Frontiers in Pharmacology最新文献

Background: Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder in children. Long Mu Ning Xin Decoction (LMNXD) shows established clinical efficacy against ADHD, yet its mechanistic basis is not fully elucidated.

Objective: This study investigates the therapeutic potential of LMNXD for ADHD and explores its underlying mechanisms of action.

Methods: Thirty spontaneously hypertensive rats (SHRs/NCrl) were randomly divided into five groups: a model (SHR) group, low-, medium-, and high-dose LMNXD (LMNXD-LD, LMNXD-MD, LMNXD-HD)groups, and a methylphenidate hydrochloride (MPH) group. Additionally, six Wistar Kyoto (WKY/NCrl) rats were designated as the control group.Behavioral performance was assessed using the open field test and Morris water maze. The expression levels of glial fibrillary acidic protein (GFAP), dopamine deceptor D1 (DRD1), and brain-derived neurotrophic factor (BDNF) in the rat hippocampus, prefrontal cortex (PFC), and striatum were evaluated by immunofluorescence, immunohistochemistry, and Western blot. Potential targets and mechanisms were explored through transcriptomic sequencing and network pharmacology, with subsequent validation by reverse transcription quantitative polymerase chain reaction (RT-qPCR).

Results: Compared to the SHR group, LMNXD ameliorated hyperactivity, impulsivity, deficits in spatial memory and learning ability in SHR/NCrl rats. It also effectively reduced GFAP expression in the hippocampus while increasing DRD1 expression in the PFC and BDNF levels in the striatum. Network pharmacology predicted that LMNXD might alleviate ADHD by acting on pathways including phosphatidylinositide 3-kinase-Akt (PI3K-Akt), calcium signaling, and cyclic adenosine monophosphate (cAMP) signaling. Consistent with this prediction, transcriptomic analysis of rat hippocampi showed that LMNXD influences the cAMP and PI3K-Akt signaling pathways, as well as serotonergic and cholinergic synapses. RT-qPCR further confirmed that LMNXD likely exerts its therapeutic effect by regulating the mRNA expression of ATPase Plasma Membrane Ca²⁺ Transporting 4 (ATP2B4), Glutamate Ionotropic Receptor NMDA Type Subunit 3A (GRIN3A), Oxytocin Receptor (OXTR), Collagen Type VI Alpha 2Chain (COL6A2), and Integrin Subunit Alpha 1 (ITGA1) within the cAMP andPI3K-Akt pathways.

Conclusion: LMNXD may ameliorates hyperactive-impulsive behaviors and improves spatial memory and learning in SHRs/NCrl rats by modulating ATP2B4, GRIN3A, OXTR, COL6A2, and ITGA1 within the cAMP and PI3K-Akt signaling pathways. This intervention also upregulates DRD1 and BDNF expression while downregulating GFAP levels.

Background: The intensive use of non-steroidal anti-inflammatory and analgesic drugs (NSAIDS) worldwide poses a challenge to scientists because of the adverse side effects. This article aims to synthesize a novel group of 1-aminoindazole-isatin Schiff base compounds considering their potency as analgesic and anti-inflammatory agents.

Methods: The synthesis of novel agents involved reflux condensation of isatin derivatives (5 mmol) and 1-aminoindazole (5 mmol) in ethanol for 2 h, which were then characterized for their structural integrity. In silico evaluation using PyRx, BIOVIA Discovery Studio, and GROMACS was performed to determine the affinity of the specific receptors and compare them with the results gained by use of standard diclofenac before preclinical evaluation using albino mice (analgesic activity) and rats (anti-inflammatory activity). The preclinical analgesic potency was analyzed via Eddy's hot plate and tail-pin methods, whereas, the anti-inflammatory potency was analyzed through carrageenan-induced paw edema against diclofenac as the standard agent.

Results: A high percentage yield of the reactions was determined (≈80%); the IR, NMR, and mass spectra showed the compounds to be stable with no shifts, justifying the accuracy of the procedure employed. The molecular docking of the ligands with two different crystal structures of proteins of interest, i.e., COX-1 and COX-2, yielded stable and the lowest binding energies, i.e., -9.6 kcal/mol for AB 12 and - 7.1 kcal/mol for diclofenac. Through molecular dynamic simulations employing GROMACS for a time period of 50 ns, AB 12 and diclofenac also yielded a thermodynamically stable and structurally folded protein and ligand complex, showing an average of 0-3 (AB 12) and 0-5 (diclofenac) hydrogen bonds with the least system fluctuations and atom deviations; furthermore, the potential energy of the complete system was stabilized at an average point of - 685,000 kj/mol for both molecules. The preclinical results showed a significant value for the ligand AB 12 (p ≤ 0.01) against the diseased control group.

