Biomaterials Science
·
2023
·Vol. 11
·期 9
·3172-3179
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IF 6.6
Wenting Li,Leihou Shao,Ji Liu,Jinhan Sheng,Qizhen Zheng,Ming Wang
Bacterial effector proteins are virulence factors that are secreted and mediate orthogonal post-translational modifications of proteins that are not found naturally in mammalian systems. They hold great promise for developing biotherapeutics by regulating malignant cell signaling in a specific and targeted manner. However, delivering bacterial effectors into disease cells poses a significant challenge to their therapeutic potential. In this study, we report on the design of a combinatorial library of bioreducible lipid nanoparticles containing disulfide bonds for highly efficient bacterial effector delivery and potential cancer therapy. A leading lipid, PPPDA-O16B, identified from the library, can encapsulate and deliver DNA plasmids into cells. The gene cargo is released in response to the reductive cellular environment that is upregulated in cancer cells, leading to enhanced gene delivery and protein expression efficiency. Furthermore, we demonstrate that PPPDA-O16B can deliver the bacterial effector protein, DUF5, to degrade mutant RAS and inactivate downstream MAPK signaling cascades to suppress cancer cell growth in vitro and in tumor-bearing mouse xenografts. This strategy of delivering bacterial effectors using biodegradable lipid nanoparticles can be expanded for cancer cell signaling regulation and antitumor studies.
研究领域:
癌症研究
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分子生物学
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纳米医学
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治疗开发
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高影响因子
Chemical Biology & Drug Design
·
2025
·Vol. 105
·期 2
·e70067
·
IF 3.3
Jingting Zeng,Zhenshuo Luo,Tiansheng Zhao,Chunhua Xia,Fanglan Liu,Na Li,Lailiang Qu,Cheng Wang
Aberrant activation of the RAS/RAF/MEK/ERK pathway occurs in more than 30% of human cancers. As part of this pathway, MEK1/2 has crucial roles in tumorigenesis, cell proliferation, and inhibition of apoptosis. At present, a number of MEK1/2 inhibitors are approved for the treatment of melanoma. However, MEK1/2 inhibitors have poor single-drug efficacy in the treatment of solid tumors and are prone to drug resistance. A series of compounds containing a diarylamine skeleton and phenylacrylamide (acrylamide) have been designed and synthesized in this paper. The most promising compound M15 showed good inhibitory activity of MEK1 (IC 50 = 10.29 nM) and good inhibitory effect on three types of solid tumor cells: MDA-MB-231(IC 50 = 2.76 μM), HepG2 (IC 50 = 2.57 μM) and A549 (IC 50 = 5.40 μM). At the same time, M15 was less toxic to human normal cells (MCF-10A IC 50 > 20 μM) and has certain stability of liver microsomes in vitro (human, t 1/2 = 27.9 min; rat, t 1/2 > 60 min). It can induce apoptosis of MDA-MB-231 cells and slow down their migration. Therefore, compound M15 acts as a novel MEK1/2 inhibitor and may be a promising candidate for solid tumor intervention.
