NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
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2025
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IF 3.1
Li Yue,Li Hailan,Sun Minhui,Chen Hong,Xiao Yao,Wang Jieman,Zhang Yuanyuan,Fang Shuhua,Kou Junping
Silibinin (Sil) is a major bioactive component of silymarin, extracted from the fruit and seeds of Silybum marianum . Silibinin meglumine (SM) is a water-soluble derivative of silibinin that has shown significant potential in liver fibrosis. However, the potential effects and underlying mechanisms of SM on acute liver failure (ALF) are still not fully understood. This study aims to find the likely mechanism. An ALF mouse model and a cell model were established with GalN/LPS. SM was administered to mice via the tail vein or to a hepatocyte line (alpha mouse liver 12, AML12). The results showed that SM particularly lowered the mortality and improved liver pathological lesions in ALF mice. Meanwhile, SM improved the levels of GSH, SOD, TNF-α, IL-6, IL-1β, and IL-10 in the liver tissues and serum. Additionally, SM enhanced cell viability and reduced oxidative stress in vitro. In the AKT/GSK3β/Nrf2/GPX4 pathway, the subpathway of AKT/GSK3β was inhibited, and the subpathway of Nrf2/GPX4 was activated by SM both in vivo and in vitro. In addition, ferrostatin-1, a ferroptosis inhibitor, and the silencing of AKT using siRNA weakened the protective effect of SM, indicating that this process is mediated in an AKT-dependent manner. All the results suggested that SM inhibits inflammation and oxidative stress by modulating the AKT/GSK3β/Nrf2/GPX4 pathway.
研究领域:
药理学
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肝脏病学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2020
·
IF 4.845
Min Jiang,Kaiyong He,Tong Qiu,Jiahui Sun,Qi Liu,Xueqiong Zhang,Hua Zheng
We induced changes in the tumor microenvironment (TME) through the synergistic actions of two drugs used in breast cancer therapy. The anti-fibrotic drug silibinin (SLB) targets tumor-associated fibroblasts and exerts immune-mediated anti-cancer effects. IPI-549, an efficient and highly selective phosphoinositide-3-kinase-gamma (PI3Kγ) inhibitor, was applied to alter the balance of immunosuppressive cells by inhibiting PI3Kγ molecules; it also promotes anti-tumor immunity. We developed nanoparticle formulations to encapsulate both drugs into the targeting carrier aminoethyl anisamide-polyethylene glycol-polycaprolactone (AEAA-PEG-PCL) respectively. The drugs were intravenously delivered in mice and resulted in an increase in anti-tumor efficacy and apoptotic tumor tissue compared with either IPI-549 or SLB alone in 4T1 breast cancer cell-derived tumors. Furthermore, a significant reduction in regulatory T (Treg) cells and myeloid suppressor cells (MDSCs) was observed. A normalized TME structure was also observed, including angiogenesis suppression, antifibrotic effects and the inhibition of collagen formation in the tumor tissue, significantly enhancing the anti-tumor effects. In summary, this combination strategy may offer an alternative treatment for breast cancer.
研究领域:
肿瘤学
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药理学
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免疫学
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纳米医学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2022
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IF 5.988
Bai Yang,Chen Jiaqi,Hu Weijian,Wang Lei,Wu Yulian,Yu Shi’an
Background: Silibinin is widely utilized drug in various cancer treatments, though its application in cholangiocarcinoma has not yet been explored. For the first time, we evaluated the anticancer potential and underlying molecular mechanism of silibinin in treatment of cholangiocarcinoma treatment.Methods: HuCCT-1 and CCLP-1 cells were chosen to be an in vitro study model and were exposed to various concentrations of silibinin for indicated times. Cell viability was evaluated by the cell counting kit-8 (CCK-8) assay and half maximal inhibitory (IC50) concentrations were calculated. Cell proliferation capacity was determined through the use of colony formation and 5-Ethynyl-2′- deoxyuridine (EdU) assays. Cell apoptosis and cycle arrest were assessed by Live/Dead staining assay and flow cytometry (FCM). The protein levels of extracellular regulated protein kinases (ERK)/mitochondrial apoptotic pathway were evaluated through western blotting (WB). Mitochondrial membrane potential changes were determined via 5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide (JC-1). A cholangiocarcinoma cell line xenograft model was used to assess the anti-tumor activity of silibinin in vivo.Results: Inhibition of the ERK protein by silibinin led to a significant decrease in mitochondrial membrane potential, which, in turn, caused Cytochrome C to be released from the mitochondria. The activation of downstream apoptotic pathways led to apoptosis of cholangiocarcinoma cells. In general, silibinin inhibited the growth of cholangiocarcinoma cell line xenograft tumors.Conclusions: Silibinin is able to inhibit cholangiocarcinoma through the ERK/mitochondrial apoptotic pathway, which makes silibinin a potential anti-tumor drug candidate for cholangiocarcinoma treatment.
