Frontiers in Pharmacology最新文献

Objective: Silicosis is characterized by silicon nodules and diffuse pulmonary fibrosis. To date, no effective therapy has been developed for the treatment of silicosis. This study aimed to investigate the effects of Galunisertib, a TGF-β receptor I kinase inhibitor, on the autophagy-lysosome system and pulmonary fibrosis in a SiO₂-induced silicotic mouse model and cells.

Methods: We established a silica-induced pulmonary fibrosis mouse and cell model. The MTT assay was used to determine the processing time and dose of cell experiments. Cell scratch assays were used to explore the effect of Galunisertib on the proliferation and migration ability of silica-stimulated fibroblasts. Cell migration was evaluated through wound healing, and the interactions between TGF-β and TRAF6/Beclin1 were verified by molecular docking and co-immunoprecipitation (Co-IP). WB and qPCR were used to detect the protein and transcription levels of TGF-β, Col-I, and α-SMA in each group, as well as the expression levels of autophagy-related protein LC3II/I, autophagy substrate protein p62, lysosome-associated membrane protein LAMP2, and pathway-related proteins TGF-β, TRAF6, and Beclin1. WB was also used to detect the expression level of apoptosis-related protein Cleaved-caspase 3 in the lung tissues and cells of mice in each group.

Results: We found that Galunisertib has good anti-fibrosis activity both in vitro and in vivo. A 4-week Galunisertib treatment markedly ameliorated inflammation and fibrosis. Moreover, the results revealed that Galunisertib inhibited the expression of TGF-β, downregulated the major fibrotic protein expression of collagen I and a-smooth muscle actin (α-SMA), thereby switching the progression of fibroblast-to-myofibroblast transition (FMT). Furthermore, Evidence from Co-IP and molecular docking assays confirmed that this inhibition also involves the suppression of TRAF6 and Beclin1. Therefore, Galunisertib administration significantly altered the protein levels of LC3 and p62, implying that the autophagy-lysosome system might be involved in pulmonary fibrosis.

Conclusion: These findings indicate that Galunisertib can modulate autophagy in pulmonary tissues of silicotic mice and fibroblast cells by suppressing the TGF-β/TRAF6/Beclin1 signaling pathway. On the other hand, Galunisertib regulates autophagy and inhibits the activation, proliferation and migration of Silica-stimulated fibroblasts, alleviating fibrosis in silicosis mice. Altogether, Galunisertib may be a potential candidate drug for preventing pulmonary fibrosis.

Objectives: Opioid Use Disorder (OUD) is a chronic medical crisis which represents significant public health challenge on global scale. We aim to provide long-term trends and future projections of OUD for effective intervention.

Methods: This study utilized data from the Global Burden of Disease (GBD) study 2021 for analysis. OUD burden was assessed using absolute numbers and age-standardized rates of incidence (ASIR), prevalence (ASPR), disability-adjusted life years (ASDR), and mortality (ASMR) per 100,000 population, with 95% uncertainty intervals (UIs). Temporal trends were analyzed using joinpoint regression. Age-period-cohort (APC) models were applied to assess the independent effects of age, time period, and birth cohort on OUD burden. Decomposition analysis quantified the relative contributions of population growth, aging, and epidemiological changes to the overall burden variation. Finally, autoregressive integrated moving average (ARIMA) models were used to forecast OUD burden through 2030.

Results: In 2021, an estimated 1.94 million new cases and 16.16 million prevalent cases of OUD were recorded globally, resulting in 11.22 million DALYs and nearly 99,556 deaths. The number of incidence, prevalence, DALYs and mortality of OUD all showed substantial increases. The age-standardized rates also increased but the margins were relatively small. The highest levels and fastest growth were observed in high-SDI regions, particularly North America. Males consistently exhibited higher DALY and mortality rates than females. The burden was greatest among individuals aged 15-49 years. Joinpoint analysis revealed fluctuating trends with notable increases after 2010. APC analysis showed peak incidence at ages 20-25 and declining risk in later birth cohorts. Decomposition analysis indicated that population growth and epidemiological changes were the main contributors to the rising burden. ARIMA forecasting predicted continued increases in incidence and DALYs but slight declines in prevalence and mortality by 2030.

