Food & Function
·
2020
·Vol. 11
·期 11
·10033-10046
·
IF 4.171
Xiaodong Ge,Chang'e Wang,Huiling Chen,Tingting Liu,Ligen Chen,Ying Huang,Feng Zeng,Bin Liu
Luteolin (LU) is a flavonoid compound and metformin hydrochloride (MH) is a kind of drug. Studies have shown that both LU and MH have the function of hypoglycemic effect. However, there are few reports indicating that LU cooperated with MH (LU·MH) can relieve lipid metabolism disorders and optimize intestinal flora compositions of high-fat diet mice. In this research, we investigated the effects of LU, MH and LU·MH on lipid metabolism disorders and intestinal flora composition in high-fat diet mice. The study found that compared with high-fat diet (HFD) alone, LU, MH and LU·MH could significantly reduce the lipid metabolism disorder. Furthermore, compared with LU or MH alone, the biochemical indicators of LU·MH were significantly improved and the results of the histopathological section also showed that LU·MH has stronger liver repair ability. It revealed that the potential mechanisms of the LU·MH alleviating lipid metabolism disorders were involved in the simultaneous regulation of SREBP-1c/FAS and SREBP-1c/ACC/Cpt-1. In addition, LU·MH could regulate the intestinal flora compositions. This includes significantly reducing the ratio of Firmicutes and Bacteroidetes(F/B) and at the family level, increasing the relative abundance of Lachnospiraceae, Helicobacteraceae, Marinifilaceae and Peptococcaceae to relieve lipid metabolism disorders. In conclusion, the work found that LU·MH regulates the signal pathway of SREBP-1c/FAS and SREBP-1c/ACC/Cpt-1 simultaneously and decreases the ratio of F/B, as well as increases the relative abundance of certain microbiota to alleviate the lipid metabolism disorders of HFD-fed mice.
研究领域:
药理学
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营养学
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微生物学
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代谢性疾病
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产品关联
DOI
PubMed
高影响因子
ACS Applied Bio Materials
·
2019
·
IF 0
Feiyi Wang,Sisi Hu,Qi Sun,Qiang Fei,Chao Ma,Cuifen Lu,Junqi Nie,Zuxing Chen,Jun Ren,Guo-Rong Chen,Guichun Yang,Xiao-Peng He,Tony D James
Currently, chemotherapy is a widely used and important treatment for cancer. However, almost all of the treatments have shortcomings associated with poor specificity and high toxicity, which results in severe side effects to normal cells and tissue. This is a very important problem, and yet, it currently remains unanswered. Therefore, the development of the method for the more effective delivery of anticancer drugs to their targets and real-time monitoring of the localization of the drugs are very important. Herein, we designed a theranostic prodrug: CPT-p-Leu, which was constructed using fluorescent camptothecin (CPT), a self-immolative linker and leucine (Leu) residue. Upon exposure to LAP (leucine aminopeptidase: LAP), the amide bond in CPT-p-Leu will be cleaved, followed by an intramolecular 1,6-elimination, which triggers the active anticancer drug (CPT) release and recovers the fluorescence of CPT. With our design, the anticancer drug, CPT, can be used as both a drug and a fluorescence reporter, making our system suitable to accurately and effectively track the released CPT distribution. Based on this strategy, CPT-p-Leu could achieve the chemoselective detection of LAP and monitoring of the anticancer drug release. Furthermore, it also provides a very convenient way to accurately determine the location of the released drug in living samples. In addition, CPT-p-Leu shows a good cell membrane permeability and enhanced cytotoxicity toward LAP overexpressing cancer cells. We anticipate that our research will facilitate the development of improved theranostic systems for cancer therapy.
研究领域:
肿瘤学
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药物化学
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分子生物学
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药物递送系统
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产品关联
DOI
PubMed
NUTRITION RESEARCH
·
2019
·
IF 2.627
Jia Wang,Tian Gao,Feng Wang,Jie Xue,Hua Ye,Meilin Xie
Luteolin , a natural flavonoid , can attenuate hepatic lipid accumulation and insulin resistance in obese mice . Therefore, we hypothesized that luteolin may also improve the abnormal glucolipid metabolism of hypertrophic myocardial cells. This study aimed to investigate the effect and possible molecular mechanisms of luteolin. Hypertrophic H9c2 cells were induced by angiotensin II/hypoxia and simultaneously treated with 2 to 8 μg/mL luteolin for 24 h. Luteolin might dose-dependently decrease intracellular total protein, atrial natriuretic peptide , and free fatty acid levels , and increase supernatant glucose levels . Western blot assay showed that luteolin could inhibit the expressions of intracellular hypoxia inducible factor-1α (HIF-1α) and glucose transporter-4 (GLUT-4) proteins, and increase the expressions of intracellular peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyltransferase-1A (CPT-1A), and pyruvate dehydrogenase kinase-4 (PDK-4) proteins. These findings demonstrate that luteolin can improve abnormal glucolipid metabolism in angiotensin II/hypoxia-induced hypertrophic H9c2 cells, and its mechanisms are related to the inhibition of HIF-1α expression and subsequent modulation of PPARα-mediated target genes, including CPT-1A, PDK-4, and GLUT-4.
