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Rheumatoid arthritis (RA), a chronic auto-immune disease, is often result of persistent and misdirectional inflammation and cannot be effectually resolved by single-target selective drugs. Present study attempted to uncover anti-arthritic efficacy and governing molecular mechanism of BLFE and its phytoconstituents berberine and rutin, with focus on dysregulated oxi-inflammation and structural integrity during articular damage using Collagen II-CFA-induced RA mice model. NMR-based phytometabolomic analysis revealed presence of phenolics and alkaloids such as berberine and rutin. BLFE, rutin and berberine remarkably mitigated Collagen II-CFA-induced disease severity index, articular damage, immune cells influx and pannus formation. An effective decrease in levels of TNF-α, IL-6, IL-1β, IFN-γ, IL-13, IL-17, MMPs, RORγt, Ob-cadherin, Cox-2, iNOS and enhancement in IL-10, IL-4 and IL-5, BMP-6/7 was observed in BLFE, rutin and berberine treatments. Molecular mechanistic analysis demonstrated reduction in expression of p-STAT-1/3, p-PI3K, p-Akt, p-JNK, p-p38, p-IκB, p-NF-κB and β-catenin via BLFE, rutin and berberine. Furthermore, reduced activation of p-ERK and p-GSK3β and enhanced splenic Tregs was only noticed in BLFE and berberine. Thus, the signifying presence of these phytoconstituents could contribute to the above-mentioned findings. These findings imply that BLFE could be beneficial for assuaging deleterious aspects of RA mediated via perturbed inflammation., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Although Berberis plant species have been advocated as immune modulators, information regarding their mechanism(s) of action is limited. Therefore, in the present study we assessed the efficacy of Berberis lycium Royle fruit extract (BLFE) in the attenuation of lipopolysaccharide (LPS)-induced oxi-inflammatory aggravation and concanavalin A (Con-A)-induced proliferation in murine peritoneal macrophages and lymphocytes, respectively. BLFE strongly suppressed production of the oxidative and inflammatory effector molecules nitric oxide (NO), reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS), inflammatory cytokines (TNF-α/IL-6/IL-1β/IFN-γ) as well as chemokines (MCP-1 and RANTES), with a concomitant enhancement in heme oxygenase-1 (HO-1) and IL-10 levels. Subsequent mechanistic analysis revealed that BLFE strongly inhibited the phosphorylation of IκBα as well as MAPKs such as extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun NH2-terminal kinase (JNK), thereby directly resulting in the suppression of nuclear factor-κB (NF-ĸB) and c-Jun activation, ultimately culminating in the observed attenuation of inflammatory molecules. Additionally, BLFE appeared to mitigate Con-A-induced proliferation of Tregs (CD3+ CD4+ CD25+) thereby suggesting its modulatory effects on adaptive immune cells. UPLC-DAD-ESI-QTOF-MS/MS of BLFE revealed the presence of major bioactive phenolics and alkaloids including chlorogenic acid, rutin, catechin and quercetin 3-D-galactoside, berberine and magnoflorine, which could have synergistically contributed to the above findings. Overall, this work provides evidence that BLFE may be effective in the mitigation of inflammatory disorders, especially those associated with NF-κB/MAPK activation.

The present investigation assessed the potential of Prunus cerasoides fruit extract (PCFE) in alleviation of inflammatory stress in response to lipopolysaccharide (LPS) and interferon-γ (IFN-γ)-stimulated murine peritoneal macrophages as well as in concanavalin A (Con A)-activated splenic lymphocytes. We observed a strong inhibition in production of nitric oxide (NO), reactive oxygen species (ROS), inflammatory cytokines (TNF-α/IL-6/IL-1β), inducible nitric oxide synthase (iNOS), and NF-kB in macrophages treated with PCFE. Splenic lymphocytes treated with PCFE also showed a reduction in Con-A-induced cell proliferation and numbers of CD3 + CD4 + T cells. Furthermore, PCFE treatment to Con A-stimulated lymphocytes decreased the production of inflammatory cytokines (TNF-α/IL-6/IL-1β) with a concomitant increase in IL-10 suggesting its possible role in alleviation of inflammation-driven Th1/Th2 immune imbalance. PCFE appeared to influence innate immune response even at lower concentrations (25 and 50 µg/ml), while such effects were more pronounced in lymphocytes only at higher concentrations (100 and 200 µg/ml). UPLC-ESI-MS of PCFE revealed the presence of major bioactive phenolics including catechin, naringin as well as ascorbic acid which could have contributed in above findings. Overall, it is indicative that P. cerasoides fruit could be a valuable source for the development of anti-inflammatory functional foods and nutraceuticals.