Conclusion: The global burden of opioid use disorder (OUD) has continued to rise since 1990, mainly driven by population growth and epidemiological changes. Although age-standardized rates have remained stable or increased slightly, regional disparities persist, with the highest burden in high-SDI areas. Forecasts suggest modest increases in incidence and DALYs by 2030, underscoring the need for sustained, adaptive policies and preventive strategies to mitigate the evolving opioid crisis.

Introduction: Genetic polymorphisms in CYP2D6 and CYP2C19 significantly influence the metabolism, efficacy, and safety of antidepressant medications. Limited data exist on the prevalence of these actionable pharmacogenetic variants in the Central Indian population. This study aimed to determine the frequency of clinically actionable Tier-1 alleles, genotypes, and metabolizer phenotypes and to evaluate their clinical relevance in patients with common mental disorders (CMDs).

Methods: A total of 509 adults diagnosed with depression and anxiety disorders and receiving SSRI & SNRI antidepressant therapy were enrolled from the Department of Psychiatry, AIIMS Bhopal. Genotyping was performed using the KASP qPCR assay, and CYP2D6 copy number variations (CNVs) were determined using the TaqMan qPCR assay.

Results: Among the Central Indian cohort, the most frequent CYP2D6 alleles were *10 (21.6%), *41 (17.3%), and *4 (10.4%), while *3 (5.7%), *6 (1.9%). CNVs, Gene deletions(*5) and Gene duplications(xN) were detected in 4.2% and 4.1% of the cohort. For CYP2C19, the *2 (37.3%), *3 (2.3%), and *17 (16.1%) alleles were observed. Non-normal metabolizer phenotypes were present in 46.2% for CYP2D6 and 74.2% for CYP2C19; CYP2D6 ultra-rapid metabolizers accounted for 5.3%. Overall, 86% of participants had at least one clinically actionable pharmacogenetic phenotype. Overall, 7.5% of patients carried CYP2D6 variants and 20.6% carried CYP2C19 variants, for which CPIC guidelines recommend alternative drug selection or dose modification.

Discussion: This study demonstrates a high prevalence of actionable CYP2D6 and CYP2C19 variants in the Central Indian population, underscoring the need for pharmacogenetic integration in psychiatric prescribing in Indian clinical settings, to enhance treatment efficacy and minimize adverse events.

Background: Inflammatory bowel disease (IBD) is a multifactorial disorder characterized by aberrant immune activation and metabolic dysregulation. Despite significant advances in understanding immune mechanisms, the temporal dynamics of metabolic alterations during intestinal inflammation and their therapeutic implications remain poorly defined.

Methods: To investigate metabolic reprogramming during colitis progression, we conducted time-resolved metabolomic profiling of the colon, mesenteric lymph nodes (MLNs), and serum in a dextran sulfate sodium (DSS)-induced murine colitis model at days 1, 3, 5, and 7 post-induction. Targeted and untargeted metabolomic analyses were integrated with pathological and immunological assessments. To assess therapeutic relevance, DSS-treated mice were administered either trigonelline, a metabolite identified in serum, or mycophenolic acid (MPA), a purine metabolism inhibitor, separately. Metabolomic profiling revealed a progressive activation of purine metabolism in colonic tissues and MLNs, correlating with enhanced immune-inflammatory responses.

Results: Trigonelline was identified as a serum biomarker positively associated with disease severity. Therapeutic treatment with either trigonelline or MPA significantly alleviated histopathological damage, reduced inflammatory cell infiltration in both the colon and MLNs, and restored the Th17/Treg cell balance. Mechanistic studies indicated that trigonelline and MPA individually suppress pro-inflammatory signaling pathways while promoting regulatory immune responses.

