ADAM8 antagonists(CD156 antagonists)、ANGPTL2拮抗剂(angiopoietin like 2 antagonists)、BRMS1刺激剂(BRMS1 transcriptional repressor and anoikis regulator stimulants)

治疗领域

肿瘤内分泌与代谢疾病泌尿生殖系统疾病

在研适应症

复发性卵巢癌

非在研适应症-

原研机构

University of Louisville

在研机构

University of Louisville

非在研机构-

最高研发阶段临床1/2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C28H38O6

InChIKeyDBRXOUCRJQVYJQ-CKNDUULBSA-N

CAS号5119-48-2

关联

项与 Withaferin A 相关的临床试验

NCT05610735 / Recruiting临床1/2期IIT

Combination Therapy With Liposomal Doxorubicin and Withaferin A (Ashwagandha, ASWD) in Recurrent Ovarian Cancer

The proposed study "combination therapy with liposomal doxorubicin and withaferin A (Ashwagandha, ASWD) in recurrent ovarian cancer" is focused to determine the feasibility and maximum tolerance dose of Ashwagandha with liposomal doxorubicin (DOXIL) in recurrent ovarian cancer patients. The study contains two parts. In part 1 (phase I), 18 patients with recurrent ovarian cancer eligible for DOXIL therapy will be recruited and three doses of Ashwagandha (2.0 g, 4.0 g and 8.0 g) in the form of tablets along with DOXIL will be evaluated for feasibility and tolerance of ASWD. In part 2 (phase II), 54 patients with recurrent ovarian cancer will be recruited and treated with DOXIL and Ashwagandha (dose determined from part 1) to evaluate the complete response (CR), partial response (PR), and stable disease (SD).

开始日期2024-05-01

申办/合作机构

The University of Missouri Health Sciences Center

CTRI/2023/07/055361 / Not yet recruiting临床2期

A Phase II Clinical Trial of Standardized Withaferin-A for the treatment of Steroid Refractory acute Graft versus Host Disease.

开始日期2023-07-31

申办/合作机构

Tata Memorial Centre

100 项与 Withaferin A 相关的临床结果

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100 项与 Withaferin A 相关的转化医学

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100 项与 Withaferin A 相关的专利（医药）

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714

项与 Withaferin A 相关的文献（医药）

2024-06-01·Phytomedicine : international journal of phytotherapy and phytopharmacology

Withaferin A, a natural thioredoxin reductase 1 (TrxR1) inhibitor, synergistically enhances the antitumor efficacy of sorafenib through ROS-mediated ER stress and DNA damage in hepatocellular carcinoma cells

Article

作者: Jin, Kaiwen ; Zhu, Ning ; Zhou, Zhiyi ; Wang, Jiabing ; Zhang, Ye ; Chen, Xi ; Chen, Guang ; Wu, Yajie ; Zhang, Yuxuan

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.

2024-04-01·Journal of ethnopharmacology

Withania somnifera root extract inhibits MGO-induced skin fibroblast cells dysfunction via ECM-integrin interaction

Article

作者: Chen, Chunyu ; Lin, Yingying ; Liu, Yanhong ; Yi, Fan ; Xiao, Peigen ; Cai, Shaochun ; Li, Li ; Liu, Xiaoxing ; Li, Dongcui

ETHNOPHARMACOLOGICAL RELEVANCE:

Withania somnifera (L.) Dunal, known as Ashwagandha, has long been used in traditional medicine in Ayurveda, India, a representative adaptogen. The main active constituents of W. somnifera are withanolides, and the root is often used as a medicine with a wide range of pharmacological activities, which can be used to treat insomnia, neurasthenia, diabetes mellitus and skin cancer.

AIM OF THE STUDY:

Whole-component qualitative and quantitative analyses were performed on W. somnifera. We explored the ameliorative effect of the adaptogen representative plant W. somnifera on the senescence events of MGO-injured fibroblasts and its action mechanism and verified the hypotheses that WS can inhibit the accumulation of AGEs and regulate the dynamic balance among the components of the ECM by modulating the expression of integrin β1 receptor; as a result, WS maintains cellular behavioural and biological functions in a normal range and retards the aging of skin from the cellular level.

