Frontiers in Pharmacology最新文献

Background: The regenerative repair following peripheral nerve injury is a complex pathophysiological process in which the immune regulatory network plays a crucial role. Conventional understanding posits that inflammatory responses impede nerve regeneration; however, recent studies reveal that immune reactions constitute a "double-edged sword": a well-timed and moderate inflammatory response is essential for initiating regeneration, whereas excessive or persistent inflammation deteriorates the regenerative microenvironment and hampers repair. This review systematically elaborates the dynamic responses of the innate and adaptive immune systems after peripheral nerve injury. We focus particularly on the phenotypic switch of macrophages from the pro-inflammatory M1 to the anti-inflammatory/reparative M2 type, the early debris-clearing function of neutrophils, the interactions between T lymphocytes and Schwann cells, as well as the intricate signaling networks formed by cytokines and chemokines. The article delves into how these immune cells and factors precisely regulate key processes in Schwann cells-such as dedifferentiation, proliferation, migration, and myelination-thereby influencing axonal regeneration and functional recovery. Finally, this review prospects the translational potential of optimizing the immune microenvironment by targeting specific immune cells or signaling pathways for treating peripheral nerve injuries. Deciphering these delicate immune regulatory mechanisms will provide a critical theoretical foundation for developing novel immunomodulatory strategies to enhance nerve regeneration.

Summary: In this review, we outline current understanding of the immune mechanisms underlying peripheral nerve regeneration, spanning from established paradigms to emerging therapeutic approaches, such as targeted immunomodulation, biomaterial-assisted microenvironment reshaping, and adoptive immune cell therapy, all of which represent promising avenues for improving functional recovery after nerve injury.

Key messages: The integration of immunology and nerve regeneration research is opening new frontiers for treatment. Harnessing the regenerative potential of the immune system while restraining its detrimental effects-through approaches such as precision modulation of macrophage polarization, neutrophil extracellular trap regulation, and T cell-Schwann cell crosstalk targeting-offers encouraging prospects for overcoming the current challenges in peripheral nerve repair.

Objective: To evaluate outcomes of different doses of esketamine in postoperative patient-controlled intravenous analgesia (PCIA) combined with preoperative intercostal nerve block (ICNB) analgesia protocol for acute postoperative pain (APP) relief in patients undergoing thoracoscopic lobectomy.

Materials and methods: A total of 360 patients scheduled for thoracoscopic lobectomy at Xuzhou Central Hospital between October 2021 and July 2023 were enrolled and randomly assigned into three groups using the random envelope method. Before anesthesia induction, all patients received ICNB, followed by general anesthesia. Group C received PCIA using sufentanil at 0.03 μg/kg/h, Group K1 received a low dose of esketamine at 0.015 mg/kg/h in PCIA, and Group K2 received a moderate dose of esketamine at 0.03 mg/kg/h in PCIA. Numerical Rating Scale (NRS) pain scores were recorded at 2, 4, 24, 48, and 72 h postoperatively. The incidence of APP within 72 h post-surgery, the requirement for rescue analgesia and the occurrence of adverse reactions, were assessed and recorded for the three groups.

Results: There were significantly lower NRS scores in Group K2 at 2, 4, 24, 48, and 72 h postoperatively, compared to Groups C and K1 (P < 0.01). However, there were no statistically significant differences in NRS scores between Group C and Group K1 (P > 0.05). The incidence of APP within 72 h postoperatively was significantly lower in Group K2, compared to Group C and Group K1 (P < 0.05). Additionally, Group C exhibited a significantly higher the incidence of postoperative nausea and vomiting (PONV) than the other two groups (P < 0.05). Group K2 demonstrated superior postoperative analgesic efficacy, including reduced rescue analgesia needs and lower opioid consumption, without affecting hospital stay length compared to Groups C and K1.

Conclusion: A dose of 0.03 mg/kg/h esketamine in PCIA combined with preoperative ICNB significantly alleviates APP in patients undergoing thoracoscopic lobectomy, reducing resting pain scores by approximately 30% at 24 h compared to sufentanil-based analgesia.

