PHYTOMEDICINE
·
2025
·
IF 8.3
Xue Yang,Jinni Yang,Anhui Wang,Yuan Zheng,Jiachun Lin,Ziwen Kong,Yuan Tian,Haijuan Dong,Zunjian Zhang,Rui Song
Background : Ulcerative colitis (UC) has demonstrated an escalating global incidence and prevalence, thereby posing substantial challenges to public health. Despite recent advancements in therapeutic interventions, the clinical management of UC remains suboptimal, underscoring the urgent need for novel treatment strategies. Saikosaponin A (SSa), a bioactive compound derived from the traditional Chinese herb Radix Bupleuri (RB), exhibits potent anti-inflammatory and immunomodulatory effects. However, its effects on UC and the underlying molecular mechanisms remain to be thoroughly explored. Purpose : This study aims to elucidate the underlying mechanisms of SSa in ameliorating UC and establish a pharmacological foundation for developing novel treatment modalities to address unmet clinical needs in UC treatment. Methods : The protective effects of SSa against DSS-induced acute colitis were evaluated in a 3% DSS-treated mouse model. Histological (H&E staining) and molecular analyses (RT-qPCR, ELISA, Western blotting, and flow cytometry) were performed to assess colonic tissue damage and inflammatory responses. Macrophage depletion via tail vein injection of clodronate liposomes confirmed the pivotal role of macrophages in UC pathogenesis and SSa's anti-inflammatory effects. The inhibitory effects of SSa on NLRP3 inflammasome activation were analyzed in vivo and in LPS/ATP-stimulated bone marrow-derived macrophages (BMDMs) using RT-qPCR, ELISA, and Western blotting. Bioinformatics analysis, targeted LC-MS/MS, and molecular docking were employed to identify potential molecular targets and mechanisms of SSa. Drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and CH25H siRNA knockdown assays were used to validate CH25H as the direct target of SSa. Results : SSa effectively attenuated DSS-induced colitis in mice by alleviating colonic inflammation, preserving intestinal barrier integrity, reducing LPS translocation, and mitigating systemic organ injury in the liver and spleen. The inflammatory response of macrophages and the production of IL-1β were identified as key pathogenic components in colitis, and the clearance of macrophages significantly ameliorated colitis progression while SSa administration post-macrophage clearance did not further alter the disease phenotype. Mechanistically, SSa inhibited the NLRP3 inflammasome activation-mediated IL-1β secretion in macrophages. The sterol metabolism played a crucial role in the activation of the NLRP3 inflammasome. SSa also restored the disturbed sterol homeostasis in the colon under inflammatory conditions, especially promoted the synthesis of 25-hydroxycholesterol (25-OHC). Further investigation revealed that SSa primarily exerts its therapeutic effects by directly targeting cholesterol 25-hydroxylase (CH25H), which promotes the production of 25-OHC and inhibits macrophage NLRP3 inflammasome activation. Conclusion : This pioneering study demonstrated the therapeutic effect of SSa on DSS-induced colitis by targeting CH25H to enhance 25-OHC biosynthesis, which subsequently inhibited NLRP3 inflammasome activation in IL-1β-producing macrophages. These findings reveal a novel mechanism of SSa in UC treatment through cholesterol metabolism-regulated cascade immune modulation, providing strong pharmacological support for its development as a potential UC therapy.
