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Plant extracts are an important source of bioactive compounds for many drug discovery programs. Given the chemical complexity, however, the identification and characterization of bioactive compounds in crude plant extracts still remain a big challenge. Moreover, complex mixture of phytochemicals generally combine the advantage of targeting multiple molecular pathways so that a desired biological response may be due to a mixture of different bioactive components. Ethno-pharmacology history and available information about the plant to be studied may help to set specific bio-assays that can predict the reputed therapeutic activity and facilitate the isolation of the bioactives responsible for that biological activity. In a collaborative effort, we have analyzed the bioactivities of Cayenne pepper (Capsicum) a spicy staple of many foods, largely used in folk medicine for its extensive curative properties. Used either topically or internally, Capsicum may help support healthy bone, joint and muscle function by reducing inflammation. It is commonly used as a general stimulant and to heal ulcers, improve circulation and boost immune system. To elucidate the mechanism of action of Capsicum at cellular level, we have studied the effects of the variety Capsicum annuum fiesta on immortalized human keratinocytes. We have analyzed cell viability, intracellular ROS levels, stress granules formation and cell cycle distribution demonstrating that C. annuum fiesta exerts a protective role reducing intracellular ROS levels in a dose-dependent manner and stimulating cell viability at low concentrations without affecting cell proliferation. Another area of interest in our lab involves the characterization of Uncaria tomentosa extract (UT-ex) that has been widely used in folk medicine to treat a variety of health conditions including skin burns and cancer. Cell viability, intracellular ROS levels and cell cycle distribution were evaluated following treatment of immortalized and transformed keratinocytes cells with UT-ex. All cell lines tested showed dose-dependent susceptibility to Uncaria cytotoxicity, untransformed HaCaT keratinocytes being, however, less sensitive than squamous carcinoma cells. Interestingly, we found that following UT-ex treatment PARP1 cleavage occurred concomitantly with the reduction of the cleaved form of Y-box binding protein 1 (YB-1), a nuclear prosurvival factor involved in DNA damage repair. Taken together, our observations suggest that Uncaria induced cell death can be ascribed to its ability to simultaneously induce oxidative DNA damage and antagonize the mechanism of DNA repair. Our data support the use of Uncaria extract as adjuvant therapy for treatment of precancerous and early forms of squamous cell carcinomas.