Clinical trial registration: https://www.chictr.org.cn/, Identifier ChiCTR2100051000.

Objective: This study aimed to assess national trends in prescription volumes, drug expenditures, and the pharmacoeconomic rationality of small-molecule targeted inhibitors used for lymphoma treatment among outpatients in China between 2016 and 2022.

Methods: Outpatient prescription data for patients diagnosed with lymphoma were obtained from the Hospital Prescription Analysis Cooperative Project database, which includes 77 hospitals distributed across six major regions of China. Annual trends in prescription volume and corresponding drug expenditures were examined. Pharmacoeconomic indicators associated with small-molecule targeted inhibitors were further analyzed to evaluate their cost-effectiveness and utilization patterns. Patient demographic characteristics, regional distribution, and categories of small-molecule targeted inhibitors were also analyzed.

Results: Prescription volumes and amounts for small-molecule targeted inhibitors in lymphoma treatment have increased annually. Furthermore, their use is supported by pharmacoeconomic evidence indicating rational and efficient medication utilization. There was a statistically significant increase in total prescriptions (P ₁ < 0.005) and overall medication expenditures (P ₂ < 0.005).

Conclusion: Between 2016 and 2022, the prescription volume of small-molecule targeted inhibitors for lymphoma increased annually, indicating their expanding clinical use. Since 2020, despite continued growth in prescriptions, drug costs have risen at a slower rate than prescriptions. This reflects that medical insurance negotiation and centralized procurement policies have effectively reduced economic burden without limiting their access to these inhibitors. Pharmacoeconomic indicators also confirm that the use of these drugs has been both reasonable and efficient, allowing for increased drug utilization while reducing financial strain.

Background: Many factors, such as lifestyle, medication, and environmental exposures, are reported to cause thyroid hormone system disruption (THSD) in humans, however studies linking THSD to health effects are sparse. Adverse Outcome Pathways (AOPs) provide mechanistic links from molecular events to adverse outcomes, with effect biomarkers serving as a tool to empirically anchor key events and health effects and to assess biological relevance.

Aim: This review aims to identify and evaluate effect biomarkers for thyroid hormone system-related AOPs for further validation in experimental and epidemiological studies.

Methods: Using AOP-wiki, we extracted and analysed thyroid-related AOPs, focusing on the eleven AOPs with mammalian evidence. We did systematic literature search to identify potential effect biomarkers for future epidemiological studies.

Results: In an AOP network analysis of the eleven thyroid-related AOPs, we identified four AOP clusters, including hippocampal alterations, impaired learning and memory, thyroid follicular cell adenomas/carcinomas, and kidney toxicity. For the clusters on hippocampal alterations and impaired learning and memory, brain-derived neurotrophic factor emerged as a promising effect biomarker. For the cluster on thyroid follicular cell adenomas/carcinomas, no promising effect biomarkers with high specificity were identified, but interleukin-34, oxidative stress, and expression of several genes were found to be related to the adverse outcome. For kidney toxicity, a panel of effect biomarkers were identified, such as clusterin, cystatin-C, kidney injury molecule-1, N-acetyl-beta-d-glucosaminidase, neutrophil gelatinase-associated lipocalin, and osteopontin.

Conclusion: This review operationalizes the AOP framework to support the use of mechanistically anchored effect biomarkers in human studies on THSD. By aligning key biological events with measurable endpoints, human matrices, and feasibility considerations, it provides a scientifically grounded path from mechanistic understanding to population research application. This enables more targeted biomonitoring, strengthens interpretation of epidemiological findings, and informs research and regulatory priorities for future validation efforts.

[This corrects the article DOI: 10.3389/fphar.2022.883057.].

Background: The leaves of Otostegia fruticosa have been used in traditional medical systems to treat diarrhea and gut spasms. In this study, we evaluate the possible gut inhibitory roles of the crude extract of O. fruticosa using mice for in vivo, rabbits for ex vivo, and selected enteric pathogenic bacteria for in vitro assays.

