Role of Autophagy and AMPK in Cancer Stem Cells: Therapeutic Opportunities and Obstacles in Cancer.

Cancer stem cells represent a resilient subset within the tumor microenvironment capable of differentiation, regeneration, and resistance to chemotherapeutic agents, often using dormancy as a shield. Their unique properties, including drug resistance and metastatic potential, pose challenges for effective targeting. These cells exploit certain metabolic processes for their maintenance and survival.

Association between dietary quality and the prevalence of periodontitis in older Korean adults aged 60 or over.

Purpose: This study investigated the association between dietary quality and the prevalence of periodontitis in older Korean adults (≥60 years of age) using data from the seventh Korea National Health and Nutrition Examination Survey (KNHANES VII, 2016-2018).

Methods: Among the 16,489 KNHANES participants from 2016-2018, those aged ≥60 years were selected as the eligible population. After applying our exclusion criteria, 3,527 participants were included in the final study population.

AMPK-mTOR Signaling and Cellular Adaptations in Hypoxia.

Cellular energy is primarily provided by the oxidative degradation of nutrients coupled with mitochondrial respiration, in which oxygen participates in the mitochondrial electron transport chain to enable electron flow through the chain complex (I-IV), leading to ATP production. Therefore, oxygen supply is an indispensable chapter in intracellular bioenergetics. In mammals, oxygen is delivered by the bloodstream.

An alcoholic extract of Thuja orientalis L. leaves inhibits autophagy by specifically targeting pro-autophagy PIK3C3/VPS34 complex.

Autophagy is a lysosome-dependent degradation program to maintain cellular homeostasis in response to a variety of stressful conditions, such as long-lived or non-functional subcellular organelles, protein aggregates, nutrient limitation, and virus/bacteria infection. Accordingly, dysregulation of autophagy is closely associated with many human pathophysiological conditions, such as neurodegenerative diseases, aging, and cancer, and autophagy is highlighted as an important therapeutic target for these human diseases. In autophagy process, PIK3C3/VPS34 complex plays important roles in autophagosome biogenesis.

mTOR as a central hub of nutrient signalling and cell growth.

The highly conserved protein kinase mechanistic target of rapamycin (mTOR; originally known as mammalian target of rapamycin) is a central cell growth regulator connecting cellular metabolism and growth with a wide range of environmental inputs as part of mTOR complex 1 (mTORC1) and mTORC2. In this Review, we introduce the landmark discoveries in the mTOR field, starting from the isolation of rapamycin to the molecular characterizations of key components of the mTORC signalling network with an emphasis on amino acid sensing, and discuss the perspectives of mTORC inhibitors in therapeutic applications.

Autophagy: An Essential Degradation Program for Cellular Homeostasis and Life.

Autophagy is a lysosome-dependent cellular degradation program that responds to a variety of environmental and cellular stresses. It is an evolutionarily well-conserved and essential pathway to maintain cellular homeostasis, therefore, dysfunction of autophagy is closely associated with a wide spectrum of human pathophysiological conditions including cancers and neurodegenerative diseases. The discovery and characterization of the kingdom of autophagy proteins have uncovered the molecular basis of the autophagy process.

The C-terminal region of ATG101 bridges ULK1 and PtdIns3K complex in autophagy initiation.

The initiation of macroautophagy/autophagy is tightly regulated by the upstream ULK1 kinase complex, which affects many downstream factors including the PtdIns3K complex. The phosphorylation of the right position at the right time on downstream molecules is governed by proper complex formation. One component of the ULK1 complex, ATG101, known as an accessory protein, is a stabilizer of ATG13 in cells.

Mitochondrial ROS-derived PTEN oxidation activates PI3K pathway for mTOR-induced myogenic autophagy.

Muscle differentiation is a crucial process controlling muscle development and homeostasis. Mitochondrial reactive oxygen species (mtROS) rapidly increase and function as critical cell signaling intermediates during the muscle differentiation. However, it has not yet been elucidated how they control myogenic signaling.

