JOURNAL OF CONTROLLED RELEASE
·
2024
·
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
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2020
·
IF 4.389
Weiwei Wu,Lingling Wang,Siying Wang
In the present study, the silibinin (SLB) was loaded into porous starch (PS) in the form of nanoparticles (SNPS) by the liquid antisolvent precipitation (LAP) method, so as to improve its solubility and bioavailability. Firstly, the different experimental parameters on drug loading (DL) of the SLB in the LAP process were optimized through the single-factor experiments. Under the optimum conditions, the DL and the encapsulation efficiency (EE) of the SNPS were 9.49 ± 0.37 % and 89.93 ± 0.64 %, respectively. Compared with free SLB and SLB nanoparticles (SN), the SNPS had a higher solubility, and was about 180.81 ± 5.32 μg/mL in artificial gastric juice (AGJ) and was about 88.91 ± 4.14 μg/mL in artificial intestinal juice (AIJ), respectively. The in vitro release study demonstrated a slow and sustained ± release of SLB from the SNPS with the SN and free SLB as controls. The pharmacokinetic results showed that the C max and AUC (0–t) of the SNPS (87.71 ± 7.24 μg/L, 439.55 ± 8.76 μg/L*h) increased when compared with the SN (60.31 ± 8.98 μg/L, 206.51 ± 12.24 μg/L*h) and free SLB (26.08 ± 1.43 μg/L, 102.63 ± 7.15 μg/L*h), showing its ability to improve SLB’s pharmacokinetic properties.
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PubMed
高影响因子
NEUROCHEMICAL RESEARCH
·
2019
·Vol. 44
·期 8
·1818-1829
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IF 2.782
Liu Bo,Liu Weiwei,Liu Panwen,Liu Xiumin,Song Xiaoyu,Hayashi Toshihiko,Onodera Satoshi,Ikejima Takashi
Excessive physical exercise (overtraining; OT) increases oxidative stress and induces damage in multiple organs including the brain, especially the hippocampus that plays an important role in learning and memory. Silibinin, a natural flavonoid derived from milk thistle of Silybum marianum , has been reported to exert neuroprotective effect. In this study, rats were subjected to overtraining exercise, and the protective effects of silibinin were investigated in these models. Morris water maze and novel object recognition tests showed that silibinin significantly attenuated memory defects in overtrained rats. At the same time, the results of Nissl, TUNEL and SA-β-gal staining showed that silibinin reversed neuronal loss caused by apoptosis, and delayed cell senescence of the hippocampus in the overtrained rats, respectively. In addition, silibinin decreased malondialdehyde (MDA) levels which is associated with reactive oxygen species (ROS) generation. Silibinin prevented impairment of learning and memory caused by excessive physical exercise in rats, accompanied by reduced apoptosis and senescence in hippocampus cells.
研究领域:
神经科学
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药理学
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运动生理学
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2017
·Vol. 38
·期 12
·1655-1662
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IF 3.223
Dong Xin-yue,Lang Tian-qun,Yin Qi,Zhang Peng-cheng,Li Ya-ping
Breast cancer is the most vicious killer for women, and tumor metastasis is one of the leading causes of breast cancer therapy failure. In this study, a new pH-sensitive polymer (polyethylene glycol-block-poly[(1,4-butanediol)-diacrylate-β-N,N-diisopropylethylenediamine], BDP) was synthesized. Based on BDP, docetaxel/silibinin co-delivery micelles (DSMs) was constructed. DSM had a well-defined spherical shape under the transmission electron microscope with average hydrodynamic diameter of 85.3±0.4 nm, and were stable in the bloodstream but could dissociate to release the chemotherapeutic agents in the low pH environment of the endo/lysosomes in the tumor cells. Compared with free drugs, DSM displayed greatly enhanced cellular uptake, higher cytotoxicity and a stronger anti-metastasis effect against mouse breast cancer cell line 4T1. In 4T1 tumor-bearing mice treated with DSM (twice a week for 3 weeks), the inhibition rate on tumor growth and metastasis reached 71.9% and 80.1%, respectively. These results reveal that DSM might be a promising drug delivery system for metastatic breast cancer therapy.