Conclusion: This study provides a comprehensive temporal map of metabolic reprogramming during colitis progression and identifies purine metabolism and trigonelline as novel therapeutic targets. These findings highlight the translational potential of multi-organ metabolomic approaches in elucidating disease mechanisms and guiding precision treatment strategies for IBD and related inflammatory conditions.

Introduction: Lilium spp., perennial bulbous plants native to the Northern Hemisphere, have long been valued in traditional medicine, particularly across Asia. The bulbs of Lilium brownii ("Bai He" in traditional Chinese medicine) have been documented since the Han dynasty as both food and medicine to nourish yin, moisten the lungs, clear heart fire, and calm the spirit-traditionally used for conditions such as depression and diabetes. Contemporary research has increasingly validated these traditional claims, revealing diverse pharmacological activities including antidepressant and antitumor effects.

Methods: A comprehensive literature review was conducted using databases including Web of Science, PubMed, ACS Publications, Google Scholar, Baidu Scholar, and CNKI, as well as the Encyclopedia of Life, Flora of China, and Plants of the World Online. Taxa recorded in the Chinese Pharmacopoeia (2025) were included: Lilium lancifolium Thunb., Lilium brownii F. E. Brown var. viridulum Baker, and Lilium pumilum DC, and related species. All relevant multilingual publications were critically evaluated and accurately cited. Chemical structures of isolated metabolites were visualized using ChemDraw v19.0.

Results: Lilium spp. are consumed in various culinary and processed forms, including steamed bulbs, flour, wine, and functional beverages. Nutritionally, they are rich in polysaccharides, saponins, dietary fibers, vitamins, amino acids, starch, pectin, phospholipids, and essential minerals such as calcium and iron. To date, 123 chemical metabolites have been isolated and characterized, with saponins, flavonoids, phenylpropanoids, and polysaccharides recognized as the principal bioactive metabolites. Pharmacological studies have demonstrated a wide range of biological activities-anti-inflammatory, antioxidant, antitumor, antidepressant, sedative, hepatoprotective, hypoglycemic, joint-protective, and immunomodulatory-observed in both in vitro and in vivo models.

Discussion: Lilium spp. represent a valuable traditional medicinal and nutritional resource with promising potential for modern therapeutic and functional applications. Their integration into health products and cosmetics continues to expand; however, clinical validation remains limited. Further well-designed clinical trials are required to confirm the efficacy, safety, and mechanisms of Lilium-derived preparations. This review highlights recent advances to support the continued scientific and industrial development of Lilium as a multifaceted natural resource.

Introduction: Methamphetamine (Meth) is a highly addictive psychostimulant that disrupts neuronal function in the medial prefrontal cortex (mPFC), inducing Meth use disorders (MUD). MUD is often complicated by HIV-associated neurocognitive disorders (HAND, a.k.a. neuroAIDS/neuroHIV), and vice versa. MUD and neuroHIV also disrupt astrocytes, altering their role in supporting normal neuron function. The mechanism(s) underlying Meth and neuroHIV's impact on astrocytes and astrocyte-neuron interplay remains unknown.

Methods: To define that, we assessed the activity of cortical astrocyte K⁺ channels that regulate extracellular K⁺ homeostasis ([K⁺]_e), and substantially neuronal excitability in the brain. HIV-1 transgenic (Tg) rats, a rodent model of neuroHIV with combined antiretroviral therapy (cART) that have no active HIV-1 replication but expression of viral proteins, were given daily repeated Meth administrations. Saline-pretreated non-Tg rats served as control. We then conducted electrophysiological assessment in mPFC astrocytes after acute Meth (20, 100 μM in bath) or daily repeated Meth administrations (5 mg/kg/day s.c. for 5 days) followed by a 3-day withdrawal.

Results: We found that both Meth and neuroHIV suppressed the activity of astrocytic K⁺ channels, regardless of subtypes. The maximum reduction occurred in response to combined Meth/neuroHIV, showing exacerbated astrocyte dysfunction. Blocking the trace amine-associated receptor 1 (TAAR1)/G protein-coupled signaling pathway abolished Meth-induced, but not neuroHIV-induced, suppression of K_2P, K_v, and K_ir channel activity.

