BRITISH JOURNAL OF PHARMACOLOGY
·
2023
·
IF 7.3
Fangzhou Lou,Zhenyao Xu,Jing Bai,Xing’e Zhao,Linlin Cui,Qun Li,Honglin Wang
Background and Purpose Psoriasis vulgaris is a refractory skin inflammatory disorder with 80% of the cases belonging to the mild-to-moderate type, which can be controlled by topical treatment. Nevertheless, the drugs for external use have not been upgraded for decades. We modified acetyl-11-keto-beta-boswellic acid (ABKA), a natural compound shown to treat psoriasis animal models, to achieve improved efficacy and solubility for external use. Experimental approach Eleven compounds were synthesized using AKBA as a lead compound, and their effects on T helper 17 (Th17) cell differentiation were screened. 3-O-cyclohexanecarbonyl-11-keto-β-boswellic acid (CKBA) potently inhibited Th17 cell differentiation and we investigated its efficacy on treating a mouse model of psoriasis along with its pharmacology and safety profile when topically or systemically delivered to several species. Key Results CKBA inhibited mouse and human Th17 cell differentiation with an IC 50 of 3.28 μM and 3.61 μM respectively and directly targeted acetyl-CoA carboxylase 1 (ACC1). Safety evaluation and toxicity tests suggested that systemically delivered high-dose CKBA for 14 days had no dose-associated adverse effects on the central nervous, hematopoietic, cardiovascular, respiratory, and digestive systems of cynomolgus monkeys. CKBA ointment permeated the skin and did not irritate or sensitize intact skin. CKBA ointment mediated dose-dependent suppression of imiquimod-induced psoriasis-like skin inflammation with slow absorption and limited bioavailability (<10% in rats and <1% in minipigs). Conclusions and Implications CKBA is safe when topically or systemically delivered to animals. The positive effects of CKBA ointment in treating a mouse model of psoriasis indicate that this is a promising psoriasis drug candidate for further development.
研究领域:
药理学
·
皮肤病学
·
免疫学
✓ 已验证
DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2026
·
IF 7.5
Yujie Peng,Meng Zhang,Libo Zhu,Wenqiang Qian,Jingjing Yan,Huidi Jiang,Yu Xin,Ying Zhang,Dongli Sun,Weidong Fei,Mengdan Zhao
Background and Purpose Endometriosis is a chronic, hormone-dependent disorder characterized by ectopic implantation of endometrial tissue, often accompanied by pain and infertility. Although the progesterone receptor modulator RU486 is effective for pain relief, its impact on lesion regression is limited, possibly due to apoptosis resistance and overexpression of PARP1 in endometriotic cells. This study aimed to evaluate the synergistic therapeutic efficacy of combining RU486 with the PARP inhibitor olaparib, focusing on reactivating p53-dependent apoptosis in endometriotic lesions. Experimental Approach Primary ectopic endometrial stromal cells (EESCs) were used to assess the effects of RU486 and olaparib on cytotoxicity, apoptosis, DNA damage, mitochondrial membrane potential, and cell migration. Mechanistic investigations included flow cytometry, western blotting, RT-qPCR, immunofluorescence, and comet assays. A murine endometriosis model was established to evaluate in vivo lesion suppression, pain behaviour, hormone levels, and treatment safety following combination therapy. Key Results RU486 and olaparib exhibited strong synergy at a 1:4 ratio, significantly enhancing apoptosis in EESCs by coactivating p53 through distinct mechanisms—transcriptional up-regulation by RU486 and posttranslational stabilization by olaparib. This synergy intensified Bax/Bcl-2-mediated mitochondrial dysfunction, caspase-3 activation, and PARP1 cleavage. In vivo, the combination therapy achieved a 77.5% lesion weight regression, significantly exceeding monotherapies, while maintaining robust analgesic effects. Histological and molecular analyses confirmed DNA damage and enhanced apoptosis in lesions. Conclusion and Implications The combination medication enhanced apoptotic sensitivity in endometriosis by restoring p53 activity through targeting hormonal signalling and DNA repair pathways. This strategy offered strong potential for clinical translation. Graphical
