Dysregulation of NRF2 in Cancer: from Molecular Mechanisms to Therapeutic Opportunities

Nuclear factor E2-related factor 2 (NRF2) plays an important role in redox metabolism and antioxidant defense. Under normal conditions, NRF2 proteins are maintained at very low levels because of their ubiquitination and proteasomal degradation via binding to the kelch-like ECH associated protein 1 (KEAP1)-E3 ubiquitin ligase complex. However, oxidative and/or electrophilic stresses disrupt the KEAP1-NRF2 interaction, which leads to the accumulation and transactivation of NRF2. During recent decades, a growing body of evidence suggests that NRF2 is frequently activated in many types of cancer by multiple mechanisms, including the genetic mutations in the KEAP1-NRF2 pathway. This suggested that NRF2 inhibition is a promising strategy for cancer therapy. Recently, several NRF2 inhibitors have been reported with anti-tumor efficacy. Here, we review the mechanisms whereby NRF2 is dysregulated in cancer and its contribution to the tumor development and radiochemoresistance. In addition, among the NRF2 inhibitors reported so far, we summarize and discuss repurposed NRF2 inhibitors with their potential mechanisms and provide new insights to develop selective NRF2 inhibitors.

Regulation and function of AMPK in physiology and diseases

5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that was originally identified as the key player in maintaining cellular energy homeostasis. Intensive research over the last decade has identified diverse molecular mechanisms and physiological conditions that regulate the AMPK activity. AMPK regulates diverse metabolic and physiological processes and is dysregulated in major chronic diseases, such as obesity, inflammation, diabetes and cancer. On the basis of its critical roles in physiology and pathology, AMPK is emerging as one of the most promising targets for both the prevention and treatment of these diseases. In this review, we discuss the current understanding of the molecular and physiological regulation of AMPK and its metabolic and physiological functions. In addition, we discuss the mechanisms underlying the versatile roles of AMPK in diabetes and cancer.

An esthetic appliance for the management of crown-root fracture: a case report

Orthodontic extrusion is usually performed by means of a fixed orthodontic appliance that utilizes arch wire attached to adjacent teeth and transfers the desired force by elastic from the wire to the root. However, clinicians often encounter cases where the bonding required for tooth traction is not possible because the adjacent teeth have been restored with ceramic or veneer. The purpose of this case report is to describe a modified orthodontic extrusion appliance that is useful when conventional orthodontic treatment is not possible. The modified appliance was fabricated using an artificial tooth, clear plastic sheeting, and a braided fiber-reinforced composite strip that covered adjacent teeth without bonding. It satisfied the esthetic and functional needs of the patient and established the optimal biologic width.