Biochanin A Ameliorates Imiquimod-Induced Psoriasis-Like Skin Inflammation in Mice by Modulating the NF-κB and MAPK Signaling Pathways.

Psoriasis is a chronic skin inflammatory disorder characterized by the hyper-activation of the immune system and the over-proliferation of epidermal keratinocytes. This study aimed to investigate the anti-psoriatic activity of Biochanin A (BCA), a phytomolecule with known anti-inflammatory and anti-cancer properties, using the IMQ-induced psoriasis-like mouse model. Network pharmacology analysis was performed to investigate the targetability of Biochanin A (BCA) against psoriasis. Psoriasis-like skin inflammation was established using BALB/c mice by topical application of IMQ (5%). BCA cream (0.3%, 1%, 3%) was applied on the skin regions every day for 6 days. The skin phenotypes-erythema and scaling were scored every day. On the 7th day, skin tissues were collected for gene expression analysis, histopathological analysis, cytokine levels determination, and western blot analysis for signaling mechanisms. The network pharmacology analysis has identified 57 common targets between psoriasis and BCA. The topical application of IMQ induced a typical psoriasis-like skin phenotype including redness, skin thickening, and plaque formation. Upon BCA treatment, the psoriasis-like symptoms were significantly reduced in a dose-dependent manner. The targets identified by the network pharmacology (MMP9, EGFR, and PTGS2) and the pro-inflammatory cytokine gene expression were found to be significantly elevated in IMQ controls, and upon BCA treatment they were found significantly reduced. The release of cytokines linked to psoriasis (IL-17A and IL-23) were significantly reduced upon BCA treatment. Furthermore, our findings demonstrated that BCA treatment alleviated the psoriasis-like symptoms via modulating NF-κB and MAPK signaling pathways. Our results demonstrate the therapeutic potential of BCA against IMQ-induced psoriasis-like skin inflammation.

Dehydrozingerone alleviates pulmonary fibrosis via inhibition of inflammation and epithelial-mesenchymal transition by regulating the Wnt/ß-catenin pathway.

In idiopathic pulmonary fibrosis (IPF), excessive collagen deposition predisposes to irreversible lung function decline, respiratory failure, and ultimately death. Due to the limited therapeutic efficacy of FDA-approved medications, novel drugs are warranted for better treatment outcomes. Dehydrozingerone (DHZ) is an analogue of curcumin that has been investigated against pulmonary fibrosis using a bleomycin-induced pulmonary fibrosis model in rats. In in vitro, TGF-ß-induced differentiation models (using NHLF, LL29, DHLF and A549 cells) were adopted to assess fibrotic markers expression and explored the mechanism of action. DHZ administration attenuated the bleomycin-induced elevation of lung index, inflammatory cell infiltrations, and hydroxyproline levels in lung tissues. Furthermore, treatment with DHZ mitigated the bleomycin-mediated elevation of extracellular matrix (ECM), epithelial-to-mesenchymal-transition (EMT), and collagen deposition markers and improved lung mechanics. In addition, treatment with DHZ significantly suppressed the BLM-induced apoptosis and rescued the BLM-induced pathological abnormalities in lung tissues. In vitro assays revealed that DHZ suppressed the expression of TGF-ß-elevated collagen deposition, EMT and ECM markers in both mRNA/protein levels. Our findings showed that DHZ has anti-fibrotic effect against pulmonary fibrosis by modulating Wnt/ß-catenin signaling, suggesting that DHZ may serve as a potential treatment option for IPF.

Targeting TGF-ß/periostin signaling by sesamol ameliorates pulmonary fibrosis and improves lung function and survival.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disorder that severely impairs lung function, by increasing lung stiffness. Sesamol, a phenolic Phyto-molecule isolated from sesame seeds, possess a rich source of protein and is known to have extensive nutritional and health effects. Here we investigated the effect of sesamol on TGF-ß/periostin-induced fibroblast differentiation in in vitro and bleomycin-induced pulmonary fibrosis in an in vivo model. Our results demonstrated that activation of (DHLF, LL29, NHLF and A549) cells with TGF-ß, elevates the epithelial to mesenchymal transition, extracellular matrix, and collagen deposition and periostin signaling marker's expression, further treatment with sesamol attenuated these markers significantly. In addition, sesamol treatment improved the TGF-ß-induced contraction and migration of cells. Mechanistic studies showed that activation of IPF cells with periostin increased the TGF-ß signaling and treatment with sesamol significantly abrogated the periostin-induced TGF-ß activation and its downstream fibrotic marker's expression. In in vivo, sesamol treatment attenuated the lung inflammation, infiltration of cells, wall thickening and the formation of fibrous bands significantly in BLM-induced fibrosis rats. Molecular studies revealed that sesamol treatment reduced the bleomycin-induced fibrotic, inflammatory, apoptotic marker's expression by modulating the TGF-ß/periostin crosstalk signaling in a dose-dependent manner. Further, treatment with sesamol dramatically improved lung function and decreased mortality. Our study first time reports the sesamol's inhibitory effects on periostin signalling. Collectively, our study demonstrated that periostin and TGF-ß seem to work in a positive-feedback loop, inducing the other, therefore, targeting TGF-ß/periostin signaling may provide a better therapeutic approach against IPF and other fibrotic disorders.

