From Krebs to Clinic: Glutamine Metabolism to Cancer Therapy

The resurgence of research into cancer metabolism has recently broadened interests beyond glucose and the Warburg effect to other nutrients, including glutamine. Because oncogenic alterations of metabolism render cancer cells addicted to nutrients, pathways involved in glycolysis or glutaminolysis could be exploited for therapeutic purposes. In this Review, we provide an updated overview of glutamine metabolism and its involvement in tumorigenesis in vitro and in vivo, and explore the recent potential applications of basic science discoveries in the clinical setting.

• Cancer cells show increased consumption of and dependence on glutamine.
• Glutamine metabolism fuels the tricarboxylic acid (TCA) cycle, nucleotide and fatty acid biosynthesis, and redox balance in cancer cells.
• Glutamine activates mTOR signaling, suppresses endoplasmic reticulum stress and promotes protein synthesis.

Read more: From Krebs to Clinic: Glutamine Metabolism to Cancer Therapy

Major metabolic and biosynthetic fates of glutamine

Source: NatureReviewsCancer

Download: From Krebs to clinic: glutamine metabolism to cancer therapy.pdf

The Pathophysiology of Defective Proteostasis in the Hypothalamus — From Obesity to Ageing

Hypothalamic dysfunction has emerged as an important mechanism involved in the development of obesity and its comorbidities, as well as in the process of ageing and age-related diseases, such as type 2 diabetes mellitus, hypertension and Alzheimer disease. In both obesity and ageing, inflammatory signalling is thought to coordinate many of the cellular events that lead to hypothalamic neuronal dysfunction. This process is triggered by the activation of signalling via the toll-like receptor 4 pathway and endoplasmic reticulum stress, which in turn results in intracellular inflammatory signalling. However, the process that connects inflammation with neuronal dysfunction is complex and includes several regulatory mechanisms that ultimately control the homeostasis of intracellular proteins and organelles (also known as 'proteostasis'). This Review discusses the evidence for the key role of proteostasis in the control of hypothalamic neurons and the involvement of this process in regulating whole-body energy homeostasis and lifespan.

Key points

• Specialized neurons of the hypothalamus control caloric intake and energy expenditure in response to hormonal, nutritional and neural signals that reflect the energy stores in the body
• Malfunction of the hypothalamus occurs in obesity and ageing, which leads to an imbalance between caloric intake and energy expenditure resulting in positive energy balance and reduced lifespan
• The excessive consumption of certain nutrients and ageing affect different aspects of proteostasis in selected neurons of the hypothalamus, contributing to neuronal dysfunction in obesity and ageing
• Inflammation is one of the most important outcomes of disturbed proteostasis to occur in the hypothalamus during obesity and ageing
• Several genetic and pharmacological approaches used to correct the defects of proteostasis and reduce inflammation have proven effective in reducing obesity and increasing lifespan in experimental models

Read more: The Pathophysiology of Defective Proteostasis in the Hypothalamus — From Obesity to Ageing

Figure 1: Control of energy balance and lifespan by the hypothalamic network. Neurons of the
medium hypothalamus respond to systemic signals of whole-body energy status. Blood levels of
insulin fluctuate acutely in response to carbohydrates present in food and chronically in response
to increased adiposity.

Source: Nature Reviews Endocrinology

Antimicrobial resistance: a collection of reviews and research papers from Nature journals

Resistance to antimicrobials is a global problem of increasing importance. Pathogens rapidly develop mutations that render current treatments ineffective. For example, resistance to carbapenems, one of the ‘last lines’ of antibiotics, is widespread and has been observed in numerous countries; resistance to artemisinin, the gold standard in malaria treatment, has also emerged. Our current arsenal of antimicrobial agents thus has a limited lifespan and new drugs are urgently needed. Tackling this resistance will require a deep understanding of microbial infections and the mechanisms through which resistance arises, as well as concerted efforts between academia and industry aimed at developing novel antimicrobial agents.

This collection consists of Reviews, Research articles, and News and Comment articles from several Nature journals, describing how antibiotic resistance emerges and detailing strategies through which new antimicrobial compounds are being discovered.

