Withanone

Dar N J , Bhat J A Molecular Neurobiology, 2017, 54(7):5061-5073.

Withanone, an Active Constituent from Withania somnifera, Affords Protection Against NMDA-Induced Excitotoxicity in Neuron-Like Cells.[Reference: WebLink]

Withania somnifera has immense pharmacologic and clinical uses. Owing to its similar pharmacologic activity as that of Korean Ginseng tea, it is popularly called as Indian ginseng. In most cases, extracts of this plant have been evaluated against various diseases or models of disease. However, little efforts have been made to evaluate individual constituents of this plant for neurodegenerative disorders.
METHODS AND RESULTS:
Present study was carried out to evaluate Withanone, one of the active constituents of Withania somnifera against NMDA-induced excitotoxicity in retinoic acid, differentiated Neuro2a cells. Cells were pre-treated with 5, 10 and 20 μM doses of Withanone and then exposed to 3-mM NMDA for 1 h. MK801, a specific NMDA receptor antagonist, was used as positive control. The results indicated that NMDA induces significant death of cells by accumulation of intracellular Ca2+, generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential, crashing of Bax/Bcl-2 ratio, release of cytochrome c, increased caspase expression, induction of lipid peroxidation as measured by malondialdehyde levels and cleavage of poly(ADP-ribose) polymerase-1 (Parp-1), which is indicative of DNA damage. All these parameters were attenuated with various doses of Withanone pre-treatment.
CONCLUSIONS:
These results suggest that Withanone may serve as potential neuroprotective agent.

Journal of Biotechnology, 2013, 168(2):229-233.

Withanone as an inhibitor of survivin: A potential drug candidate for cancer therapy.[Reference: WebLink]

Survivin, the smallest inhibitor of apoptosis protein, which has been reported to be highly expressed in almost all known cancers, plays a dual role in survival as well as the proliferation of cancer cells. It inhibits apoptosis by inhibiting caspases as well as facilitating mitosis by becoming a part of chromosomal passenger complex through its BIR5 domain.
METHODS AND RESULTS:
Docking studies carried out with herbal ligand Withanone derived from roots of Withania somnifera have shown strong binding affinity of −19.1088 kJ/mol with BIR5 domain of survivin and in turn interferes with inhibitory action against caspases and may lead to apoptosis. Binding of Withanone at BIR5 domain of survivin may also interfere with chromosomal passenger complex and lead to halt the mitotic process within the cancer cell.
CONCLUSIONS:
Docking studies support various experimental outcomes and suggest Withanone as a potential candidate molecule in cancer therapy.

Cytokine, 2017:S1043466617303332.

Multifunctional neuroprotective effect of Withanone, a compound from Withania somnifera roots in alleviating cognitive dysfunction.[Reference: WebLink]

Alzheimer's disease (AD) is a chronic disorder that slowly worsens and impairs the person's memory, learning, reasoning, judgment, communication and familiar tasks with loss of orientation. AD is characterized clinically by cognitive deficit and pathologically by the deposition of β amyloid plaques, neurofibrillary tangles, associated with degeneration of the cholinergic forebrain.
METHODS AND RESULTS:
Withanone (WS-2), a compound isolated from root extract of Withania somnifera at doses administered orally/day to wistar rats for duration of 21 days showed significant improvement in the cognitive skill by inhibiting amyloid β-42 and attenuated the elevated levels of pro-inflammatory cytokines like TNF alpha, IL-1 beta, IL-6, MCP-1, Nitric oxide, lipid peroxidation and both β- and γ- secretase enzymatic activity. Administration of WS-2 also significantly reversed the decline in acetyl choline and Glutathione (GSH) activity. None of the treatments that are available today alter the underlying causes of this terminal disease. Few preliminary clinical treatments have demonstrated that some plant medicines do ameliorate and improve memory and learning in patients with mild-to-moderate AD.
CONCLUSIONS:
WS-2 showed promise in AD treatment because of cognitive benefits and more importantly, mechanisms of action with respect to the fundamental pathophysiology of the disease, not limited to the inhibition of AChE, but also include the modification of Aβ processing, protection against oxidative stress and anti-inflammatory effects.

International Journal of Biochemistry & Cell Biology, 2012, 44(3):0-504.

Withanone binds to mortalin and abrogates mortalin–p53 complex: Computational and experimental evidence.[Reference: WebLink]

Mortalin binds to p53 tumor suppressor protein and sequesters it in the cytoplasm. This results in an inhibition of the transcriptional activation and control of centrosome duplication functions of p53, thus contributing to human carcinogenesis. Abrogation of mortalin–p53 interaction and reactivation of p53 function could be a valid proposition for cancer therapy.
METHODS AND RESULTS:
In the present study, we first investigated in silico the interaction of Withanone, a withanolide with anticancer activity, with mortalin. We found that Withanone could bind to mortalin in a region, earlier predicted critical for binding to p53. Cationic rhodacyanine dye, MKT-077 has also shown to bind the same region and kill cancer cells selectively. We report the molecular dynamic simulations revealing the thermodynamic and structural stability of the Withanone–mortalin complexes. We also demonstrate the experimental evidence of abrogation of mortalin–p53 complex by Withanone resulting in nuclear translocation and functional reactivation of p53 in human cancer cells.
CONCLUSIONS:
The present study establishes a molecular interaction basis that could be used for screening and development of anticancer drugs with low toxicity to normal cells. Accurate knowledge of the 3D structure of mortalin would further enhance the potential of such analyses to understand the molecular basis of mortalin biology and mortalin based cancer therapy.