Discussion: Collectively, these findings demonstrate that Meth and neuroHIV inhibit astrocyte function, which could exacerbate mPFC neuronal dysfunction in MUD and/or neuroHIV. They also suggest that Meth- and neuroHIV-induced astrocytic K⁺ channel function was mediated by TAAR1-and/or chemokine receptor-coupled signaling pathways.

The therapeutic targeting of peroxisome proliferator-activated receptor gamma (PPARγ) for type 2 diabetes (T2D) remains a double-edged sword: while thiazolidinediones are efficacious, their severe side effects necessitate the discovery of safer modulators. We propose a novel nutrient-centred hypothesis that thiamine (vitamin B1), an essential micronutrient, may act as a natural ligand for PPARγ. To investigate this, we adopted a translational approach. Molecular docking and dynamics simulations established that thiamine forms a stable, high-affinity interaction with the PPARγ ligand-binding domain. Functionally, in 3T3-L1 adipocytes, thiamine induced adipogenesis and PPARγ-response element binding with a potency analogous to rosiglitazone, suggesting direct agonistic activity. Corroborating these mechanistic insights at the clinical level, a new meta-analysis of randomized controlled trials demonstrates that high-dose benfotiamine, a synthetic thiamine derivative, significantly improves neuropathic and vascular outcomes in T2D patients. While the contribution of thiamine's established antioxidant effects to these clinical benefits cannot be ruled out, the synergy of computational, cellular, and human evidence provides a compelling foundation for our hypothesis. This study suggests that thiamine could act as a PPARγ ligand and serve as a safer treatment option for metabolic disorders, which needs to be tested in vivo.

Background: Medicinal plants and natural products are essential for healthcare systems globally, and, at the same time, they are a part of ecosystems and have major socioeconomic importance in many regions of the world. However, climate change has threatened their supply and sustainability. In this review, we map the current state of research on how climate change affects medicinal plants, focusing on ecological shifts, traditional uses, changes in bioactive metabolites, and adaptation strategies.

Methods: This scoping review, which was conducted following the PRISMA-ScR guidelines, involved comprehensive searches in PubMed, Scopus, and Web of Science of studies published between 2004 and 2024. Data were extracted to summarize study characteristics, climate change factors, species distribution, bioactive metabolites and marker compounds variations, and healthcare implications.

Results: A total of 219 studies were included, showing a significant increase in publication after 2021. Most studies were conducted in Asia, especially in China and India, whereas Europe, Africa, and South America remain underrepresented. The review covers 367 medicinal plant species, including high-altitude, climate-sensitive species such as Nardostachys jatamansi and Paris polyphylla. Of these, 40.6% are classified as threatened by the IUCN, and 59.4% remain unevaluated, which shows significant conservation gaps. Research methods have evolved from basic experiments to advanced computational approaches, notably species distribution modeling (SDM), with MaxEnt being the most widely used. Although climate change is projected to increase habitat suitability for 70 species, it has also led to a decline in suitable habitats for 106 species, range shifts in 94 species, and placed 33 species at the risk of extinction and habitat loss. The ecological changes also impact traditional accessibility and the reliability of medicinal plant-based therapies. Moreover, shifts in bioactive metabolite production, including both increases and decreases, are linked to several environmental factors, such as rising temperatures, elevated CO₂, reduced precipitation, and drought stress.

Conclusion: Climate change is reshaping the ecology and pharmacological value of medicinal plants. Although adaptation strategies exist, their implementation remains limited. An interdisciplinary, coordinated response is urgently needed to ensure sustainable production and use. This will also require a paradigm shift in all aspects of ethnopharmacological research and development.

Introduction: Fibrates are effective triglyceride-lowering drugs, but they may affect bile acid metabolism, raising concerns about biliary adverse drug events (ADEs).