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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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2013
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IF 3.458
Pengfei Xu,Qi Yin,Jianan Shen,Lingli Chen,Haijun Yu,Zhiwen Zhang,Yaping Li
Tumor metastasis is the leading cause of breast cancer-related mortality and remains to be the principal obstacle for the successful chemotherapy of breast cancer . To block metastasis of breast cancer, silibinin-loaded lipid nanoparticles (SLNs) containing TPGS and phosphatidylcholine were designed and prepared by a thin-film hydration method. The optimized SLNs were approximately 45 nm in particle size with high stability in serum, which were further demonstrated to be efficiently uptaken by MDA-MB-231 breast cancer cells. Importantly, the SLNs could accumulate within tumor tissues with high efficiency and amounts. Compared with free silibinin , SLNs exhibited much stronger inhibitory effects on the invasion and migration of MDA-MB-231 cells through the downregulation of MMP-9 and Snail. More importantly, systematic in vivo evaluations demonstrated that SLNs treatment group resulted in 67% and 39% less pulmonary metastases formation than saline treatment group in the spontaneous and blood vessel metastasis models, respectively. Interestingly, the blank lipid nanoparticles without silibinin were also found, for the first time, to possess the efficient anti-metastatic capabilities to some extent. The biocompatibility assay reveals that SLNs treatment did not exhibit obvious systemic toxicity in two mouse models. Therefore, SLNs are the promising delivery systems against metastasis of breast cancer cells.
研究领域:
肿瘤学
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药剂学
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分子生物学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2023
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IF 5.6
La Yan,Juanyu Zhou,Lu Yuan,Jinbao Ye,Xudong Zhao,Gang Ren,Haiyang Chen
Inflammatory bowel diseases (IBDs) are characterized by chronic relapsing intestinal inflammation that causes digestive system dysfunction. For years, researchers have been working to find more effective and safer therapeutic strategies to treat these diseases. Silibinin (SIL), a flavonoid compound extracted from the seeds of milk thistle plants, possesses multiple biological activities and is traditionally applied to treat liver diseases. SIL is also widely used in the treatment of a variety of inflammatory diseases attributed to its excellent antioxidant and anti-inflammatory effects. However, the efficacy of SIL against IBDs and its mechanisms remain unclear. In this study, using Drosophila melanogaster as a model organism, we found that SIL can effectively relieve intestinal inflammation caused by dextran sulfate sodium (DSS). Our results suggested that SIL supplementation can inhibit the overproliferation of intestinal stem cells (ISCs) induced by DSS, protect intestinal barrier function, acid-base balance, and intestinal excretion function, reduce intestinal reactive oxygen species (ROS) levels and inflammatory stress, and extend the lifespan of Drosophila . Furthermore, our study demonstrated that SIL ameliorates intestinal inflammation via modulating the c-Jun N-terminal kinase (JNK) signaling pathway in Drosophila . Our research aims to provide new insight into the treatment of IBDs.
