JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Yongyan Zhu,Ao Duan,Qianqian Yu,Shuo Tian,Zishan Zhou,Ping Li,Dongmei Pan,Huaming Tao,Quanhong Zhu
Ethnopharmacological relevance Fangji Huangqi Decoction (FHD) is a classical Chinese compound formula for treating rheumatoid arthritis (RA) with satisfactory effects. FHD is reputed for its ability to tonify qi with strengthening exterior, and dispel wind while removing dampness, but its mechanisms and bioactive compounds for treating RA remain unclear. Aim of the study The aim of this study was to explore the key target and bioactive compounds that were responsible for FHD-mediated improvements in RA. Materials and methods Using network pharmacology, we discovered that cyclooxygenase-2 (COX-2) was the key target of FHD against RA. We utilized a ligand fishing technique with COX-2 immobilized magnetic beads to recognize the bioactive components that act on COX-2. Then we carried out an in vitro assay of COX-2 enzyme inhibition and in vivo assay of carrageenan-induced inflammation and collagen-induced arthritis (CIA) to validate the bioactive effects of these captured ingredients. In the CIA assay, micro-CT, hematoxylin‒eosin staining and safranin-O/fast green staining were employed to assess the influence of the captured ligand on bone damage, pathological injury and cartilage destruction, respectively. Immunohistochemistry (IHC) and enzyme-linked immunosorbent assays (ELISAs) were used to detect the expression of COX-2 target in the ankle joint. interleukin-6 (IL-6) levels in the serum were also detected by ELISA. Molecular docking was used to reveal the binding mechanism of the COX-2 protein and the captured ligand. Results Eleven ligands, including tetrandrine, fangchinoline, cyclanoline, licochalcone B, ononin, calycosin and liquiritin, were specifically bound to the COX-2 protein, as determined by ultrahigh-performance liquid chromatography–mass spectrometry (UPLC–MS), seven of which were present at high levels. One ligand, tetrandrine, not only had a great inhibitory effect on COX-2 enzyme activity but also significantly reduced carrageenan-induced inflammation. In the CIA assay, middle- and high-dose tetrandrine (25 and 50 mg/kg) had effects comparable to those of FHD and celecoxib on ameliorating RA symptoms in CIA mice via the COX-2 target. Furthermore, compared with the low-dose tetrandrine group (12.5 mg/kg), the FHD group exhibited significantly lower arthritis index scores and serum IL-6 expression, although the content of tetrandrine in FHD extract solution was approximately 0.1% of that in the low-dose tetrandrine group. Conclusions Hence, we inferred that tetrandrine was the main bioactive component responsible for the effects of FHD against RA by suppressing the expression of the COX-2 protein and inhibiting the enzyme catalytic activity of COX-2. The reason for these effects may be that tetrandrine can interact with the residue Tyr385 of COX-2, the enzymatic catalytic site of COX-2 to transform arachidonic acid (AA) to prostaglandin E2 (PGE2), and thereby reduce the production of prostaglandins and inflammatory metabolites. Moreover, in addition to tetrandrine, FHD contains other compounds that could supplement the activity of tetrandrine when FHD was used to treat RA, which is manifested the “multi-component” characteristic of how Traditional Chinese Medicine formulas treat diseases.
研究领域:
民族药理学
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药物化学
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炎症研究
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PubMed
高影响因子
Drug Design Development and Therapy
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2021
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IF 4.162
Wenqian Shang,Jing Zhang,Haibo Song,Shunfei Zhu,Aimin Zhang,Yushuang Hua,Shujun Han,Yan Fu
Background Endometrial cancer (EC) is one of the most common gynaecological malignancies, and its incidence has been rising over the past decade. Tetrandrine, a bisbenzylisoquinoline alkaloid, has been isolated from a vine used in traditional Chinese medicine, Stephania tetrandra . However, the key mechanism of tetrandrine in EC is still unclear. Purpose This research was designed to predict the molecular mechanisms of tetrandrine against EC based on network pharmacology and to further verify these predictions by in vitro experiments. Methods The potential therapeutic targets of tetrandrine against EC were predicted by using public databases. Afterwards, the protein–protein interaction (PPI) network of the common targets was constructed, and the key gene targets were obtained. Biological function and pathway enrichment analyses were performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Furthermore, molecular docking and in vitro experiments were carried out to verify the predictions. The cell counting kit‑8 (CCK‑8) assay, Hoechst 33258 staining, flow cytometry analysis, qRT-PCR, Western blot analysis and an immunofluorescence assay were performed. Results Our findings identified 111 potential therapeutic targets of tetrandrine against EC. We obtained 7 key gene targets from the PPI network analysis. Furthermore, GO enrichment analysis indicated that these targets were mainly associated with metabolic processes, responses to stimulus, and biological regulation. The KEGG pathway analysis showed that the common targets were mainly distributed in the PI3K/Akt signalling pathway. A potential interaction of tetrandrine with Akt1 was revealed by molecular docking. In addition, in vitro experiments showed that tetrandrine significantly inhibited cell proliferation and induced apoptosis in Ishikawa and HEC-1-B cells in dose- and time-dependent manners. The results also revealed that tetrandrine can downregulate the expression of Bcl-2 and upregulate the expression of Bax at the mRNA level. The mRNA levels of Akt were not significantly different in the various tetrandrine (0, 10 and 20µM) groups. However, Western blot analysis demonstrated that the protein expression ratios of p-Akt/Akt decreased at the protein level. The results were further confirmed by immunofluorescence assays. Conclusion Based on bioinformatic analysis and experimental verification, our findings demonstrated that tetrandrine exerted tumour-suppressive effects on EC by regulating the PI3K/Akt signalling pathway.