研究领域:
药理学
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心脏病学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2023
·Vol. 21
·期 1
·1-15
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IF 10.2
Tan Xi,Wang Chenhui,Zhou Hong,Zhang Shuting,Liu Xuhan,Yang Xiangliang,Liu Wei
Typical chemo-immunotherapy against malignant carcinoma, is characterized by the combined application of chemotherapeutic agents and monoclonal antibodies for immune checkpoint blockade (ICB). Temporary ICB with antibodies would not depress tumor intrinsic PD-L1 expression and potential PD-L1 adaptive upregulation during chemotherapy, thus exerting limited immunotherapy efficacy. Herein, we developed novel polymer-lipid hybrid nanoparticles (2-BP/CPT-PLNs) for inducing PD-L1 degradation by inhibiting palmitoylation with bioactive palmitic acid analog 2-bromopalmitate (2-BP) to replace PD-L1 antibody (αPD-L1) for ICB therapy, thus achieving highly efficient antitumor immune via immunogenic cell death (ICD) induced by potentiated chemotherapy. GSH-responsive and biodegradable polymer-prodrug CPT-ss-PAEEP10 assisted as a cationic helper polymer could help to stabilize 2-BP/CPT-PLNs co-assembled with 2-BP, and facilitate the tumor site-specific delivery and intracellular release of water-insoluble camptothecin (CPT) in vivo. 2-BP/CPT-PLNs would reinforce cytotoxic CD8+ T cell-mediated antitumor immune response via promoting intratumoral lymphocytes cells infiltration and activation. 2-BP/CPT-PLNs significantly prevented melanoma progression and prolonged life survival of mice beyond the conventional combination of irinotecan hydrochloride (CPT-11) and αPD-L1. Our work first provided valuable instructions for developing bioactive lipid analogs-derived nanoparticles via lipid metabolism intervention for oncotherapy.Graphical Abstract
研究领域:
纳米技术
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癌症治疗
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免疫学
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药学
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产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2024
·
IF 8.2
Xin Wang,Bo Peng,Cheng Zhang,Mengqi Wu,Wenping Xu,Jiagao Cheng,Liming Tao,Zhong Li,Yang Zhang
The pesticide acetochlor (ACT) is a chiral isomer commonly detected in the global environment, yet its specific impacts on liver function remain poorly understood. We utilized zebrafish and L02 cells as research models to comprehensively investigate how ACT and its chiral isomers affect the liver. Our investigations unveiled that the R , Rac , and S isomers of ACT disrupt hepatic lipid transport, catabolism, and synthesis, leading to delayed yolk sac absorption and the accumulation of lipids in zebrafish embryos. These isomers induce oxidative stress in the liver of zebrafish embryos, reducing antioxidant levels and enzyme activity . The accumulated lipids in the liver render it susceptible to oxidative stress, further exacerbating hepatocyte damage. Hepatocyte damage manifests as extensive vacuolization of liver cells and alterations in liver morphology, which are induced by R , Rac , and S . Furthermore, we elucidated the molecular mechanisms underpinning the disturbance of hepatic lipid metabolism by R , Rac , and S in L02 cells. These compounds stimulate lipid synthesis through the upregulation of the AMPK/SREBP-1c/FAS pathway while inhibiting lipolysis via downregulation of the PPAR-α/CPT-1a pathway. Remarkably, our results highlight that S exhibits significantly higher hepatotoxicity in comparison to R . This study provides valuable insights into the hepatic effects of ACT chiral isomers.
