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.
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高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2026
·
IF 7.5
Honglian Li,Zhihao Ni,Yuzhen Rao,Junzhe Zhang,Huiyi Guo,Haoxing Yuan,Hao Yang,Jiayun Chen,Chan Yang,Jigang Wang,Yu Rao,Shuwen Liu
Background and Purpose Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE) that symbolizes a primary contributor of morbidity and mortality. Dihydroartemisinin (DHA; artenimol) shows good therapeutic effects on LN. Its pharmacological target remains unclear. Proteolysis targeting chimeras (PROTAC) technology was used to identify the targets of DHA in LN treatment. Experimental Approach The activity of a novel compound termed A1 was assessed through cytotoxicity and anti-inflammatory assays in vitro . The target of DHA was screened by the A1 integrating with proteomics and then validated via western blotting, co-immunoprecipitation (Co-IP), immunofluorescence, molecular docking, cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) in vitro. Twenty-four-hour proteinuria, inflammatory cytokines, serum biochemical indicators, immune complex deposition and renal pathological injury were detected. Adeno-associated virus-mediated RNA interference in silencing CARD6 was conducted in vivo to comprehensively evaluate the effect and the target of DHA on MRL/lpr mice. Key Results CARD6 was the most notably degraded protein affected by A1 that identified as the target of DHA. Specifically, DHA interacted with CORE-CARD6 at the 481–949aa region. DHA blocked CARD6 to inhibit RIP2/NF-κB pathway, which manifested anti-inflammatory properties in vivo and in vitro . Silencing CARD6 ameliorated the inflammatory response of MRL/lpr mice. Notably, the inhibition effects of DHA on the MRL/lpr mice were abrogated when CARD6 was depleted. Conclusion and Implications CARD6 was a therapeutic target of DHA for LN management. This finding highlights the great potential of using PROTAC technology to effectively identify therapeutic targets of natural products. Graphical CARD6 was the most notably degraded protein affected by the novel compound PROTAC A1 that was identified as the target of dihydroartemisinin (artenimol; DHA) for lupus nephritis (LN) treatment. DHA demonstrated anti-inflammatory properties in vitro and renal protective effect in vivo by targeting CARD6/RIP2/NF-κB signalling pathway.
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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.
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高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2017
·Vol. 174
·期 8
·672-688
·
IF 5.491
Hang Zeng,Yiming Jiang,Pan Chen,Xiaomei Fan,Dongshun Li,Aiming Liu,Xiaochao Ma,Wen Xie,Peiqing Liu,Frank J Gonzalez,Min Huang,Huichang Bi
Background and Purpose Currently, ursodeoxycholic acid and obeticholic acid are the only two FDA-approved drugs for cholestatic liver diseases. Thus, new therapeutic approaches need to be developed. Here we have evaluated the anti-cholestasis effects of Schisandrol B (SolB), a bioactive compound isolated from Schisandra sphenanthera . Experimental Approach Hepatoprotective effect of SolB against intrahepatic cholestasis, induced by lithocholic acid (LCA), was evaluated in mice. Metabolomic analysis and gene analysis were used to assess involvement of pregnane X receptor (PXR). Molecular docking, cell-based reporter gene analysis and knockout mice were used to demonstrate the critical role of the PXR pathway in the anti-cholestasis effects of SolB. Key Results SolB protected against LCA-induced intrahepatic cholestasis. Furthermore, therapeutic treatment with SolB decreased mortality in cholestatic mice. Metabolomics and gene analysis showed that SolB accelerated metabolism of bile acids, promoted bile acid efflux into the intestine, and induced hepatic expression of the PXR-target genes Cyp3a11, Ugt1a1 , and Oatp2, which are involved in bile acid homeostasis. Mechanistic studies showed that SolB activated human PXR and up-regulated PXR target genes in human cell lines. Additionally, SolB did not protect Pxr -null mice from liver injury induced by intrahepatic cholestasis, thus providing genetic evidence that the effect of SolB was PXR-dependent. Conclusion and Implications These findings provide direct evidence for the hepatoprotective effects of SolB against cholestasis by activating PXR. Therefore, SolB may provide a new and effective approach to the prevention and treatment of cholestatic liver diseases.