研究领域:
药理学
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免疫学
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分子生物学
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胃肠病学
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DOI
PubMed
高影响因子
Molecular Medicine Reports
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2019
·Vol. 20
·期 2
·1383-1392
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IF 1.851
Zhewen Dong,Wenxiang Zhang,Siyu Chen,Chang Liu
Hypercholesterolemia is one of the major risk factors for the occurrence and development of atherosclerosis. The most common drugs used to treat hypercholesterolemia are 3‑hydroxy‑3‑methyl‑glutaryl‑CoA reductase inhibitors, known as statins. Statins induce a beneficial increase in the levels of the low density lipoprotein receptor (LDLR) and additionally upregulate proprotein convertase subtilisin/kexin type 9 (PCSK9), which leads to LDLR degradation. This process causes a negative feedback response that attenuates the lipid lowering effects of statins. Therefore, the development of PCSK9 inhibitors may increase the lipid‑lowering functions of statins. In the present study, a drug‑screening assay was developed using the human PCSK9 promoter, based on data from a dual‑luciferase reporter assay, and the efficacies of various compounds from Traditional Chinese Medicine were examined. Among the compounds examined, SIL was demonstrated to function by targeting PCSK9. It was identified that SIL treatment decreased the expression levels of PCSK9 in HepG2 cells by decreasing the activity of the PCSK9 promoter in a dose‑and time‑dependent manner. Notably, SIL antagonized the statin‑induced phosphorylation of the p38 MAPK signaling pathway. The present study suggested that SIL may be developed as a novel PCSK9 inhibitor that may increase the efficiency of statin treatment.
研究领域:
药理学
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分子生物学
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心血管疾病
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PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Yifu Lyu,Xiuyi Yang,Lei Yang,Jinyu Dai,Huanyu Qin,Yunuo Zhou,Yunan Huang,Yanmei Wang,Di Wu,Qindai Shuai,Qilong Li,Xiaofei Xin,Lifang Yin
Lipid nanoparticle-mediated co-delivery of siRNA and small molecule holds a great potential to treat metabolic dysfunction-associated steatotic liver disease (MASLD). However, targeted delivery of therapeutics to hepatocytes remains challenging. Taking the advantage of rising low density lipoprotein receptor/very-low density lipoprotein receptor (LDLR/VLDR) levels in MASLD, the biological fate of dinonylamine-ethylene glycol chlorophosphate-1-nonanol (DNNA-COP-NA) based lipid nanoparticles (LNPs) was oriented to liver tissues via apolipoprotein E (ApoE)-LDLR/VLDLR pathway. We then adopted a three-round screening strategy to optimize the formulation with both high potency and selectivity to deliver siRNA-HIF-1α (siHIF1α) and silibinin (SLB) payloads to hepatocytes. The optimized SLB/siHIF1α-LNPs mediates great siRNA delivery and transfection of hepatocytes. In high fat diet (HFD)- and carbon tetrachloride (CCl 4 )-induced mouse models of MASLD, SLB/siHIF1α-LNPs enabled the silencing of hypoxia inducible factor-1α (HIF-1α), a therapeutic target primarily expressed by hepatocytes, leading to significantly reduced inflammation and liver fibrosis synergized with SLB. Moreover, it is demonstrated the hepatocyte-targeting delivery of SLB/siHIF1α-LNPs has the potential to restore the immune homeostasis by modulating the population of Tregs and cytotoxic T cells in spleen. This proof-of-concept study enable siRNA and small molecule co-delivery to hepatocytes through intrinsic variation of targeting receptors for MASLD therapy.