Methods: Castor-oil-induced diarrhea was used to assess the diarrheal protection of the extract in mice, while CaCl₂-induced excitatory concentration-response curves (CRCs) and isoprenaline-induced inhibitory CRCs were constructed for isolated rabbit intestines to explore Ca⁺⁺ channel blockade and phosphodiesterase (PDE) inhibitory-like pathways, respectively. Moreover, the antibacterial activity of the extract was tested against selected bacteria.

Results: The extract protected mice from castor-oil-mediated diarrhea significantly compared to the saline control group at doses of 200 and 400 mg/kg. In the isolated jejunum, the extract inhibited both spontaneous and high K⁺-depolarized contractions at comparable concentrations in a dose-dependent manner (0.01-1 mg/mL) similar to papaverine, which is a dual inhibitor of the PDE enzymes and L-type Ca⁺⁺ channels. The indirect functionality of the papaverine-like dual inhibitory actions of the extract was confirmed when pretreatment with the crude extract displaced the Ca⁺⁺ excitatory CRCs to the right with suppression of the maximum response, similar to verapamil; moreover, the PDE inhibitory effect was authenticated by a leftward shift in the isoprenaline-induced inhibitory CRCs. The extract showed bactericidal activity with a resultant minimum inhibitory concentration (MIC) of 550 μg/mL against Escherichia coli, Shigella sonnei, and Salmonella typhimurium, whereas the extended-spectrum β-lactamase-producing E. coli strain was found to be sensitive to a higher concentration of the extract (MIC of 675 μg/mL).

Conclusion: The present study is a pilot report on the detailed pharmacodynamics of the antispasmodic effects of the crude extract of O. fruticosa, with possible dual inhibition of the Ca⁺⁺ channels and PDE-like effects, which provides a sound basis for its medicinal usage in hyperactive gut disorders. The O. fruticosa extract was further demonstrated to be effective against both enteric and non-enteric pathogens, which might support its use in the treatment of infectious diarrhea.

Purpose: This study aimed to systematically evaluate the pharmacokinetics, bioequivalence, and safety of a single postprandial oral dose of testosterone undecanoate (TU) and its originator drug Andriol Testocaps^® in healthy postmenopausal Chinese women, providing theoretical support for optimizing hormone replacement therapy protocols.

Methods: A randomized, open-label, two-treatment, four-period, single-center, single-dose crossover clinical trial was conducted at Xinxiang Central Hospital. Participants received single oral doses of 40 mg TU or Andriol Testocaps^® in each period. Serial blood samples were collected from 0 to 24 h post-dose.

Results: The average adjusted geometric mean ratios (GMR) (90% CI) for the primary PK parameters C_max, AUC_0-t, and ${\text{AUC}}_{0-\infty }$ were 102.20% (90.32%-115.63%), 99.85% (92.82%-107.41%), and 99.79% (92.90%-107.20%). All 90% CI for C_max, AUC_0-t, and ${\text{AUC}}_{0-\infty }$ fell within the 80%-125% bioequivalence range. The two drugs showed comparable results for the other PK parameters. These results indicate that the two drugs were bioequivalent.

Conclusion: TU demonstrated bioequivalence to Andriol Testocaps^® under fed conditions in Chinese healthy participants, with comparable safety and tolerability profiles. These results advocate the clinical application of generic TU as a potential alternative to originator drug Andriol Testocaps^® in the treatment.

Introduction: Revstone®, a polyherbal formulation available in capsule and syrup forms, is designed to treat kidney-related disorders. However, its renoprotective efficacy remains insufficiently validated. In this study, we aimed to evaluate and compare the renoprotective potential of Revstone® capsule and syrup formylations in Wistar rats.