Objective: In this study, we used spontaneous reporting system databases to evaluate the association between fibrates and biliary ADEs. This study has been reported in accordance with the Reporting of a Disproportionality Analysis for Drug Safety Signal Detection Using Individual Case Safety Reports in PharmacoVigilance guidelines.

Methods: We used data from the Japanese Adverse Drug-Event Report (JADER) and the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) databases. The signal detection metrics employed were reporting odds ratio (ROR), proportional reporting ratio, Bayesian confidence propagation neural network, and Gamma-Poisson Shrinker. We also conducted stratified disproportionality and time-to-onset analyses.

Results: We identified 58 and 260 unique individual case safety reports from the JADER and FAERS databases, respectively. Primary disproportionality analysis of all fibrates in the JADER dataset revealed an ROR of 3.74 [2.88-4.85]. All other signal detection metrics also exhibited statistically significant associations. In the stratified disproportionality analysis, pemafibrate showed significant signals across all strata, confirming the robustness of the signal. In the Weibull analysis for pemafibrate, the shape parameter (β) was 1.59 [1.17-2.56], indicating an increasing trend in ADE reporting with continued pemafibrate use.

Conclusion: A significant signal for biliary ADEs was detected for fibrates in both databases, with a particularly consistent association for pemafibrate. Regular hepatobiliary monitoring and individualized patient management are recommended.

Introduction: Maintaining hemodynamic stability during anesthesia is crucial for patients with congenital heart disease. Remimazolam, a novel benzodiazepine, offers advantages, such as rapid onset, quick recovery, stable hemodynamics, and mild respiratory depression. We aimed to assess the effects of a single intravenous dose of remimazolam on hemodynamics in children with congenital heart disease.

Methods: This self-controlled before-and-after study enrolled 40 children undergoing elective cardiac catheterization and transcatheter interventional closure at Shanghai Children's Hospital between June and September 2024. No special preoperative medications were administered. After entering the operating room, noninvasive hemodynamic parameters, such as heart rate (HR), mean arterial pressure (MAP), oxygen saturation (SPO₂), cardiac output (CO), and cardiac index (CI) were monitored. During the cardiac catheterization procedure, invasive hemodynamic parameters-including superior vena cava pressure (SVCP), right atrial pressure (RAP), right ventricular pressure (RVP), and pulmonary artery pressure (PAP)-were measured according to surgical requirements. Subsequently, remimazolam (0.3 mg/kg) was administered intravenously, and the same parameters were remeasured 3 min later. The impact of remimazolam on hemodynamics in children with CHD was evaluated by comparing the changes in these indicators before and after drug administration.

Results: Five patients were excluded due to incomplete data, leaving 35 for analysis (sex, 11 male, 24 female; median age, 6.67 [interquartile range: 4-11.5 years]). Following intravenous administration of remimazolam, all non-invasive hemodynamic parameters remained stable, showing no statistically significant differences before versus after medication: HR [(104.31 ± 20.27) vs. (104.91 ± 19.76) bpm, P = 0.485], MAP [61 (58, 65) vs. 61 (57, 66) mmHg, P = 0.313], CO [3.2 (2.34, 3.5) vs. 3 (2.41, 3.7) L/min, P = 0.133], and CI [3.3 (3, 3.6) vs. 3.3 (3, 3.71) L/min/m², P = 0.292]. Similarly, no statistically significant differences were observed in right heart system pressures before and after administration: mRAP [8 (6, 10) vs. 8.5 (6.75, 10.25) mmHg, P = 0.064] and mPAP [15.5 (14, 19) vs. 16 (14, 19.5) mmHg, P = 0.517]. No adverse reactions such as bradycardia, hypotension, or hypertension were observed after intravenous injection of remimazolam.

Conclusion: During sevoflurane-maintained anesthesia, co-administration of remimazolam provides good hemodynamic stability for children with left-to-right shunt congenital heart disease undergoing cardiac catheterization.