PHYTOMEDICINE
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2025
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IF 8.3
Xiaodong Sun,Bingqing Qin,Ai Guo,Jianjun Gui,Jingjing Weng,Junjie Ye,Shenglan Feng,Ming Sang
Background Withaferin A (WFA), a naturally occurring compound, has shown promise as a therapeutic agent for Parkinson's disease (PD), a neurodegenerative disorder associated with motor and gastrointestinal dysfunctions. However, its effects on gut microbiota metabolism remain poorly understood. Purpose This study aimed to elucidate the neuroprotective mechanisms of WFA in a PD mouse model by investigating its regulation of gut microbiota composition, metabolic pathways, and correlations with brain spatial metabolomics. Methods Human SNCA-transgenic (A53T) mice were treated with WFA and evaluated using behavioral tests, immunohistochemistry, Western blot, and ELISA to assess motor/cognitive functions and PD-related pathology. Gut microbiota composition was analyzed via 16S rRNA sequencing, while untargeted fecal metabolomics and brain spatial metabolomics were employed to identify metabolic alterations. Results WFA significantly improved motor performance, alleviated cognitive deficits, restored intestinal barrier integrity, and reduced neuroinflammation. It elevated the abundance of anti-inflammatory gut bacteria (e.g., Bifidobacterium, Dubosiella, Akkermansia ) and reversed 55 fecal metabolites linked to sphingolipid metabolism, serotonergic synapses, and neuroactive ligand- receptor interactions. Spatial metabolomics revealed WFA's regulation of sphingolipid signaling pathways, including sphingosine kinase (Sphk1), ceramidase, sphingosine 1-phosphate receptor (S1PR5), and endocannabinoid receptor CB2 expression. Correlation analysis indicated a link between brain metabolite content and gut microbiota abundance. Conclusion Our findings highlight a potential mechanism of WFA that repairs neurons by modulating the sphingolipid signaling pathway within the microbiota-gut-brain axis.
研究领域:
神经科学
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微生物学
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药理学
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代谢组学
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DOI
PubMed
高影响因子
JOURNAL OF MATERIALS SCIENCE
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2019
·Vol. 55
·期 4
·1702-1714
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IF 3.442
Shao Qi,Feng Yechen,Wang Wenwu,Wang Min,Li Binbin,El Tahchi Mario,Yin Yixia
Chemotherapeutic drugs have shown some limitations in anti-tumor treatment, such as drug resistance, high toxicity and limited regime of clinical uses. Natural products have attracted extensive attention as potential source of unmodified chemical compounds for disease treatment. Withaferin A (WA) has the potential to inhibit multiple human tumors, but it is hardly available for oral administration due to its low water solubility and its side effects. We developed a methoxy poly(ethylene glycol) (mPEG) conjugated poly( d , l -lactide- co -glycolide) (PLGA) drug carrier particles to encapsulate WA for pancreatic cancer treatment. The results showed that WA does not lose its physicochemical properties after encapsulation, and our drug carriers are completely degraded within 1 month. We used the WA-loaded mPEG–PLGA particles for pancreatic cancer cell treatment where it exhibited stronger inhibition than free drug (WA) at the early treatment stage. Our formulation of the drug carriers provides an efficient encapsulation of WA that allows it bonding with heat shock proteins, thereby reducing the expression of AKT and CDK4 proteins to induce apoptosis in cancer cells. Together, our data demonstrate that mPEG–PLGA loaded with WA can achieve the design goals for cancer therapy given its advantages of sustained release and degradation property to reduce the side effect of WA, which provides a possibility for WA to be used in clinical applications.
