The molecular mechanisms underlying arecoline-induced cardiac fibrosis in rats.

The areca nut is one of the most commonly consumed psychoactive substances worldwide, with an estimated consumption by approximately 10% of the world's population, especially in some regions of South Asia, East Africa, and the tropical Pacific. Arecoline, the major areca nut alkaloid, has been classified as carcinogenic to humans as it adversely affects various organs, including the brain, heart, lungs, gastrointestinal tract, and reproductive organs. Earlier studies have established a link between areca nut chewing and cardiac arrhythmias, and yet research pertaining to the mechanisms underlying cardiotoxicity caused by arecoline is still preliminary. The main purpose of this study is to test the hypothesis that arecoline causes cardiac fibrosis through transforming growth factor-ß (TGF-ß)/Smad-mediated signaling pathways. Male Wistar rats were injected intraperitoneally with low (5 mg/kg/day) or high (50 mg/kg/day) doses of arecoline for 3 weeks. Results from Masson's trichrome staining indicated that arecoline could induce cardiac fibrosis through collagen accumulation. Western blot analysis showed that TGF-ß and p-Smad2/3 protein expression levels were markedly higher in the arecoline-injected rat hearts than in those of the control rats. Moreover, arecoline upregulated other fibrotic-related proteins, including SP1-mediated connective tissue growth factor expression. Tissue-type plasminogen activator and its inhibitor, plasminogen activator inhibitor, and matrix metalloproteinase (MMP) 9 were upregulated, and the inhibitor of MMP9 was downregulated. This study provides novel insight into the molecular mechanisms underlying arecoline-induced cardiac fibrosis. Taken together, the areca nut is a harmful substance, and the detrimental effects of arecoline on the heart are similar to that caused by oral submucous fibrosis.

Fisetin mediated apoptotic cell death in parental and Oxaliplatin/irinotecan resistant colorectal cancer cells in vitro and in vivo.

Irinotecan (CPT11) and Oxaliplatin have been used in combination with fluorouracil and leucovorin for treating colorectal cancer. However, the efficacy of these drugs is reduced due to various side effects and drug resistance. Fisetin, a hydroxyflavone possess anti-proliferative, anti-cancer, anti-inflammatory, and antioxidant activity against various types of cancers. Apart from that, fisetin has been shown to induce cytotoxic effects when combined with other known chemotherapeutic drugs. In this study, we aimed to investigate whether Fisetin was capable of sensitizing both Irinotecan and Oxaliplatin resistance colon cancer cells and explored the possible signaling pathways involved using In vitro and In vivo models. The results showed that Fisetin treatment effectively inhibited cell viability and apoptosis of CPT11-LoVo cells than Oxaliplatin (OR) and parental LoVo cancer cells. Western blot assays suggested that apoptosis was induced by fisetin administration, promoting Caspase-8, and Cytochrome-C expressions possibly by inhibiting aberrant activation of IGF1R and AKT proteins. Furthermore, fisetin inhibited tumor growth in athymic nude mouse xenograft model. Overall, our results provided a basis for Fisetin as a promising agent to treat parental as well as chemoresistance colon cancer.

Doxorubicin induced apoptosis was potentiated by neferine in human lung adenocarcima, A549 cells.

Doxorubicin (DOX) is the best anticancer agent that has ever been used, but acquired tumor resistance and dose limiting toxicity are major road blocks. Concomitant use of natural compounds is a promising strategy to overcome this problem. Neferine, a proven anticancer agent is found in green embryos of lotus seed. The study demonstrates that neferine acts as an effective enhancer of DOX-induced cell death in A549 cells through ROS mediated apoptosis with MAPK activation and inhibition of NF-κB nuclear translocation. Cotreatment of cells with neferine significantly enhanced intracellular DOX-accumulation. Neferine and DOX in combination also triggered oxidative stress through intracellular Ca(2+) accumulation and dissipation of mitochondrial membrane potential in addition to significant loss of cellular antioxidant pool. The MAPK inhibitor effectively decreased the cell-death induced by neferine and DOX. Pretreatment of cells with glutathione reversed the apoptosis induced by combined regimen and recovered the Bcl2/Bax ratio. Moreover, neferine treatment significantly increased the cell viability of DOX-treated cardiomyocytes indicating a possible protective role of neferine towards DOX-induced cardiotoxicity. Taken together, our results suggest that a strategy of using neferine and DOX in combination could be helpful to increase the efficacy of DOX and to achieve anticancer synergism by curbing the toxicity.