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2026
·
IF 7.5
Wen-yuan Zhang,Qian-qian Wei,Tao Zhang,Chunmei Geng,Hai-yan Wu,Chang-shui Wang,Jing Chen,Lei Feng,Pei Jiang
Background and Purpose Despite breakthroughs in immunotherapy and targeted therapies, chemotherapy remains indispensable in oncology. Experimental Approach This study seeks to pinpoint key pathways in doxorubicin (DOX)-treated mouse hippocampus, utilising comprehensive transcriptomic and metabolomic analyses, and validating the mechanisms in vitro and in vivo. Key Results Our multi-omics investigation revealed that sustained DOX exposure induced significant down-regulation of 5-aminolevulinate synthase 2 (ALAS2) and its catalytic product 5-aminolevulinic acid (5-ALA) in the hippocampal region. ALAS2 deficiency was specific to hippocampal neurons, which were more sensitive to oxidative damage than astrocytes or microglia. In vivo and in vitro studies demonstrated that 5-ALA administration or ALAS2 overexpression protected the brain from DOX-induced neurotoxicity. ALAS2 catalyses the condensation of glycine and succinyl-CoA to form 5-ALA, the key precursor of haem. Beyond its role in erythropoiesis, haem is a metabolite that modulates cellular redox homeostasis through interactions with the BACH1 (BTB and CNC homology 1)/NRF2 (nuclear factor erythroid 2 like 2) pathway. We found that DOX suppressed the ALAS2/5-ALA axis, thereby enhancing BACH1 stability. This stabilised BACH1 competes with NRF2 for binding to antioxidant response elements (AREs) in target gene promoters. Conversely, reinforcing the ALAS2/5-ALA axis elevated intracellular haem levels, promoting BACH1 degradation and enhancing NRF2 activity. Using a zebrafish model, we further highlighted the antioxidant and neuroprotective role of 5-ALA against DOX-induced neurotoxicity. Conclusions and Implications In conclusion, this study elucidates a novel endogenous neuroprotective mechanism wherein the ALAS2/5-ALA axis modulates the BACH1/NRF2 pathway. 5-ALA shows promise for repurposing to mitigate chemotherapy-associated neurotoxicity. Graphical
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2026
·
IF 7.5
Yufen Xu,Xiaoli Tan,Xiaodong Lv,Qi Yang,Xingxing Ke,Wenyu Chen
Background and Purpose IGF2BP1 stabilizes oncogenic mRNAs via m6A binding to drive lung adenocarcinoma (LUAD) progression, yet how this modification orchestrates immune evasion remains unclear. Experimental Approach Bioinformatics, RT-qPCR and Western Blotting (WB) first profiled IGF2BP1 expression in LUAD. RNA pull-down, IL-11 stability assays, ELISA and confocal imaging screened and validated IGF2BP1/IL-11 as the key oncogenic axis. ELISA, cytotoxicity experiments and flow cytometry were applied in the exploration of the function of the IGF2BP1/IL-11 axis in LUAD. Bioinformatics analysis, IGF2BP1 half-life detection, WB and ubiquitination experiments were employed to identify the interaction between KCTD10 and IGF2BP1. Allograft experiments were conducted to validate the impact of the KCTD10/IGF2BP1/IL-11 axis on tumour immune escape. Clinical correlation analysis was based on samples of LUAD patients before and after PD-1/PD-L1 inhibitor treatment. Key Results IGF2BP1 was up-regulated in LUAD, exhibiting an association with adverse prognosis. Mechanistically, we observed that IGF2BP1 stabilized IL-11 mRNA in an N6-methyladenosine (m6A)-dependent manner, leading to higher protein expression of IL-11, thereby dampening the cytotoxicity and proliferation of CD8 + cells as well as the expression of TNF-α, IFN-γ and IL-2. Furthermore, KCTD10 overexpression facilitated ubiquitination and degradation of IGF2BP1, and its combination with an anti-IL-11 monoclonal antibody dramatically enhanced therapeutic efficacy. Conclusion and Implications These findings reveal that KCTD10 degrades IGF2BP1 by ubiquitination, regulates m6A modification of IL-11, and restrains immune evasion in LUAD. Our study identifies potential targets for immunotherapy and proffers new therapeutic options for LUAD patients.