Sinigrin Attenuates the Dextran Sulfate Sodium-induced Colitis in Mice by Modulating the MAPK Pathway.

Ulcerative colitis (UC) is an intestinal inflammatory disease characterised by the loss of intestinal crypts, edema, mucosal ulceration, and infiltration of inflammatory cells in the mucosa. The current study aimed to investigate the protective and therapeutic effects of sinigrin and underlying mechanisms in a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis. DSS-induced colitis models were used to demonstrate sinigrin's therapeutic/protective action. Mice were orally administered with sinigrin (15 mg/kg or 30 mg/kg) for a period of 12 days in both prophylactic and therapeutic models. Animal weights, stool consistency, and bleeding parameters were measured throughout the experimental period. After the experimental period, colon lengths were measured, and colon tissues were harvested to determine the levels of oxidative stress-inducing factors (nitrates and MDA levels) and anti-oxidant components (GSH, SOD, and catalase). Furthermore, gene expression analysis, IL-17 levels, and inflammatory marker expressions were measured using RT-qPCR, ELISA, and immunohistochemical methods respectively. Furthermore, histopathological observations and elucidation of the mechanism of action were determined using H&E analysis and Western blot analysis. Sinigrin treatment (in both prophylactic and therapeutic models) significantly mitigated the DSS-induced body weight loss, attenuated the colon length shrinkage, and improved the disease index score (p < 0.001). Further results revealed that sinigrin's protective/therapeutic effect is associated with a significant attenuation of pro­inflammatory cytokine production (p < 0.001), reversing the anti-oxidant enzyme levels (p < 0.001) and substantial improvement (2 folds) of the disruption of the colonic morphology in colon tissues compared to DSS control. Immunohistochemical analysis showed that sinigrin treatment remarkably reduced the DSS-induced myeloperoxidase, neutrophil elastase, and CD68 expression in colon tissues. Additionally, sinigrin successfully abrogated the DSS-induced IL-17 levels (p < 0.001) and improved the colonic barrier in colon tissues. Overall, these results demonstrated that sinigrin exerts protective and therapeutic effects on DSS­induced colitis, by enhancing the anti-oxidant enzymes and suppressing the intestinal inflammatory cascade of markers by regulating the MAPK pathway.

Dehydrozingerone ameliorates thioacetamide-induced liver fibrosis via inhibition of hepatic stellate cells activation through modulation of the MAPK pathway.

Hepatic fibrosis is a progressive consequence of injury to the liver cells. Liver fibrosis causes hepatic dysfunction and also plays a key role in the pathogenesis of other chronic ailments. Dehydrozingerone (DHZ) is a half-structural analogue of curcumin and is known to have several therapeutic benefits. However, the impact of DHZ on liver fibrosis was not investigated. The current investigation attempted to determine the anti-fibrotic effect of DHZ against thioacetamide-induced liver fibrosis in rats and TGF-ß-induced differentiation in human HSC-LX2 cells and to uncover the possible mechanisms. In in-vivo, DHZ significantly reduced the TAA-induced liver index and ameliorated the liver functional parameters. TAA elevated the fibrotic marker's expression in TAA control, on the other hand, DHZ treatment significantly mitigated the same in mRNA and protein levels. Additionally, these findings were supported by histological investigations and immunohistochemistry studies of the fibrotic marker's expressions. DHZ treatment effectively reduced oxidative stress by increasing catalase activity and decreased the expression of inflammatory markers (myeloperoxidase and neutrophil-elastase) in liver tissues. Additionally, collagen staining and histological findings confirmed that DHZ administration significantly reduced TAA induced pathological deformities and elevated collagen levels. In-vitro results showed that TGF-ß-induced differentiation was suppressed by DHZ treatment in a dose-dependent manner. Mechanistic approaches in HSC-LX2 and liver tissues revealed that DHZ treatment mitigated fibrosis by modulating the MAPK-pathway. Overall, these results show that DHZ exhibited anti-fibrotic action by reducing fibrotic markers and their activities through regulation of the MAPK-pathway, suggesting that DHZ may be a promising therapeutic molecule for liver fibrosis.

Ethanolic extract of Boswellia ovalifoliolata bark and leaf attenuates doxorubicin-induced cardiotoxicity in mice.

The aim of the study was to investigate the potential protective effect of ethanolic extract of Boswellia ovalifoliolata (BO) bark and leaf against doxorubicin (DOX)-induced cardiotoxicity in mice. Ethanolic extracts of BO bark (400 mg/kg) and leaves (250 mg/kg) were given orally to mice for 9 consecutive days and DOX (15 mg/kg; i.p.) was administered on the seventh day. Extract protected against DOX-induced ECG changes. It significantly inhibited DOX-provoked glutathione depletion and accumulation of malondialdehyde. The decrease in antioxidant enzyme activities of catalase, superoxide dismutase, glutathione peroxidase in cardiac tissue were significantly (p<0.05) mitigated after treatment with BO bark and leaf extracts. Pretreatment with BO significantly (p<0.05) restored the levels of DOX-induced rise of SGPT, SGOT, serum lactate dehydrogenase and creatine kinase-MB levels. These findings suggest that ethanolic extract of BO has protective effects against DOX-induced cardiotoxicity.