Mesua assamica (King & Prain) kosterm. bark ethanolic extract attenuates rheumatoid arthritis via down-regulating TLR4/NF-κB/COX-2/iNOS and activation of Nrf2/HO-1 pathways: A comprehensive study on in-vitro and in-vivo models.

ETHNOPHARMACOLOGICAL RELEVANCE: Rheumatoid arthritis (RA) is a multifactorial, polygenic inflammatory disease. Mesua assamica (King & Prain) Kosterm. (MA) is an endangered medicinal plant indigenous to South Asia, primarily to Assam in India. The tree bark is claimed to possess anti-inflammatory, anti-diabetic, anti-cancer, and anti-malarial properties; nevertheless, its role in RA has not been elucidated. Hence, this study aims to investigate the in-vitro and in-vivo anti-arthritic effects of Mesua assamica bark ethanolic extract (MAE). AIM OF THE STUDY: This study aims to investigate the anti-rheumatic potential of MAE in-vitro on RAW 264.7 cells for its anti-oxidant and anti-inflammatory activities and in-vivo on the CFA-induced adjuvant arthritis in the rat model. MATERIALS AND METHODS: We investigated the possible therapeutic effects of MAE in-vitro using RAW 264.7 cells triggered by LPS. Meanwhile, adult Wistar rats were injected intradermally with 100 µl of CFA to induce arthritis, and they were given MAE orally at doses of 100 and 200 mg/kg for up to 28 days. Paw volume analysis, X-ray radiography, anti-oxidant levels analysis, gene and protein expression studies, and histological analysis were carried out to assess the effects of MAE in-vivo. RESULTS: MAE significantly mitigated the inflammation by reducing ROS levels and dropped the nitrite, PGE2, and COX-2 levels enhanced by LPS in-vitro. At the same time, MAE treatment reduced the paw and joint inflammation and increased the immune organ index in the CFA rats. Histopathology data revealed that MAE mitigated the CFA-induced lesions of the ankle joints and synovial tissues. Similarly, MAE significantly abated the secretion of pro-inflammatory cytokines, inhibited the protein expression of TLR4, NF-кB, COX-2, and iNOS, as well as improved the Nrf2 and HO-1 levels in-vitro and in-vivo. CONCLUSION: All the results highlighted the anti-rheumatic potential of MAE in RA in-vitro and in-vivo by inhibiting the TLR4/NF-кB/COX-2/iNOS and promoting the Nrf2/HO-1 signaling axis.

Aldose reductase and cancer metabolism: The master regulator in the limelight.

It is strongly established that metabolic reprogramming mediates the initiation, progression, and metastasis of a variety of cancers. However, there is no common biomarker identified to link the dysregulated metabolism and cancer progression. Recent studies strongly advise the involvement of aldose reductase (AR) in cancer metabolism. AR-mediated glucose metabolism creates a Warburg-like effect and an acidic tumour microenvironment in cancer cells. Moreover, AR overexpression is associated with the impairment of mitochondria and the accumulation of free fatty acids in cancer cells. Further, AR-mediated reduction of lipid aldehydes and chemotherapeutics are involved in the activation of factors promoting proliferation and chemo-resistance. In this review, we have delineated the possible mechanisms by which AR modulates cellular metabolism for cancer proliferation and survival. An in-depth understanding of cancer metabolism and the role of AR might lead to the use of AR inhibitors as metabolic modulating agents for the therapy of cancer.

Loganic acid protects against ulcerative colitis by inhibiting TLR4/NF-κB mediated inflammation and activating the SIRT1/Nrf2 anti-oxidant responses in-vitro and in-vivo.

