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Withaferin A is known to regulate this receptor by activating or suppressing its activity and thus modulate the nuclear receptor-mediated transcriptional activation [1,37,38,42].
The study by Lee and colleagues is opening new avenues and a promising therapeutic approach in the treatment of metabolic syndrome which constitutes obesity, diabetes, fatty liver disease and hypertension [1,2]. Leptin, a satiety hormone is involved in the regulation of various metabolic and physiological parameters such as food intake, energy expenditure, reproduction, immune function and glucose homeostasis [1,45].
Thus, reduced leptin signaling leads to an excessive intake of food leading to obesity [46,47]. Here, authors show that increased ER stress in hypothalamic neurons leads to leptin resistance and obesity [1,47].
It was observed that celastrol increased leptin sensitivity by reducing diet-induced ER stress and leptin resistance [1,48].
They have also elucidated the leptin sensitization role of Withaferin A. Withania Somnifera plant. Furthermore, Withaferin A also increased the potency of leptin. Thus, Withaferin A was shown to reduce diet-induced ER stress and block reduction in energy expenditure and thereby improve glucose homeostasis in obese mice .
It is well known that leptin has pivotal roles in obesity but there are no developments in leptin centric obesity treatment until now. It is known that gradually over the course of past two-decade, a ray of hope for leptin-oriented treatment of obesity is diminished and many scientists attempted to resensitize the brain to treat the people with obesity but, they failed [42,45—47]. Here, in this study authors discusses about unsuccessful efforts of scientists on leptin resensitizing effects in the brain of obese people.
Withaferin A was also shown to block reduction in energy expenditure in DIO mice when compared to vehicle. Furthermore, the effect of this compound was analyzed on the glucose metabolism by glucose tolerance test GTT and insulin tolerance test ITT. In addition, DIO mice treated with Withaferin A showed a greater response to insulin when compared to mice treated with vehicle.
Withaferin A had no effect on the lean mice. Based on current study and its LXR-a ligand functions it can be also used in the treatment of other constituents of metabolic syndrome such as cardiovascular disease, dyslipidemia etc.
The schematic representation of multiple therapeutic targets of Withaferin A. References  J. Lee, J. Liu, X. Feng, et al. Piao, Z. Canguo, L. Wenjie, et al. Ven Murthy, P. Ranjekar, C. Ramassamy, M.
Agents Med. Singh, M. Bhalla, P. Gilca, An overview on Ashwagandha: a Rasayana rejuvenator of ayurveda, Afr.
Mishra, B. Singh, S. Winters, Ancient medicine, modern use: Withania somnifera and its potential role in integrative oncology, Altern. Tiwari, S. Chakraborty, M.
Saminathan, K. Dhama, S. Singh, Ashwagandha Withania somnifera : role in safeguarding health, immunomodulatory effects, combating infections and therapeutic applications: a review, J.
Mishra, V. Tiwari, Natural products: an evolving role in future drug discovery, Eur. Ji, X. Li, H. Zhang, Natural products and drug discovery. EMBO Rep. Beutler, Natural products as a foundation for drug discovery, Curr.
Gupta, R. Goel, A. Agarwal, M. Asif, N. Sangwan, R. Sangwan, P. Kumar Trivedi, Comparative transcriptome analysis of different chemotypes elucidates withanolide biosynthesis pathway from medicinal plant Withania somnifera, Sci.
Kataria, N. Shah, S. Beverly, D. Neville, and R. Science — Wenger, V. Butler, E. Haber, and T. Lechat, M.
Mudgett-Hunter, M. Margolies, E. Goldstein, A.
Fuccello, D. Norman, C. Shield, R. Colvin, and A. Transplantation 42 5 Steinman, J. Rosenbaum, S. Sriram, and H. USA — Waldor, S. Sriram, H. McDevitt, and L. Adelman, D. Watling, and H. Wofsy and W. Sriram, R. Hardy, L. Herzenberg, L. Lanier, M. Lim, and L. Clift and R. Cobbold, G. Martin, S. Qin, and H. Steinman, I.
Mellman, W. Muller, and Z. Pearse and M. Shen and H. Diener, U. Like The Mystery Method , it gives both the theory and the practice of the act of seduction.
The book is designed to be read in parallel with the Routines Manual.
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