As new drugs are developed, it is essential to appropriately translate the drug dosage from one animal species to another. A misunderstanding appears to exist regarding the appropriate method for allomet‐ric dose translations, especially when starting new animal or clinical studies. The need for education regarding appropriate translation is evident from the media response regarding some recent studies where authors have shown that resveratrol, a compound found in grapes and red wine, improves the health and life span of mice. Immediately after the online publication of these papers, the scientific community and popular press voiced concerns regarding the relevance of the dose of resveratrol used by the authors. The animal dose should not be extrapolated to a human equivalent dose (HED) by a simple conversion based on body weight, as was reported. For the more appropriate conversion of drug doses from animal studies to human studies, we suggest using the body surface area (BSA) normalization method. BSA correlates well across several mammalian species with several parameters of biology, including oxygen utilization, caloric expenditure, basal metabolism, blood volume, circulating plasma proteins, and renal function. We advocate the use of BSA as a factor when converting a dose for translation from animals to humans, especially for phase I and phase II clinical trials.—Reagan‐Shaw S., Nihal, M., Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 22, 659–661 (2007)

Significance: Antioxidant and redox signaling (ARS) events are regulated by critical molecules that modulate antioxidants, reactive oxygen species (ROS) or reactive nitrogen species (RNS), and/or oxidative stress within the cell. Imbalances in these molecules can disturb cellular functions to become pathogenic. Sirtuins serve as important regulators of ARS in cells. Recent Advances: Sirtuins (SIRTs 1–7) are a family of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases with the ability to deacetylate histone and nonhistone targets. Recent studies show that sirtuins modulate the regulation of a variety of cellular processes associated with ARS. SIRT1, SIRT3, and SIRT5 protect the cell from ROS, and SIRT2, SIRT6, and SIRT7 modulate key oxidative stress genes and mechanisms. Interestingly, SIRT4 has been shown to induce ROS production and has antioxidative roles as well. Critical Issues: A complete understanding of the roles of sirtuins in redox homeostasis of the cell is very important to understand the normal functioning as well as pathological manifestations. In this review, we have provided a critical discussion on the role of sirtuins in the regulation of ARS. We have also discussed mechanistic interactions among different sirtuins. Indeed, a complete understanding of sirtuin biology could be critical at multiple fronts. Future Directions: Sirtuins are emerging to be important in normal mammalian physiology and in a variety of oxidative stress-mediated pathological situations. Studies are needed to dissect the mechanisms of sirtuins in maintaining redox homeostasis. Efforts are also required to assess the targetability of sirtuins in the management of redox-regulated diseases. Antioxid. Redox Signal . 28, 643–661.

The polyphenolic compounds present in green tea show cancer chemopreventive effects in many animal tumor models. Epidemiologic studies have also suggested that green tea consumption might be effective in the prevention of certain human cancers. We investigated the effect of green tea polyphenols and the major constituent, epigallocatechin-3-gallate, on the induction of apoptosis (programmed cell death) and regulation of cell cycle in human and mouse carcinoma cells. Human epidermoid carcinoma cells (cell line A431), human carcinoma keratinocyte (cell line HaCaT), human prostate carcinoma cells (cell line DU145), mouse lymphoma cells (cell line L5178Y), and normal human epidermal keratinocytes (NHEKs) were used. Apoptosis was assessed by 1) the formation of internucleosomal DNA fragments by agarose gel electrophoresis, 2) confocal microscopy, and 3) flow cytometry after tagging the DNA fragments by fluorescence label. The distribution of cells in different phases of the cell cycle was analyzed by flow cytometry. Treatment of A431 cells with green tea polyphenols and its components, epigallocatechin-3-gallate, epigallocatechin, and epicatechin-3-gallate, resulted in the formation of internucleosomal DNA fragments, characteristic of apoptosis. Treatment with epigallocatechin-3-gallate also resulted in apoptosis in HaCaT, L5178Y, and DU145 cells, but not in NHEK. Confocal microscopy and flow cytometry confirmed the findings. The DNA cell cycle analysis showed that in A431 cells, epigallocatechin-3-gallate treatment resulted in arrest in the G0-G1 phase of the cell cycle and a dose-dependent apoptosis. Green tea may protect against cancer by causing cell cycle arrest and inducing apoptosis. It needs to be evaluated in human trials.

Polo-like kinase 1 (Plk1) overexpression has been shown to occur in a wide range of tumors, prompting research and development of Plk1 inhibitors as a means of cancer treatment. This review discusses recent advances in the development of Plk1 inhibitors for cancer management. Plk1 inhibition has been shown to cause mitotic block and apoptosis of cells with higher mitotic index and therefore higher Plk1 expression. The potential of Plk1 inhibitors as cancer therapeutics has been widely investigated. However, a complete understanding of Plk1 biology/mechanism is yet to be fully achieved. Resistance to certain chemotherapeutic drugs has been linked to Plk1 overexpression, and Plk1-mediated mitotic events such as microtubule rearrangement have been found to reduce the efficacy of chemotherapeutic agents. The Plk1 inhibitor volasertib has shown considerable promise in clinical studies, having reached phase III trials. However, preclinical success with Plk1 inhibitors has not translated well into clinical success. In our view, combined therapies targeting other relevant pathways together with Plk1 may be vital to combat issues observed with monotherapy, especially resistance. In addition, research should also be directed toward understanding the mechanisms of Plk1 and designing additional next generations of specific, potent Plk1 inhibitors to target cancer. Mol Cancer Ther; 15(7); 1427–35. ©2016 AACR.

Significance: Oxygen and circadian rhythmicity are essential in a myriad of physiological processes to maintain homeostasis, from blood pressure and sleep/wake cycles, down to cellular signaling pathways that play critical roles in health and disease. If the human body or cells experience significant stress, their ability to regulate internal systems, including redox levels and circadian rhythms, may become impaired. At cellular as well as organismal levels, impairment in redox regulation and circadian rhythms may lead to a number of adverse effects, including the manifestation of a variety of diseases such as heart diseases, neurodegenerative conditions, and cancer. Recent Advances: Researchers have come to an understanding as to the basics of the circadian rhythm mechanism, as well as the importance of the numerous species of oxidative stress components. The effects of oxidative stress and dysregulated circadian rhythms have been a subject of intense investigations since they were first discovered, and recent investigations into the molecular mechanisms linking the two have started to elucidate the bases of their connection. Critical Issues: While much is known about the mechanics and importance of oxidative stress systems and circadian rhythms, the front where they interact has had very little research focused on it. This review discusses the idea that these two systems are together intricately involved in the healthy body, as well as in disease. Future Directions: We believe that for a more efficacious management of diseases that have both circadian rhythm and oxidative stress components in their pathogenesis, targeting both systems in tandem would be far more successful. Antioxid. Redox Signal. 19, 192–208