研究领域:
免疫学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
NEUROSCIENCE LETTERS
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2017
·
IF 2.18
Xue-Qin Chen,Shu-Jiao Chen,Wen-Na Liang,Miao Wang,Cheng-Fu Li,Shuang-Shuang Wang,Shu-Qi Dong,Li-Tao Yi,Can-Dong Li
Accumulating studies have shown that a traditional Chinese decoction Chaihu-Shugan-San produced the antidepressant-like effects in rodents including in perimenopausal. Previous studies and our preliminary study indicated that saikosaponin A, one of the main constituents of Chaihu-Shugan-San, enhanced brain-derived neurotrophic factor (BDNF) expression in rats. Herein, this study aimed to evaluate the antidepressant-like effects of saikosaponin A in perimenopausal rats exposed to chronic unpredictable mild stress (CUMS). The sucrose preference test, novelty-suppressed feeding test and forced swimming test were performed after administration of saikosaponin A for 4 weeks. Serum corticotrophin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosterone levels, as well as hypothalamus CRH and hippocampal glucocorticoid receptor were measured. In addition, pro-inflammatory cytokines such as interleukin-1beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in the hippocampus were detected for evaluation of the neuroinflammation. Further, BDNF levels and its receptor TrkB were also determined. Our results indicated that four-week treatment with saikosaponin A increased sucrose preference, decreased latency to feed in the novelty-suppressed feeding test and reduced the immobility time in the forced swimming test. In addition, saikosaponin A restored the dsyregulation of HPA axis and neuroinflammation in rats exposed to CUMS. Moreover, saikosaponin A promoted BDNF-TrkB signaling in the hippocampus. This study demonstrates that saikosaponin A produced the antidepressant-like effects in rats, which may be mediated by restoration of neuroendocrine, neuroinflammation and neurotrophic systems in the hippocampus during perimenopausal.
研究领域:
药理学
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神经科学
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内分泌学
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精神病学
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DOI
PubMed
高影响因子
Chemical Biology & Drug Design
·
2023
·Vol. 102
·期 1
·115-125
·
IF 3
Yan Zhang,Kun Dai,Dedong Xu,Hua Fan,Nannan Ji,Di Wang,Yunlu Zhao,Rui Liu
Saikosaponin A (SSA) has been revealed to have anti-breast cancer (BC) effect. However, the association between SSA and BC glycolysis is obscure. We want to probe the function and mechanism of SSA on BC glycolysis. Kaplan–Meier plotter revealed the relationship between STAT3 and the survival curve of BC. The protein kinase B (Akt)/signal transducer and activator of transcription 3 (STAT3) pathway and the viability in cells treated with or without 0, 5, 10, and 15 μM SSA were assessed by Western blot and cell counting kit-8. The biological behaviors, lactate, and ATP contents, glucose uptake, and Akt/STAT3 pathway-related markers in BC cells treated with colivelin or SSA were evaluated using cell function experiments, kit, and Western blot. Then, the impacts of colivelin and SSA on BC cells were tested again. The overexpressions of p-STAT3 and p-Akt in BC cells were weakened by 5, 10, and 15 μM SSA. Colivelin boosted the BC cell viability and proliferation and impeded apoptosis, while SSA did the opposite. Meanwhile, colivelin intensified lactate and ATP contents, glucose uptake, and Akt/STAT3 pathway-related markers level in BC cells, while SSA was the opposite. The modulation of SSA on the biological behavior, lactate and ATP productions, glucose uptake, and Akt/STAT3 pathway was rescued by colivelin. Our research unveiled new insights into SSA as a valuable candidate therapeutic agent for weakening glycolysis, and protruded the Akt/STAT3 pathway as a latent molecular target for SSA and glycolysis modulation.
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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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Chenghao Bi,Yawei Zhao,Jinxia Wei,Wenjie Bi,Songsong Wang,Luyao Hu,Yujia Gu,Liu Yang,Huiru Liu,Liwen Han,Yubo Li
