. Conventional detection methods [e.g., gas chromatography-mass spectrometry (GC-MS) and enzyme-linked immunosorbent assay (ELISA)] suffer from poor portability and instability of antibody inactivation in complex matrices, hindering on-site analysis.

Methods: This study proposed a novel "electrostatic adsorption-driven cascade reaction chain" strategy for rapid detection of acetylcholinesterase (AChE) activity and OPs. Leveraging the electrostatic self-assembly between a positively charged acetylcholine chloride (ACh, 26.47 ± 1.63 mV) and a negatively charged choline oxidase (CHO, -30.81 ± 1.85 mV), a nanoscale fluorescence sensor (CA-B NPs) was constructed by encapsulating the Azo-Bodipy 685. This design created a spatially confined and componentially co-localized nanoreactor that restricted substrate diffusion distance to the nanoscale and utilized a dual-enzyme cascade system (AChE-CHO) to yield a signal amplification effect.

Results: The obtained CA-B NPs exhibited excellent analytical performance, including: (1) a low detection limit of 4.1 ng/mL for triazophos; (2) high recovery of 88.13%-113.09% in complex Citrus reticulata Blanco matrices, along with strong anti-interference capabilities by organically dividing the reaction and detection sections; (3) a total assay time of only 20 min for real samples, suitable for rapid, on-site, high-throughput screening.

Discussion: This study not only embedded the entire reaction chain [AChE-CHO-hydrogen peroxide (H₂O₂)] into the sensor to improve space utilization efficiency and detection efficiency, but also established a novel paradigm for enzyme spatial organization based on electrostatic complementarity, providing new insights into the rational design of nanostructured multi-enzyme sensing platforms.

Introduction: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with limited therapeutic options and poor prognosis, highlighting the urgent need for novel targets and effective agents. PCID2 (PCI-domain containing protein 2) has recently been recognized as a potential therapeutic target; however, specific inhibitors remain unidentified. Natural products, particularly monomeric compounds derived from traditional Chinese medicine (TCM), provide an important source for novel anticancer candidates.

Methods: A molecular docking-based virtual screening of TCM-derived compounds were used to identify small molecules targeting PCID2. The binding interaction between the top candidate, 1,2,3,4,6-Penta-O-galloyl-β-D-glucose (β-PGG), and PCID2 was validated using surface plasmon resonance (SPR). The cytotoxicity and effects of β-PGG on HCC cell proliferation, migration, invasion, apoptosis, and cell cycle progression were evaluated in vitro. Exploratory analysis related to mechanisms were performed via Western blotting.

Results: β-PGG was identified as a promising PCID2-targeting compound by molecular docking, and SPR confirmed its direct binding to PCID2. β-PGG significantly reduced HCC cell proliferation, migration, and invasion, while inducing apoptosis and cell cycle arrest. Treatment with β-PGG impeded the G0/G1 or S phase to G2/M phase. Mechanistically, β-PGG decreased PCID2 expression and downregulated Cyclin D1 and CDK6. At higher concentrations, β-PGG also suppressed PI3K and Akt phosphorylation.

Discussion: β-PGG exhibits potent anti-HCC activity by modulating PCID2 expression, PI3K/Akt signaling, and cell cycle regulation, and it represents a promising lead compound with PCID2-targeting potential. This study not only support a rationale for further exploration of PCID2 as a therapeutic target in HCC but also provide valuable insights into the discovery of novel lead compounds from TCM for liver cancer treatment.

Background: Liu Shen Wan (LSW), a commercial Chinese polyherbal preparation (CCPP), is frequently utilized as an adjuvant treatment for herpes zoster and postherpetic neuralgia (HZ and PHN). Nevertheless, the clinical efficacy and safety of this treatment remain uncertain.

Purpose: This study aims to systematically evaluate the efficacy and safety of LSW as adjunctive treatment in treating HZ/PHN.

Methods: A comprehensive search was conducted across PubMed, Web of Science, Embase, Cochrane Library, ClinicalTrials.gov, and four Chinese databases. Eligibility criteria (PICOS) included the following: (1) patients with HZ/PHN; (2) LSW as adjunctive therapy (experimental group); (3) conventional treatment only (control group); (4) primary outcomes: vesicle cessation, scab formation, VAS, and PHN incidence; secondary outcomes: scab shedding time, time to pain resolution, duration of pain persistence, PHN efficacy, and adverse reactions; and (5) RCTs. Risk of bias was assessed using ROB 2.0, and data synthesis/analysis used RevMan 5.4. No restrictions on language.

