Frontiers in Pharmacology
·
2022
·
IF 5.988
Chuyao Liao,Di Wang,Siyuan Qin,Ying Zhang,Jie Chen,Ruijie Xu,Fengguo Xu,Pei Zhang
Irinotecan (CPT-11) in combination with 5-fluorouracil and leucovorin is a first-line chemotherapy regimen for the treatment of colorectal cancer; however, its clinical application is limited by the dose-limiting gastrointestinal toxicity of colitis. In our previous studies, several bile acids (BAs) were found significantly elevated in the colon of the CPT-11-induced rat colitis model. On the other hand, NLRP3 inflammasome has been reported to play important roles in mediating colitis. Interestingly, BA was stated to activate the NLRP3 inflammasome in some studies, while in some other reports, it showed an inhibitory effect. We assumed that the inflammatory status in different circumstances might have contributed to the controversial findings. In this study, we first discovered, under non-inflammatory conditions, that supplementing BA could activate the NLRP3 inflammasome in THP-1-differentiated macrophages and promote inflammation. In lipopolysaccharide (LPS)-induced inflammatory macrophages, however, BA inhibited the NLRP3 inflammasome and reduced inflammation. Further experiments demonstrated that Takeda G protein-coupled receptor 5 (TGR5) is essential in mediating the inhibitory effect of BA, while phospho-SP1 (p-SP1) is key to the activation. Furthermore, we applied the above findings to ameliorate CPT-11-caused colitis in rats by inhibiting SP1 with mithramycin A (MitA) or activating TGR5 using oleanolic acid (OA). Our findings may shed light on the discovery of effective interventions for reducing dose-limiting chemotherapy-induced colitis.
研究领域:
肿瘤学
·
胃肠病学
·
免疫学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INORGANIC CHEMISTRY COMMUNICATIONS
·
2025
·
IF 5.4
Xiaoyu Li,Guangru Chu,Zhen Zhou,Jiashen Fan,Liying Cui,Zhongkai Liu,Shengkai Liu,Yujie Fu,Zhiguo Liu
In this study, chitooligosaccharide (CHO) was used as a template to synthesis of 50 nm mesoporous silica nanoparticles (MSNs) with high specific surface area and pore volume. The MSNs nanopaticles have been characterized by SEM, TEM, DLS, FTIR, TGA, XRD and XPS spectrometry. The CHO templated MSNs nanoparticles featured with very high specific surface area (1443.7 m 2 g −1 ) and pore volume (2.171 cm 3 g −1 ). The MSNs surface was further modified by the chitosan (CHI) layer and the folic acid (FA). Under the optimized conditions, the anticancer drug CPT-11 has a loading efficiency of 378 mg/g and the drug release efficiency is 40.8 % in 24 h. In vitro tests on the prepared MSNs-CHI-FA loaded with CPT-11 against human breast cancer cells indicated that the nano-formulation with drug concentration of 20 μg/mL successfully enhanced folate receptor-mediated endocytosis by the cellular uptake and significantly improved CPT-11 inhibitory against the cancer cells to 58.1 %
研究领域:
材料科学与工程
·
药学
·
生物医学工程
✓ 已验证
产品关联
DOI
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
·
药理学
·
微生物学
·
分子生物学
·
胃肠病学
✓ 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.
✓ 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
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2023
·
IF 17.1
Ke Li,Kun Xu,Shaopeng Liu,Ye He,Meijun Tan,Yulan Mao,Yulu Yang,Jing Wu,Qian Feng,Zhong Luo,Kaiyong Cai
Low-temperature photothermal therapy (PTT) is a noninvasive method that harnesses the photothermal effect at low temperatures to selectively eliminate tumor cells, while safeguarding normal tissues, minimizing thermal damage, and enhancing treatment safety. First we evaluated the transcriptome of tumor cells at the gene level following low-temperature treatment and observed significant enrichment of genes involved in cell cycle and heat response-related signaling pathways. To address this challenge, we have developed an engineering multifunctional nanoplatform that offered an all-in-one strategy for efficient sensitization of low-temperature PTT. Specifically, we utilized MoS2 nanoparticles as the photothermal core to generate low temperature (40–48 °C). The nanoplatform was coated with DPA to load CPT-11 and Fe2+ and was further modified with PEG and iRGD to enhance tumor specificity (MoS2/Fe@CPT-11-PEG-iRGD). Laser- and acid-triggered release of CPT-11 can significantly increase intracellular H2O2 content, cooperate with Fe2+ ions to increase intracellular lipid ROS content, and activate ferroptosis. Furthermore, CPT-11 induced cell cycle arrest in the temperature-sensitive S-phase, and increased lipid ROS levels contributed to the degradation of HSPs protein expression. This synergistic approach could effectively induce tumor cell death by the sensitized low-temperature PTT and the combination of ferroptosis and chemotherapy. Our nanoplatform can also maximize tumor cell eradication and prolong the survival time of tumor-bearing mice in vivo. The multifunctional approach will provide more possibilities for clinical applications of low-temperature PTT and potential avenues for the development of multiple tumor treatments.
研究领域:
纳米技术
·
癌症治疗
·
生物医学工程
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光热疗法
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2017
·Vol. 7
·期 69
·43621-43635
·
IF 3.108
Huanyu Guan,Xiaoming Wang,Shiping Wang,Yang He,Jiajing Yue,Shanggao Liao,Yuanda Huang,Yue Shi
Shengjiang Xiexin decoction (SXD) exerts protective effects against gastrointestinal injury induced by irinotecan hydrochloride (CPT-11). The intestinal bacteria-associated in vitro pharmacokinetics of 16 components of SXD in normal rats and those with CPT-11-induced gastrointestinal toxicity were compared in this study. A sensitive and reproducible ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) method was developed for the quantification of 16 components of SXD in a rat intestinal bacteria incubation system, using naringin, naringenin and tetrahydropalmatine as internal standards (ISs). The samples were prepared via salting-out assisted liquid–liquid extraction (SALLE) with NaCl to reduce matrix effects. Chromatographic separation was performed on a sub-2 μm analytical column with acetonitrile and 0.1% aqueous formic acid as mobile phase. All of the analyzed components and ISs were detected via multiple reaction monitoring (MRM) scanning with electrospray ionization. The proposed method was successfully applied for the in vitro pharmacokinetic analysis of the multiple components of a complex mixture consisting of a traditional Chinese medicine (TCM) and an intestinal bacterial incubation system. The pharmacokinetic parameters of some flavonoid glycosides and aglycones in the rats with CPT-11-induced gastrointestinal toxicity were significantly different (p < 0.05, p < 0.01) from those in the normal rats, which suggested that consumption of CPT-11 could qualitatively and/or quantitatively alter the intestinal bacteria as well as the metabolic activities of enzymes. The in vitro pharmacokinetic analysis of these components in the intestinal bacterial incubation system provided valuable information for achieving a deeper understanding of the mechanisms involved in the alteration of intestinal bacteria induced by CPT-11 and further in vivo pharmacokinetic research on SXD. The intestinal bacteria-based pharmacokinetic method could benefit the study of interactions between TCMs and chemical drugs in clinical use.
研究领域:
药理学
·
中药学
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胃肠病学
·
分析化学
✓ 已验证
DOI
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2023
·Vol. 21
·期 1
·1-15
·
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
·
癌症治疗
·
免疫学
·
药学
✓ 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）