✓ 已验证
DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2026
·
IF 7.5
Chang Liu,Zhuoqun Wang,Linxin Zhang,Di Yang,Zhihong Zhang,Xiaoli Cui,Ali H. Eid,Mengyang Wang
Background and Purpose Fangchinoline (FAN), a bioactive bisbenzylisoquinoline alkaloid from Stephania tetrandra , shows protective potential against angiotensin II (Ang II)-induced hypertensive heart failure (HF), particularly involving mitophagy and ferroptosis, remain unclear. We investigated the effects of FAN on Ang II-induced cardiac remodelling and HF. Experimental Approach A hypertensive heart failure model was established in C57BL/6 mice via 4-week Ang II infusion. FAN was administered during the final 2 weeks. Cardiac function was assessed by echocardiography and pathological remodelling was evaluated by histological staining. RNA sequencing of cardiac tissue was performed to investigate the mechanism of anti-heart failure action of FAN. The potential binding proteins of FAN were verified by molecular docking, drug affinity response target stability (DARTS), cellular thermal shift assay (CETSA) and surface plasmon resonance assay (SPR). In vitro , neonatal rat ventricular myocytes (NRVMs) were used to investigate the effects of FAN on cellular hypertrophy, mitophagy and ferroptosis. Key Results In vivo , FAN treatment significantly ameliorated cardiac hypertrophy, dysfunction and fibrosis. These protective effects were independent of blood pressure-lowering actions. Mechanistically, FAN activates PGC-1α to enhance mitophagy and suppress STAT6-PPARγ signalling, thereby inhibiting ferroptosis and restoring redox homeostasis. In vitro , FAN reduced Ang II-induced NRVM hypertrophy, ROS production and mitochondrial membrane potential depolarisation, and confirmed the modulation of mitophagy and ferroptosis markers. Conclusions and Implications We demonstrate that FAN alleviates Ang II-induced HF through a mechanism involving the activation of PGC-1α-mediated mitophagy and regulation of the STAT6-PPARγ pathway, ultimately suppressing cardiomyocyte ferroptosis. These results offer new perspectives for HF treatment. Graphical FAN mitigates HF by engaging PGC-1α-mediated mitophagy and STAT6-PPARγ to counteract ferroptosis.
✓ 已验证
DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2026
·
IF 7.5
Mei Feng,Xin Yang,Kuo Yao,Ke-Fan Yang,Xiang-Yi Zhan,Ming-Sheng Zhou,Hui Jia
Background and Purpose Previous studies have found that activation of the γ-secretase/NICD-PXR/Notch pathway can induce Taxol resistance in triple-negative breast cancer (TNBC) to limit its therapeutic effect. Accordingly, inhibition of the γ-secretase/Notch pathway maybe an effective strategy to enhance Taxol chemosensitivity in TNBC. We have already found that cimigenoside (CG), the active ingredient of Cimicifuga dahurica (Turcz.) Maxim, can inhibit γ-secretase activity. Experimental Approach The dynamic interaction between the natural γ-secretase inhibitor CG and γ-secretase catalytic core presenilin-1 (PSEN-1) was revealed by molecular dynamics simulations and in vitro enzyme activity experiments. The biological characterisation and in vivo role of CG in increasing Taxol sensitivity of TNBC were investigated. The regulatory effect of CG on the γ-secretase/RBPJ-PXR axis was studied through dual luciferase reporter gene assays, nuclear cytoplasmic separation experiments, and western blot assays. Key Results CG stably binds to the PSEN-1 protein cavity to inhibit γ-secretase activity. In vitro studies showed that CG significantly enhanced the inhibition of cell proliferation, migration and invasion, as well as the promotion of apoptosis of MDA-MB-231/Taxol cells by Taxol. CG enhanced the inhibitory effect of Taxol on subcutaneous tumours and lung metastatic TNBC in vivo. Mechanistically, CG inhibited the transcriptional activity of RBPJ by targeting γ-secretase, interfered with the interaction between RBPJ and pregnane X receptor (PXR), down-regulated the expression of PXR-regulated metabolic enzymes and transport proteins, and enhanced the sensitivity of TNBC to Taxol. Conclusions and Implications We show that CG enhances the chemical sensitivity of TNBC by regulating the γ-secretase/RBPJ-PXR axis. Graphical
