Strategies to Mitigate Chemotherapy and Radiation Toxicities That Affect Eating

Background: Cancer and its therapy is commonly associated with a variety of side effects that impact eating behaviors that reduce nutritional intake. This review will outline potential causes of chemotherapy and radiation damage as well as approaches for the amelioration of the side effects of cancer during therapy. Methods: Information for clinicians, patients, and their caregivers about toxicity mitigation including nausea reduction, damage to epithelial structures such as skin and mucosa, organ toxicity, and education is reviewed. Results: How to anticipate, reduce, and prevent some toxicities encountered during chemotherapy and radiation is detailed with the goal to improve eating behaviors. Strategies for health care professionals, caregivers, and patients to consider include (a) the reduction in nausea and vomiting, (b) decreasing damage to the mucosa, (c) avoiding a catabolic state and muscle wasting (sarcopenia), and (d) developing therapeutic alliances with patients, caregivers, and oncologists. Conclusions: Although the reduction of side effects involves anticipatory guidance and proactive team effort (e.g., forward observation, electronic interactions, patient reported outcomes), toxicity reduction can be satisfying for not only the patient, but everyone involved in cancer care.

GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis

Cancer metabolism is rewired to support cell survival in response to intrinsic and environmental stressors. Identification of strategies to target these adaptions is an area of active research. We previously described a cytosolic aspartate aminotransaminase (GOT1)-driven pathway in pancreatic cancer used to maintain redox balance. Here, we sought to identify metabolic dependencies following GOT1 inhibition to exploit this feature of pancreatic cancer and to provide additional insight into regulation of redox metabolism. Using pharmacological methods, we identify cysteine, glutathione, and lipid antioxidant function as metabolic vulnerabilities following GOT1 withdrawal. We demonstrate that targeting any of these pathways triggers ferroptosis, an oxidative, iron-dependent form of cell death, in GOT1 knockdown cells. Mechanistically, we reveal that GOT1 inhibition represses mitochondrial metabolism and promotes a catabolic state. Consequently, we find that this enhances labile iron availability through autophagy, which potentiates the activity of ferroptotic stimuli. Overall, our study identifies a biochemical connection between GOT1, iron regulation, and ferroptosis.

The Role of DAMPS in Burns and Hemorrhagic Shock Immune Response: Pathophysiology and Clinical Issues. Review

Severe or major burns induce a pathophysiological, immune, and inflammatory response that can persist for a long time and affect morbidity and mortality. Severe burns are followed by a “hypermetabolic response”, an inflammatory process that can be extensive and become uncontrolled, leading to a generalized catabolic state and delayed healing. Catabolism causes the upregulation of inflammatory cells and innate immune markers in various organs, which may lead to multiorgan failure and death. Burns activate immune cells and cytokine production regulated by damage-associated molecular patterns (DAMPs). Trauma has similar injury-related immune responses, whereby DAMPs are massively released in musculoskeletal injuries and elicit widespread systemic inflammation. Hemorrhagic shock is the main cause of death in trauma. It is hypovolemic, and the consequence of volume loss and the speed of blood loss manifest immediately after injury. In burns, the shock becomes evident within the first 24 h and is hypovolemic-distributive due to the severely compromised regulation of tissue perfusion and oxygen delivery caused by capillary leakage, whereby fluids shift from the intravascular to the interstitial space. In this review, we compare the pathophysiological responses to burns and trauma including their associated clinical patterns.

Could Exogenous Insulin Ameliorate the Metabolic Dysfunction Induced by Glucocorticoids and COVID-19?

The finding that high-dose dexamethasone improves survival in those requiring critical care due to COVID-19 will mean much greater usage of glucocorticoids in the subsequent waves of coronavirus infection. Furthermore, the consistent finding of adverse outcomes from COVID-19 in individuals with obesity, hypertension and diabetes has focussed attention on the metabolic dysfunction that may arise with critical illness. The SARS coronavirus itself may promote relative insulin deficiency, ketogenesis and hyperglycaemia in susceptible individuals. In conjunction with prolonged critical care, these components will promote a catabolic state. Insulin infusion is the mainstay of therapy for treatment of hyperglycaemia in acute illness but what is the effect of insulin on the admixture of glucocorticoids and COVID-19? This article reviews the evidence for the effect of insulin on clinical outcomes and intermediary metabolism in critical illness.