研究领域:
环境毒理学
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分子生物学
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细胞生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2026
·
IF 6.8
Yangyang Zhang,Xia Cao,Zong Hou,Zhiqiang Liu,Shu Liu
Ethnopharmacological relevance Xiao Chai Hu Tang (XCHT) is a classic Chinese herbal formula traditionally used for gastrointestinal disorders. Although XCHT alleviates irinotecan (CPT-11)-induced diarrhea, whether it confers the dual benefit of concurrently reducing intestinal toxicity and enhancing antitumor apoptosis remains unknown. Aim of the study To determine whether XCHT confers dual benefits in CPT-11-treated colorectal cancer (CRC), elucidate the underlying mechanisms, and identify the active constituents responsible. Materials and methods A DMH/DSS-induced CRC rat model was established to evaluate XCHT in CPT-11 therapy. Intestinal barrier integrity, inflammation, and tumor apoptosis were assessed. Effects were validated in SN-38-treated NCM-460 (barrier protection, anti-inflammation) and HCT-116 cells (synergistic apoptosis). Systemically absorbed constituents were identified by HPLC-Q-Orbitrap MS and functionally validated. Results XCHT mitigated CPT-11-induced toxicity in CRC rats by restoring tight junction proteins (ZO-1, occludin) and suppressing NLRP3 inflammasome-mediated inflammation (IL-1β, IL-18, IL-6, TNF-α), with these effects recapitulated in SN-38-treated NCM-460 cells. XCHT also enhanced CPT-11-induced apoptosis in tumor tissues and synergized with SN-38 in HCT-116 cells, as evidenced by increased Bax/Bcl-2 ratio. Among 17 systemically absorbed compounds, baicalein, baicalin, and wogonin were identified as key contributors to barrier protection and anti-inflammation, while baicalein and isoliquiritin were associated with the synergistic pro-apoptotic effect with SN-38 in functional screening. Conclusion XCHT improves CPT-11's therapeutic index by protecting intestinal barrier, suppressing NLRP3 inflammasome, and enhancing tumor apoptosis through distinct bioactive constituents. These findings provide a pharmacochemical and mechanistic foundation for its adjunctive use in CRC treatment.
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Xue Bai,Jianjun Deng,Zhiguang Duan,Rongzhan Fu,Chenhui Zhu,Daidi Fan
Background Gastrointestinal mucositis stands as one of the most severe side effects of irinotecan (CPT-11). however, only palliative treatment is available at present. Therefore, there is an urgent need for adjunctive medications to alleviate the side effects of CPT-11. Purpose In this study, our objective was to explore whether ginsenoside Rh4 could serve as a modulator of the gut microbiota and an adjunctive agent for chemotherapy, thereby alleviating the side effects of CPT-11 and augmenting its anti-tumor efficacy. Study design A CPT-11-induced gastrointestinal mucositis model was used to investigate whether ginsenoside Rh4 alleviated CPT-11-induced gastrointestinal mucositis and enhanced the anti-tumor activity of CPT-11. Methods In this study, we utilized CT26 cells to establish a xenograft tumor model, employing transcriptomics, genomics, and metabolomics techniques to investigate the impact of ginsenoside Rh4 on CPT-11-induced gastrointestinal mucositis and the effect on the anti-tumor activity of CPT-11. Furthermore, we explored the pivotal role of gut microbiota and their metabolites through fecal microbiota transplantation (FMT) experiments and supplementation of the key differential metabolite, hyodeoxycholic acid (HDCA). Results The results showed that ginsenoside Rh4 repaired the impairment of intestinal barrier function and restored intestinal mucosal homeostasis in a gut microbiota-dependent manner. Ginsenoside Rh4 treatment modulated gut microbiota diversity and upregulated the abundance of beneficial bacteria, especially Lactobacillus_reuteri and Akkermansia_muciniphila , which further regulated bile acid biosynthesis, significantly promoted the production of the beneficial secondary bile acid hyodeoxycholic acid (HDCA), thereby alleviating CPT-11-induced gut microbiota dysbiosis. Subsequently, ginsenoside Rh4 further alleviated gastrointestinal mucositis through the TGR5-TLR4-NF-κB signaling pathway. On the other hand, ginsenoside Rh4 combination therapy could further reduce the weight and volume of colon tumors, promote tumor cell apoptosis, and enhance the anti-tumor activity of CPT-11 by inhibiting the PI3K-Akt signaling pathway, thus exerting a synergistic anti-tumor effect. Conclusion In summary, our findings confirm that ginsenoside Rh4 can alleviate CPT-11-induced gastrointestinal mucositis and enhance the anti-tumor activity of CPT-11 by modulating gut microbiota and its related metabolites. Our study validates the potential of ginsenoside Rh4 as a modulator of the gut microbiota and an adjunctive agent for chemotherapy, offering new therapeutic strategies for addressing chemotherapy side effects and improving chemotherapy efficacy.