✓ 已验证
DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2026
·
IF 7.5
Jing Jin,Yao Jin,Rong Zhang,Ying Li,Zhi-Ying Zhou,Jin-Peng Feng,Yan-Tong Liu,Zhi-Jie Sun,Zhi-Yin Xiao,De-Li Dong
Background and Purpose Bladder cancer remains a significant burden on public health globally. Carbon monoxide (CO) has emerged as a promising therapeutic agent for cancers because of its key role in inducing mitochondrial dysfunction and metabolic reprogramming in cancer cells; however, its clinical translation has been hindered by systemic toxicity because of its binding to haemoglobin, which is avoided by localised intravesical therapy via the bladder. This study aimed to develop and characterise a novel manganese(I)-based CO releasing molecular MnCORM as a therapeutic agent against bladder cancer. Experimental Approach A new MnCORM chelate of a quinoline derivative was synthesised and characterised, and its anti-cancer efficacy was assessed using a 2D bladder cancer cell model, a 3D tumour spheroid model, and a murine orthotopic bladder cancer model. Molecular mechanisms were explored via staining assays, transmission electron microscopy (TEM) and western blots. Key Results MnCORM inhibited cell viability and induced cell death in T24 and RT112 bladder cancer cells. MnCORM activated AMPK, whereas the AMPK inhibitor Compound C mitigated MnCORM-induced cytotoxicity in T24 cancer cells. MnCORM induced AMPK-triggered and Drp1-dependent mitochondrial fission, promoted reactive oxygen species (ROS) accumulation, and induced mitophagy-associated cell death. The inhibitory effect of MnCORM on tumour growth was validated in a 3D tumour spheroid model and further proven in an orthotopic bladder cancer model in nude mice after intravesical instillation of MnCORM (1 mg kg −1 ). Conclusions and Implications Our work shows that MnCORM could be potentially applied for bladder cancer therapy through intravesical instillation with less systemic toxicity. Graphical
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2026
·
IF 7.5
Guanlin Zhou,Chao Wang,Chengwei Wu,Wei Zhang
Background and Purpose Assessing chemoresistance in cancer cells is crucial for chemotherapy treatment. Current assessment methods usually rely on biochemical reagents and are labour-intensive and time-consuming. Increasing evidence has revealed links between drug-induced changes in cell mechanical properties and cell viability. However, a method that can assess drug efficacy and chemoresistance using drug-induced variation in cellular mechanical parameters is still lacking. Experimental Approach MCF7 and MCF7/ADR breast cancer cells were incubated with doxorubicin (DOX), and the changes in viscoelastic mechanical parameters were measured using atomic force microscopy (AFM) indentation. The cell viability was measured using CCK-8 assays and fluorescence staining. Using support vector machine (SVM)-assessed mechanical separability, the classification index ( σ ) and drug resistance index ( η ) were proposed as mechanical indicators of drug efficacy and chemoresistance, respectively. Key Results DOX treatment increased the elastic modulus, equilibrium elastic modulus and apparent viscosity of cells, and decreased the power-law exponent. The extent of these changes increased with DOX concentration. The consistent trends between σ and Mahalanobis distance, combined with Hotelling's T 2 significance analysis, supported σ as an indicator of mechanical-parameter separability. The changes in cell viability were consistent with changes in σ and η . Conclusion and Implications The σ values reflected drug efficacy, whereas η provided an indicator of chemoresistance. The proposed method offers a simple, rapid, and label-free complement to in vitro drug-sensitivity testing. Graphical
✓ 已验证
产品关联
DOI
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2025