Read more: Antimicrobial resistance: a collection of reviews and research papers from Nature journals

Source: nature

The mechanisms and functions of spontaneous neurotransmitter release

Fast synaptic communication in the brain requires synchronous vesicle fusion that is evoked by action potential-induced Ca2+ influx. However, synaptic terminals also release neurotransmitters by spontaneous vesicle fusion, which is independent of presynaptic action potentials. A functional role for spontaneous neurotransmitter release events in the regulation of synaptic plasticity and homeostasis, as well as the regulation of certain behaviours, has been reported. In addition, there is evidence that the presynaptic mechanisms underlying spontaneous release of neurotransmitters and their postsynaptic targets are segregated from those of evoked neurotransmission. These findings challenge current assumptions about neuronal signalling and neurotransmission, as they indicate that spontaneous neurotransmission has an autonomous role in interneuronal communication that is distinct from that of evoked release.

Key points

• Synaptic terminals can release neurotransmitter by spontaneous vesicle fusion that is independent of presynaptic action potentials.
• The traditional view of spontaneous neurotransmitter release suggests that spontaneous events occur randomly in the absence of stimuli owing to low-probability conformational changes in the vesicle fusion machinery.
• Recent studies have identified key distinctions between the synaptic vesicle fusion machineries that perform spontaneous versus evoked neurotransmitter release.
• In mammalian hippocampal synapses and at the Drosophila melanogaster neuromuscular junction, spontaneous and evoked neurotransmitter release events show some spatial segregation and activate distinct populations of postsynaptic receptors.
• Segregation of spontaneous neurotransmission enables selective neuromodulation that is independent of evoked release.
• In mammalian hippocampal synapses and at the D. melanogaster neuromuscular junction, spontaneous release events activate specific postsynaptic signal transduction cascades that maintain synaptic efficacy or regulate structural plasticity and synaptic development.
• Novel strategies that selectively target spontaneous release events are needed to address whether spontaneous release can signal independently during ongoing activity in intact neuronal circuits.
• Introduction

Introduction

Our current insights into the mechanisms underlying synaptic transmission originate from experiments that were conducted in the 1950s by Bernard Katz and colleagues. A key aspect of these studies was the discovery of spontaneous neurotransmitter release events, which seemed to occur in discrete 'quantal' packets. This fundamental observation enabled the complex and seemingly intractable nature of action potential-evoked neurotransmission to be analyzed and understood on the basis of its unitary components. Although the original work solely relied on electrophysiological analysis, later studies that used electron microscopy provided visual validation of the hypothesis that neurotransmission occurs through fusion of discrete synaptic vesicles that contain neurotransmitters with the presynaptic plasma membrane.

Read more: The mechanisms and functions of spontaneous neurotransmitter release

Figure 3: Segregation of spontaneous and evoked neurotransmission.

Source: Nature Reviews Neuroscience

Targeting Tumor Metastasis

Tumour metastasis, the movement of tumour cells from a primary site to progressively colonize distant organs, is a major contributor to the deaths of cancer patients. Therapeutic goals are the prevention of an initial metastasis in high-risk patients, shrinkage of established lesions and prevention of additional metastases in patients with limited disease. Instead of being autonomous, tumour cells engage in bidirectional interactions with metastatic microenvironments to alter antitumour immunity, the extracellular milieu, genomic stability, survival signalling, chemotherapeutic resistance and proliferative cycles. Can targeting of these interactions significantly improve patient outcomes? In this Review preclinical research, combination therapies and clinical trial designs are re-examined.

Metastases, or the consequences of their treatment, are the greatest contributors to deaths from cancer. Clinical metastatic disease results from several selective forces. Pathways that fuel initial tumorigenesis, described as the 'trunk' of a cancer evolutionary tree, can also endow tumour cells with metastatic properties and de novo drug resistance. Two types of 'limb' pathway emerge from the tree trunk: events that induce acquired resistance to therapy and pathways that induce or accelerate metastasis to distant organs1. Cancer therapy has largely concentrated on druggable targets in the trunk tumorigenesis pathways, such as receptor tyrosine kinases, and uses sequential and combination therapies to minimize drug resistance.

Read more: Targeting Tumor Metastasis

Source: NatureReviewsCancer