研究领域:
肿瘤学
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药理学
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分子生物学
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高影响因子
FASEB JOURNAL
·
2026
·Vol. 40
·期 4
·e71580
·
IF 4.3
Liujie Zheng,Yinhua Ni,Suyao Xie,Yitian Ji,Jiahong Dong,Lanjun Fu,Zhengwei Fu,Juan Jin,Qiang He
Acute kidney injury (AKI) is a serious complication of cisplatin chemotherapy, requiring new preventive therapies. Germacrone, a sesquiterpenoid derived from Rhizoma Curcuma , has multiple pharmacological effects, including anti-inflammatory, antiapoptotic, and antioxidant effects. The current study aimed to investigate the effect and mechanism of germacrone on AKI. Single high-dose and multiple low-dose cisplatin-induced AKI and AKI-chronic kidney disease (CKD) transition mouse models were used to determine the preventive effect of germacrone, with the mechanism explored in HK-2 and Raw264.7 cells. A breast cancer tumor-bearing model was developed to determine whether the nephron-protective effects of germacrone affect the anticancer properties of cisplatin. Here, we found that germacrone significantly alleviated AKI and fibrosis in cisplatin-treated mice, as demonstrated by decreased serum creatinine and blood urea nitrogen (BUN) levels and improved renal pathology. Germacrone attenuated cisplatin-induced apoptosis and inflammation in vivo and in vitro. RNA sequencing revealed that germacrone restored cisplatin-induced gene dysregulation and regulated inflammation and apoptosis through the PI3K/AKT and Ras/MAPK pathways. Inhibition of these pathways abrogated the renoprotective effect of germacrone in vitro. Moreover, germacrone reduced macrophage activation and induced an M2-dominant shift in macrophage polarization in the kidneys and Raw264.7 cells via similar pathways. Furthermore, germacrone protected the kidneys without affecting the chemotherapeutic effects of cisplatin on a mouse model of breast cancer. Therefore, germacrone is expected to have universal renoprotective effects across different AKI models and a tumor-bearing model through similar signaling pathways, suggesting its potential as a clinical adjuvant therapy for reducing nephrotoxicity in patients receiving cisplatin chemotherapy. Graphical Germacrone alleviates inflammation and apoptosis in cisplatin-injured kidneys by activating PI3K/AKT and suppressing Ras/MAPK signaling, thereby protecting against acute kidney injury (AKI) in mice. This renoprotection is reinforced by its ability to drive an M2-dominant macrophage shift both in vivo and in vitro, ultimately restoring tubular integrity and renal function.
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PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2025
·
IF 4
Siye Zhou,Jiayun Li,Dongping Chen,Zhixuan Xu,Kudousi Kuerban,Qiang Liu,Muhammad Irfan Waris,Wenwu Wu,Nannan Lv,Jianting Fan
Hyphantria cunea , a globally significant quarantine pest, causes severe ecological and economic impacts in invaded regions. Attractants are environment-friendly and valuable pest management tools for H. cunea control. In this study, we identified that the combination of β-ocimene with sex pheromone components was strongly attractive to H. cunea males. This attractant combination activates the Ras signaling pathway and stimulates Ca 2+ in male adults following exposure. Feeding and oviposition behavior results demonstrated that H. cunea prefers Morus alba over Platanus × acerifolia , Metasequoia glyptostroboides , and Taxodium distichum . In the fresh branches of M. alba with leaves, the relative abundance of β-ocimene (36.33 ± 0.41 %) was significantly higher than the other hosts. Electroantennography recordings, behavioral choice assays, and field trapping trials showed that the combination of β-ocimene with sex pheromone components significantly enhanced male response and attraction. The number of trapped males using β-ocimene/ sex pheromone blend was 3.7-fold higher than that of sex pheromone or β-ocimene alone in the field, indicating a synergistic effect of adding β-ocimene to sex pheromone. The molecular mechanism of β-ocimene/sex pheromone synergism was further analyzed. After exposure to the attractant, the Ras signaling pathway in the heads of males are activated ( HcILP and HcPLCε1 are upregulated, while HcRasGAP and HcPLD are downregulated), which further stimulates the expression of IP3 and Ca 2+ . The activation of Ca 2+ may be the key reason for its higher attraction to males. These findings provide a theoretical basis for the selection and mechanistic understanding of attractants for H. cunea , offering insights for attractant-based pest control strategies.