研究领域:
肝病学
·
药理学
·
分子生物学
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高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2017
·Vol. 175
·期 5
·840-854
·
IF 5.491
Yali Zhang,Tingting Xu,Zheer Pan,Xiangting Ge,Chuchu Sun,Chun Lu,Hongjin Chen,Zhongxiang Xiao,Bing Zhang,Yuanrong Dai,Guang Liang
Background and Purpose Acute lung injury (ALI) is a challenging clinical syndrome, which manifests as an acute inflammatory response. Myeloid differentiation protein 2 (MD2) has an important role in mediating LPS-induced inflammation. Currently, there are no effective molecular-based therapies for ALI or viable biomarkers for predicting the severity of disease. Recent preclinical studies have shown that shikonin, a natural naphthoquinone, prevents LPS-induced inflammation. However, little is known about the underlying mechanisms. Experimental Approach The binding affinity of shikonin to MD2 was analysed using computer docking, surface plasmon resonance analysis and elisa . In vitro , the anti-inflammatory effect and mechanism of shikonin were investigated through elisa , real-time quantitative reverse transcription PCR, Western blotting and immunoprecipitation assay. In vivo , lung injury was induced by intratracheal administration of LPS and assessed by changes in the histopathological and inflammatory markers. The underlying mechanisms were investigated by immunoprecipitation in lung tissue. Key Results Shikonin directly bound to MD2 and interfered with the activation of toll-like receptor 4 (TLR4) induced by LPS. In cultured macrophages, shikonin inhibited TLR4 signalling and pro-inflammatory cytokine production. These effects were produced through suppression of key signalling proteins including the NF-κB and the MAPK pathway. We also showed that shikonin inhibits MD2–TLR4 complex formation and reduces LPS-induced inflammatory responses in a mouse model of ALI. Conclusions and Implications Our studies have uncovered the mechanism underlying the biological activity of shikonin in ALI and suggest that the targeting of MD2 may prove to be beneficial as a treatment option for this condition.
研究领域:
药理学
·
免疫学
·
分子生物学
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PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2019
·Vol. 176
·期 14
·2627-2641
·
IF 6.583
Zheng Xu,Chunpeng Zou,Weihui Yu,Sujing Xu,Lan Huang,Zia Khan,Jingying Wang,Guang Liang,Yi Wang
Background and Purpose Hypertension adversely affects the kidney and is the second leading cause of kidney failure. Overproduction of angiotensin II greatly contributes to the progression of hypertensive kidney disease. Angiotensin II has recently been shown to activate STAT3 in cardiovascular cells. However, the underlying mechanisms of STAT3 activation by angiotensin II and downstream functional consequences in the kidneys are not fully understood. Experimental Approach C57BL/6 mice were treated with angiotensin II by subcutaneous infusion for 1 month to develop nephropathy. Mice were treated with either adeno-associated virus expressing STAT3 shRNA or STAT3 inhibitor, S3I-201. Human archival kidney samples from five patients with hypertension and five individuals without hypertension were also examined. In vitro, STAT3 was blocked using siRNA or STAT3 inhibitor S3I-201 in the renal proximal tubular cell line, NRK52E, after exposure to angiotensin II. Key Results Angiotensin II activated STAT3 in kidney epithelial cells through engaging toll-like receptor 4 (TLR4) and JAK2, which was independent of IL-6/gp130 and angiotensin AT 1 receptors. Angiotensin II-mediated STAT3 activation increased fibrotic proteins and resulted in renal dysfunction. Both STAT3 inhibition by the low MW compound S3I-201 and TLR4 deficiency normalized renal fibrosis and dysfunction caused by Ang II in mice, without affecting hypertension. Conclusions and Implications Our study reveals a novel mechanism of STAT3 activation, induced by angiotensin II, in kidney tissues and highlights a translational significance of a STAT3 inhibitor as potential therapeutic agent for hypertensive kidney disease.