Results: A total of 21 RCTs (n = 1,478) were included. Meta-analysis demonstrated that LSW plus conventional treatment significantly outperformed conventional treatment alone in shortening vesicle cessation time [MD = -1.44, 95% CI (-1.66, -0.93), p < 0.00001, I² = 70%], accelerating scab formation (MD = -1.72, 95% CI (-2.09, -1.35), p < 0.00001, I² = 38%), reducing scab shedding time (MD = -2.22, 95% CI (-3.64, -0.80), p = 0.002, I² = 36%), decreasing time to pain resolution (MD = -2.46, 95% CI (-3.52, -1.39), p < 0.00001, I² = 0%), and shortening pain persistence duration (MD = -1.97, 95% CI (-2.49, -1.46), p < 0.00001, I² = 86%). Additionally, the combination therapy reduced PHN incidence (RR = 0.24, 95% CI (0.10, 0.57), p = 0.001, I² = 0%), improved PHN efficacy (OR = 6.11, 95% CI (2.91, 12.82), p < 0.00001, I² = 61%), and lowered adverse reactions (RR = 0.60, 95% CI (0.37, 0.96), p = 0.03, I² = 0%). No serious drug-related adverse events were reported.

Conclusion: Adjunctive LSW therapy demonstrates potential to shorten herpes lesion healing time, improve treatment outcomes, and effectively prevent postherpetic neuralgia compared to conventional treatment alone. It also significantly reduces both the duration of pain and the overall disease course. Nevertheless, limitations in the current evidence base, including study quality and quantity, necessitate further rigorous investigation to confirm the long-term efficacy and safety profile of this combined intervention.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/, identifier CRD42024595203.

Background: Plant-derived active substances are increasingly recognized as potential adjuvant therapies in breast cancer treatment, with emerging evidence suggesting their positive impact on both treatment outcomes and quality of life (QoL). This study aims to evaluate the effects of fifteen active substances-soy capsules, Helixor A, Viscum album [L.] extracts, Withania somnifera, Paullinia cupana, P. ovata husk, ginseng, curcumin, Jollab, ginger, fermented soybean extract, mistletoe extract, robuvit®, peppermint extract, and Chlorella extract-on QoL in patients with breast cancer (BC).

Methods: A comprehensive literature search was performed across PubMed, EMBASE, Cochrane Library, and Web of Science up to January 2025. The primary outcomes of interest included QoL, fatigue, pain, physical functioning, nausea, and role and emotional functioning. Statistical analyses were carried out using StataMP 15.1 software. Treatment efficacy was assessed using Surface Under the Cumulative Ranking Curve (SUCRA) probabilities. Additionally, cluster analysis was conducted to examine the multidimensional effects of natural extracts across these seven clinical outcomes.

Results: After screening, 18 eligible studies were included, encompassing 2062 patients and evaluating 15 substances. The analysis incorporated patient-reported outcomes from multiple trials: QoL (11 studies), fatigue (10 studies), pain (8 studies), physical functioning (8 studies), nausea (7 studies), role functioning (7 studies), and emotional functioning (7 studies). Based on SUCRA values, Withania somnifera was identified as the most effective treatment for enhancing QoL (99.4%) (SMD = 4.66, 95% CI: 3.47-5.85), physical functioning (100.0%) (SMD = 7.78, 95% CI: 6.61-8.96), role functioning (100.0%) (SMD = 8.10, 95% CI: 6.89-9.32), and emotional functioning (100.0%) (SMD = 5.71, 95% CI: 4.81 to 6.61) were more effective than the standard treatment. Moreover, Withania somnifera was found to be the most promising option for reducing fatigue (99.9%), pain (100.0%), and nausea (98.6%).

Conclusion: The network meta-analysis indicates that Withania somnifera was effective in enhancing quality of life and contributed to a reduction in therapeutic side effects in BC patients. Our findings support the therapeutic potential of plant bioactive substances in breast cancer care; however, further clinical validation of their efficacy is warranted.

Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD420251006422.

Introduction: Diabetic nephropathy (DN) is a major complication of diabetes, with renal fibrosis leading to progressive renal function decline. Understanding interventions for renal injury and fibrosis in DN is vital, and given its complex pathogenesis, new therapeutic agents are urgently needed.

Methods: The DN model was established using db/db mice, which received balanophora polysaccharide (BPS) treatment. The therapeutic efficacy of BPS for DN was evaluated by measuring body weight, fasting blood glucose (FBG), lipid profiles, renal function parameters, serum inflammatory factors, and histopathological changes. Furthermore, the underlying mechanisms by which BPS exerted its therapeutic effects were investigated using transmission electron microscopy (TEM), immunohistochemistry (IHC), immunofluorescence (IF), and Western blotting.

Results: BPS significantly reduced body weight, as well as fasting blood glucose (FBG) and lipid levels in db/db mice. Additionally, it improved renal function and effectively alleviated renal injury. Moreover, BPS decreased the expression of extracellular matrix (ECM) proteins and inhibited ECM deposition, thereby alleviating the progression of renal fibrosis in DN and reducing cell apoptosis. Notably, BPS effectively inhibited the activity of NLRP3 inflammasome in the renal tissue of db/db mice, which in turn mitigated renal inflammatory response and fibrosis.

Conclusion: BPS can improve renal injury and renal fibrosis in db/db diabetic nephropathy mice, which may be related to the decrease of apoptosis, inhibition of inflammation, reduction of ECM, and regulation of NLRP3 inflammasome. This study provides a scientific basis for the clinical application of BPS in the treatment of renal fibrosis in DN and is expected to promote the drug development and clinical application of BPS.

