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// Sumit Mukherjee 1, 3, 5, * , Priya Ranjan Debata 5, 8, * , Rahman Hussaini 5 , Kaushiki Chatterjee 2, 4 , Juliet N.E. Baidoo 1, 3 , Samay Sampat 5 , Anita Szerszen 6 , Joseph P. Navarra 7 , Jimmie Fata 2 , Elena Severinova 6, 9 , Probal Banerjee 1, 5 and Mario R. Castellanos 6 1 Department of Chemistry, The College of Staten Island (CUNY), New York, NY, USA 2 CUNY Doctoral Program in Biology, CUNY Graduate Center, New York, NY, USA 3 CUNY Doctoral Program In Biochemistry, CUNY Graduate Center, New York, NY, USA 4 Department of Biology, The College of Staten Island (CUNY), New York, NY, USA 5 Center of Developmental Neuroscience, The College of Staten Island (CUNY), New York, NY, USA 6 Division of Research, Department of Medicine, Staten Island University Hospital (Northwell Health), New York, NY, USA 7 College of Pharmacy and Health Sciences, St. John’s University, New York, NY, USA 8 Current Address: Department of Zoology North Orissa University Baripada, Mayurbhanj, Odisha, India 9 Current Address: Cell Biology and Molecular Medicine, Rutgers University, Newark, NJ, USA * These authors contributed equally to this work Correspondence to: Probal Banerjee, email: probal.banerjee@csi.cuny.edu , probalbanerjee@yahoo.com Keywords: curcumin, cervical cancer, human papillomavirus, synergism, combination index Received: May 31, 2016 Accepted: September 02, 2016 Published: March 29, 2017 ABSTRACT Curcumin (from curry) (C) is highly potent against cervical cancer cells (CCC), but poor bioavailability has limited its clinical use. Similar natural polyphenols resveratrol (from grapes) (R), and epicatechin gallate (from green tea) (E) also display activity against CCC. By treating CCC (HeLa) with C, E, or R, or combinations of these compounds, we computed combination indices and observed a strong synergism among C, E, and R at the unique molar ratio 4:1:12.5. This combination, named as TriCurin, rapidly down regulated HPV18 E6 and NF-kB expression while concomitantly inducing the tumor suppressor protein p53 in HeLa cells. In the mouse c-Ha-ras and HPV16 E6, E7-expressing TC-1 CCC, both C and TriCurin elicited suppression of E6, induction of both p53 and acetyl-p53 (activated p53), and activation of caspase-3, but the TriCurin-evoked changes were several-fold greater than that produced by curcumin (4.7-fold for E6 inhibition, and 2-fold, 6-fold, and 1.7-fold for the induction of p53, acetyl-p53, and active caspase-3, respectively). Consequently, TriCurin was more potent in killing TC-1 and HeLa cells. Intralesional TriCurin treatment of tumors generated in mice by subcutaneously implanting the TC-1 CCC caused an 80–90% decrease in tumor growth. The ability of C to eliminate HeLa cells was significantly stabilized when delivered as TriCurin than when delivered alone. Topical application of TriCurin dispersed in a cream base afforded efficient transfer of C across the skin. Subcutaneous TriCurin injection yielded no adverse effect in tumor-naive healthy mice. Thus, TriCurin is a safe and promising therapeutic agent against HPV-associated disease.

The global health threat of antimicrobial resistance has created a pressing need to develop practical alternatives to conventional antibiotic agents. Peptide mimetic synthetic amphiphilic polymers are known to non-specifically disrupt the bacterial cell surface thus leading to highly hindered bacterial resistance development. We investigated the antibacterial activities of a terpolymer macromolecular architecture with a combination of 6-carbon and 2-carbon spacer arms (distance from polymer backbone to pendent cationic center) interspersed with counits with hydrophobic side groups. A random copolymer with a combination of 6-carbon spacer arm repeat units (60 mol%) and 2-carbon spacer arm (40 mol%) units is moderately active against bacteria and shows very low hemolytic activity. Incorporation of comonomer units with alkyl side groups, by replacing different levels of 2-carbon spacer arm counit, led to substantial increments in antibacterial activities without detrimental effects on hemolytic activities leading to highly selective (bacteria over red blood cells) antibacterial activity. Time-kill studies revealed rapid bactericidal activity of the terpolymer against both Staphylococcus aureus and Escherichia coli with 100% killing efficiency achieved within 1 h of polymer treatment, corresponding to a 5-log reduction of bacterial colony forming units. These results indicate the high potential of this amphiphilic terpolymer architecture in the development of alternatives to antibiotics.

Summary Methylation of histone 3 at lysine 9 (H3K9) constitutes a roadblock for cellular reprogramming. Interference with methyltransferases or activation of demethylases by the cofactor ascorbic acid (AA) facilitates the derivation of induced pluripotent stem cells (iPSCs), but possible interactions between specific methyltransferases and AA treatment remain insufficiently explored. We show that chemical inhibition of the methyltransferases EHMT1 and EHMT2 counteracts iPSC formation in an enhanced reprogramming system in the presence of AA, an effect that is dependent on EHMT1. EHMT inhibition during enhanced reprogramming is associated with rapid loss of H3K9 dimethylation, inefficient downregulation of somatic genes, and failed mesenchymal-to-epithelial transition. Furthermore, transient EHMT inhibition during reprogramming yields iPSCs that fail to efficiently give rise to viable mice upon blastocyst injection. Our observations establish novel functions of H3K9 methyltransferases and suggest that a functional balance between AA-stimulated enzymes and EHMTs supports efficient and less error-prone iPSC reprogramming to pluripotency., Graphical Abstract, Highlights • EHMT function during mouse cell reprogramming is modulated by ascorbic acid (AA) • EHMT inhibition counteracts reprogramming in the presence of AA • EHMT inhibition in the presence of AA results in global erasure of H3K9 dimethylation • Cells reprogrammed in the presence of EHMT inhibitor are functionally impaired, In this article, Stadtfeld and colleagues show that the activity of a specific repressive histone methyltransferase is important for efficient cellular reprogramming under conditions that favor global histone demethylation. Their observations suggest that a balance between antagonizing chromatin modifiers is important to achieve faithful resetting of the epigenome during the generation of induced pluripotent stem cells.

Cervical cancer is one of the most common cancers in women living in developing countries. Due to a lack of affordable effective therapy, research into alternative anticancer compounds with low toxicity such as dietary polyphenols has continued. Our aim is to determine whether two structurally similar plant polyphenols, resveratrol and pterostilbene, exhibit anticancer and anti-HPV (Human papillomavirus) activity against cervical cancer cells. To determine anticancer activity, extensive in vitro analyses were performed. Anti-HPV activity, through measuring E6 protein levels, subsequent downstream p53 effects, and caspase-3 activation, were studied to understand a possible mechanism of action. Both polyphenols are effective agents in targeting cervical cancer cells, having low IC50 values in the µM range. They decrease clonogenic survival, reduce cell migration, arrest cells at the S-phase, and reduce the number of mitotic cells. These findings were significant, with pterostilbene often being more effective than resveratrol. Resveratrol and to a greater extent pterostilbene downregulates the HPV oncoprotein E6, induces caspase-3 activation, and upregulates p53 protein levels. Results point to a mechanism that may involve the downregulation of the HPV E6 oncoprotein, activation of apoptotic pathways, and re-establishment of functional p53 protein, with pterostilbene showing greater efficacy than resveratrol.