MATERIALS AND METHODS:

In this study, the components of WS were first qualitatively and quantitatively analysed by HPLC fingerprinting and LC-MS detection. Second, a model of MGO-induced injury of CML-overexpressing fibroblasts was established. ELISA was used to detect CML expression and the synthesis of key extracellular matrix ECM protein components COL1, FN1, LM5 and TNC synthesis; CCK-8 was used to detect cell viability; EDU was used to detect cell proliferation capacity; fluorescence was used to detect cell adhesion capacity; and migration assay were used to detect cell migration capacity; qRT-PCR was used to detect the regulatory pathway TGF-β1 and MMP-2, MMP-9 in ECMs; immunofluorescence was used to detect the expression of ITGB1; and WB was used to detect the expression of COL1, FN1, LM5, Tnc, TGF-β1, MMP-2, MMP-9 and ITGB1.

RESULTS:

In total, 27 active ingredients were analysed from WS, which mainly consisted of withanolide components, such as withaferin A and withanolide A. Based on the model of MGO-induced fibroblast senescence injury, WS significantly inhibited CML synthesis. By up-regulating the expression of integrin β1, it upregulated the expression of the TGF-β1 gene, which is closely related to the generation of ECMs, downregulated the expression of the MMP-2 and MMP-9 genes, which are closely related to the degradation of ECMs, maintained the dynamic balance of the four types of ECMs, and improved cell viability as well as proliferation, migration and adhesion abilities.

CONCLUSIONS:

WS can prevent cellular behavioural dysfunction and delay skin ageing by reducing the accumulation of CML, upregulating the expression of the ITGB1 receptor, maintaining the normal function of ECM-integrin receptor interaction and preventing an imbalance between the production and degradation of protein components of ECMs. The findings reported in this study suggest that WS as a CML inhibitor can modulate ECM-integrin homeostasis and has great potential in the field of aging retardation.

2024-03-01·Journal of ethnopharmacology

Clinical pharmacokinetic evaluation of Withania somnifera (L.) Dunal root extract in healthy human volunteers: A non-randomized, single dose study utilizing UHPLC-MS/MS analysis

Article

作者: Jagtap, Shubham ; Parmar, Vijay ; Vaidya, Vidyadhar G ; Girme, Aboli ; Bhatt, Ankit ; Ganu, Gayatri ; Mulay, Vallabh ; Modi, Siddharth J ; Saste, Ganesh ; Naik, Ninad N ; Hingorani, Lal

ETHNOPHARMACOLOGICAL RELEVANCE:

Withania somnifera (L.) Dunal; (Solanaceae), commonly known as Ashwagandha, is one of the most significant medicinal herbs in 'Ayurveda', a traditional Indian medicine used for centuries with evidence in scriptures. Ashwagandha was mentioned in old Ayurvedic medical literature such as Charaka Samhita and Sushruta Samhita for improving weight and strength, with multiple citations for internal and exterior usage in emaciation and nourishing the body. Ethnopharmacological evidence revealed that it was used to relieve inflammation, reduce abdominal swelling, as a mild purgative, and treat swollen glands. The root was regarded as a tonic, aphrodisiac, and emmenagogue in the Unani tradition of the Indian medicinal system. Further, Ashwagandha has been also described as an Ayurvedic medicinal plant in the Ayurvedic Pharmacopoeia of India extending informed therapeutic usage and formulations. Despite the widespread ethnopharmacological usage of Ashwagandha, clinical pharmacokinetic parameters are lacking in the literature; hence, the findings of this study will be relevant for calculating doses for future clinical evaluations of Ashwagandha root extract.

AIM:

This study aimed to develop a validated and highly sensitive bioanalytical method for quantifying withanosides and withanolides of the Ashwagandha root extract in human plasma to explore its bioaccessibility. Further to apply a developed method to perform pharmacokinetics of standardized Withania somnifera (L.) Dunal root extract (WSE; AgeVel®/Witholytin®) capsules in healthy human volunteers.

METHODS:

A sensitive, reliable, and specific ultra-high pressure liquid chromatography-mass spectrometry (UHPLC-MS/MS) method was developed and validated for the simultaneous quantification of five major withanosides and withanolides (withanoside IV, withanoside V, withanolide A, withaferin A, and 12-deoxy-withastramonolide) in human plasma. Further for the study, eighteen healthy male volunteers (18-45 years) were enrolled in a non-randomized, open-label, single period, single treatment, clinical pharmacokinetic study and given a single dose (500 mg) of WSE (AgeVel®/Witholytin®) capsules containing not less than 7.5 mg of total withanolides under fasting condition. Later, pharmacokinetic profiles were assessed using the plasma concentration of each bioactive constituent Vs. time data.