研究领域:
药理学
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肿瘤学
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分子生物学
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生物信息学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2024
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IF 4.4
Chu Simeng,Yang Wei,Lu Yujie,Li Junjie,Peng Jiamin,Liu Wenjuan,Jiang Min,Bai Gang
Introduction: Tetrandrine (Tet) is the main pharmacological component of Stephania tetrandra S. Moore, which is a well-documented traditional Chinese medicine known for its diuretic and antihypertensive properties. Unraveling the specific targets and mechanisms of Tet involved in inducing diuresis and mitigating hypertension can provide valuable insights into its therapeutic effects. This study aimed to explore the diuretic and antihypertensive targets and mechanisms of Tet using chemical biology coupled with activity analyses in vivo and in vitro.Methods: The diuretic effects of Tet were evaluated using a water-loaded mouse model. The direct target proteins for the diuretic and antihypertensive effects of Tet were determined using chemical biology. Furthermore, the molecular mechanism of Tet binding to target proteins was analyzed using a multidisciplinary approach based on the structure and function of the proteins. Finally, the effects of the Tet-targeted protein on downstream signaling pathways and blood pressure were evaluated in hypertensive model rats.Results: Tet exhibited significant antihypertensive and potassium-preserving diuretic effects. The mechanism underlying these effects involves the modulation of the enzyme activity by covalent binding of Tet to Cys423 of CYP11A1. This interaction alters the stability of heme within CYP11A1, subsequently impeding electron transfer and inhibiting aldosterone biosynthesis.Discussion: This study not only revealed the mechanism of the diuretic and antihypertensive effects of Tet but also discovered a novel covalent inhibitor of CYP11A1. These findings contribute significantly to our understanding of the therapeutic potential of Tet and provide a foundation for future research in the development of targeted treatments for hypertension.
研究领域:
药理学
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化学生物学
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心血管研究
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分子生物学
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2024
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IF 6.6
Zhengyu Fang,Peihong Lin,Rui Gao,Wenjing Yang,Aizhen Zhou,Wenying Yu
Background Tetrandrine (Tet), a bisbenzylisoquinoline alkaloid, is a potential candidate for cancer chemotherapy. However, Tet has poor aqueous solubility and a short half-life, which limits its bioavailability and efficacy. Liposomes have been widely utilized to enhance the bioavailability and efficacy of drugs.Methods In this study, Tet-loaded stealth liposomes (S-LPs@Tet) were prepared by ethanol injection method. Furthermore, physicochemical characterisation, biopharmaceutical behaviour, therapeutic efficacy, and biocompatibility of S-LPs@Tet were assessed.Results The prepared S-LPs@Tet had an average particle size of 65.57 ± 1.60 nm, a surface charge of −0.61 ± 0.10 mV, and an encapsulation efficiency of 87.20% ± 1.30%. The S-LPs@Tet released Tet in a sustained manner, and the results demonstrated that the formulation remained stable for one month. More importantly, S-LPs significantly enhanced the inhibitory ability of Tet on the proliferation and migration of lung cancer cells, and enabled Tet to escape phagocytosis by immune cells. Furthermore, in vivo studies confirmed the potential for long-circulation and potent tumor-suppressive effects of S-LPs@Tet. Moreover, ex vivo and in vivo safety experiments demonstrated that the carrier material S-LPs exhibited superior biocompatibility.Conclusion Our research suggested that S-LPs@Tet has potential applications in lung cancer treatment.