Objective: The aim of this study was to assess the acute toxicity profile of Revstone® capsule and syrup following Organisation for Economic Co-operation and Development (OECD) guidelines and compare their efficacy in reversing renal damage based on biochemical, histological, and functional markers.

Methodology: Acute oral toxicity testing was conducted according to the OECD 423 guidelines, and rats were observed for 14 days for mortality, behavioural and clinical changes, body weight variations, and gross necropsy findings. For efficacy evaluation, nephrotoxicity was induced by gentamicin (80 mg/kg i.p. for 7 days). Rats were divided into seven groups, namely, the normal control, disease control, Revstone® syrup (low and high dose), Revstone® capsule (low and high dose), and standard drug control (valsartan 10 mg/kg). Renal function was assessed from serum creatinine, blood urea nitrogen, and uric acid levels. Oxidative stress markers such as malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) were measured, and histopathological evaluation of kidney tissue was performed. Data were analysed using one-way ANOVA followed by Tukey's post hoc test (p < 0.05).

Results: Gentamicin significantly elevated renal markers (p < 0.001). Revstone® syrup at high dose markedly reduced creatinine (p < 0.001), while both formulations improved oxidative stress and renal histology. The syrup formulation was more effective, indicating its potential for future clinical application.

Conclusion: Revstone® capsule and syrup demonstrated significant renoprotective activities in gentamicin-induced nephrotoxicity in rats.

Gastric cancer has become one of the most common cancers globally. Sapodilla or known as Manilkara zapota (L.) P. Royen, has been traditionally applied for cough, cold, and diarrhea. The detailed mechanisms in modulating sapodilla leaf 70% ethanol extract against HGT-1 human gastric cancer cell line have yet to be fully studied. Apoptosis induction was evaluated using an Annexin V-FITC/PI staining kit with flow cytometry. Caspase-3 and -8 expression were determined by colorimetric analysis. To explore the molecular mechanisms of action of the 70% ethanol extract of sapodilla leaves in HGT-1 cells, quantitative real-time PCR (qPCR) was performed. Overall analyses demonstrated that sapodilla leaf 70% ethanol extract was cytotoxic and suppressed the growth of HGT-1 cells. The 70% ethanol extract of sapodilla leaves significantly suppressed the proliferation of HGT-1 cells. Moreover, it enhanced the expression of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), while concurrently suppressing the transcriptional activities of nuclear factor-kappa B (NF-κB) and inducible nitric oxide synthase (iNOS). Results indicate that sapodilla leaf 70% ethanol extract has an anti-gastric cancer effect via modulation of multiple signaling pathways. Sapodilla leaf 70% ethanol extract demonstrates promising potential as an anti-gastric cancer agent.

Bisphosphonates (BPs), widely used anti-resorptive agents for osteoporosis and cancer-related bone metastasis, can paradoxically contribute to medication-related osteonecrosis of the jaw (MRONJ). Our previous work showed that periodontal ligament stem cells (PDLSCs) from MRONJ patients display severely impaired osteogenesis; however, how BPs directly regulate PDLSC function remains unclear. In this study, human PDLSCs were exposed to graded concentrations of zoledronate (ZOL, 0.01-10 μM) to characterize dose-dependent effects on cell viability, apoptosis, and osteogenic differentiation. High-dose ZOL markedly reduced proliferation, induced apoptosis, and strongly inhibited osteogenesis. In contrast, low-dose ZOL promoted osteogenic differentiation in vitro, enhanced mineralization, and increased ectopic bone formation in vivo. Transcriptomic and molecular analyses revealed that ZOL activated Wnt/β-catenin and MAPK signaling, and blockade of either pathway attenuated the osteogenic enhancement. These findings demonstrate a double-edged-sword effect of BPs on PDLSCs: low-dose ZOL enhances osteogenesis through coordinated activation of Wnt/β-catenin and MAPK pathways, whereas high-dose exposure is cytotoxic and suppresses regenerative potential. The results underscore the necessity of precise BP dose control to maximize periodontal regeneration while minimizing MRONJ risk.