·
IF 7.7
Wenjing Wei,Abudureyimu Alimujiang,Zehua Zhang,Zulipikaer Wusiman,Xiangran Liu,Yong Zhu,Yipeng Bai,Ziqi Zhu,Zhijian Li,Dengqiu Xu,Shixia Huo
Background and Purpose Vitiligo, a common depigmenting skin disorder, is characterised by the selective loss of melanocytes, which leads to distinctive non-scaly, chalky-white macules. Galangin is a flavonoid found in galangal and propolis; our previous study highlighted the therapeutic potential of galangin. However, the contributions of galangin to restoring skin pigmentation and maintaining immune homeostasis, as well as its detailed molecular roles in vitiligo management, have not been fully elucidated. Experimental Approach We used C57BL/6J mice with H 2 O 2 -induced vitiligo or imiquimod-induced erythema, to test the anti-vitiligo effects and anti-inflammatory effects of galangin. Other techniques used included immunoprecipitation-mass spectrometry, pull-down assays, Autodock and surface plasmon resonance (SPR) analysis in cultured cells. Key Results Galangin exerted anti-inflammatory and antioxidant effects through two mechanisms, promoting melanocyte proliferation while inhibiting macrophage proliferation. Using immunoprecipitation-mass spectrometry, pull-down assays, Autodock and SPR analyses, we found that galangin bound to annexin A2 and promoted its degradation in macrophages. This interaction led to inhibition of macrophage proliferation, activation and polarisation. In vivo, galangin significantly improved skin conditions in mice with H 2 O 2 -induced vitiligo or imiquimod-induced erythema. Furthermore, annexin A2 knockout abolished the protective effects of galangin in these models. Conclusions and Implications Galangin bound to annexin A2 and promoted its degradation in macrophages, decreasing release of inflammatory factors and chemokines. These findings provide experimental evidence supporting the potential application of galangin in clinical treatments for vitiligo and highlight ANXA2 as a promising therapeutic target for managing this condition.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2024
·
IF 6.8
Bing Shang,Yaqiong Dong,Bo Feng,Jingyan Zhao,Zhi Wang,Debbie C. Crans,Xiaoda Yang
Background and Purpose Metal-based therapeutic agents are limited by the required concentration of metal-based agents. Hereby, we determined if combination with 17β-oestradiol (E2) could reduce such levels and the therapy still be effective in type 2 diabetes mellitus (T2DM). Experimental Approach The metal-based agent (vanadyl acetylacetonate [VAC])– 17β-oestradiol (E2) combination is administered using the membrane-permeable graphene quantum dots (GQD), the vehicle, to form the active GQD–E2–VAC complexes, which was characterized by fluorescence spectra, infrared spectra and X-ray photoelectron spectroscopy. In db / db type 2 diabetic mice, the anti-diabetic effects of GQD–E2–VAC complexes were evaluated using blood glucose levels, oral glucose tolerance test (OGTT), serum insulin levels, homeostasis model assessment (homeostasis model assessment of insulin resistance [HOMA-IR] and homeostasis model assessment of β-cell function [HOMA-β]), histochemical assays and western blot. Key Results In diabetic mice, GQD–E2–VAC complex had comprehensive anti-diabetic effects, including control of hyperglycaemia, improved insulin sensitivity, correction of hyperinsulinaemia and prevention of β-cell loss. Co-regulation of thioredoxin interacting protein (TXNIP) activation by the combination of metal complex and 17β-oestradiol contributed to the enhanced anti-diabetic effects. Furthermore, a potent mitochondrial protective antioxidant, coniferaldehyde, significantly potentiates the protective effects of GQD–E2–VAC complexes. Conclusion and Implications A metal complex–E2 combinatorial approach achieved simultaneously the protection of β cells and insulin enhancement at an unprecedented low dose, similar to the daily intake of dietary metals in vitamin supplements. This study demonstrates the positive effects of combination and multi-modal therapies towards type 2 diabetes treatment. Graphical