研究领域:
昆虫学
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害虫管理
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分子生物学
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生态学
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PubMed
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GENE
·
2022
·
IF 3.913
Xiang Li,Nan Wang,Yutong Wu,Yidan Liu,Ruoyu Wang
Background Aldehyde dehydrogenase 6 family member A1 (ALDH6A1) is associated with multiple diseases, but its pathogenesis in colon cancer (CC) is ambiguous and needs further study so that this research explores the function of ALDH6A1 in CC. Methods The level of ALDH6A1 in colon adenocarcinoma (COAD), CC tissues, and cells was measured by starBase v2.0, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot. Post transfection with overexpressed (oe)-ALDH6A1, cell biological behaviors, as well as apoptosis-, matrix metalloproteinase (MMP)-, and rat sarcoma virus (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway-related markers were measured by cell function experiments, qRT-PCR, and western blot. Next, the effects of small interfering RNA targeting ALDH6A1 (si-ALDH6A1) and RAS/RAF inhibitor (MCP110) on cell biological behaviors, as well as apoptosis-, MMP-, and RAS/RAF/MEK/ERK pathway-related markers were detected again. Results ALDH6A1 was low-expressed in COAD, CC tissues, and cells. Oe-ALDH6A1 weakened cell vitality, migration and invasionbut facilitated apoptosis; while it reduced expression levels of Bcl-2, MMP-2, MMP-9 and the RAS/RAF/MEK/ERK pathway-related markers but promoted Bax level. However, the regulation of si-ALDH6A1 on cell biological behaviors and related genes was opposite to that of oe-ALDH6A1. Moreover, MCP110 rescued the regulation of si-ALDH6A1 on cell biological behaviors, expressions of apoptosis- MMP- as well as RAS/RAF/MEK/ERK pathway-related markers. To sum up, ALDH6A1 attenuated CC progression by down-regulating the expressions of RAS/RAF/MEK/ERK pathway-related markers.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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高影响因子
Journal of Neuroinflammation
·
2025
·Vol. 22
·期 1
·1-29
·
IF 10.1
Wu Hanxue,Qiu Zihan,Mu Junya,Wang Yi,Wang Jiawei,Han Yue,Yang Ruijie,Yuan Shenglan,Yuan Miao,Yang Rui,Chen Xingjuan,Sun Qi,Li Fanni,Xiao Lei,Zhang Ming,Xu Jiaxi
Hypertension increases risks for cognitive impairment and Alzheimer’s disease (AD). In renal patients with both hypertension and cognitive decline, via rest-state fMRI, their cerebral cortical region showed maintained cerebral blood flow (CBF), but reduced signals of blood-oxygen-level-dependent (BOLD). In mice, although CBF was unchanged, deoxycorticosterone acetate (DOCA)-salt treatment markedly reduced cerebrovascular reactivity, with altered transcriptomic pattern in cortical endothelial cells (ECs) and astrocytes, showing downregulated expression of glucose transport 1 ( GluT1 ) but upregulated metabolic reprogramming. Lipidomic analysis using prefrontal cortex (PFC) further revealed enhanced catabolism of glycerophospholipids and accumulation of free fatty acids. In the PFC of hypertensive mice, neurodegenerative alterations were observed, including reduced number of neuronal dendritic spines and more expression of phosphorylated Tau (p-Tau). Via both morphological and molecular tests, we identified that DOCA-salt hypertension was associated with significant mitochondrial injury and upregulated lysine succinylation in the PFC neurons. Upregulated lysine succinylation was largely mitochondria-located, and they were functionally enriched in gluconeogenesis-related energy metabolic pathways, the tricarboxylic acid (TCA) cycle, oxidative stress, and neurodegenerative diseases. In hypertensive mice, angiotensinogen ( Agt ) expression was markedly upregulated in most astrocytes, together with neuronal expression of Agtr1a . In cultured neuronal cells, angiotensin II (ang II) elevated mitochondrial membrane potential and ATP biosynthesis. In mice with neuronal AT 1a R knockout (AT1N), DOCA-salt failed to induce cognitive impairment. Additionally, DOCA-salt-associated reduction of acetylcholine, accumulation of p-Tau, and upregulation of lysine succinylation were not observed in AT1N mice. Direct anti-hypertensive treatment did not abolish DOCA-salt-related pathological phenotypes, and enhanced lysine succinylation was not detected in hypertension models induced by norepinephrine or L-NAME. Our data provide evidence that hypertension induced metabolic rearrangement (enhanced energy metabolism from non-glucose source and upregulated mitochondrial oxidative phosphorylation) in the neuro-vascular unit, due to downregulated glucose uptake in ECs. Increased neuronal energy consumption, via local ang II/AT 1 R signaling, further exacerbated mitochondrial stress and neurodegenerative alterations. Together, by multi-omics analysis, this study provided novel insights regarding how hypertension increases the risk for age-related cognitive impairment.