研究领域:
肿瘤学
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药理学
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微生物学
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分子生物学
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2019
·Vol. 7
·期 9
·3683-3692
·
IF 5.251
Zongjun Liu,Tuo Li,Fang Han,You Wang,Yang Gan,Junhui Shi,Tianran Wang,Muhammad Luqman Akhtar,Yu Li
Synergistic cancer starvation/ROS-mediated/chemo-therapy is developed through a cascade reaction with enzyme glucose oxidase (GOX) modified on the surface of an Fe-based metal organic framework (MOF(Fe)) and drug camptothecin (CPT) loaded into the cavities of MOF(Fe). Once internalized by tumor cells, GOX catalyzes endogenous glucose into hydrogen peroxide (H2O2) and gluconic acid (H+) enabling starvation therapy through choking off energy (glucose) supply. Meanwhile, the acidic micro-environment of tumor enhanced by the generated H+ degrades the MOF(Fe) simultaneously releasing CPT for chemotherapy and Fe3+, catalyzing H2O2 into one of the strongest reactive oxygen species (ROS) ˙OH enabling ROS-mediated therapy. Both in vitro and in vivo results show remarkable tri-modal synergistic anticancer effects. This work may shed some light on the development of novel multi-modal cancer therapies without any external intervention.
研究领域:
生物医学工程
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癌症研究
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材料科学
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化学工程
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2021
·
IF 5.279
Ruiqian Duan,Xiao Guan,Kai Huang,Yu Zhang,Sen Li,Ji’an Xia,Meng Shen
A high-fat diet (HFD) causes hyperlipidemia, which worsens disturbances in bile acid (BA) metabolism and gut microbiota. This study aimed to investigate the regulation of flavonoids from whole-grain oat (FO) on BA metabolism and gut microbiota in HFD-induced hyperlipidemic mice. The experiment results showed that FO improved serum lipid profiles and decreased body weight and lipid deposition in HFD-fed mice. Through real-time qualitative polymerase chain reaction (RT-qPCR) and Western blot assays, by up-regulating the expression of PPARα, CPT-1, CYP7A1, FXR, TGR5, NTCP, and BSTP, and down-regulating those of SREBP-1c, FAS, and ASBT, FO suppressed lipogenesis, promoted lipolysis and BA synthesis, and efflux to faeces via the FXR pathway. 16s rRNA sequencing revealed that FO significantly increased Akkermansia and significantly decreased Lachnoclostridium, Blautia, Colidextribacter, and Desulfovibrio. Spearman’s correlation analysis showed that these bacteria were strongly correlated with hyperlipidemia-related parameters. Therefore, our results indicated that FO possessed an antihyperlipidemic effect via regulating the gut–liver axis, i.e., BA metabolism and gut microbiota.
研究领域:
营养学
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生物化学
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微生物学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN POLYMER JOURNAL
·
2019
·
IF 3.621
Mengzhen Wang,Junjie Yan,Cong Li,Xinyu Wang,Jianjun Xiong,Donghui Pan,Lizhen Wang,Yuping Xu,Xiaotian Li,Min Yang
Poly(amide-imide)s (PAIs) present limited use in bioapplications due to their poor aqueous solubility and difficulty in functional accessibility. Herein, we prepared PAI-based prodrugs by leveraging aliphatic PAIs as the polymer scaffolds and conjugating camptothecin (CPT) via thiol-disulfide exchange reaction. The degree of CPT attachment can be smoothly controlled by initial feed ratios of PEG and a pyridinedisulfide-modified CPT precursor. Due to the abundant secondary amine groups in PAI backbones, amphiphilic PAI-CPT prodrugs self-assembled into cationic nanoparticles and showed an efficient cellular internalization (<2 h). The presence of disulfide linkers between PAI scaffolds and CPT endowed PAI-CPT prodrugs a reductive-responsive drug release profile. Moreover, when PAI-CPT prodrug nanoparticles were further used as nanocarriers, doxorubicin (DOX) was additionally encapsulated and variable nanomorphologies (nanospheres, branched nanoparticles) were obtained, and an enhanced chemotherapy efficacy was achieved as well.