SSA alleviates poly(I:C)-induced viral-like acute lung injury. • SSA restores mitochondrial homeostasis by recovering mitophagy flux. • eIF3f is identified as a direct molecular target of SSA. • SSA inhibits p62 K48-linked ubiquitination via eIF3f to relieve mitophagy blockade. Background Acute lung injury (ALI) is marked by an exaggerated inflammatory response, elevated oxidative stress, and impaired mitochondrial function, while effective targeted therapeutic strategies remain scarce. Saikosaponin A (SSA), a major active component of Bupleurum , exhibits anti-inflammatory activity, yet its direct targets and mechanisms in viral ALI remain unclear. Purpose This study aims to determine the mechanism of action and molecular target of SSA in viral ALI. Methods Poly(I:C)-induced viral-mimetic ALI models were established in both mice and BEAS-2B cells to explore the protective effects of SSA. Mitochondrial function was evaluated by detecting mitochondrial membrane potential, mitochondrial reactive oxygen species (MitoROS) levels, mitochondrial permeability transition pore (mPTP) opening, and oxygen consumption rate (OCR). Autophagy and mitophagy flux were further assessed via Western blotting, immunofluorescence staining, transmission electron microscopy (TEM), and the mCherry-GFP-LC3B reporter assay. Potential molecular targets of SSA were identified through drug affinity responsive target stability combined mass spectrometry (DARTS-MS), cellular thermal shift assay (CETSA), molecular docking, molecular dynamics simulation, and surface plasmon resonance (SPR), followed by validation using small interfering RNA (siRNA), single guide RNA (sgRNA), and adeno-associated virus (AAV)-mediated eif3f knockdown. Results SSA significantly mitigated poly(I:C)-triggered pulmonary inflammatory responses, oxidative stress, and lung tissue injury. Mechanistically, poly(I:C) induction caused mitochondrial dysfunction and mitophagy flux blockade, accompanied by the accumulation of LC3B and p62. SSA restored mitochondrial homeostasis by restoring mitophagy flux, rather than merely activating general autophagy. Further experiments identified eIF3f as a direct binding target of SSA. SSA suppressed abnormal K48-linked ubiquitination of p62 through targeting eIF3f, thereby maintaining p62 stability and alleviating mitophagy flux blockade. Deficiency of eIF3f markedly attenuated the protective effects of SSA. Conclusion SSA alleviates viral-like ALI by targeting eIF3f to regulate p62 ubiquitination and restore mitophagy flux, thereby identifying a novel SSA-eIF3f-p62 regulatory axis. During viral acute lung injury, excessive ROS production and inflammation severely impair mitochondrial function, leading to aberrant activation of mitophagy accompanied by marked blockage of autophagic flux. SSA targets eIF3f and regulates the ubiquitination-driven accumulation of p62, thereby modulating the p62-mediated selective autophagy pathway. This regulation restores mitophagic flux, improves mitochondrial function, and ultimately alleviates acute lung injury. Download: Download high-res image (179KB) Download: Download full-size image
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DOI
高影响因子
PHYTOMEDICINE
·
2020
·
IF 4.268
Xiaotian Qi,Jing Liu,Xiaoyu Li,Mengyue Fan,Nana Huang,Rong Sun
Background Despite granulocyte colony-stimulating factor (GCSF) is widely used in clinical, cancer chemotherapy induced neutropenia (CCIN) infection and infection-related mortality is high for lack of functionally mature neutrophils . Generating functional neutrophils is new therapeutic approaches to reduce CCIN-associated infection and mortality. Saikosaponin a (SSA) is one of the major bioactive components of Radix Bupleuri (RB) and exerts immunoregulatory effects. Purpose The present study aims to investigate the efficacy and mechanism of SSA in CCIN therapy. Methods SSA was applied both in vitro and in vivo to assess the efficacy of CCIN therapy. The differentiation of neutrophils was measured by Nitroblue tetrazolium (NBT) reduction assay and Giemsa staining assay. The neutrophil differentiation related real-time transcription factors were detected by quantitative PCR (RT-qPCR) and Western Blot . Bacteria killing assay was used to assess the ability of fighting infection. Network pharmacology was employed to explore the mechanism network, and the predicted pathways were validated by Western Blot. Results We found that SSA contributed to generate functional mature neutrophils which capable of fighting infection both in vitro and in vivo . Network pharmacology prediction showed 55 pathways were predicted involved in SSA against CCIN. Further validation showed that CBL-ERK1/2 pathway was activated by SSA, which could upregulate PU.1 and CEBPβ expression leading to neutrophil differentiation. Conclusions Our findings suggest a natural regimen SSA regenerates microbicidal neutrophils to effectively reduce CCIN-associated infection via activating CBL-ERK1/2 pathway, providing a rationale for future therapeutic approaches.