研究领域:
药剂学
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肿瘤学
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药物递送系统
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纳米技术
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DOI
PubMed
高影响因子
Applied Materials Today
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2025
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IF 6.9
Xinyan Chen,Xiao Yu,Hao Feng,Panpan Shang,Muhammad Shafiq,Zhengchao Yuan,Cheng Li,Zewen Wang,Zhenchao Liu,Yuan Yao,Mohamed EL-Newehy,Meera Moydeen Abdulhameed,Yan Xiong,Yuan Xu,Xiumei Mo
The effectiveness of tendon regeneration is impeded by an excessive inflammatory response as well as uncontrolled proliferation of fibroblasts. Transplantation of tendon substitutes which can balance inflammatory response while constrict aberrant proliferation of fibroblasts is a key to promote functional tendon regeneration. The objective of this study was to design electrospun tetrandrine-loaded polylactic acid/silk fibroin (PLLA/SF) nanofibers and then fabricate them into knitted scaffolds. Briefly PLLA micron yarns were coated with PLLA/SF nanofibers and processed into knitted scaffolds. The incorporation of tetrandrine into fibers resulted in a significant suppression of fibroblast proliferation ( p < 0.05) and promoted macrophage polarization into anti-inflammatory phenotypes, with a CD206/CD68 ratio increase of 2.5-fold compared to the control. Additionally, knitted scaffolds delayed the inflammatory response and enhanced collagen production at the repair site in vivo . Taken together, our approach of simultaneously harnessing structural and biological cues in the form of an antiproliferative and anti-inflammatory therapeutic alongside PLLA/SF-coated nanoyarns afforded knitted scaffolds. The bifunctional regulation of tetrandrine simultaneously addressing inflammation resolution and fibrotic inhibition represents a strategic advance over existing mono-functional drug-loaded scaffolds.
研究领域:
生物医学工程
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再生医学
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DOI
高影响因子
Scientific Reports
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2025
·Vol. 15
·期 1
·39418
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IF 3.9
Liu Huan,Zou Qin,Xiang Tao,Zhu Rui,Chen Zigui,Chen Rui
Subarachnoid hemorrhage (SAH) is a common cerebrovascular disease that can lead to cognitive impairment. Although tetrandrine (Tet) has been proposed as a potential therapeutic agent, its efficacy in the treatment of SAH has not been fully explored. To investigate Tet effects on SAH, a rat model was established and divided into an SAH + vehicle and an SAH + Tet group. Cognitive function and behavioral performance were assessed using the Morris water maze and open field tests. Inflammatory cytokine levels were measured by ELISA, and hippocampal injury was evaluated by hematoxylin-eosin (HE) staining. Neuronal loss was quantified using Nissl staining, while neuronal density was assessed via immunofluorescence. The expression of the TLR4/NF-κB signaling pathway related-proteins was examined by Western blotting, and 16 S rRNA sequencing was conducted to determine differences in gut microbiota composition across the groups. Tet treatment significantly reduced mNSS and SAH assessment scores in SAH rats, suggesting an improvement in neurological and cognitive function. Behavioral analysis demonstrated that Tet increased escape latency, movement speed, and total distance in the Morris water maze. Histological staining revealed attenuated hippocampal damage and decreased neuronal death in the Tet-treated group. These neuroprotective effects were accompanied by reduced expression of TLR4 and NF-κB pathway components, as well as decreased secretion of LPS, TNF-α, IL-1β, and IL-6. Notably, Tet modulated the gut microbiota, restoring microbial diversity and abundance, and this modulation was associated with changes in the CYP51 metabolic pathway. Tet improves cognitive function and reduces neuronal injury in SAH rats by regulating the gut microbiota and its associated CYP51 metabolic pathway, thereby suppressing activation of the TLR4/NF-κB signaling cascade.
研究领域:
神经科学
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药理学
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胃肠病学
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微生物组研究
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
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IF 5.6
Weixin Li,Zhuqi Huang,Yue Luo,Yaqian Cui,Mingjiang Xu,Wu Luo,Gaojun Wu,Guang Liang
Atherosclerosis (AS) is a chronic inflammatory disease. Recent studies have showed that stimulator of interferon genes (STING), an important protein in innate immunity, mediates pro-inflammatory activation of macrophages in the development of AS. Tetrandrine (TET) is a natural bisbenzylisoquinoline alkaloid isolated from Stepania tetrandra and possesses anti-inflammatory activities, with unknown effects and mechanisms in AS. In this study, we explored the anti-atherosclerotic effects of TET and investigated the underlying mechanisms. Mouse primary peritoneal macrophages (MPMs) are challenged with cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) or oxidized LDL (oxLDL). We found that pretreatment with TET dose-dependently inhibited cGAMP- or oxLDL-induced STING/ TANK-binding kinase 1 (TBK1) signaling, then suppressing nuclear factor kappa-B (NF-κB) activation and pro-inflammatory factor expression in MPMs. ApoE -/- mice were fed a high-fat diet (HFD) to develop an atherosclerotic phenotype. Administration of TET at 20 mg/kg/day significantly reduced HFD-induced atherosclerotic plaques, accompanied with decreased macrophage infiltration, inflammatory cytokine production, fibrosis, and STING/TBK1 activation in aortic plaque lesions. In summary, we demonstrate that TET inhibits STING/TBK1/NF-κB signaling pathway to reduce inflammation in oxLDL-challenged macrophages and alleviate atherosclerosis in HFD-fed ApoE -/- mice. These findings proved that TET could be a potential therapeutic candidate for the treatment of atherosclerosis-related diseases.