Discussion: The ligand AB 12, AB 14 and AB 15 is exceptional as an analgesic and anti-inflammatory agent. AB 12 further showed stable hydrogen bonds with protein COX-2 for 50 ns in comparison with diclofenac. Based on this study, these molecules can be considered best for future studies regarding the toxicological profile.

Escitalopram is widely regarded as a well-tolerated selective serotonin reuptake inhibitor (SSRI) with a favorable safety profile. However, severe adverse events can occur even at therapeutic doses in susceptible individuals. Here, we report a rare case of simultaneous life-threatening Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH) and cardiac toxicity induced by standard-dose escitalopram. A 51-year-old female (weight 50 kg) presented with severe fatigue and anorexia. Initial laboratory results revealed profound hyponatremia (116.1 mmol/L). Following sodium supplementation, serum sodium paradoxically decreased to 114.7 mmol/L ("desalination phenomenon"), while urinary sodium excretion was markedly elevated (220 mmol/24 h) alongside significant hypouricemia (76 μmol/L), confirming the diagnosis of SIADH. Concurrently, the patient manifested significant cardiac toxicity, including sinus bradycardia (41-55 bpm) and marked QTc prolongation (570 ms). Pharmacogenetic analysis identified the CYP2C19 *1/*2 genotype (Intermediate Metabolizer). Despite the therapeutic dosage (10 mg/day) and a non-toxic serum concentration (5 ng/mL measured 72 h post-discontinuation), the patient exhibited severe toxicity, likely driven by "phenoconversion" due to low muscle mass and physiological vulnerability, exacerbated by a pharmacodynamic synergism with low-dose quetiapine. Discontinuation of medications and strict fluid management resulted in complete resolution of both hyponatremia and arrhythmia. The causality was assessed as "probable" for both drugs using the Naranjo Algorithm, and the drug-drug interaction was rated as "probable" using the Drug Interaction Probability Scale (DIPS). This case highlights that genotype-phenotype mismatch, combined with pharmacodynamic synergism (escitalopram-quetiapine interaction), can precipitate severe neuro-cardiac toxicity even at therapeutic levels. It underscores that severe neuro-cardiac toxicity can occur even at therapeutic levels due to individual vulnerability. Therefore, routine monitoring of electrolytes and electrocardiograms (ECG) remains indispensable for patient safety, as pharmacogenetic screening and therapeutic drug monitoring may not predict such idiosyncratic reactions in resource-constrained settings.

Introduction: Ischemia is an important cause of acute kidney injury (AKI). Ischemia-induced hypoxia rapidly induces activation of the Jun amino-terminal kinase (JNK) in tubular epithelial cells of the kidney, and blockade of this enzyme is protective in short-term animal models of renal ischemia. However, the clinical translation of this finding requires a water-soluble JNK inhibitor. This study investigated whether KRev-202, a soluble prodrug of the potent and selective JNK inhibitor CC930, can prevent ischemia-induced AKI and whether short-term inhibition of JNK can prevent AKI from transitioning to renal fibrosis.

Methods: In a rat model of bilateral renal ischemia/reperfusion injury (IRI), the animals received prophylactic treatment with KRev-202, the parent compound (CC-930), or a vehicle by oral gavage, starting 1 h prior to surgery.

Results and discussion: In study 1, the animals were killed on day 1 after IRI to assess the AKI peak. Vehicle-treated animals exhibited a 4.5-fold increase in plasma creatinine levels, substantial tubular necrosis, increased tubular damage markers, and inflammation on day 1. Both KRev-202 and CC-930 treatment inhibited JNK activation, caused a 50% reduction in plasma creatinine levels, and substantially reduced tubular necrosis, tubular damage, and inflammation. In studies 2 and 3, treatments were administered from -1 h until day 4, and then the animals were killed on days 7 and 21, respectively. Compared to the vehicle group, a 4-day treatment with KRev-202 or CC-930 improved the recovery of tubular structure on day 7 and substantially reduced the development of renal fibrosis on day 21. Furthermore, KRev-202 treatment administered only during the first 24 h of IRI provided the same benefits as the 4-day treatment regimen, demonstrating the importance of early blockade of this pathway. In conclusion, KRev-202 is a new water-soluble JNK inhibitor with therapeutic potential for preventing ischemia-induced AKI.

Background: As a natural flavonoid, quercetin has anti-inflammatory and anti-oxidative activities. Studies confirm its beneficial effect on asthma, but the underlying mechanism remains unclear. This study aimed to systematically evaluate quercetin's efficacy in treating asthma, explore its regulatory role in asthma-related autophagy and associated signaling pathways, and provide new insights for asthma treatment research.