研究领域:
药理学
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肿瘤学
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免疫学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2023
·
IF 3.4
Ping Yin,Xi Han,Li Yu,Huifen Zhou,Jiehong Yang,Ying Chen,Ting Zhang,Haitong Wan
Bupleurum and Paeonia are common compatibilities for the treatment of depression, most of which are used in classical prescriptions. The main active ingredients saikosaponin A (SSA) and paeoniflorin (PF) have significant therapeutic effects on poststroke depression (PSD). However, the pharmacokinetic (PK) behavior based on the combination of the two components has not been reported in rats. The aim of this study was to compare the pharmacokinetic characteristics of combined administration of SSA and PF in normal and PSD rats. Plasma samples were collected after SSA and PF were injected into the rat tail vein, and plasma pretreatments were analyzed by HPLC. Based on the concentration levels of SSA and PF in plasma, Drug and Statistics 3.2.6 (DAS 3.2.6) software was used to establish the blood drug concentration model. PK data showed that compared with the normal rats, the values of related parameters t 1/2α , AUC (0−t) , AUC (0-∞) were decreased in diseased rats, while the values of CL 1 was increased. These findings suggest that PSD can significantly affect the PK parameters of SSA-PF. This study established a PK model to explore the time-effect relationship, in order to provide experimental and theoretical support for clinical application.
研究领域:
药理学
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神经科学
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中药学
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产品关联
DOI
PubMed
高影响因子
XENOBIOTICA
·
2016
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IF 1.723
Rui-Ping Ye,Zhen-Dong Chen
1. The expression and function of P-glycoprotein (P-gp) is associated with the phenotype of multidrug resistance (MDR). Saikosaponin A (SSA) is a triterpenoid saponin isolated from Radix Bupleuri. This study was mainly designed to understand effects of SSA on MDR in MCF-7/ADR and HepG2/ADM cells.2. MDR reversal was examined as the alteration of cytotoxic drugs IC50 in resistant cells in the presence of SSA by MTT assay, and was compared with the non-resistant cells. Apoptosis and uptake of P-gp substrates in the tumor cells were detected by flow cytometry. Western blot was performed to assay the expression of P-gp.3. Our results demonstrate SSA could increase the chemosensitivity of P-gp overexpressing HepG2/ADM and MCF-7/ADR cells to doxorubicin (DOX), vincristine (VCR) and paclitaxel. SSA promoted apoptosis of MCF-7/ADR cells in the presence of DOX. Moreover, it could also increase the retention of P-gp substrates DOX and rhodamine 123 in MCF-7/ADR cells, and decrease digoxin efflux ratio in Caco-2 cell monolayer. Finally, a mechanistic study showed that SSA reduced P-gp expression without affecting hydrolytic activity of P-gp.4. In conclusion, our findings suggest that SSA could be further developed for sensitizing resistant cancer cells and used as an adjuvant therapy together with anticancer drugs to improve their therapeutic efficacies.
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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中医药学
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DOI
PubMed
高影响因子
IEEE Photonics Journal
·
2024
·Vol. 16
·期 4
·1-9
·
IF 2.1
Wenying Zhou,Xue Han,Yanjun Wu,Guochao Shi,Shiqi Xu,Mingli Wang,Wenzhi Yuan,Jiahao Cui,Zelong Li
An effective SERS-based detection method assisted by machine learning algorithm has been developed to intelligently identify the pharmacodynamic substances in traditional Chinese medicine (TCM) which aided in the quality control and identification of TCM. In this work, the ultrasensitive grating-like core-shell Ag@SiO2@Cu@moth wing (Ag@SiO2@Cu@MW) SERS platform was explored which can precisely control the intergap distances by adjusting the thickness of the SiO2 layer. This SERS platform demonstrated reproducibility and reliability, with a low relative standard deviation (RSD) of 7.38% and an enhancement factor (EF) of 2.49 × 107. The optimized Ag30@SiO2(4)@Cu20@MW substrate were then applied in the accurately analyzing pharmacodynamic substances. Specifically, the label-free SERS analysis showed the distinct spectral features for Jujuboside A, Saikosaponin A and Timosaponin A-III. Machine learning algorithms, such as principal component analysis (PCA), decision tree (DT), support vector machine (SVM), k-nearest neighbors (kNN) were employed and further in differentiating with the three pharmacodynamic substances Raman spectrum groups. These results indicate that SERS technology in combination with machine learning algorithms can not only achieve rapid and accurate detection of different types of pharmacodynamic substances, but also promote the modernization and international application of TCM.
研究领域:
分析化学
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中医药学
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生物医学工程
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）