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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DOI
PubMed
高影响因子
RSC Advances
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2017
·Vol. 7
·期 86
·54379-54390
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IF 3.108
Weiwei Wu,Yuangang Zu,Lingling Wang,Li Wang,Yuanyuan Li,Yanjie Liu,Mingfang Wu,Xiuhua Zhao,Xinxin Zhang
Silibinin (SLB) is reported to possess multiple biological activities. However, due to its poor water solubility and poor absorption after oral administration, its clinical therapeutic effects have been limited. Thus, an experiment is designed to prepare SLB nanoparticles by the liquid antisolvent precipitation (LAP) technique to improve its solubility and bioavailability. Firstly, we applied single-factor experiments to investigate the effects of various factors on the mean particle size (MPS) of SLB nanoparticles in the LAP process, and the optimal conditions obtained were: HPMC concentration 3 mg mL−1, precipitation temperature 55 °C, SLB concentration 35 mg mL−1, antisolvent/solvent volume ratio 10, dropping speed 1 mL min−1, stirring speed 800 rpm and stirring time 5 min. A SLB nanosuspension with a MPS of 132.3 nm was obtained under the optimum conditions. The SLB nanoparticles were obtained by the freeze-drying method, and characterized using various analytical techniques such as SEM, FTIR, XRD DSC, and TG. The experimental data revealed that SLB nanoparticles were transformed into an amorphous form without changing the chemical structure, and had a higher solubility, and were about 36.9 mg mL−1 (free SLB was about 0.09 mg mL−1) in artificial gastric juice (AGJ) and about 59.71 mg mL−1 (free SLB was about 0.03 mg mL−1) in artificial intestinal juice (AIJ). The dissolution rate of SLB nanoparticles was also obviously higher than that of free SLB, and was about 48.2 times and 153.8 times that of free SLB in AGJ and in AIJ. Furthermore, the results of a bioavailability study in rats showed that the Cmax value of SLB nanoparticles (398.580 ng mL−1) was apparently higher than that of free SLB (26.070 ng mL−1), and the AUC (0 → t) value of SLB nanoparticles (965.666 ng mL−1 h−1) was about 6.48 times greater than that of free SLB (149.124 ng mL−1 h−1), so the SLB nanoparticles had a higher bioavailability than free SLB. The inhibitory effect of SLB nanoparticles on HepG2 cells was also higher by lower IC50 than that of free SLB. Taken together, the present study suggests that the SLB nanoparticles can become a new oral drug formulation with high bioavailability and produce a better response for its clinical applications.
研究领域:
药剂学
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药物化学
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生物医学
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DOI
高影响因子
ACS Pharmacology & Translational Science
·
2023
·
IF 6
Baofei Yan,Xian Zheng,Yun Wang,Jingwen Yang,Xingyu Zhu,Mengmeng Qiu,Kexin Xia,Yongan Wang,Mian Li,Sipan Li,Xinai Ma,Jianjun Xie,Fengtao Li,Tingming Fu,Wei Li
Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological entity that is typically characterized by intrahepatic ectopic steatosis. Nowadays, NAFLD has surpassed viral hepatitis and become the most common chronic liver disease worldwide, which poses a great threat to human health. Silibinin (Sil), a well-known natural product, has been widely used in clinical treatment for liver disorders and exhibited therapeutic potential for NAFLD. However, the suitability of Sil for NAFLD treatment still requires further investigation due to its limited absorption and low bioavailability. This study aimed to construct a Sil-loaded liposome (Sil-Lip) to overcome the limitations of Sil, thereby enhancing its beneficial effects on NAFLD and then investigate the underlying mechanisms of action of Sil-Lip. Herein, Sil-Lip was fabricated by a well-established thin-film dispersion method and carefully characterized, followed by evaluating their therapeutic efficacy using high-fat diet-induced NAFLD mice and free fatty acid -stimulated HepG2 cells. Then, liver transcriptome analysis and 16S ribosomal RNA (16S rRNA) sequencing were utilized to elucidate the potential mechanisms of action of Sil-Lip. Our data indicated that Sil-Lip harbored good gastrointestinal tract stability, mucus layer permeation, and excellent oral absorption and bioavailability. In vivo and in vitro NAFLD models demonstrated that Sil-Lip had better effects in alleviating lipid metabolism disorders, insulin resistance, and inflammation than did Sil alone. Further investigations revealed that the beneficial effects of Sil-Lip were mediated by modulating intrahepatic insulin resistance-related and nuclear factor-kappa B (NF-κB) signaling pathways and extrahepatic gut microbiota. Our study confirmed that Sil-Lip can effectively improve the absorption and bioavailability of Sil, resultantly potentiating its ameliorative effects on NAFLD through modulating intrahepatic insulin resistance-related and NF-κB signaling pathways and extrahepatic gut microbiota.