Methods: In vivo, ovalbumin (OVA)-induced asthma model mice were first successfully established, then randomly assigned to five groups: control, asthma model, low/high-dose quercetin, and dexamethasone positive control. ELISA, histopathological staining, immunohistochemistry and Western blot were used to assess quercetin's therapeutic effect and molecular mechanism. To complement the in vivo findings from the OVA-induced asthmatic mouse model, in vitro experiments were conducted using the human bronchial epithelial cell line BEAS-2B. Specifically, the cell line was stimulated with TNF-α and IL-4 to establish an inflammatory model, further validating quercetin's regulation of autophagy and inflammation.

Results: In vivo, quercetin reduced inflammatory cell count and proinflammatory cytokine levels in asthmatic mice's bronchoalveolar lavage fluid (BALF), lowered serum IgE, and alleviated lung inflammatory infiltration and pathological damage. It also inhibited lung autophagy and activated the PI3K/Akt/mTOR signaling pathway. In vitro, consistent with in vivo findings, quercetin downregulated proinflammatory factors and autophagy-related proteins in TNF-α/IL-4-stimulated BEAS-2B cells. In addition, the PI3K/Akt/mTOR signaling pathway is also activated by quercetin.

Conclusion: Quercetin attenuates airway inflammation and lung damage in asthmatic mice. Its therapeutic effect is associated with the modulation of PI3K/Akt/mTOR signaling pathway activity and the regulation of excessive autophagy, which provides new potential approaches and mechanistic insights for asthma treatment.

Introduction: Severe asthma is characterized by persistent uncontrolled symptoms despite optimal standard therapy and/or by the need for high-intensity treatment to maintain control. Thymic stromal lymphopoietin (TSLP) is a key innate cytokine that promotes bronchial inflammation in both T2-high and T2-low asthma, thus representing a suitable therapeutic target. Tezepelumab, a human monoclonal antibody designed to block TSLP, has been shown to be able to dampen airway inflammation and improve patients' symptoms and overall outcomes.

Methods: This study evaluated the effectiveness of tezepelumab in patients with severe asthma in a real-world clinical setting, examining its capacity to induce clinical remission and improve radiological markers of disease. Twenty patients with severe uncontrolled asthma received subcutaneous tezepelumab at a dose of 210 mg every 4 weeks. Clinical, functional, biologic, and radiological data were collected at baseline and after 12 months of treatment.

Results: The results showed a significant increase in Asthma Control Test (ACT) score, from baseline 11.70 ± 1.78 to 20.15 ± 1.38 (p < 0.0001). Oral corticosteroid (OCS) intake decreased from 12.50 mg/day (5.00-25.00) to 0.00 mg/day (0.00-3.75) (p < 0.0001), and the rate of yearly exacerbations lowered from 2.0 (2.0-3.0) to 0.0 (0.0-1.0) (p < 0.0001). There was also a notable increase in pre-bronchodilator forced expiratory volume in 1 s (FEV₁), from baseline 57.15% ± 17.18% to 66.35% ± 18.09% (p < 0.001). Clinical remission was achieved by 30% of patients, while 55% reached partial remission. Radiologically, the Mucus Plug Score (MPS) decreased from 5.36 ± 2.85 to 3.94 ± 2.69 (p < 0.0001), and radiological metrics showed inverse correlations with functional parameters. In simple logistic regression analysis, lower MPS values at baseline and at follow-up were significantly associated with higher odds of achieving complete clinical remission at 12 months of add-on tezepelumab therapy.

Conclusion: In summary, tezepelumab induced significant benefits in patients with severe asthma in this real-world cohort, improving symptoms, lung function, and radiological outcomes.

[This corrects the article DOI: 10.3389/fphar.2025.1599745.].

Background: Patients with stage III-IV colorectal cancer (CRC) face poor prognosis due to metastases and limited treatment options. In China, cinobufacini capsules are widely used as a complementary medicine, but evidence for their clinical value remains insufficient.

Methods: Systematic searches were conducted across seven databases, including Chinese National Knowledge Infrastructure (CNKI), WanFang Database, China Biological Medicine Database (CBM), PubMed, Embase, the Cochrane Library, and Web of Science, from their inception to 30 June 2025. The primary outcome was disease control rate (DCR), and the secondary outcomes were objective response rate (ORR), CD4⁺ T cells, carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125 (CA-125), and adverse reactions. This study strictly followed the PRISMA guidelines and used RevMan 5.3, Stata 15, and GRADEpro for data analysis.