研究领域:
肾病学
·
药理学
·
分子生物学
·
心血管疾病
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PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2021
·Vol. 178
·期 24
·4808-4825
·
IF 8.74
Yan-Fei Yang,Hui Dong,Yan Shen,Lei Li,Michael Lazarus,Wei-Min Qu,Zhi-Li Huang
Background and Purpose Modafinil is a potent eugeroic (wakefulness-promoting) drug that is prescribed to treat narcolepsy and has a low incidence of abuse. Although previous studies have shown that modafinil-induced arousal depends on the dopamine receptors and transporters, the specific part/s of the dopamine transmitter system underlying this mechanism remained unclear. Here, we investigated the role of mesencephalic dopamine neurons in modafinil-evoked arousal. Experimental Approach A dopamine indicator (dLight1.1) was employed to detect dopamine changes in the nucleus accumbens (NAc) and dorsal striatum. We specifically lesioned mesencephalic dopamine neurons via diphtheria toxin (DTA) in the dopamine transporter (DAT)-Cre mice. Then, the sleep–wake states were recorded to evaluate the effect of modafinil on arousal. Finally, the extent of DTA-induced lesions was determined by immunohistochemistry. Key Results Modafinil promptly increased dopamine levels in the NAc and dorsal striatum in a dose-dependent manner. Lesioning of dopamine neurons in the substantia nigra pars compacta (SNc) or ventral tegmental area (VTA) had no significant effects on physiological sleep–wake cycles. Modafinil at 90 mg·kg −1 increased continuous wakefulness for 355 min in control mice. However, these effects were slightly decreased by 6.7% in the SNc-lesioned mice and were prominently diminished by 32.8% in VTA-lesioned mice. Furthermore, the modafinil-induced arousal was completely blocked in the SNc-VTA-lesioned mice, whereas lesions of the dorsal raphé nucleus had no effect. Conclusion and Implications Taken together, our findings indicate that mesencephalic dopamine neurons are essential for modafinil-induced arousal. Graphical
研究领域:
神经科学
·
药理学
·
睡眠医学
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高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2019
·Vol. 176
·期 24
·4639-4652
·
IF 6.583
Mengjing Zhao,Huan Zhao,Jiangming Deng,Lianxia Guo,Baojian Wu
Background and Purpose Whether and how circadian clock proteins regulate drug detoxification are not known. Here, we have assessed the effects of CLOCK (a core circadian clock protein) on drug metabolism and detoxification. Experimental Approach Regulation by CLOCK protein of drug-metabolizing enzymes was assessed using Clock knockout ( Clock −/− ) mice and Hepa-1c1c7/AML-12 cells. The relative mRNA and protein levels were determined by qPCR and Western blotting respectively. Toxicity and pharmacokinetic experiments were performed with Clock −/− and wild-type mice after intraperitoneal injection of coumarin or cyclophosphamide. Transcriptional gene regulation was investigated using luciferase reporter, mobility shift, and chromatin immunoprecipitation (ChIP) assays. Key Results Clock deletion disrupted hepatic diurnal expressions of a number of drug-metabolizing enzymes in mice. In particular, CYP2A4/5 expressions were markedly down-regulated, whereas CYP2B10 was up-regulated. Positive regulation of Cyp2a4/5 and negative regulation of Cyp2b10 by CLOCK were confirmed in Hepa-1c1c7 and AML-12 cells. Based on a combination of luciferase reporter, mobility shift, and ChIP assays, we found that CLOCK activated Cyp2a4/5 transcription via specific binding to E-box elements in promoter region and repressed Cyp2b10 transcription through REV-ERBα/β (two target genes of CLOCK and transcriptional repressors of Cyp2b10 ). Furthermore, Clock ablation sensitized mice to coumarin toxicity by down-regulating CYP2A4/5-mediated metabolism (a detoxification pathway) and to cyclophosphamide toxicity by up-regulating CYP2B10-mediated metabolism (generating the toxic metabolite 4-hydroxycyclophosphamide). Conclusion and Implications CLOCK protein regulates metabolism by the cytochrome P450 family and drug detoxification. The findings improve our understanding of the crosstalk between circadian clock and drug detoxification.
