Metabolic Profiles Associated With Metformin Efficacy in Cancer

Metformin is one of the most commonly prescribed medications for the treatment of type 2 diabetes. Numerous reports have suggested potential anti-cancerous and cancer preventive properties of metformin, although these findings vary depending on the intrinsic properties of the tumor, as well as the systemic physiology of patients. These intriguing studies have led to a renewed interest in metformin use in the oncology setting, and fueled research to unveil its elusive mode of action. It is now appreciated that metformin inhibits complex I of the electron transport chain in mitochondria, causing bioenergetic stress in cancer cells, and rendering them dependent on glycolysis for ATP production. Understanding the mode of action of metformin and the consequences of its use on cancer cell bioenergetics permits the identification of cancer types most susceptible to metformin action. Such knowledge may also shed light on the varying results to metformin usage that have been observed in clinical trials. In this review, we discuss metabolic profiles of cancer cells that are associated with metformin sensitivity, and rationalize combinatorial treatment options. We use the concept of bioenergetic flexibility, which has recently emerged in the field of cancer cell metabolism, to further understand metabolic rearrangements that occur upon metformin treatment. Finally, we advance the notion that metabolic fitness of cancer cells increases during progression to metastatic disease and the emergence of therapeutic resistance. As a result, sophisticated combinatorial approaches that prevent metabolic compensatory mechanisms will be required to effectively manage metastatic disease

Improving Long-Term Coastal Resiliency: A Living Shoreline Design for Chelsea Creek

The City of Chelsea, Massachusetts is prone to habitual flooding due to low elevation, continued erosion, and a need for improved coastal stabilization infrastructure. In order to protect the vulnerable communities of Chelsea in a sustainable manner, the City is considering the implementation of a living shoreline along a portion of Chelsea Creek alongside the Chelsea Street Bridge. Using a site suitability matrix, comprehensive cost analysis, and review of potential environmental impacts, our team designed a living shoreline consisting of multiple features, such as switchgrass, coir logs, a salt marsh, an oyster sill, and reef balls. In addition, the team outlined an implementation strategy, which included a suggested construction plan, key maintenance concerns, and a permitting analysis

Stable Isotope Tracer Analysis in Isolated Mitochondria from Mammalian Systems

Mitochondria are a focal point in metabolism, given that they play fundamental roles in catabolic, as well as anabolic reactions. Alterations in mitochondrial functions are often studied in whole cells, and metabolomics experiments using 13C-labeled substrates, coupled with mass isotopomer distribution analyses, represent a powerful approach to study global changes in cellular metabolic activities. However, little is known regarding the assessment of metabolic activities in isolated mitochondria using this technology. Studies on isolated mitochondria permit the evaluation of whether changes in cellular metabolic activities are due to modifications in the intrinsic properties of the mitochondria. Here, we present a streamlined approach to accurately determine 13C, as well as 12C enrichments in isolated mitochondria from mammalian tissues or cultured cells by GC/MS. We demonstrate the relevance of this experimental approach by assessing the effects of drugs perturbing mitochondrial functions on the mass isotopomer enrichment of metabolic intermediates. Furthermore, we investigate 13C and 12C enrichments in mitochondria isolated from cancer cells given the emerging role of metabolic alterations in supporting tumor growth. This original method will provide a very sensitive tool to perform metabolomics studies on isolated mitochondria

Defining the incidence and risk factors of colistin-induced acute kidney injury by KDIGO criteria.

BACKGROUND:Acute kidney injury (AKI) remains a treatment-limiting toxicity of colistin. Recently developed clinical practice guidelines from the Kidney Disease: Improving Global Outcomes (KDIGO) group have harmonized definitions of AKI, but have not been widely applied to patients receiving colistin. METHODS:We retrospectively defined AKI by KDIGO definitions among adult patients receiving intravenous colistin for ≥ 3 days. Risk factors for AKI within 48 hours and 7 days of initiating colistin were determined by multivariable logistic regression. RESULTS:Among 249 patients treated with colistin, rates of AKI were 12% and 29% at 48 hours and 7 days, respectively. At 48 hours, patients in the intensive care unit were at increased risk for AKI. Within 7 days, colistin daily doses >5mg/kg, chronic liver disease, and concomitant vancomycin were independent predictors. Seven percent of patients required renal replacement therapy at a median of 5 days (range: 3-7) following colistin initiation. CONCLUSION:Safe use of colistin is promoted by early detection of AKI with KDIGO criteria, avoiding nephrotoxins, and limiting duration of therapy

AMPK Maintains Cellular Metabolic Homeostasis through Regulation of Mitochondrial Reactive Oxygen Species

Reactive oxygen species (ROS) are continuously produced as a by-product of mitochondrial metabolism and eliminated via antioxidant systems. Regulation of mitochondrially produced ROS is required for proper cellular function, adaptation to metabolic stress, and bypassing cellular senescence. Here, we report non-canonical regulation of the cellular energy sensor AMP-activated protein kinase (AMPK) by mitochondrial ROS (mROS) that functions to maintain cellular metabolic homeostasis. We demonstrate that mitochondrial ROS are a physiological activator of AMPK and that AMPK activation triggers a PGC-1α-dependent antioxidant response that limits mitochondrial ROS production. Cells lacking AMPK activity display increased mitochondrial ROS levels and undergo premature senescence. Finally, we show that AMPK-PGC-1α-dependent control of mitochondrial ROS regulates HIF-1α stabilization and that mitochondrial ROS promote the Warburg effect in cells lacking AMPK signaling. These data highlight a key function for AMPK in sensing and resolving mitochondrial ROS for stress resistance and maintaining cellular metabolic balance

Rates of acute kidney injury by baseline (A) serum creatinine value and (B) creatinine clearance.

<p>Note (A). Rates of acute kidney injury were significantly higher for patients with a baseline serum creatinine value ≥1.01 mg/dL compared to ≤0.6 mg/dL at 48 hours (<i>P</i> = 0.01) and 7 days (<i>P</i> = 0.01).</p

Factors associated with colistin-induced Acute Kidney Injury (AKI).

<p>Factors associated with colistin-induced Acute Kidney Injury (AKI).</p