Therapy for intracerebral hemorrhage (ICH) remains elusive, in part dependent on the severity of the hemorrhage itself as well as multiple deleterious effects of blood and its breakdown products such as hemin and free iron. While oxidative injury and genomic damage have been seen following ICH, the details of this injury and implications remain unclear. Here, we discovered that, while free iron produced mostly reactive oxygen species (ROS)-related single-strand DNA breaks, hemin unexpectedly induced rapid and persistent nuclear and mitochondrial double-strand breaks (DSBs) in neuronal and endothelial cell genomes and in mouse brains following experimental ICH comparable to that seen with γ radiation and DNA-complexing chemotherapies. Potentially as a result of persistent DSBs and the DNA damage response, hemin also resulted in senescence phenotype in cultured neurons and endothelial cells. Subsequent resistance to ferroptosis reported in other senescent cell types was also observed here in neurons. While antioxidant therapy prevented senescence, cells became sensitized to ferroptosis. To address both senescence and resistance to ferroptosis, we synthesized a modified, catalytic, and rapidly internalized carbon nanomaterial, poly(ethylene glycol)-conjugated hydrophilic carbon clusters (PEG-HCC) by covalently bonding the iron chelator, deferoxamine (DEF). This multifunctional nanoparticle, DEF-HCC-PEG, protected cells from both senescence and ferroptosis and restored nuclear and mitochondrial genome integrity in vitro and in vivo. We thus describe a potential molecular mechanism of hemin/iron-induced toxicity in ICH that involves a rapid induction of DSBs, senescence, and the consequent resistance to ferroptosis and provide a mechanistic-based combinatorial therapeutic strategy.

Colorectal cancer (CRC) is now perceived as a multistep process characterized by the accumulation of genetic alterations in oncogenes and tumor suppressor genes. Plant-derived compounds are receiving considerable attention for their potential role in reducing cancer risk. Luteolin, a bioflavonoid present in many fruits and vegetables, possesses antioxidant, anti-inflammatory and antiproliferative properties. This study was designed to investigate the possible role of luteolin administration on Phase 1 and 2 enzymes and NF-E2-related factor 2 (Nrf2)/keap1 pathway. Male Balb/C mice were divided into four groups: normal control, Azoxymethane (AOM)-induced, AOM-induced and luteolin treated, normal control treated with luteolin. CRC was induced by administration of AOM (15 mg/kg body weight) intraperitoneally (i.p.) once a week for three weeks. Luteolin administration (1.2 mg/kg body weight/day) significantly alleviated Phase1 enzymes in colon and liver, it increased the levels of phase 2 enzymes. Luteolin modulates the expressions of GST-α, µ and also the expression of Nrf2. Collectively, results of our hypothesis show that luteolin is a novel candidate for treating CRC.

Cancer is a multistep process that typically occurrs over an extended period of time, beginning with initiation followed by promotion and progression. Colon cancer is the leading cause of morbidity and mortality worldwide. For a variety of reasons, patients prefer naturally occurring dietary substances over synthetic agents to prevent cancer. Luteolin, a bioflavonoid, possesses antioxidant, anti-inflammatory, and antiproliferative effects. We analyzed the in vitro anticancer and apoptosis-inducing property of luteolin using HCT-15 colon adenocarcinoma cells. Cell viability was assessed using trypan blue assay at different concentrations. Luteolin at a concentration of 100 µM (IC50) decreased the expressions of non-P-β-catenin, phosphorylated (inactive) glycogen synthase kinase-3β, and cyclin D1 expressions in HCT-15 cells, which were confirmed by Western blot analysis. Luteolin also promoted substantial cell cycle arrest at the G2/M phase in HCT-15 cells, and it induces apoptosis in HCT-15 cells, as revealed by flow cytometric analysis. Furthermore, Western blot analysis showed that luteolin treatment enhanced the expression of Bax and caspase-3, whereas the expression of Bcl-2 was suppressed. Together, the results of this study revealed that luteolin can act as a potent inhibitor of HCT-15 proliferation and can be used as an agent against colon cancer.

The present investigation deals with the antimetastatic role of luteolin (LUT) by inhibiting matrix metalloproteinase (MMP)-9 and -2 in azoxymethane (AOM)-induced colon carcinogenesis in Balb/C mice. Animals received AOM at a dosage of 15 mg/kg body weight intraperitoneally once a week for 3 weeks. AOM-induced mice was treated with LUT (1.2 mg of LUT/kg body weight/day orally). After the experimental period, the tumor markers such as γ-glutamyl transferase (GGT), 5′ nucleotidase (5′ND), cathepsin-D (Cat-D), and carcinoembroyonic antigen (CEA) were elevated upon induction with AOM. Subsequent treatment with LUT results in the reduction of the tumor markers was recorded. The expressions of MMP-9 and MMP-2 were analyzed by reverse transcription–polymerase chain reaction (RT-PCR) and immunofluorescence methods. The expressions of MMP-9 and MMP-2 were increased during AOM induction and upon treatment with LUT reduced the expressions. RT-PCR analysis of tissue inhibitor of matrix metalloproteinase ( TIMP)- 2 was limited during AOM-induced colorectal cancer (CRC). Supplementation of LUT increased the expression of TIMP-2. To conclude, LUT acts as an antimetastatic agent by suppressing MMP-9 and MMP-2 productions and upregulating TIMP-2 expression, thereby suggesting that LUT can be a chemotherapeutic agent against CRC.

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