Results: The analysis showed that the combination therapy resulted in a higher DCR (RR = 1.18, 95% CI: 1.10-1.25; P < 0.0001) and ORR (RR = 1.40, 95% CI: 1.23-1.60; P < 0.0001), reduced CEA levels (WMD = -7.84, 95% CI: -10.43 to -5.23; P < 0.0001), CA-125 levels (WMD = -9.36, 95% CI: -12.80 to -5.92; P < 0.0001), and CA19-9 levels (WMD = -11.38, 95% CI: -12.66 to -10.11; P < 0.0001), as well as higher CD4⁺ T-cell levels (WMD = 2.74, 95% CI: 1.99-3.49; P < 0.0001). Additionally, the combination therapy could decrease the incidence of adverse reactions including leukocyte toxicity (RR = 0.59, 95% CI: 0.48-0.71; P < 0.0001), gastrointestinal toxicity (RR = 0.79, 95% CI: 0.62-0.99; P = 0.03), and myelosuppression (RR = 0.65, 95% CI: 0.46-0.92; P = 0.01). The level of evidence was assessed as moderate for DCR and low for ORR.

Conclusion: Cinobufacini combined with oxaliplatin-based chemotherapy may enhance short-term efficacy, immune function, and safety in advanced CRC. However, due to limitations of existing RCTs, these findings should be interpreted cautiously, and further large-scale, high-quality trials are required.

Background: Sorafenib is a tyrosine kinase inhibitor (TKI) used to treat hepatocellular carcinoma (HCC), but this drug causes clinically significant toxicities in approximately 50% of patients. Given the high frequency and severity of these side effects, it is necessary to develop new, safer drugs to treat this cancer.

Purpose: Novel 2,6,9-trisubstituted pyrimidine derivatives were synthesised and evaluated as potential antitumour agents for HCC.

Materials and methods: Twelve compounds (6a-l) were obtained by a four-step synthetic procedure using a simple and efficient methodology in which two key reactions were promoted by microwave irradiation. Subsequently, compounds 6a-l were evaluated in vitro for cytotoxic activity against the HCC cell line HepG2 and other cell lines; in vivo in the HepG2 xenograft tumour model; and in silico (docking and dynamic simulations).

Results and discussion: Compound 6e proved to be the most promising of this series (IC₅₀ = 5.6 µM), as well as being more index selective than sorafenib and with lower cytotoxicity in Vero cells (18.92 µM). In addition, 6e was further evaluated in Huh-7 cells and demonstrated selectivity for HCC. Docking studies on the proposed targets, VEGFR-2 and B-raf, indicated that 6e could bind to them with binding energies and interaction patterns similar to those of sorafenib. The 6e interaction pattern at the VEGFR-2 binding site was corroborated by dynamic studies over 100 ns. A possible mechanism of 6e-induced HepG2 cell death was investigated. Experiments on caspases-3, -7, -8, -9, Apaf-1, Cyt-c, ERK1/2, and p53 showed that they were all activated, whereas Bcl-2 was inhibited by 6e in HepG2 cells. Furthermore, 6e induced the accumulation of reactive oxygen species (ROS) in HepG2 cells. These results suggest that apoptosis in HepG2 was caused by: (i) a caspase-dependent pathway and (ii) changes in the cellular levels of Bcl-2 family proteins and ROS. In addition, 6e attenuated the growth of HepG2 xenograft tumours in mice at a dose of 1 mg/kg for 3 weeks.

Conclusion: Based on these results, this pyrimidine derivative could be an interesting compound for the design of new agents against HCC.

Introduction: Obstructive nephropathy is a major cause of chronic kidney disease (CKD), characterized by progressive renal fibrosis with limited treatment options. CD206⁺ macrophages have emerged as key drivers of fibrogenesis, yet targeted strategies against this subset remain undeveloped.

Methods: Using human ureteropelvic junction obstruction (UPJO) tissues and a murine unilateral ureteral obstruction (UUO) model, we assessed the accumulation of CD206⁺ macrophages and the progression of fibrosis. The therapeutic peptide RP-182, which selectively targets CD206, was administered daily to UUO mice. Histological, molecular, and flow cytometric analyses were performed to evaluate renal injury, fibrosis, inflammation, and macrophage polarization. In vitro studies using bone marrow-derived macrophages elucidated the mechanisms underlying the action of RP-182.

Results: CD206⁺ macrophages were significantly enriched in human UPJO kidneys and UUO mice, correlating with fibrosis severity. RP-182 treatment attenuated collagen deposition, α- SMA expression, tubular damage, and inflammatory cell infiltration in UUO kidneys. In vitro, RP-182 selectively inhibited IL-4/IL-13-induced M2 polarization and suppressed TGF- β-triggered macrophage-to-myofibroblast transition (MMT) in M2 macrophages, while sparing M1 responses. Mechanistically, RP-182 downregulated β-catenin signaling, a pathway crucial for M2 programming and MMT.

Discussion: Our findings demonstrate that RP-182 alleviates obstructive renal fibrosis by specifically targeting CD206⁺ macrophages, inhibiting their M2 polarization and MMT via β-catenin suppression. This work highlights RP-182 as a novel macrophage- directed therapeutic candidate for progressive kidney fibrosis.