研究领域:
药理学
·
分子生物学
·
昼夜节律
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PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2018
·Vol. 175
·期 22
·4209-4217
·
IF 6.81
Chaonan Ye,Kun Han,Jinxiu Lei,Kui Zeng,Su Zeng,Haixing Ju,Lushan Yu
Background and Purpose The concentrative nucleoside transporter 2 (CNT2) mediates the uptake of both natural nucleosides and nucleoside-derived drugs. Therefore, it is important both physiologically and pharmacologically. However, CNT2 expression is significantly repressed in colorectal cancer (CRC). Here, we have elucidated the mechanism(s) underlying CNT2 repression in CRC. Experimental Approach Repression of CNT2 in tumour samples from patients with CRC was identified using Western blot and RT-qPCR. The histone acetylation state at the CNT2 promoter region was then evaluated with chromatin immunoprecipitation and trichostatin A (TSA) treatment. To find the key enzyme responsible for hypoacetylation at the CNT2 promoter region, siRNA knockdown and RT-qPCR were used. Effects of combining HDAC inhibitors and cladribine were studied in HCT15 and HT29 cells. Key Results Histone deacetylase 7 was significantly up-regulated in CRC, leading to histone hypoacetylation at the CNT2 promoter region, especially at sites H3K9Ac, H3K18Ac and H4Ac. This hypoacetylation condensed the chromatin structure and reduced CNT2 expression. All these effects were reversed by treatment with TSA, a histone deacetylase inhibitor. In HCT15 and HT29 cells, inhibition of histone deacetylase increased cell uptake and decreased IC 50 for cladribine. Conclusions and Implications Histone hypoacetylation due to increased levels of histone deacetylase 7 results in CNT2 repression in CRC tumour tissue and could lead to decreased uptake of and consequent resistance to nucleoside anti-cancer agents. Such resistance could be overcome by combining inhibitors of histone deacetylase with the nucleoside anti-cancer agent.
研究领域:
肿瘤学
·
分子生物学
·
药理学
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PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2019
·Vol. 176
·期 17
·3336-3349
·
IF 6.583
Hao Liu,Meng-Jing Zhao,Zi-Ying Wang,Qiao-Qiao Han,Hai-Yun Wu,Xiao-fang Mao,Yong-Xiang Wang
Background and Purpose d -Amino acid oxidase (DAAO) is a flavine adenine dinucleotide-containing flavoenzyme and specifically catalyses oxidative deamination of d -amino acids. This study aimed to explore the association between increased cerebral DAAO expression or enzymic activity and the development of cerebral ischaemia. Experimental Approach A mouse model of transient (90 min) middle cerebral artery occlusion (MCAO) was established, and western blotting, enzymic activity assay, and fluorescent immunostaining techniques were used. Key Results The expression and enzymic activity of DAAO increased over time in the cortical peri-infarct area of the mice subjected to transient MCAO. The DAAO was specifically expressed in astrocytes, and its double immunostaining with the astrocytic intracellular marker, glial fibrillary acidic protein, in the cortical peri-infarct area was up-regulated following ischaemic insult, with peak increase on Day 5 after MCAO. Single intravenous injection of the specific and potent DAAO inhibitor Compound SUN reduced the cerebral DAAO enzymic activity and attenuated neuronal infarction and neurobehavioural deficits with optimal improvement apparent immediately after the MCAO procedure. The neuroprotective effect was dose dependent, with ED 50 values of 3.9–4.5 mg·kg −1 . Intracerebroventricular injection of the DAAO gene silencer siRNA/DAAO significantly reduced cerebral DAAO expression and attenuated MCAO-induced neuronal infarction and behavioural deficits. Conclusions and Implications Our results, for the first time, demonstrated that increased cerebral astrocytic DAAO expression and enzymic activity were causally associated with the development of neuronal destruction following ischaemic insults, suggesting that targeting cerebral DAAO could be a potential approach for treatment of neurological conditions following cerebral ischaemia.