Ursolic Acid Causes Cell Death in PC-12 Cells by Inducing Apoptosis and Impairing Autophagy.

Ursolic acid (UA) is a natural pentacyclic triterpene that has various biological activities, including anticancer and anti-inflammatory effects. This study investigated the ability of UA to cause cell death in pheochromocytoma (PC-12) cells. UA was cytotoxic to PC-12 cells (half-maximum inhibitory concentration=53.

Induction of Cell Death by Betulinic Acid through Induction of Apoptosis and Inhibition of Autophagic Flux in Microglia BV-2 Cells.

Betulinic acid (BA), a natural pentacyclic triterpene found in many medicinal plants is known to have various biological activity including tumor suppression and anti-inflammatory effects. In this study, the cell-death induction effect of BA was investigated in BV-2 microglia cells. BA was cytotoxic to BV-2 cells with IC₅₀ of approximately 2.

MTORC1-mediated NRBF2 phosphorylation functions as a switch for the class III PtdIns3K and autophagy.

NRBF2/Atg38 has been identified as the fifth subunit of the macroautophagic/autophagic class III phosphatidylinositol 3-kinase (PtdIns3K) complex, along with ATG14/Barkor, BECN1/Vps30, PIK3R4/p150/Vps15 and PIK3C3/Vps34. However, its functional mechanism and regulation are not fully understood. Here, we report that NRBF2 is a fine tuning regulator of PtdIns3K controlled by phosphorylation.

Targeting of AMP-activated protein kinase: prospects for computer-aided drug design.

Dysregulation of energy homeostasis has been implicated in a number of human chronic diseases including diabetes, obesity, cancer, and inflammation. Given the functional attributes as a central regulator of energy homeostasis, AMP-activated protein kinase (AMPK) is emerging as a therapeutic target for these diseases, and lines of evidence have highlighted the need for rational and robust screening systems for identifying specific AMPK modulators with a therapeutic potential for preventing and/or curing these diseases. Areas covered: Here, the authors review the recent advances in the understanding of three-dimensional structures of AMPK in relationship with the regulatory mechanisms, potentials of AMPK as a therapeutic target in human chronic diseases, and prospects of computer-based drug design for AMPK.

Bacterial Overexpression and Denaturing Purification of VPS34-Binding Domain of Beclin 1.

As a scaffolding subunit of the PIK3C3/VPS34 complex, Beclin 1 recruits a variety of proteins to class III phosphatidylinositol-3-kinase (VPS34), resulting in the formation of a distinct PIK3C3/VPS34 complex with a specific function. Therefore, the investigation of a number of Beclin 1 domains required for the protein-protein interactions will provide important clues to understand the PIK3C3/VPS34 complex, of which Beclin1-VPS34 interaction is the core unit. In the present study, we have designed a bacterial overexpression system for the Beclin 1 domain corresponding to VPS34 binding (Vps34-BD) and set up the denaturing purification protocol due to the massive aggregation of Vps34-BD in .

Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 activator that protects mice from diet-induced nonalcoholic steatohepatitis.

Oxidative stress is important for the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a chronic disease that ranges from hepatic steatosis to nonalcoholic steatohepatitis (NASH). The nuclear factor erythroid 2-related factor 2-Kelch-like ECH associated protein 1 (Nrf2-Keap1) pathway is essential for cytoprotection against oxidative stress. In this study, we found that oxidative stress or inflammatory biomarkers and TUNEL positive cells were markedly increased in NASH patients compared to normal or simple steatosis.

Novel pharmacological modulators of autophagy: an updated patent review (2012-2015).

Autophagy is a lysosome-dependent degradation pathway that maintains cellular homeostasis in response to a variety of cellular stresses. Accumulating reports based on animal models have indicated the importance of this catabolic program in many human pathophysiological conditions, including diabetes, neurodegenerative diseases, aging, and cancers. Therefore, autophagy has been highlighted as a novel therapeutic target with a wide range of beneficial effects on human diseases.

AMPK activators: mechanisms of action and physiological activities.

AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, which coordinates metabolic pathways and thus balances nutrient supply with energy demand. Because of the favorable physiological outcomes of AMPK activation on metabolism, AMPK has been considered to be an important therapeutic target for controlling human diseases including metabolic syndrome and cancer. Thus, activators of AMPK may have potential as novel therapeutics for these diseases.

Rag GTPase in amino acid signaling.

Rag small GTPases were identified as the sixth subfamily of Ras-related GTPases. Compelling evidence suggests that Rag heterodimer (RagA/B and RagC/D) plays an important role in amino acid signaling toward mechanistic target of rapamycin complex 1 (mTORC1), which is a central player in the control of cell growth in response to a variety of environmental cues, including growth factors, cellular energy/oxygen status, and amino acids. Upon amino acid stimulation, active Rag heterodimer (RagA/B(GTP)-RagC/D(GDP)) recruits mTORC1 to the lysosomal membrane where Rheb resides.

Systematic analyses of the ultraviolet radiation resistance-associated gene product (UVRAG) protein interactome by tandem affinity purification.

Ultraviolet radiation resistance-associated gene product (UVRAG) was originally identified as a protein involved in cellular responses to UV irradiation. Subsequent studies have demonstrated that UVRAG plays as an important role in autophagy, a lysosome-dependent catabolic program, as a part of a pro-autophagy PIK3C3/VPS34 lipid kinase complex. Several recent studies have shown that UVRAG is also involved in autophagy-independent cellular functions, such as DNA repair/stability and vesicular trafficking/fusion.

AMPK and autophagy in glucose/glycogen metabolism.

Glucose/glycogen metabolism is a primary metabolic pathway acting on a variety of cellular needs, such as proliferation, growth, and survival against stresses. The multiple regulatory mechanisms underlying a specific metabolic fate have been documented and explained the molecular basis of various pathophysiological conditions, including metabolic disorders and cancers. AMP-activated protein kinase (AMPK) has been appreciated for many years as a central metabolic regulator to inhibit energy-consuming pathways as well as to activate the compensating energy-producing programs.

Advances in Anthrax Detection: Overview of Bioprobes and Biosensors.

Anthrax is an infectious disease caused by Bacillus anthracis. Although anthrax commonly affects domestic and wild animals, it causes a rare but lethal infection in humans. A variety of techniques have been introduced and evaluated to detect anthrax using cultures, polymerase chain reaction, and immunoassays to address the potential threat of anthrax being used as a bioweapon.

Development of in vitro PIK3C3/VPS34 complex protein assay for autophagy-specific inhibitor screening.

Autophagy is an important catabolic program to respond to a variety of cellular stresses by forming a double membrane vesicle, autophagosome. Autophagy plays key roles in various cellular functions. Accordingly, dysregulation of autophagy is closely associated with diseases such as diabetes, neurodegenerative diseases, cardiomyopathy, and cancer.

Screening methods for AMP-activated protein kinase modulators: a patent review.

Introduction: AMP-activated protein kinase (AMPK) functions as a cellular energy gauge that maintains cellular homeostasis and has been suggested to play important roles in tumorigenesis, lifespan and autophagy. Accordingly, AMPK is a potential target of drugs for controlling a growing number of human diseases ranging from metabolic disorders to cancer, highlighting the need for rational and robust screening systems for identifying compounds that modulate AMPK.

Areas Covered: The relevant screening methods in the patent and scientific literature were analyzed, and key features of direct AMPK modulators are discussed in the context of their physiological relevance and the three-dimensional structure of the AMPK complex.

Cryptotanshinone induces G1 cell cycle arrest and autophagic cell death by activating the AMP-activated protein kinase signal pathway in HepG2 hepatoma.

AMP-activated protein kinase (AMPK) performs a pivotal function in energy homeostasis via the monitoring of intracellular energy status. Once activated under the various metabolic stress conditions, AMPK regulates a multitude of metabolic pathways to balance cellular energy. In addition, AMPK also induces cell cycle arrest or apoptosis through several tumor suppressors including LKB1, TSC2, and p53.