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PubMed
高影响因子
International Journal of Nanomedicine
·
2025
·
IF 6.5
Feifei Han,Haiping Wang,Li Wang,Limei Fan,Sibei Peng,Xiaoying Hou,Xiji Shu,Binlian Sun,Yuchen Liu
Introduction Metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by excessive fat accumulation in the liver, is the most prevalent cause of chronic liver disease globally. The clinical use of pharmacological agents such as silibinin and sorafenib is limited due to poor water solubility, low bioavailability, and potential side effects, necessitating innovative therapeutic approaches.Methods In this study, we developed self-assembled, carrier-free microparticles of silibinin and sorafenib (SIL-SOR-MPs) using magnetic stirring and evaluated their therapeutic effects on MASLD both in vitro and in vivo.Results Compared to free SIL and free SOR, SIL-SOR-MPs significantly reduced lipid accumulation in HepG2 cells and effectively alleviated hepatic steatosis and liver damage in mice. Mechanistic investigations further showed that SIL-SOR-MPs more effectively down-regulated lipid synthesis genes and up-regulated genes involved in lipid oxidation.Discussion In summary, our study highlights that carrier-free SIL-SOR-MPs demonstrate the ability to reverse the progression of MASLD and present a promising therapeutic strategy.
研究领域:
药理学
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肝脏病学
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产品关联
DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2022
·
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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DOI
PubMed
高影响因子
ISME Journal
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2025
·
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
PHYSIOLOGY & BEHAVIOR
·
2019
·
IF 2.635
Panwen Liu,Lingyu Cui,Bo Liu,Weiwei Liu,Toshihiko Hayashi,Kazunori Mizuno,Shunji Hattori,Yuko Ushiki-Kaku,Satoshi Onodera,Takashi Ikejima
Alzheimer's disease (AD) is a neurodegenerative disease, mainly characterized by cognitive dysfunction and memory impairment. Due to its pathological similarities to type 2 diabetes mellitus (T2DM), such as β-amyloid deposition, oxidative stress, inflammation, disordered glucose metabolism, impaired signaling pathways of insulin and insulin-like growth factor-1 (IGF-1), we speculate that AD is another form of brain diabetes. Clarifying the relationship between T2DM and AD is important for us to better understand the exact pathological mechanisms of AD. Silibinin, a polyphenolic flavonoid extracted from the seeds of Silybum marianum , exerts hepatoprotective, anti- diabetic and neuroprotective effects. Streptozotocin (STZ), which is used to disrupt the insulin signal transduction pathway, could well mimic the sporadic AD models by intracerebroventricular (ICV) injection. Therefore, we selected ICV injection of STZ (ICV-STZ) to investigate the neuroprotective effects of silibinin in rats and to make a foundation for further exploring the relationship between AD and T2DM. ICV-STZ obviously caused memory damage, sharply reduced the number of nissl bodies and destroyed morphological structure of hippocampal neuronal cells, while silibinin attenuated the damages. Moreover, silibinin significantly decreased STZ-induced tau hyperphosphorylation (ser404) in hippocampus and cerebral cortex, markedly inhibited apoptosis of neurons induced by STZ, and up-regulated insulin signal transduction pathway. Silibinin exerts neuroprotective effect in STZ-treated rats, indicating the potential of silibinin for the treatment of AD patients with T2DM in future.
研究领域:
神经科学
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药理学
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内分泌学
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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
NEUROCHEMICAL RESEARCH
·
2016
·Vol. 41
·期 7
·1662-1672
·
IF 2.472
Song Xiaoyu,Zhou Biao,Zhang Pingping,Lei Di,Wang Yubin,Yao Guodong,Hayashi Toshihiko,Xia Mingyu,Tashiro Shin-ichi,Onodera Satoshi,Ikejima Takashi
Silibinin, a flavonoid derived from the herb milk thistle ( Silybum marianum ), has been used as a hepato-protectant in the clinical treatment of liver disease. In the present study, the effect of silibinin on lipopolysaccharide (LPS)-induced neuroinflammatory impairment in rats is investigated. Injection of LPS into lateral ventricle caused learning and memory impairment. Rats were treated with silibinin to see the effect in comparison with resveratrol as a positive control. Y-maze and Morris water maze tests showed that silibinin significantly attenuated memory damage caused by LPS treatment. At the molecular analysis, the levels of IL-1β and of IL-4 in the hippocampus were decreased and enhanced, respectively, by the treatment with silibinin. NF-κB expression was attenuated by silibinin treatment. Furthermore, generation of total reactive oxygen species (ROS) in the hippocampus was elevated in silibinin-treated groups, and so were the expressions of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB). At the same time, LPS-induced reduction of neurons in hippocampus was reversed by silibinin. In conclusion, silibinin ameliorated the impairment of learning and memory of LPS-injection rats, possibly due to the activation of ROS–BDNF–TrkB pathway in the hippocampus as well as the suppression of inflammatory response. This study gives an insight on the beneficial consequences of ROS in central nervous system. Silibinin might be a potential candidate drug for neurodegenerative diseases.
研究领域:
神经科学
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药理学
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免疫学
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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）