研究领域:
神经科学
·
药理学
·
分子生物学
·
神经病学
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PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2019
·Vol. 177
·期 3
·687-700
·
IF 6.583
Huihong Zeng,Huan Li,Mengzhen Yue,Ying Fan,Jiaoqi Cheng,Xincheng Wu,Rui Xu,Wuping Yang,Manjun Li,Jiahui Tang,Hongping Chen,Bohai Kuang,Guangqin Fan,Qingxian Zhu,Lijian Shao
Background and Purpose Damage to intestinal epithelial cells and mucosa limits the effectiveness of several anti-cancer chemotherapeutic agents but the underlying mechanism (s) remain unknown. Little is known of how enteric nervous system regulates proliferation, differentiation, impairment, and regeneration of intestinal stem cells. Here we have investigated the effects of isoprenaline on the damaged intestinal stem cells induced by chemotherapeutic treatments in mice. Experimental Approach The effects of inhibiting sympathetic and parasympathetic nerves on intestinal stem cells were examined in male C57BL/6J mice. Protection by isoprenaline of intestinal stem cells was assessed in the presence or absence of 5-fluorouracil (5FU) or cisplatin. Cellular apoptosis, cell cycle, PI3K/Akt signalling, and NF-κB signalling in intestinal stem cells were mechanistically evaluated. Key Results The sympathetic nerve inhibitor 6-OHDA decreased the number and function of intestinal stem cells. 5FU or cisplatin treatment damaged both intestinal stem cells and sympathetic nerves. Notably, isoprenaline accelerated the recovery of intestinal stem cells after 5FU or cisplatin treatment. This protective effect of isoprenaline on damaged intestinal stem cells was mediated by β 2 -adrenoceptors. The benefits of isoprenaline were mainly mediated by inhibiting cellular apoptosis induced by 5FU treatment, which might contribute to fine-tuning regulating NF-κB signalling pathway by isoprenaline administration. Conclusions and Implications Treatment with isoprenaline is a new approach to ameliorate the damage to intestinal stem cells following exposure to cancer chemotherapeutic agents.
研究领域:
药理学
·
肿瘤学
·
胃肠病学
·
神经科学
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高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2014
·Vol. 171
·期 23
·5252-5264
·
IF 4.99
Jing Han,Lidan Sun,Xun Huang,Zheng Li,Chenyu Zhang,Hai Qian,Wenlong Huang
Background and Purpose The short biological half-life limits the therapeutic use of glucagon-like peptide-1 (GLP-1) and chemical modification to improve the interaction of peptides with serum albumin represents an effective strategy to develop long-acting peptide analogues. Coumarin, a natural product, is known to bind tightly to plasma proteins and possesses many biological activities. Therefore, we designed and synthesized a series of coumarin-modified GLP-1 derivatives, hypothesizing that conjugation with coumarin would retain the therapeutic effects and prolong the biological half-life of the conjugates. Experimental Approach Four cysteine-modified GLP-1 analogues (1–4) were prepared using Gly 8 -GLP-1(7–36)-NH 2 peptide as a starting point. These analogues were conjugated with two coumarin maleimides to yield eight compounds (conjugates 6–13) for testing. Activation of human GLP-1 receptors, stability to enzymic inactivation in plasma and binding to human albumin were assessed in vitro . In vivo , effects on oral glucose tolerance tests (OGTT) in rats and on blood glucose levels in db/db mice were studied. Key Results Most conjugates showed well preserved receptor activation efficacy, enhanced albumin-binding properties and improved in vitro plasma stability and conjugate 7 was selected to undergo further assessment. In rats, conjugate 7 had a longer circulating t 1/2 than exendin-4 or liraglutide. A prolonged antidiabetic effect of conjugate 7 was observed after OGTT in rats and a prolonged hypoglycaemic effect in db/db mice. Conclusions and Implications Cysteine-specific coumarin conjugation with GLP-1 offers a useful approach to the development of long-acting incretin-based antidiabetic agents. Conjugate 7 is a promising long-lasting GLP-1 derivative deserving further investigation.
研究领域:
药理学
·
糖尿病研究
·
药物化学
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PubMed
高影响因子
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