研究领域:
药学
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肿瘤学
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生物医学工程
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DOI
高影响因子
Bioengineered
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2021
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IF 3.269
Xia Zhao,Jing Wang,Liying Tang,Pei Li,Jing Ru,Yuzhi Bai
The study was designed to explore the effects of Withaferin A (WFA) on hyperuricemia-induced kidney injury and its action mechanism. Potassium oxonate (PO) was employed to establish the hyperuricemic mouse model. The pathological changes of renal tissue were evaluated by hematoxylin-eosin and masson trichrome staining. The levels of creatinine, blood urea nitrogen (BUN), uric acid (UA) and xanthine oxidase (XOD) were detected using corresponding commercial kits. Expressions of collagen-related and apoptosis-associated proteins in renal tissues were, respectively, evaluated by immunofluorescence and western blotting. Cell apoptosis was detected by TUNEL assay, and transporter expressions using western blotting. Followed by WFA, NRK-52E cells were treated with UA before evaluation of apoptosis and fibrosis. Results indicated that WFA ameliorated renal damage, improved kidney function, and decreased levels of creatinine, BUN, UA, and XOD in PO-induced hyperuricemic mice. Furthermore, WFA significantly prevented renal fibrosis and increased the expression of collagen-related proteins. Similarly, WFA markedly inhibited renal apoptosis, accompanied by changes of apoptosis-related proteins. Importantly, expression of transporters responsible for the secretion of organic anion transporter 1 (OAT1), OAT3, ATP-binding cassette subfamily G member 2 (ABCG2) was remarkably enhanced whereas that of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) was reduced in renal tissues of mice with hyperuricemia. In vitro study revealed that WFA notably ameliorated UA-induced cell fibrosis and apoptosis. Taken together, WFA improves kidney function by decreasing UA via regulation of XOD and transporter genes in renal tubular cells.
研究领域:
药理学
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肾病学
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分子生物学
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DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2023
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IF 4.3
Yuan Liang,Qiuyan Jiang,Haoyang Zou,Jingqi Zhao,Jie Zhang,Li Ren
Glucocorticoids have been widely applied to various clinical treatment, however some serious side effects may occur during the treatment. It is widely known that glucocorticoids produce a marked effect through binding to glucocorticoid receptor (GR). As withaferin A can provide multiple health benefits, this work aims to confirm withaferin A as a potential selective GR modulator with anti-inflammatory effect. Fluorescence polarization assay confirmed that withaferin A could steadily bind to GR with an IC 50 value of 203.80 ± 0.36 μM. Meanwhile, glucocorticoid receptor translocation of withaferin A was measured by nuclear fractionation assay. Dual luciferase reporter assay showed that withaferin A did not activate GR transcription. Furthermore, withaferin A decreased the GR-related protein expression with less side effects. The result of molecular docking showed that hydrogen-bonding and hydrophobic interactions contributed to the binding of withaferin A with GR. In addition, the GR-withaferin A complex maintained a stable binding throughout the dynamics simulation process. Enzyme-linked immunosorbent assay showed that withaferin A inhibited the production of cytokines, confirming its anti-inflammatory effect. These findings indicate that withaferin A is a potential selective GR modulator and this work may provide a research basis for developing dietary supplements and nutraceuticals against inflammation.
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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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2023
·
IF 7.9
Xi Chen,Ning Zhu,Yajie Wu,Ye Zhang,Yuxuan Zhang,Kaiwen Jin,Zhiyi Zhou,Guang Chen,Jiabing Wang
Background Sorafenib (Sora), a multi-target tyrosine kinase inhibitor, is widely recognized as a standard chemotherapy treatment for advanced hepatocellular carcinoma (HCC). However, drug resistance mechanisms hinder its anticancer efficacy. Derived from Withania somnifera , Withaferin A (WA) exhibits remarkable anti-tumor properties as a natural bioactive compound. This study aimed to examine the mechanisms that underlie the impacts of Sora and WA co-treatment on HCC. Methods Cell proliferation was evaluated through colony formation and MTT assays. Flow cytometry was employed to determine cellular apoptosis and reactive oxygen species (ROS) levels. The evaluation of apoptosis-related protein levels, DNA damage, and endoplasmic reticulum stress was conducte utilizing IHC staining and western blotting. Moreover, the caspase inhibitor Z-VAD-FMK, ATF4 siRNA, ROS scavenger N-acetyl cysteine (NAC), and TrxR1 shRNA were used to elucidate the underlying signaling pathways. To validate the antitumor effects of Sora/WA co-treatment, in vivo experiments were ultimately executed using Huh7 xenografts. Results Sora/WA co-treatment demonstrated significant synergistic antitumor impacts both in vivo and in vitro . Mechanistically, the enhanced antitumor impact of Sora by WA was achieved through the inhibition of TrxR1 activity, resulting in ROS accumulation. Moreover, ROS generation induced the activation of DNA damage and endoplasmic reticulum (ER) stress pathways, eventually triggering cellular apoptosis. Pre-treatment with the antioxidant NAC significantly inhibited ROS generation, ER stress, DNA damage, and apoptosis induced by Sora/WA co-treatment. Additionally, the inhibition of ATF4 by small interfering RNA (siRNA) attenuated Sora/WA co-treatment-induced apoptosis. In vivo , Sora/WA co-treatment significantly suppressed tumor growth in HCC xenograft models and decreased TrxR1 activity in tumor tissues. Conclusion Our study suggests that WA synergistically enhances the antitumor effect of Sora, offering promising implications for evolving treatment approaches for HCC.