Section
Graphical
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BIOCHEMICAL PHARMACOLOGY
·
2019
·
IF 4.825
Wensong Yao,Zhen Lin,Peiying Shi,Bing Chen,Gang Wang,Jianyong Huang,Yuxia Sui,Qicai Liu,Shaoguang Li,Xinhua Lin,Qicai Liu,Hong Yao
Colorectal cancer (CRC) is one of the most common malignant tumors worldwide and tends to have drug resistance. Delicaflavone (DLF), a novel anticancer agent of biflavonoid from Selaginella doederleinii Hieron , showed strong anti-CRC activities, which has not yet been reported. In this study, we investigated the effects and possible anti-CRC mechanism of DLF in vitro and in vivo . It was shown that DLF significantly inhibited the cells viability and induced G2/M phase arrest, apoptosis , the loss of mitochondrial membrane potential (Δψm), generation of ROS and increase of intracellular Ca 2+ in HT29 and HCT116 cells by MTT assay, TEM, flow cytometry and inverted fluorescence microscope. Western blot and qPCR assays results further confirmed DLF induced caspase-dependent apoptosis and inhibited PI3K/AKT/mTOR and Ras/MEK/Erk signaling pathways in CRC cells. Meanwhile, DLF significantly suppressed the tumor growth via activation of Caspase-9 and Caspase-3 protein and decrease of ki67 and CD34 protein without apparent side effects in vivo . In summary, these results indicated DLF induced ROS-mediated cell cycle arrest and apoptosis through ER stress and mitochondrial pathway accompanying with the inhibition of PI3K/AKT/mTOR and Ras/MEK/Erk signaling cascade. Thus DLF could be a potential therapeutic agent for CRC.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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高影响因子
ACTA PHARMACOLOGICA SINICA
·
2021
·Vol. 43
·期 7
·1843-1856
·
IF 6.15
Huang Qiu-ju,Liao Guo-chao,Zhuang Xue-rong,Yang Meng-lan,Yao Jing-jing,Deng Jian-hua,Zhang Yan-min,Wang Ying,Qi Xiao-xiao,Pan Dong-feng,Guan Yang,Huang Zhi-ying,Zhang Feng-xue,Liu Zhong-qiu,Lu Lin-lin
Ras has long been viewed as a promising target for cancer therapy. Farnesylthiosalicylic acid (FTS), as the only Ras inhibitor has ever entered phase II clinical trials, has yielded disappointing results due to its strong hydrophobicity, poor tumor-targeting capacity, and low therapeutic efficiency. Thus, enhancing hydrophilicity and tumor-targeting capacity of FTS for improving its therapeutic efficacy is of great significance. In this study we conjugated FTS with a cancer-targeting small molecule dye IR783 and characterized the anticancer properties of the conjugate FTS-IR783. We showed that IR783 conjugation greatly improved the hydrophilicity, tumor-targeting and therapeutic potential of FTS. After a single oral administration in Balb/c mice, the relative bioavailability of FTS-IR783 was increased by 90.7% compared with FTS. We demonstrated that organic anion transporting polypeptide (OATP) and endocytosis synergistically drove the uptake of the FTS-IR783 conjugate in breast cancer MDA-MB-231 cells, resulting in superior tumor-targeting ability of the conjugate both in vitro and in vivo. We further revealed that FTS-IR783 conjugate could bind with and directly activate AMPK rather than affecting Ras, and subsequently regulate the TSC2/mTOR signaling pathway, thus achieving 2–10-fold increased anti-cancer therapeutic efficacy against 6 human breast cancer cell lines compared to FTS both in vivo and in vitro. Overall, our data highlights a promising approach for the modification of the anti-tumor drug FTS using IR783 and makes it possible to return FTS back to the clinic with a better efficacy.