研究领域:
药学
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分子生物学
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肝病学
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纳米技术
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DOI
PubMed
高影响因子
Drug Design Development and Therapy
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2022
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IF 4.319
Rong Xu,Siyan Qiu,Jie Zhang,Xiaoli Liu,Ling Zhang,Haizhu Xing,Min You,Man Wang,Yuting Lu,Peng Zhang,Jing Zhu
Background: Silibinin (Sil), a flavonoid lignan-like natural compound derived from milk thistle seeds, has been used to treat hepatic diseases, including early-phase hepatocirrhosis and fatty liver, for many years. However, its poor water solubility limits its gastrointestinal absorption and bioavailability. It clinical use has been limited due to its slow onset of action. Faced with this problem, research on the derivatives of silibinin has been receiving much attention. Purpose: A series of silibinin derivatives with good biosafety and higher hepatoprotective activity were obtained by a safe, efficient and green chemical synthesis method. Patients and methods: First, the carbonyl group in the structure of silibinin was used to obtain silibinin Schiff base derivatives by dehydration condensation with the carboxyl group in the sulfur-containing amino acid. Next, relevant experiments were performed to characterize the structure, physical form and solubility of the derivatives. Then, toxicity tests of the derivatives were performed in LO-2 cells and SD rats to evaluate their biosafety. Finally, the anti-inflammatory and antiapoptotic activities were observed using a carbon tetrachloride (CCl 4 )-induced acute liver injury model in C57BL/6J mice using silibinin as a control. Results: The studies showed that SS and ST behaved as amorphous substances and showed a significant increase in solubility compared to silibinin. These two derivatives showed low toxicity in biosafety tests and higher bioactivity (anti-inflammatory and anti-apoptotic) than silibinin against acute liver injury induced by CCl 4 . Conclusion: Two silibinin derivatives (SS and ST) obtained by the Schiff base reaction improved the solubility of the silibinin parent nucleus in biological media with the help of the hydrophilic and amorphous morphology of the ligand. The low toxicity in vivo and in vitro ensures the biosafety of the derivatives. The hepatoprotective activity (anti-inflammatory and anti-apoptotic) was significantly improved compared to silibinin.
研究领域:
药理学
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肝病学
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药物化学
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毒理学
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产品关联
DOI
PubMed
高影响因子
ISME Journal
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2025
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IF 10
Yan Baofei,Zheng Xian,Lu Danya,Li Ting,Chen Xi,Shao Zhitao,Fu Tingming
Microbiota-associated factors are increasingly recognized as significant contributors to the progression of ulcerative colitis, and microbial modulation has emerged as an effective therapy for this condition. The herbal compound silibinin has demonstrated properties that modulate gut microbiota. Herein, we investigated the response of gut microbiota to silibinin in ameliorating colitis, using a mouse model of colitis coupled with antibiotic exposure. Results indicated that antibiotic pretreatment negated the benefits of silibinin in mice with colitis. Furthermore, fecal microbiota transplantation involving silibinin-modulated gut microbiota further substantiated the gut microbiota-dependent effects of silibinin. Within the metabolic profiles of silibinin-regulated microbiota, we identified that Alistipes-associated (R)-2,3-dihydroxy-isovalerate exhibited the most pronounced anti-inflammatory effects in vitro and demonstrated protective effects against colitis. Moreover, (R)-2,3-dihydroxy-isovalerate reinstated the protective effects of silibinin in mice with colitis under antibiotic exposure. These effects were primarily mediated via the targeting of the colonic GABA transporter 3 by (R)-2,3-dihydroxy-isovalerate. We further revealed that the retinoic acid receptor β and the retinoid-related orphan nuclear receptor γt may mediate the impact of silibinin-derived microbiota and (R)-2,3-dihydroxy-isovalerate on colitis. Additionally, the knockdown of colonic GABA transporter 3 diminished the impact of silibinin on the GABA transporter 3/retinoic acid receptor β/retinoid-related orphan nuclear receptor γt axis and colitis. Our findings highlight that (R)-2,3-dihydroxy-isovalerate, enriched from microbiota derived from silibinin, can target the GABA transporter 3/retinoic acid receptor β/retinoid-related orphan nuclear receptor γt axis, which is essential for anti-colitis properties of silibinin-regulated microbiota.