Reduced light access promotes hypocotyl growth via autophagy-mediated recycling

Plant growth ultimately depends on fixed carbon, thus the available light for photosynthesis. Due to canopy light absorption properties, vegetative shade combines reduced light and a low red to far-red ratio (LRFR). In shade-avoiding plants, these two conditions independently promote growth adaptations to enhance light access. However, how these conditions, differing in photosynthetically-available light, similarly promote growth remains unknown. Here, we show that Arabidopsis seedlings adjust metabolism according to light conditions to supply resources for hypocotyl growth enhancement. Transcriptome analyses indicate that reduced light induces starvation responses, suggesting a switch to a catabolic state to promote growth. Accordingly, reduced light promotes autophagy. In contrast, LRFR promotes anabolism including biosynthesis of plasma-membrane sterols downstream of PHYTOCHROME-INTERACTING FACTORs (PIFs) acting in hypocotyls. Furthermore, sterol biosynthesis and autophagy are indispensable for shade-induced hypocotyl growth. We conclude that vegetative shade enhances hypocotyl growth by combining autophagy-mediated recycling and promotion of specific anabolic processes.

Engineered Peptide-Functionalized Hydrogels Modulate the RNA Transcriptome of Human Nucleus Pulposus Cells In Vitro

Degeneration and aging of the nucleus pulposus (NP) of the intervertebral disc (IVD) is accompanied by alterations in NP cell phenotype marked by a shift towards a fibroblast-like, catabolic state. We have recently demonstrated an ability to manipulate the phenotype of human adult degenerative NP cells through 2D culture upon poly(ethylene glycol) (PEG) based hydrogels dually functionalized with integrin- and syndecan-binding laminin-mimetic peptides (LMPs). In the present study, we sought to understand the transcriptomic changes elicited through NP cell interactions with the LMP-functionalized hydrogel system (LMP gel) by examining targets of interest a priori and by conducting unbiased analysis to identify novel mechanosensitive targets. The results of gene specific analysis demonstrated that the LMP gel promoted adult degenerative NP cells to upregulate 148 genes including several NP markers (e.g. NOG and ITGA6) and downregulate 277 genes, namely several known fibroblastic markers. Additionally, 13 genes associated with G protein-coupled receptors, many of which are known drug targets, were identified as differentially regulated following culture upon the gel. Furthermore, through gene set enrichment analysis we identified over 700 pathways enriched amongst the up- and downregulated genes including pathways related to cell differentiation, notochord morphogenesis, and intracellular signaling. Together these findings demonstrate the global mechanobiological effects induced by the LMP gel and confirm the ability of this substrate to modulate NP cell phenotype.

Molecular Mechanisms and Treatment of Sarcopenia in Liver Disease: A Review of Current Knowledge

Sarcopenia is characterized by progressive and generalized loss of skeletal muscle mass and strength that occurs with aging or in association with various diseases. The condition is prevalent worldwide and occurs more frequently in patients with chronic diseases owing to the intrinsic relationship of muscles with glucose, lipid, and protein metabolism. Liver cirrhosis is characterized by the progression of necro-inflammatory liver diseases, which leads to fibrosis, portal hypertension, and a catabolic state, which causes loss of muscle tissue. Sarcopenia is of significant concern in the state of liver cirrhosis because sarcopenia has been associated with higher mortality, increased hospital admissions, worse post-liver transplant outcomes, decreased quality of life, and increased risk for other complications associated with cirrhosis. Therefore, sarcopenia is also an important feature of liver cirrhosis, representing a negative prognostic factor and influencing mortality. An increased understanding of sarcopenia could lead to the development of novel therapeutic approaches that could help improve the cognitive impairment of cirrhotic patients; therefore, we present a review of the mechanisms and diagnosis of sarcopenia in liver disease and existing therapeutic approaches.

The Protective Role of Alpha-Ketoglutaric Acid on the Growth and Bone Development of Experimentally Induced Perinatal Growth-Retarded Piglets

The effect of alpha-ketoglutaric acid (AKG) supplementation to experimentally-induced, perinatal growth-retarded piglets was examined. Sows were treated with a synthetic glucocorticoid (Gc) during the last 25 days of pregnancy, and after the birth, piglets were randomly divided into three groups depending on the treatment. The Gc/Gc + AKG and Gc/AKG groups born by Gc-treated sows after the birth were treated with Gc or Gc + AKG for 35 days. Significantly lower serum growth hormone, IGF-I, osteocalcin, leptin, and cortisol concentrations were observed in the Gc/Gc + AKG group, while the bone alkaline phosphatase activity was significantly higher. Serum insulin concentration was higher in the control group. Serum alanine, lysine, histidine, and tryptophan concentrations were higher in the Gc/Gc + AKG and Gc/AKG groups. The perinatal action of Gc significantly affects histomorphometry of articular cartilage and trabecular bone and bone mechanics. The results clearly showed that dietary AKG had positive effects with regards to the profile of free amino acids. Taking into account the function of AKG as an energy donor and stimulator of collagen synthesis, it can be concluded that the anabolic role of AKG may be the main mechanism responsible for its protective effect against the GC-induced perinatal intensified catabolic state.