研究领域:
心血管疾病
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免疫学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2026
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IF 6
Sijie Zhou,Zeqi Liu,Yangrui Du,Qian Zheng,Zhiyu Du
Postoperative corneal haze, driven by aberrant TGF-β1-mediated fibrosis, remains a formidable clinical challenge following refractive surgery. Current steroid therapies are compromised by severe side effects, including steroid-induced glaucoma. Herein, we report a nanoparticle (CCB@TET) comprising a tetrandrine-loaded bovine serum albumin core and a 3-carboxyphenylboronic acid-modified chitosan shell for corneal haze prevention. The optimized nanoplatform (202 nm, +35 mV) exhibited high drug loading (39.25%) and sustained release. The shell coating endowed dual transport mechanisms: mucoadhesion via electrostatic interaction and reversible tight junction opening via occludin downregulation, facilitating enhanced transcorneal permeation. In vitro, CCB@TET suppressed human corneal stromal cell migration and myofibroblast transdifferentiation without compromising epithelial wound healing. In a rabbit transepithelial photorefractive keratectomy haze model, topical CCB@TET outperformed free tetrandrine and clinical fluorometholone, while avoiding steroid-induced intraocular pressure elevation. Mechanistically, CCB@TET was found to suppress the TGF-β1/Smad signaling cascade through ITGB6 downregulation, as revealed by transcriptomic screening and biochemical validation. This study presents a rationally designed nanoplatform for safe and effective prevention of postoperative corneal haze. Postoperative corneal haze remains a clinical challenge due to severe side effects of current anti-fibrotic agents. Herein, a core–shell nanoplatform (CCB@TET) was developed by surface-decorating tetrandrine-loaded bovine serum albumin nanoparticles with 3-carboxyphenylboronic acid-modified chitosan. The dual-functional shell enables prolonged precorneal retention via sialic acid-binding and enhanced transcorneal permeation through reversible tight junction modulation. In a rabbit Trans-PRK haze model, topical CCB@TET outperformed clinical fluorometholone in haze suppression while completely avoiding steroid-induced intraocular pressure elevation. Mechanistically, CCB@TET targets integrin β6 to block TGF-β1/Smad signaling, suppressing myofibroblast activation and restoring stromal transparency with normalized collagen arrangement. Download: Download high-res image (181KB) Download: Download full-size image
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BIOMEDICINE & PHARMACOTHERAPY
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2022
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IF 7.419
Kaifang Yi,Shuobo Liu,Peiyi Liu,Xingwei Luo,Jinfeng Zhao,Fengbin Yan,Yushan Pan,Jianhua Liu,Yajun Zhai,Gongzheng Hu
It has been recognized that colistin resistance is a growing problem that seriously impairs the clinical efficacy of colistin against bacterial infections. One strategy that has been proven to have therapeutic effect is to overcome the widespread emergence of antibiotic-resistant pathogens by combining existing antibiotics with promising non-antibiotic agents. In this work, antibiotic susceptibility testing, checkerboard assays and time-kill curves were used to investigate the antibacterial activity of the individual drugs and the potential synergistic activity of the combination. The molecular mechanisms of tetrandrine in combination with colistin were analyzed using fluorometric assay and Real-time PCR. To predict possible interactions between tetrandrine and MCR-1, molecular docking assay was taken. Finally, we evaluated the in vivo efficacy of tetrandrine in combination with colistin against MCR-positive Salmonella . Overall, the combination of tetrandrine and colistin showed significant synergistic activity. In-depth mechanistic analysis showed that the combination of tetrandrine with colistin enhances the membrane-damaging ability of colistin, undermines the functions of proton motive force (PMF) and efflux pumps in MCR-positive bacteria. The results of molecular docking and RT-PCR analyses showed that tetrandrine not only affects the expression of mcr -1 but is also an effective MCR-1 inhibitor. Compared with colistin monotherapy, the combination of tetrandrine with colistin significantly reduced the bacterial load in vivo. Our findings demonstrated that tetrandrine serves as a potential colistin adjuvant against MCR-positive Salmonella .