RESULTS:

For all five constituents, the bioanalytical method demonstrated high selectivity, specificity, and linearity. There was no carryover, and no matrix effect was observed. Furthermore, the inter-day and intra-day precision and accuracy results fulfilled the acceptance criteria. Upon oral administration of WSE capsules, C_max was found to be 0.639 ± 0.211, 2.926 ± 1.317, 2.833 ± 0.981, and 5.498 ± 1.986 ng/mL for withanoside IV, withanolide A, withaferin A, and 12-deoxy-withastramonolide with T_max of 1.639 ± 0.993, 1.361 ± 0.850, 0.903 ± 0.273, and 1.375 ± 0.510 h respectively. Further, withanoside V was also detected in plasma; but its concentration was found below LLOQ.

CONCLUSION:

The novel and first-time developed bioanalytical method was successfully applied for the quantification of five bio-active constituents in human volunteers following administration of WSE capsules, indicating that withanosides and withanolides were rapidly absorbed from the stomach, have high oral bioavailability, and an optimum half-life to produce significant pharmacological activity. Further, AgeVel®/Witholytin® was found safe and well tolerated after oral administration, with no adverse reaction observed at a 500 mg dose.

项与 Withaferin A 相关的新闻（医药）

2024-01-10

·Science Daily

ALS: Blocking inflammation to reduce symptoms

In people with amyotrophic lateral sclerosis (ALS), changes in neurons appear to activate immune cells. Lowering the inflammation could reduce the symptoms of the disease, according to a new study. In people with amyotrophic lateral sclerosis (ALS), changes in neurons appear to activate immune cells. Lowering the inflammation could reduce the symptoms of the disease, according to a study led by Chantelle Sephton, a professor at Université Laval's Faculty of Medicine. ALS is caused by the loss of upper motor neurons, located in the brain, and lower motor neurons, which extend from the spinal cord to the muscles. Using a genetically modified mouse model, Chantelle Sephton and her team found that structural changes in the upper neurons occurred prior to disease symptoms. The study suggests that these morphological changes send a signal to microglia and astrocytes, the immune cells of the central nervous system. When they arrive, their effect is protective, but if they stay too long, they become toxic to neurons. This leads to a reduction in synaptic connections between motor neurons in the brain and spinal cord, which in turn results in a reduction in synaptic connections with muscles. These changes lead to atrophy and loss of motor function. Given this correlation between symptoms and immune response, the research team wondered whether it might be possible to restore synaptic connections by blocking inflammation. " We tested a semi-synthetic drug based on Withaferin A, an extract of the Ashwagandha plant, which has been used for thousands of years in traditional Indian medicine," explains CERVO Research Center affiliate Chantelle Sephton. The drug blocks inflammation and allows motor neurons to return to a more normal state. "We have noticed that neurons regenerate in the absence of activated immune cells. The dendrites of motor neurons start to grow and make connections again, increasing the number of synapses between motor neurons and muscles," reports the researcher. This seems a promising way of improving ALS symptoms, whether the disease is familial or sporadic, since both types are associated with inflammation. Other diseases where inflammation plays a role, such as Alzheimer's, could benefit from this approach. The study was published in the scientific journal Acta Neuropathologica Communications. The signatories are Mari Carmen Pelaez, Antoine Desmeules, Pauline Gelon, Bastien Glasson, Laetitia Marcadet, Alicia Rodgers, Daniel Phaneuf, Silvia Pozzi, Paul Dutchak, Jean-Pierre Julien and Chantelle Sephton.

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
复发性卵巢癌	临床2期	-	University of Louisville	2022-11-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


AACR2020	N/A	肿瘤	-	Withaferin A (Ashwagandha)	鏇廠繭選築糧鑰憲範製(糧鹽襯餘願築製觸構簾) = 衊觸範衊醖範選範壓願夢膚願蓋衊製鑰淵繭糧 (淵製鬱築膚鏇鬱襯鑰選 )	-	2020-08-15
AACR2014	N/A	胶质母细胞瘤辅助	-	Withaferin A	醖獵顧簾夢選獵範繭淵(壓襯顧夢簾夢鏇鹽顧願) = 積壓夢壓蓋醖觸窪鬱積壓蓋構膚觸鹽範醖齋獵 (糧遞顧積餘獵齋鹹鏇構 )	积极	2014-10-01
ARVO2007	N/A	-	-	Withaferin A	壓遞淵壓鹹醖觸觸艱艱(襯餘製襯艱選製遞製網) = 壓顧顧衊鑰構糧鑰憲鏇網簾獵鹹餘鹹觸鏇憲夢 (糧鏇選壓積製夢鬱糧繭 )	-	2007-05-01