Anti-Inflammatory and Anti-Arthritic Efficacies of an Indian Traditional Herbo-Mineral Medicine “Divya Amvatari Ras” in Collagen Antibody-Induced Arthritis (CAIA) Mouse Model Through Modulation of IL-6/IL-1β/TNF-α/NFκB Signaling
Authors: Sachin Shridhar Sakat
Deepika Joshi
Acharya Balkrishna
Kheemraj Joshi
Abhishek Gupta
Kunal Bhattacharya
Kamal Joshi
Anurag Varshney
Ravikant Ranjan
Sandeep Paudel
Journal: Frontiers in Pharmacology (2019)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: Ayurveda; Divya Amvatari Ras; cytokines; herbo-mineral formulation; in vivo studies
Affiliations: Drug Discovery and Development Division, Patanjali Research Institute, Haridwar, India., University of Patanjali, Patanjali Yog Peeth, Haridwar, India., Center for Nanotechnology and Nanotoxicology, Harvard T.H. Chan School of Public Health, Boston, MA, United States.

Abstract:  Rheumatoid arthritis (RA) is defined as a chronic autoimmune inflammatory disorder that causes damage to limb joints and progressive injuries to secondary organs. Medical practitioners prescribe Methotrexate (MTX) as standard care medicine for treating RA. However, the long-term application of MTX has shown to have adverse health-related effects. Divya Amvatari Ras (DAR), an Indian Ayurvedic herbo-mineral formulation, has been described in ancient texts to provide relief from RA inflammation associated distress. Therefore, in the present study, we explored the biocompatibility, anti-inflammatory, and anti-arthritic efficacy of DAR using in vivo and in vitro disease models. Using carrageenan (CA)-stimulated Wistar rat paw edema model, we showed a reduction in inflammation-induced paw edema at human equivalent dose of DAR. Anti-rheumatic efficacy of DAR was studied using collagen-antibody cocktail (C-Ab) Induced Arthritis (CAIA) mouse model. The onset of RA in the CAIA mice was determined using parameters such as the increase in arthritis score, and induction of disease associated lesions in the ankle and knee joints, and increase in mechanical and thermal hyperalgesia. Treatment of CAIA animals with a human equivalent dose of DAR significantly reversed the RA-associated pathogenesis. These effects were comparable with the standard of care RA drug, MTX. DAR acted at multiple levels of inflammation associated with RA to reduce progressive pathogenesis. Animal serum biochemistry showed DAR was capable of ameliorating RA induced increase in liver enzyme Alanine Aminotransferase (ALT) and pro-inflammatory cytokine interleukin 6 (IL-6). In the lipopolysaccharide stimulated THP-1 cells, DAR was found to inhibit the release of IL-6, IL-1β, TNF-α, and upstream inflammatory gene regulatory protein, NFκB. The study endorsed the anti-arthritic and anti-inflammatory activity of the Indian Traditional herbo-mineral medicine, DAR. These results also confirm that DAR was highly biocompatible and would show minimal health-related side effects than those associated with standard of care MTX. Taken together, we show that the DAR could be utilized as a promising alternative or complementary therapy for treating rheumatoid arthritis. 

Retracted: No

PubPeer comments:
 Three photos in: Front. Pharmacol. 10:659. doi: 10.3389 fphar.2019.00659 Received: 27 October 2018; Accepted: 21 May 2019; Published: 01 July 2019, seem to have previously appeared in: Sci Rep 9, 8025 (2019). https: doi.org 10.1038 s41598-019-44485-9; Received 23 October 2018; Accepted 17 May 2019; Published 29 May 2019 I have not yet looked at how these were described to see if the reflect the same results published twice or whether the images were used to represent different experiments. Update (perhaps someone can sort this): Frontiers: (B) (i) NC animal showed normal digits (yellow arrow), foot (blue arrow), and ankle (red arrow); (ii) development of digits, foot, and ankle edema in the DC animal; (iii) reduction of the digits, foot, and ankle edema in collagen antibody-induced arthritis (CAIA) mice treated with DAR; and (iv) MTX. Scientific Reports : Paw and Ankle Edema Modification by Ashwashila. (A) Normal control (NC) Balb c mice showing digits (yellow arrow), foot (blue arrow) and ankle (red arrow). (B) Development of digits, foot and ankle edema in collagen antibody-induced arthritis (CAIA) disease control (DC) animal. (C) Reduction in the inflammation of digits, foot and ankle edema in CAIA mice treated with 353u2009mg kg dose of Ashwashila (ASHW) every day for two weeks. (D) Reduction in inflammation of digits, foot and ankle edema in CAIA mice treated with 0.38u2009mg kg dose of Methotrexate (MTX) every alternate day for two weeks (MTX). *** Closeup ![file] *** Full figures ![file] , 
 #1 The present paper does cite the first author s previous Sci.Rep. paper, but only to establish the growing popularity and therefore validity of Ayurvedic products.  Traditional herbal Indian medicine or u201cAyurvedau201d is a widely accepted treatment regime in South Asia for centuries and is gaining popularity in other parts of the world, even as an alternative or additive therapy (Ravishankar and Shukla, 2007; Balkrishna et al., 2019a; Balkrishna et al., 2019b). The product promoted by the Sci.Rep paper was Ashwashilau2019, a herbo-mineral formulation containing aqueous extract of u2018Ashwagandhau2019 (Withania somnifera, family: Solanaceae) commonly known as u2018Indian Winter Cherryu2019 or u2018Indian Ginsengu2019; and dry powder of u2018Shilajitu2019 found as a blackish-brown exudate present on the rocks of the Himalayas between Arunachal Pradesh and Kashmir, in India . Conversely, the present product  contains herbal extracts of Terminalia chebula, Terminalia bellirica, Emblica officinalis, Plumbago zeylanica, Commiphora mukul, and Ricinus communis, along with herbally processed mercury (Hg) and sulfur (S) . Mercury. So the appearance of identical rodent paws in the two papers can only be attributed to coincidence. ,