研究领域:
药理学
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肿瘤学
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分子生物学
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PHYTOMEDICINE
·
2026
·
IF 11.3
Wen-Biao Zu,Zhao-Jie Wang,Dong-Mei Tang,Qin-Yu Lu,Yan-Yan Zhu,Zhong-Shun Zhou,Mei-Zhen Wei,Xiao-Dong Luo
Background Fungal diseases affect over one billion individuals worldwide and represent a significant public health concern. Oral candidiasis (OC) is a common fungal infection primarily caused by Candida albicans. Eriocapitella rivularis is a traditional medicinal herb for the treatment of oral fungal infections. Purpose This study aimed to identify potent antifungal compounds from E. rivularis and elucidate their underlying mechanisms of action. Methods Bio-guided isolation combined with network pharmacology was used to identify anti- C. albicans compounds from E. rivularis , followed by metabolomics analysis to explore potential regulatory pathways. Antifungal activity and synergistic efficacy were evaluated using broth microdilution, checkerboard, and time-kill assays. Biofilm inhibition was assessed through quantitative and biochemical analyses. Reverse transcription quantitative polymerase chain reaction was performed to elucidate molecular mechanisms. An in vivo murine OC model was employed to verify efficacy. Results Prosapogenin CP4 disrupted the fungal cell wall, targeted ergosterol to induce plasma membrane permeabilization, inactivated mitochondrial function, and inhibited hyphal growth, potentially through interference with ABC transporters, modulation of cAMP export, and induction of metabolic disorders. Prosapogenin CP4 and ursolic acid exhibited a synergistic inhibitory effect against fluconazole-resistant C. albicans (FICI = 0.375) with low resistance. This combination regulated genes in the Ras/cAMP/PKA signalling pathway, significantly inhibited biofilm formation and reduced fungal burden, inflammatory responses, and fungal colonisation in murine oral tissues, with efficacy comparable or superior to that of nystatin. Conclusion The finding presents a synergistic phytomedicine strategy using two triterpenoids from E. rivularis as a promising therapeutic approach for OC, particularly biofilm-associated infections.
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EPILEPSY RESEARCH
·
2026
·
IF 2.3
Jiahao Liu,Jiawei Li,Ruting Fu,Liya Fang,Yuanyuan Liu,Ruici Liu,Deming Kong,Zhimei Jiang,Lei Liu,Luchuan Wang,Chao Gong,Pei Zeng,Youdi Fu,Xinru Zhu,Jin Guo,Shaobo Zhou
Upregulation of Casr and Gnb1 was observed in both PTZ- and KA-induced acute epilepsy mouse models. • Twenty-four hours post-seizure, reduced levels of Ras pathway activity markers were observed in association with hippocampal neuronal damage. • Vitamin D 3 mitigated brain injury by downregulating Casr , modulating the Ras pathway, and exerting neuroprotective effects. Objective This study aimed to investigate the neuroprotective effects of vitamin D 3 (cholecalciferol, hereinafter referred to as VitD) in acute epilepsy mouse models by examining its modulation of the calcium-sensing receptor ( Casr ), the Ras signalling pathway, and the potential mediator role of guanine nucleotide-binding protein subunit beta-1 ( Gnb1 ). Methods Acute epilepsy was induced in 135 C57BL/6 J mice via intraperitoneal injection(i.p.) of pentylenetetrazole (PTZ) or kainic acid (KA). Mice were randomly assigned to receive VitD pretreatment, valproate (VPA) emergency treatment, or a combination of VitD and Salirasib, a Ras pathway inhibitor. Seizure behaviours and electroencephalography (EEG) were recorded to confirm successful model establishment and to assess the efficacy of interventions. Hippocampal tissue was analysed for histopathological changes, as well as protein and mRNA expression levels of Casr, Gnb1, and Ras pathway-related molecules ( Kras , Raf-1 , Mek , Erk ) using western blot (WB) and quantitative real-time polymerase chain reaction (qRT-PCR). Results Both PTZ and KA models showed