Ulcerative colitis (UC) is an idiopathic, chronic disorder of the intestines characterized by excessive inflammation and oxidative stress. Loganic acid (LA) is an iridoid glycoside reported to have antioxidant and anti-inflammatory properties. However, the beneficial effects of LA on UC are unexplored yet. Thus, this study aims to explore the potential protective effects of LA and its possible mechanisms. In-vitro models were employed using LPS-stimulated RAW 264.7 macrophage cells, and Caco-2 cells, whereas an in-vivo model of ulcerative colitis was employed using 2.5% DSS in BALB/c mice. Results indicated that LA significantly suppressed the intracellular ROS levels and inhibited the phosphorylation of NF-κB in both RAW 264.7 and Caco-2 cells, contrarily LA activated the Nrf2 pathway in RAW 264.7 cells. In DSS-induced colitis mice, LA significantly alleviated the inflammation and colonic damage by decreasing the pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α, and IFN-γ), oxidative stress markers (MDA, and NO), and also expression levels of various inflammatory proteins (TLR4 and NF-кB) which was evidenced by immunoblotting. On the contrary, the release of GSH, SOD, HO-1, and Nrf2 were profoundly increased upon LA treatment.Subsequently, molecular docking studies showed that LA interacts with active site regions of target proteins (TLR4, NF-κB, SIRT1, and Nrf2) through hydrogen bonding and salt bridge interaction. The current findings demonstrated that LA could exhibit a protective effect in DSS-induced ulcerative colitis through its anti-inflammatory and anti-oxidant effects via inactivating the TLR4/NF-κB signaling pathway and activating the SIRT1/Nrf2 pathways.

Mesua assamica (King&Prain) kosterm. Bark ethanolic extract attenuates chronic restraint stress aggravated DSS-induced ulcerative colitis in mice via inhibition of NF-κB/STAT3 and activation of HO-1/Nrf2/SIRT1 signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Mesua Assamica (King & prain) Kosterm. (MA) is an evergreen endemic medicinal tree available in Assam in India and other parts of south Asia. The bark of the plant is traditionally used for ant-malarial activity and treating fevers. It was reported to have anti-oxidant, anti-inflammatory, anti-diabetic, anti-cancer and anti-malarial properties, but no research findings have been reported about its protective activity on intestinal inflammatory disorders like ulcerative colitis (UC) yet. AIM OF THE STUDY: The aim of the current study is to evaluate the anti-ulcerative property of ethanolic extract of MA (MAE) in-vitro on GloResponse™ NF-кB-RE-luc2P HEK 293 cells for its anti-oxidant and anti-inflammatory activities and in-vivo chronic restraint stress aggravated dextran sodium sulfate (DSS)-induced UC model. MATERIALS AND METHODS: The chemical constituents of MAE were identified by LC-MS/MS. The in-vitro effects of MAE on GloResponse™ NF-кB-RE-luc2P HEK 293 cells stimulated with TNF-α 30 ng/ml were investigated for its potential therapeutic effects. Parameters such as body weights, behavioural, colonoscopy, colon lengths and spleen weights were measured and recorded in chronic restraint stress aggravated DSS-induced UC model in C57BL/6 mice. Histological, cytokines and immunoblotting analysis in the colon tissues were determined to prove its anti-inflammatory and anti-oxidant activities. RESULTS: MAE poses significant anti-oxidant and anti-inflammatory activity in-vitro in GloResponse™ NF-кB-RE-luc2P HEK 293 cells evidenced by DCFDA and immunoflourescence assay. MAE treatment at 100 mg/kg and 200 mg/kg for 14 consecutive days has reduced Disease activity Index (DAI), splenomegaly and improved the shortened colon length and sucrose preference in mice. MAE treatment has increased the levels of anti-oxidants like GSH and reduced the levels of MDA, MPO and nitrite levels in colon tissues. Moreover, MAE has ameliorated neutrophil accumulation, mucosal and submucosal inflammation and crypt density evidenced by histopathology. Furthermore, MAE treatment significantly reduced the increased pro-inflammatory cytokines like IL-6, IL-1ß and TNF-α. we found from immunoblotting that there is a concomitant decrease in protein expression of NF-κB, STAT3 signalling cascades and phosphorylation of IKBα with an increase in Nrf2, SOD2, HO-1 and SIRT1 in colon tissues. In addition, we have performed molecular docking studies confirming that phytochemicals present in the MAE have a stronger binding ability and druggability to the NF-κB, Nrf2 and SIRT1 proteins. CONCLUSIONS: MAE exhibited significant anti-colitis activity on chronic restraint stress aggravated DSS-induced ulcerative colitis via regulating NF-κB/STAT3 and HO-1/Nrf2/SIRT1 signaling pathways.