研究领域:
微生物学
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药理学
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传染病学
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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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2015
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IF 3.65
Lejiao Jia,Zhenyu Li,Jingyi Shen,Dandan Zheng,Xiaona Tian,Hejian Guo,Ping Chang
The objective of the study is to fabricate multifunctional mesoporous silica nanoparticles for achieving co-delivery of conventional antitumor drug paclitaxel (PTX) and the multidrug resistance reversal agent tetrandrine (TET) expecting to overcome multidrug resistance of MCF-7/ADR cells. The nanoparticles were facile to prepare by self-assemble in situ drug loading approach. Namely, PTX and TET were solubilized in the cetyltrimethylammonium bromide (CTAB) micelles and simultaneously silica resources hydrolyze and condense to form nanoparticles. The obtained nanoparticles, denoted as PTX/TET-CTAB@MSN, exhibited pH-responsive release property with more easily released in the weak acidic environment. Studies on cellular uptake of nanoparticles demonstrated TET could markedly increase intracellular accumulation of nanoparticles. Furthermore, the PTX/TET-CTAB@MSN suppressed tumor cells growth more efficiently than only delivery of PTX (PTX-CTAB@MSN) or the free PTX. Moreover, the nanoparticle loading drugs with a PTX/TET molar ratio of 4.4:1 completely reversed the resistance of MCF-7/ADR cells to PTX and the resistance reversion index was 72.3. Mechanism research showed that both TET and CTAB could arrest MCF-7/ADR cells at G1 phase; and besides PTX arrested cells at G2 phase. This nanocarrier might have important potential in clinical implications for co-delivery of multiple drugs to overcome MDR.
研究领域:
纳米技术
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药物科学
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癌症研究
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药物递送系统
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生物医学工程
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DOI
PubMed
高影响因子
BMC INFECTIOUS DISEASES
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2015
·Vol. 15
·期 1
·1-7
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IF 2.613
Zhang Zhe,Yan Jie,Xu Kaijin,Ji Zhongkang,Li Lanjuan
Background Tetrandrine is a natural chemical product purified from fourstamen stephania root which recently has been shown to act similarly as synthesized drug efflux pump inhibitor verapamil. The aim of the study is to examine whether tetrandrine could potentiate anti-tubercular drugs to which Mycobacterium tuberculosis (MTB) has turned resistant via efflux mechanisms.Methods We screened 200 MTB clinical isolates using drug sensitivity test to look for those who have turned resistant to the drugs most probably due to efflux mechanisms. We found 29 isoniazid (INH) and ethambutol (EMB) - dual resistant (IEDR) strains. Then we tested if treatment with tetrandrine or verapamil could reverse drug resistance to INH and/or EMB in IEDR isolates.Results There is a parallel resistance among EMB- and INH-resistant strains in the tested clinical isolates. Among INH-resistant strains, 65% was also EMB-resistant. This suggests an involvement of efflux mechanisms which can lead to dual drug resistance in IEDR clinical isolates. Similar to a synthesized efflux pump inhibitor verapamil, tetrandrine treatment together with INH or EMB brought down the MICs from the clinical level of drug resistance to the sensitive range of both drugs. The effective rate reached 82% among IEDR clinical isolates.Conclusion sCombinational application of tetrandrine with INH or EMB increased drug efficacy. Drugs like tetrandrine may help to reduce drug dosage thus alleviate side effects.
研究领域:
微生物学
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药理学
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传染病学
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DOI
PubMed
高影响因子
JOURNAL OF LIQUID CHROMATOGRAPHY & RELATED TECHNOLOGIES
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2014
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IF 0.638
Zhisheng Xie,Xinjun Xu,Chunyan Xie,Zhikun Liang,Mei Yang,Jieyun Huang,Depo Yang
Tetrandrine and fangchinoline were successfully separated by reversed-phase flash chromatography on a manually-packed C18 column from Radix Stephania tetrandra. After recrystallization by acetone, 13 mg of fangchinoline and 21 mg of tetrandrine were obtained from 100 mg Stephania tetrandra extract, with their relative content 98.78% and 98.19%, respectively. Their structures were characterized by UV, IR, MS, and NMR. The established method was simple, fast, and reproducible, which can be applied to the preparation of reference substances of tetrandrine and fangchinoline.
研究领域:
植物化学
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药物化学
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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）