Background: The treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has shifted from androgen deprivation therapy (ADT) alone to doublet or triplet regimens building on ADT. However, the cost-effectiveness analysis of first-line treatments for mHSPC in China is uncertain. This study aims to perform a 10-year horizon health economic evaluation to comparatively analyze the cost-effectiveness of eight treatment regimens for mHSPC from the perspective of China's healthcare system, including (1) ADT alone and ADT plus one of the following: (2) docetaxel, (3) abiraterone, (4) apalutamide, (5) enzalutamide, (6) rezvilutamide, (7) darolutamide and docetaxel, (8) abiraterone and docetaxel.

Methods: Partitioned survival model was developed to evaluate the cost-effectiveness of eight first-line treatment regimens for mHSPC. Drug costs were primarily extracted from pharmaceutical databases. The key outcomes were quality adjusted life years (QALYs), costs and the incremental cost-effectiveness ratio (ICER). Willingness-to-pay (WTP) threshold was set as three-time China's gross domestic product (GDP) per capita (US$38,024) per QALY.

Results: For costs, the 10-year cost estimates ranged from US$120,844 for ADT alone to US$216,294 for darolutamide plus ADT with docetaxel. For clinical effectiveness, enzalutamide plus ADT yielded the highest QALYs (4.55), while ADT alone gained lowest QALYs (3.01). For cost-effectiveness, the three treatment regimens of ADT alone, abiraterone plus ADT and enzalutamide plus ADT constituted the cost-effectiveness frontier. Abiraterone plus ADT emerged as the most cost-effective strategy, indicative of an ICER of US$17437.16 per QALY, substantially below WTP threshold.

Conclusion: Abiraterone plus ADT was likely to be cost-effective for mHSPC treatment at a WTP threshold of three-time per capita GDP per QALY.

Introduction: Research suggests kappa-opioid receptors (KORs) modulate drug use and stress-related behaviors. While some findings indicate KORs could influence initial susceptibility to opioid use disorder (OUD), few studies have examined whether variations in the gene encoding the receptor (OPRK1) relate to clinically-relevant behavioral variation among current opioid users. This study examined whether OPRK1 polymorphisms predicted opioid-abstinence phenotypes in three separate but conceptually-linked aims: (1) retrospective self-report of number of lifetime heroin-quit attempts at screening, (2) prospective assessment of opioid-abstinence initiation during a two-week buprenorphine (8 mg/day sublingual) outpatient stabilization period, and (3) prospective assessment of opioid lapse during a three-week buprenorphine dose-tapering outpatient period (4-mg/day, 2-mg/day and 0-mg/day during weeks 1-3, respectively).

Methods: OPRK1 genotype and opioid-abstinence phenotype data (urinalysis and self-report) were obtained from current regular heroin users. Genotype-phenotype analyses controlled for self-identified race and heroin-use duration.

Results: OPRK1 rs7817710 (intron) T/T homozygotes (n = 145) reported significantly more heroin-quit attempts than G/T heterozygotes (n = 86) or G/G-homozygotes (n = 35). During outpatient buprenorphine stabilization, OPRK1 rs6989250 (intron) C/C homozygotes (n = 43) provided a significantly lower proportion of opioid-free urine samples than G-allele carriers (n = 7). During buprenorphine dose tapering, OPRK1 rs3802281 (3'UTR) C-allele carriers (n = 21) and rs7817710 G-allele carriers (n = 11) lapsed to opioid use significantly more slowly than T/T homozygotes at either locus (n = 17 and n = 16, respectively). The rs3802281-rs7817710 haplotype block was associated with Experiment 1 binary phenotypes.

Conclusion: These findings implicate OPRK1 genetic variation in several opioid-abstinence phenotypes. These results, if replicated, could improve understanding of the course and treatment of OUD.

Background: Pulmonary fibrosis (PF) is a life-threatening lung disease. PF develops under the influence of various damaging agents. To study new therapeutic strategies, a PF model with intratracheal administration of bleomycin (BLM) is used.

Methods: We studied the effect of different doses of BLM. The study was performed on male SD rats. BLM was administrated at doses of 0.5, 1.5, 2.5, 3, and 5 mg/kg. Animals were observed for 21 days for the following parameters: the overall health status, body weight gain, and external respiratory function. On the 22nd day, the lung weight, cellular composition of the bronchoalveolar fluid (BALF), and hydroxyproline content were determined, and the degree of lung fibrosis was histologically assessed.

Results: With an increase in the BLM dose, the overall health status deteriorates, the function of external respiration worsens, BALF neutrophilic infiltration increases, and PF severity increases. The least marked PF manifestations were observed after the administration of BLM at a dose of 0.5 mg/kg, and the most marked manifestations were observed after the administration of BLM at a dose of 5 mg/kg.

Conclusion: Results obtained in the study demonstrate a dose-dependent effect of BLM on the PF severity, which provides information that will help select BLM dose suitable for obtaining desired degree of PF in animal models.