Abstract
Chronic inflammation induced hyper-proliferation, and migration of keratinocytes are pathological hallmarks of psoriasis. Extracts from Sphaeranthus spp. demonstrate pharmacological activity in-vitro and in-vivo. However, the activity in modulating disease relevant pathways in psoriasis has not been reported. In the current study, a standardized herbal extract from Sphaeranthus indicus (NPS31807) was used to study the mechanistic activity under conditions of inflammation, keratinocyte proliferation and migration using cell based and gene expression assays. NPS31807 treatment reduced levels of pro-inflammatory cytokines from human macrophages and activated epidermal keratinocytes in a dose dependent manner. Treatment with NPS31807 diminished NFκB and AP-1 transcription activity in human macrophages. Lowered nuclear translocation of p65 sub-unit in macrophages by treatment confirmed reduced activity of NFκB. Gene expression profiling showed attenuated expression of genes involved with inflammation such as TNF signaling, and angiogenesis by NPS31807. Inhibition of angiogenesis and matrix metalloproteinase production in keratinocytes was confirmed using RTq-PCR assays. Pretreatment with NPS31807 led to significant reduction of STAT3 phosphorylation and mitogen induced cellular migration. NPS31807 induced inhibition of proliferative genes and BrdU uptake in epidermal keratinocytes. In summary, our study provides novel molecular insights into the anti-inflammatory, anti-migratory and anti-proliferative properties of NPS31807. In summary, NPS31807, an extract from Sphaeranthus indicus can be used as therapeutic option in inflammatory and auto-immune conditions such as psoriasis.
Highlights
Standardized herbal formulations represent an attractive therapeutic option due to their potential for synergistic action on multiple targets in disease conditions [1]
We evaluated the effect of NPS31807 on pro-inflammatory cytokine production from human monocytic cell line (THP-1) and normal human epidermal keratinocytes (NHEK), since these cells are known to release significant amount of pro-inflammatory cytokines in lesional skin
NPS31807 (1 μg/ml) treatment reduced expression of IL-8 to 3.2(±1.2)-fold (Figure 2(c)). This potent inhibition in levels of proinflammatory cytokine levels showed that NPS31807 mediates anti-inflammatory activity in macrophages and keratinocytes
Summary
Standardized herbal formulations represent an attractive therapeutic option due to their potential for synergistic action on multiple targets in disease conditions [1]. Macrophages and dendritic cells play a pivotal role by releasing pro-inflammatory cytokines, which in turn activate keratinocytes to undergo aberrant hyper-proliferation and differentiation [7]. These inflammatory and hyper-proliferative responses by immune cells and keratinocytes in psoriatic skin are largely mediated through the activation of numerous transcription (e.g. NFκB, AP-1 and CEBP-β) and growth factors (e.g. EGF, KGF) [8]. Current therapeutics such as Infliximab and Etanercept cause abrogation of cytokine mediated signaling in immune cells and keratinocytes [9, 10].
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