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
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2018
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IF 2.559
Shuxian Xia,Yinglei Miao,Side Liu
Withaferin A (WA) is an active steroidal lactone derived from the herbal plant Withania somnifera , which exhibits antitumor activity with reactive oxygen species (ROS) modulating in a variety of cancer models, such as breast cancer, lung cancer and pancreatic cancer. However, to the best of our knowledge, the direct effect and mechanism of WA on CRC cells has not been previously determined. The present study investigated the anti-tumor effects of WA on CRC cells in vitro, and explored the mechanisms of action. The flow cytometry was applied for detecting the accumulation of ROS with the treatment of withaferin A. We performed the flow cytometry and western blot to evaluate the withaferin A induced apoptosis and cell cycle arrest in human colon cancer cells. And to verify the ROS accumulation induced mitochondrial dysfunction after the treatment of withaferin A, fluorescence microscope and western blot were applied. WA exerted a dose-dependent cytotoxic effect on HCT-116 and RKO cells. The effect was associated with ROS-mediated cell cycle arrest and the expression of apoptotic proteins. In addition, WA promoted ROS production and decreased mitochondrial membrane potential accompanying with mitochondrial dysfunction. Taken together, these results strongly indicated that WA directly inhibits cell growth and induces apoptosis in CRC cells through ROS-mediated mitochondrial dysfunction and JNKs pathway, and WA may be a promising potential candidate for therapeutic application of CRC.
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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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
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IF 11.3
Chenghu Xie,Cunxin Zhang,Ying Zhang,Liyi Chen,Xiao He,Xinzhou Xie,Kang Li,Xiaodong Wang,Chaoliang Lv
Virtual screening and experimental validation identified Withaferin A as a candidate therapy for spinal cord injury. • Withaferin A attenuates NF‑κB signaling by reducing p65 phosphorylation and promoting an anti‑inflammatory macrophage phenotype. • Molecular modeling and experimental validation confirm covalent binding of Withaferin A to p65 Cys160 via Michael addition. • Withaferin A enhances neuronal regeneration, restores motor function, preserves axonal integrity, and promotes angiogenesis in SCI mice. Background Spinal cord regeneration after injury remains a major clinical challenge due to the persistent inflammatory microenvironment associated with immune cell infiltration. Withaferin A (WA), a natural anti-inflammatory steroidal lactone with potential NF-κB-modulating activity, was identified by network-based screening as a candidate for spinal cord injury (SCI) and selected for further study. Purpose This study aimed to identify and evaluate potential anti-inflammatory small-molecule therapeutics for SCI using a network-based drug screening strategy. Study Design Experimental study combining computational drug screening, in vitro macrophage assays and in vivo SCI mouse models. Methods Network pharmacology identified 296 candidate drugs targeting 113 SCI-related genes. Five top candidates, selected for chemical diversity and accessibility, were tested in LPS-stimulated in vitro models for effects on macrophage polarization and cytokine release. Molecular docking was used to predict drug–target interactions. The lead compound, WA, was then evaluated in SCI mice for inflammation, angiogenesis, neuroregeneration and motor recovery. Results WA showed the strongest anti-inflammatory activity, dose-dependently inhibiting LPS-induced M1 polarization and TNF-α/IL-6 secretion while promoting M2 polarization and IL-4/IL-10 secretion. Integrated computational and experimental analyses identified Cys160 in a hydrophobic pocket of NF-κB p65 as the covalent binding site of WA. In vivo , WA modulated macrophage polarization, reduced inflammatory mediator secretion, increased VEGF immunoreactivity and promoted neuroregeneration and motor recovery. Conclusion WA exerts significant anti-inflammatory and neuroregenerative effects in SCI models. It also increases VEGF immunoreactivity, suggesting a potential pro-angiogenic effect after injury. These findings support WA as a promising therapeutic candidate for SCI. Download: Download high-res image (272KB) Download: Download full-size image
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DOI
PubMed
高影响因子
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