研究领域:
药理学
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微生物学
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免疫学
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胃肠病学
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代谢组学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
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2016
·Vol. 37
·期 7
·941-949
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IF 3.166
Sun Hui-ping,Su Jing-han,Meng Qing-shuo,Yin Qi,Zhang Zhi-wen,Yu Hai-jun,Zhang Peng-cheng,Wang Si-ling,Li Ya-ping
Aim: To improve the therapeutic efficacy of cancer treatments, combinational therapies based on nanosized drug delivery system (NDDS) has been developed recently. In this study we designed a new NDDS loaded with an anti-metastatic drug silibinin and a photothermal agent indocyanine green (ICG), and investigated its effects on the growth and metastasis of breast cancer cells in vitro . Methods: Silibinin and ICG were self-assembled into PCL lipid nanoparticles (SIPNs). Their physical characteristics including the particle size, zeta potential, morphology and in vitro drug release were examined. 4T1 mammalian breast cancer cells were used to evaluate their cellular internalization, cytotoxicity, and their influences on wound healing, in vitro cell migration and invasion. Results: SIPNs showed a well-defined spherical shape with averaged size of 126.3±0.4 nm and zeta potential of −10.3±0.2 mV. NIR laser irradiation substantially increased the in vitro release of silibinin from the SIPNs (58.3% at the first 8 h, and 97.8% for the total release). Furthermore, NIR laser irradiation markedly increased the uptake of SIPNs into 4T1 cells. Under the NIR laser irradiation, both SIPNs and IPNs (PCL lipid nanoparticles loaded with ICG alone) caused dose-dependent ablation of 4T1 cells. The wound healing, migration and invasion experiments showed that SIPNs exposed to NIR laser irradiation exhibited dramatic in vitro anti-metastasis effects. Conclusion: SIPNs show temperature-sensitive drug release following NIR laser irradiation, which can inhibit the growth and metastasis of breast cancer cells in vitro .
研究领域:
肿瘤学
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药剂学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2023
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IF 8.2
Liping Yin,Wenhao Duan,Yanai Chen,Danyang Chen,Yong Wang,Shuai Guo,Jianglei Qin
Serious side effects of chemotherapy drugs greatly limited the anticancer performance, while targeted drug delivery could improve the therapeutic effect and reduce side effects. In this work, biodegradable hydrogel was fabricated from pectin hydrazide (pec-H) and oxidized carboxymethyl cellulose (DCMC) for localized Silibinin delivery in lung adenocarcinoma treatment. The self-healing pec-H/DCMC hydrogel showed blood compatibility and cell compatibility both in vitro and in vivo , and could be degraded by enzymes. The hydrogel also formed fast fit for injectable applications and showed sustained drug release characteristic sensitive to pH based on acylhydrzone bond cross-linked networks. The Silibinin, as a specific lung cancer inhibiting drug targets TMEM16A ion channel, was loaded into the pec-H/DCMC hydrogel to treat the lung cancer in mice model. The results showed that the hydrogel loaded Silibinin significantly enhanced the anti-tumor efficiency in vivo and greatly reduced the toxicity of the Silibinin. Based on the dual effect of improving efficacy and reducing side effects, the pec-H/DCMC hydrogel with Silibinin loading have broad application prospects to inhibit lung tumor growth in clinic.
研究领域:
药学
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材料科学
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肿瘤学
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生物医学工程
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DOI
PubMed
高影响因子
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
·
2026
·
IF 5.2
Liangyong Shao,Xiaohan Zhang,Jiamei Xin,Baorui Li,Huiyong Lian,Jiao Xie,Kai Yu,Ye Zhang,Hao Wang
Silibinin had both anti-obesity and anti-aging effects. • The effects of Silibinin on obesity and aging were linked to the IIS pathway. • Network pharmacology and molecular docking verified Silibinin 's anti-obesity mechanism. Although silibinin (SIL), from milk thistle, has been reported to promise health promotion and disease treatment, the potential mechanism of SIL in improving obesity is still unknown. The fat accumulation was decreased by 78% and 49% in cellular and high glucose-induced (HGI) Caenorhabditis elegans ( C.elegans ) models. The decreased lipid droplets in both average size and quantity in the cytoplasm of the liver and EWATs were obtained by histology (hematoxylin & eosin) experiments. The promoted health effects in lifespan, stress ability, antioxidant ability, changed lipofuscin accumulation, pharyngeal pumping rate, and aging-related indexes of exercise were also confirmed. The increased expressions of daf-2, akt-1, daf-16, and skn-1 , combined with the downstream target genes of IIS-mediated mTOR signaling factors ( pha-4, hlh-30, lgg-1, and unc-51 ) and adipose-related factors ( nhr-49, fat-5, fat-6, and fat-7 ) in C. elegans were verified through the insulin/insulin-like growth factor-1 signaling pathway. SIL was proposed as a potential adjuvant remedy or nutraceutical for improving obesity and promoting health. Download: Download high-res image (146KB) Download: Download full-size image
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高影响因子
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