研究领域:
药理学
·
糖尿病
·
治疗学
·
纳米技术
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2025
·
IF 7.7
Junli Peng,Nan Yang,Zhen Qiao,Ningning Wei,KeWei Wang,Yanru Zhang
Background and Purpose As a polymodal biosensor, the TRPA1 ion channel undergoes rapid opening and closing, a dynamic process known as gating that defines the fundamental function and modulation of ion channels. TRPA1 gating is primarily regulated by chemical and mechanical stimuli. However, whether and how TRPA1 gating transduces the biological function of pain sensation is poorly understood. Experimental Approach A series of photoswitchable TRPA1 probes (PSTRAPs1–4) were designed and synthesized. Whole-cell patch clamp recordings of hTRPA1 channels expressed in CHO cells were performed to test whether PSTRAPs could optically switch TRPA1 channel function. Site-directed mutagenesis was conducted to identify the binding site of PSTRAPs on the extracellular surface of TRPA1. In a mouse model of cheek pain, intracutaneous injection of PSTRAPs elicited pain sensation in response to photoswitching. Key Results PSTRAP-2 and PSTRAP-4 reversibly modulate TRPA1 channel function with spatiotemporal resolution. These azobenzene photoswitches can activate and deactivate TRPA1 currents expressed in CHO cells upon switching between blue light and darkness. Structural-activity relationship (SAR) analysis of PSTRAPs1–4 combined with site-directed mutagenesis revealed a residue Y926 between the pore helix 1 and 2 critical for the interaction between the PSTRAPs and TRPA1. In a mouse cheek pain model, photochemical gating of TRPA1 by intracutaneous injections of photoswitchable PSTRAP-2 and PSTRAP-4 induced pain perception in response to photoswitching cycles. Conclusion and Implications Our identification of these photoswitches not only provides small molecule tools for probing and understanding TRPA1 channel gating but also holds developmental potential for pain modulation. Graphical
研究领域:
神经科学
·
药理学
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2025
·
IF 7.7
Wenxian Chen,Tongzhu Jin,Yilin Xie,Changsheng Zhong,Huiying Gao,Lei Zhang,Jin Ju,Ting Cheng,Mengyang Li,Huifang Wang,Zhenbo Yang,Qin Deng,Zhimin Du,Haihai Liang
Background and Purpose Emerging evidence indicated that the excessive lipid droplets (LDs) accumulation and lipotoxicity play a significant role in the development of diabetic cardiomyopathy (DCM), yet the regulatory mechanisms governing the function of cardiac LDs are still unknown. Lipophagy has been shown to be involved in the maintenance of LDs homeostasis. The objective of this study was to explore the mechanism of lipophagy in cardiomyocytes and investigate whether berberine could mitigate DCM by modulating this pathway. Experimental Approach Bioinformatics analysis identified disorders of lipid metabolism and autophagy in DCM. To carry out further research, db/db mice were utilized. Furthermore, H9C2 cells treated with palmitic acid were employed as a model to explore the molecular mechanisms involved in myocardial lipotoxicity. Key Results The results showed that lipophagy was impaired in DCM. Mechanistically, sirtuin 3 (SIRT3) was demonstrated to regulate lipophagy in cardiomyocytes. SIRT3 was down-regulated in DCM. Conversely, activation of SIRT3 by the activator nicotinamide riboside (NR) could promote lipophagy to alleviate PA-induced lipotoxicity in H9C2 cells. Moreover, berberine administration markedly mitigated diabetes-induced cardiac dysfunction and hypertrophy in db/db mice, which dependent on SIRT3-mediated lipophagy. Conclusion and Implications Collectively, SIRT3 could moderate cardiac lipotoxicity in DCM by promoting lipophagy, suggesting that the regulation of SIRT3-mediated lipophagy may be a promising strategy for treating DCM. The findings indicate that the therapeutic potential of berberine for DCM is associated with lipophagy.
研究领域:
心血管医学
·
代谢生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）