AKR1B1 inhibition using NARI-29-an Epalrestat analogue-alleviates Doxorubicin-induced cardiotoxicity via modulating Calcium/CaMKII/MuRF-1 axis.

The clinical use of doxorubicin (Dox) is narrowed due to its carbonyl reduction to doxorubicinol (Doxol) implicating resistance and cardiotoxicity. Hence, in the present study we have evaluated the cardioprotective effect of AKR1B1 (or aldose reductase, AR) inhibitor NARI-29 (epalrestat (EPS) analogue) and its effect in the Dox-modulated calcium/CaMKII/MuRF1 axis. Initially, the breast cancer patient survival associated with AKR1B1 expression was calculated using Kaplan Meier-plotter (KM-plotter). Further, breast cancer, cardiomyoblast (H9c2), and macrophage (RAW 264.7) cell lines were used to establish the in vitro combination effect of NARI-29 and Dox. To develop the cardiotoxicity model, mice were given Dox 2.5 mg/kg (i.p.), biweekly. The effect of AKR1B1 inhibition using NARI-29 on molecular and cardiac functional changes was measured using echocardiography, fluorescence-imaging, ELISA, immunoblotting, flowcytometry, High-Performance Liquid Chromatography with Fluorescence Detection (HPLC-FD) and cytokine-bead array methods. The bioinformatics data suggested that a high expression of AKR1B1 is associated with significantly low survival of breast cancer patients undergoing chemotherapy; hence, it could be a target for chemo-sensitization and chemo-prevention. Further, in vitro studies showed that AKR1B1 inhibition with NARI-29 has increased the accumulation and sensitized Dox to breast cancer cell lines. However, treatment with NARI-29 has alleviated the Dox-induced toxicity to cardiomyocytes and decreased the secretion of inflammatory cytokines from RAW 264.7 cells. In vivo studies revealed that the NARI-29 (25 and 50 mg/kg) has prevented the functional, histological, biochemical, and molecular alterations induced by Dox treatment. Moreover, we have shown that NARI-29 has prevented the carbonyl reduction of Dox to Doxol in the mouse heart, which reduced the calcium overload, prevented phosphorylation of CaMKII, and reduced the expression of MuRF1 to protect from cardiac injury and apoptosis. Hence in conclusion, AKR1B1 inhibitor NARI-29 could be used as an adjuvant therapeutic agent with Dox to prevent cardiotoxicity and synergize anti-breast cancer activity.

Perillyl alcohol attenuates rheumatoid arthritis via regulating TLR4/NF-κB and Keap1/Nrf2 signaling pathways: A comprehensive study onin-vitro and in-vivo experimental models.

BACKGROUND: Rheumatoid arthritis is a chronic and idiopathic autoimmune disorder. Perillyl alcohol (POH) is a monoterpene which can be extracted from widely available essential oils and is known for its strong anti-inflammatory and anti-oxidant properties. HYPOTHESIS/PURPOSE: Recent studies have been proven that inhibitors of farnesyltransferase enzyme showed significant anti-arthritic activity. POH is one such natural molecule having anti-inflammatory and anti-oxidant properties by inhibiting farnesyltransferase enzyme which further down regulates NF-κB and Nrf2 via Ras/Raf/MAPK pathway. Also, the effect of POH against rheumatoid arthritis is not known yet. Hence, the present research was intended to assess the anti-arthritic potential of POH in-vitro and in-vivo. METHODS: The in-vitro effects of POH on RAW 264.7 cells stimulated with LPS 1 µg/ml were investigated to its potential therapeutic effects. CFA 100 µl was intradermally administered to rats for the induction of arthritis. POH 100 mg/kg and 200 mg/kg administered topically from day 1 to day 28. Paw volumes measured, radiography analysis, anti-oxidant status, Gene expression studies, western blot analysis and histological analysis were performed to check the effects of POH. RESULTS: Our in-vitro findings suggested that POH inhibits inflammation by suppressing reactive oxygen species (ROS), NF-кB and Nrf2 signaling axis. Besides this, POH also rescinded the nitrate levels, pro-inflammatory cytokine levels like IL-1ß, IL-6 and TNF-α also PGE2 and COX-2 levels induced by LPS in murine macrophages. Additionally, our in-vivo results revealed that POH conscientiously alleviated CFA induced inflammation by restoring arthritis index, body weight, nitrosative, lipid peroxidation assays. Macroscopically through measuring paw volumes and X-ray, it was evidenced that POH has decreased inflammation and bone erosion. Not only in-vitro but also in-vivo, POH has abridged cytokine levels IL-1ß, IL-6, and TNF-α. Histopathological evaluation presented POH treatment alleviated joint inflammation, pannus formation, and bone erosion significantly. Moreover, POH suppressed the protein expression of NF-кB, COX-2, iNOS and improved Nrf2, and SOD2 levels in paw tissues estimated by western blotting. CONCLUSION: POH was effective in ameliorating LPS stimulation mediated oxidative stress and pro-inflammatory cytokines in RAW 264.7 cells in-vitro and FCA induced arthritis in rats in-vivo through its anti-inflammatory effects via regulating TLR4/NF-κB and Keap1/Nrf2 signaling pathways..

Phytochemistry and polypharmacology of cleome species: A comprehensive Ethnopharmacological review of the medicinal plants.

ETHNOPHARMACOLOGICAL RELEVANCE: Cleome species in particular (C. gynandra Linn, C. viscosa Linn, C. rutidosperma DC, C. felina Linn.), commonly known as spider flowers, belong to the genus of flowering plants in Cleomaceae family. Found primarily in the African countries (Kenya, Tanzania, Egypt, South Africa, and Nigeria), Asian countries (India and Afghanistan), European countries (Italy), and also in other countries like Brazil and Austria. These plants are commonly cultivated as a vegetable crop for their nutritional benefits, and the leaves are widely consumed for their health-promoting effects. The different parts of the plants, such as leaves, seeds, flowers, and roots, are used to treat acute and chronic inflammatory disorders, hepatotoxicity, malaria, fungal diseases, and cancer. AIM OF THE STUDY: Detailed investigations in underlining the molecular mechanisms and their wide variety of effects in treating various diseases remain ambiguous. The review focuses on an in-depth discussion of studies targeting phytochemistry and polypharmacology. Thus, the review aims to recapitulate the therapeutic potential of the components of Cleome involved in the treatment of a wide variety of ailments from ancient times were collected and presented along with strategies aiming for future studies. MATERIALS AND METHODS: The information provided is collected from several scientific databases (PubMed, Elsevier, ScienceDirect) and traditional medicine books, and other professional websites. RESULTS AND CONCLUSION: Investigations and current evidence revealed that the different chemical constituents present in cleome species possess various health-promoting effects along with the aerial parts showing promising traditional uses in traditional healing and culinary. An explorative survey in the current review highlights the traditional healing effects along with a broad scope of studies that can be performed in the future.