successful seizure induction with associated hippocampal neuronal damage. Casr and Gnb1 expression were upregulated in both models, more prominently in the KA group, while Ras pathway activity was suppressed. VitD pretreatment reduced seizure frequency, delayed seizure onset, and alleviated neuronal damage—particularly in the PTZ model. VitD downregulated Casr , upregulated Gnb1 , and partially restored Ras pathway activity. Co-treatment with Salirasib enhanced neuroprotection and reduced Gnb1 expression. VPA similarly increased Gnb1 expression and suppressed Ras pathway activity. Conclusion VitD exerts neuroprotective effects in acute epilepsy, potentially through regulation of Casr and the Ras signalling pathway. In this context, Gnb1 likely acting as a downstream potential mediator linking Casr activation to Ras signalling. These findings highlight VitD’s potential as a neuroprotective agent in epilepsy and provide new insights into the molecular mechanisms underlying its action.
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高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2019
·
IF 6.054
Zhikun Liu,Meng Wang,Hengshan Wang,Lei Fang,Shaohua Gou
Inhibiting/disturbing the RAS/RAF pathway may benefit the treatment of cancer and overcome the resistance. Utilizing such a pathway as the target, nine styrylbenzylsulfone derivatives generated from the platinum-based modification of the side chain of Rigosertib were designed. Among them, compound 29 showed the most potent antitumor activity in vitro with IC50 values at the nanomolar level against the tested tumor cell lines and 1000-fold higher than cisplatin against the multidrug resistant cells (A549/CDDP, A549/DOX, and SKOV-3/CDDP cells), while it showed only moderate cytotoxicity against normal cells (HEUVC cells). Compound 29 could clearly disturb signaling transduction between RAS and CRAF by directly bonding to CRAF and inhibit CRAF activation. Besides, the enhanced intracellular platinum level made 29 more potent than cisplatin in DNA damage, reactive oxygen species accumulation, and mitochondrial membrane potential decrease. Moreover, 29 induced apoptosis by the endogenous pathway and efficiently inhibited tumor growth in the A549 xenograft model without side effects.
研究领域:
肿瘤学
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药理学
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分子生物学
·
化学
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高影响因子
Frontiers in Plant Science
·
2023
·
IF 5.6
Haihong Chen,Yiyi Hu,Guanpin Yang,Pingping Li,Jingru Yin,Xiaoqing Feng,Qiong Wu,Jingyu Zhang,Baoheng Xiao,Zhenghong Sui
Macropinocytosis is an endocytic process that plays an important role in animal development and disease occurrence but until now has been rarely reported in organisms with cell walls. We investigated the properties of endocytosis in a red alga, Gracilariopsis lemaneiformis . The cells non-selectively internalized extracellular fluid into large-scale endocytic vesicles (1.94 ± 0.51 μm), and this process could be inhibited by 5-(N-ethyl-N-isopropyl) amiloride, an macropinocytosis inhibitor. Moreover, endocytosis was driven by F-actin, which promotes formation of ruffles and cups from the cell surface and facilitates formation of endocytotic vesicles. After vesicle formation, endocytic vesicles could be acidified and acquire digestive function. These results indicated macropinocytosis in G. lemaneiformis . Abundant phosphatidylinositol kinase and small GTPase encoding genes were found in the genome of this alga, while PI3K, Ras, and Rab5, the important participators of traditional macropinocytosis, seem to be lacked. Such findings provide a new insight into endocytosis in organisms with cell walls and facilitate further research into the core regulatory mechanisms and evolution of macropinocytosis.
研究领域:
植物学
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细胞生物学
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分子生物学
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危险品化学品经营许可证（带存储）