研究领域:
聚合物化学
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药学
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纳米医学
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癌症治疗
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DOI
高影响因子
Acta Biomaterialia
·
2023
·
IF 9.7
Yuan Chen,Zhuo Yao,Peilian Liu,Qida Hu,Yong Huang,Li Ping,Fu Zhang,Honglin Tang,Tao Wan,Yuan Ping,Bowen Li
Chemotherapeutics have been recommended as the standard protocol for inoperable patients with triple-negative breast cancer (TNBC) at advanced stage, yet limited success has been achieved in prolonging survival rates by this monotherapy. A major reason for this failure is the chemo-resistance from traditional apoptotic pathways resulting in poor therapeutic effect. Ferroptosis has become a powerful modality of no-apoptotic cell death, which can effectively evade chemo-resistance in apoptotic pathways. Herein, we propose an active-targeting small-molecular self-assembly nano-prodrug for co-delivery of chemotherapeutics (CPT), Ferrocene (Fc) and GPX4 inhibitor (RSL3) to overcome the chemo-resistance from traditional apoptotic pathways. In this nano-prodrug, the disulfide linkage not only serves as a GSH-responsive trigger, but also exhibits a stable self-assembly behavior that forms nanoparticle . Interestingly, the RSL3 can be loaded during this self-assembly process that forms a three-components nano-prodrug. In tumor environment, the high GSH level can disassemble the nano-prodrug to trigger the release of the parent drug, which can improve the therapeutic effect by synergistic effects of ferroptosis and apoptosis. In different TNBC mice models, the nano-prodrug is encapsulated into RGD-modified phospholipid micelles (DSPE-PEG2000-RGD) and exhibits high anti-tumor and anti-metastasis efficacy, especially in orthotopic models. The application of ferroptosis to assist the enhancement of chemotherapeutics may serve as a promising strategy for TNBC treatment. Statement of significance Chemotherapeutics have been recommended as the standard of care for palliative and adjuvant treatment in patients with triple-negative breast cancer (TNBC), yet limited success has been achieved in prolonging the overall survival of patients by this monotherapy. A major reason for this failure is the chemo-resistance from traditional apoptotic pathways resulting in poor therapeutic effect. Thus, the co-delivery of the apoptosis and ferroptosis drug may overcome or evade the resistance in chemotherapy-induced apoptotic pathways and provide a promising strategy to combat TNBC. In this work, we developed a small-molecular self-assembly nano-prodrug for co-delivery of chemotherapeutics (CPT), Ferrocene (Fc) and ferroptosis resistance inhibitor (RSL3), which could overcome the chemo-resistance and improve the therapeutic effect by synergistic effects of ferroptosis and apoptosis.
研究领域:
肿瘤学
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药物科学
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纳米技术
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癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2018
·
IF 4.235
Mengjing Zhao,Tianpeng Zhang,Fangjun Yu,Lianxia Guo,Baojian Wu
Carboxylesterases (CES) are a family of phase I enzymes that play an important role in xenobiotic clearance and lipid metabolism. Here, we investigate a potential role of E4 promoter-binding protein 4 (E4bp4) in regulation of Ces and CPT-11 (irinotecan, a first-line drug for treating colorectal cancer) pharmacokinetics in mice. Mouse hepatoma Hepa-1c1c7 cells were transfected with Rev-erbα expression plasmid or siRNA targeting E4bp4. The relative mRNA and protein levels of Ces enzymes in the cells or the livers of wild-type and E4bp4-deficient (E4bp4 −/− ) mice were determined by qPCR and Western blotting , respectively. Transcriptional regulation of Ces by E4bp4/Rev-erbα were investigated using luciferase reporter, mobility shift, and co-immunoprecipitation (Co-IP) assays. Pharmacokinetic studies were performed with wild-type and E4bp4 −/− mice after intraperitoneal injection of CPT-11. E4bp4 ablation down-regulated an array of hepatic Ces genes in mice. E4bp4 −/− mice also showed reduced Ces-mediated metabolism and elevated systemic exposure of CPT-11, a well-known Ces substrate. Consistently, E4bp4 knockdown reduced the expression of Ces genes ( Ces2b , Ces2e and Ces2f ) in Hepa-1c1c7 cells. Furthermore, Rev-erbα repressed the transcription of Ces2b, whereas E4bp4 antagonized this repressive action. Co-IP experiment confirmed a direct interaction between E4bp4 and Rev-erbα. Through a combination of promoter analysis and mobility shift assays, we demonstrated that Rev-erbα trans-repressed Ces (Ces2b) through its specific binding to the -767 to-754 bp promoter region. In conclusion, E4bp4 regulates Ces enzymes through inhibition of the transrepression activity of Rev-erbα, thereby impacting the metabolism and pharmacokinetics of Ces substrates.
研究领域:
药理学
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分子生物学
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遗传学
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肝病学
✓ 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）