Changes In Organic Metabolism Research Articles

Metabolic homeostasis in fungal infections from the perspective of pathogens, immune cells, and whole-body systems.

SUMMARYThe ability to overcome metabolic stress is a major determinant of outcomes during infections. Pathogens face nutrient and oxygen deprivation in host niches and during their encounter with immune cells. Immune cells require metabolic adaptations for producing antimicrobial compounds and mounting antifungal inflammation. Infection also triggers systemic changes in organ metabolism and energy expenditure that range from an enhanced metabolism to produce energy for a robust immune response to reduced metabolism as infection progresses, which coincides with immune and organ dysfunction. Competition for energy and nutrients between hosts and pathogens means that successful survival and recovery from an infection require a balance between elimination of the pathogen by the immune systems (resistance), and doing so with minimal damage to host tissues and organs (tolerance). Here, we discuss our current knowledge of pathogen, immune cell and systemic metabolism in fungal infections, and the impact of metabolic disorders, such as obesity and diabetes. We put forward the idea that, while our knowledge of the use of metabolic regulation for fungal proliferation and antifungal immune responses (i.e., resistance) has been growing over the years, we also need to study the metabolic mechanisms that control tolerance of fungal pathogens. A comprehensive understanding of how to balance resistance and tolerance by metabolic interventions may provide insights into therapeutic strategies that could be used adjunctly with antifungal drugs to improve patient outcomes.

Abstract 1625: Lung and kidney metabolism altered by cancer-induced cachexia

Abstract Introduction: Cachexia is a complex metabolic syndrome that affects nearly 80% of pancreatic ductal adenocarcinoma (PDAC) patients. Major symptoms of cancer induced cachexia include loss of skeletal muscle weight with or without fat loss and reduced physical activity [1, 2]. Cancer cachexia may lead to multiple organ dysfunction and metabolic abnormalities [3]. To date there are no known cures for this condition. Our ongoing studies have focused on understanding the metabolic impact of PDAC induced cachexia in vital organs using 1H magnetic resonance spectroscopy (MRS) of organ extracts to expand our understanding of this syndrome. Here we have focused on understanding the metabolic changes occurring in the lungs and kidneys using our well established PDAC xenograft models. We compared organ changes in mice with cachexia-inducing xenografts (Pa04C) to mice with non-cachexia-inducing xenografts (Panc1) and normal mice. We have previously established significant weight loss in Pa04C tumor bearing mice compared to Panc1 tumor bearing mice [4]. Methods: Panc1 cells were obtained from ATCC and Dr. Maitra kindly provided Pa04C cells. Cancer cells were inoculated in the right flank of six to eight week old male severe combined immunodeficient mice. Kidneys and lungs from normal mice and from Pa04C and Panc1 tumor bearing mice (n=5 per group), excised from euthanized mice once tumors were ~300 mm3, were snap frozen and stored at -80°C prior to dual phase extraction. 1H MRS was performed on the water phase. All 1H MR spectra were acquired on a 750 MHz MR spectrometer. All data processing analyses and quantification were performed with TOPSPIN 3.5 software. Statistical analysis was performed with MetaboAnalyst software [5]. Result and Discussion Multivariate principal component analysis of lung and kidney data identified a clear separation between the Pa04C tumor-bearing group compared to the Panc1 tumor bearing group and normal mice. Significant differences in several metabolites were observed in the lungs and kidneys of Pa04C tumor bearing mice compared to Panc1 tumor bearing mice and normal mice. Significant metabolic differences were detected in amino acids, BCAA, glutathione, acetate, histidine, phenylalanine and tyrosine in the lung and kidney. These metabolic changes can influence the function of these organs. Our results support an expanded understanding of the changes in organ metabolism that may occur with cancer-induced cachexia and with cancer in general that may contribute to morbidity and poor treatment response. Acknowledgement: This work was supported by NIH R35CA209960 and R01CA193365. Ref: 1. Fearon K et al, The Lancet Oncology. 2011; 2. Penet MF, Bhujwalla ZM. Cancer journal. 2015; 3. Argiles JM et al, Nature reviews Cancer. 2014; 4. Winnard PT, Jr. et al, Cancer research. 2016; 5. Xia J, Wishart DS. Nature protocols. 2011. Citation Format: Raj Kumar Sharma, Santosh K. Bharti, Paul T. Winnard, Marie-France Penet, Zaver M. Bhujwalla. Lung and kidney metabolism altered by cancer-induced cachexia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1625.

Abdominal compartment syndrome in childhood: the role of near infrared spectroscopy for the early detection of the organ dysfunction

We found very interesting the manuscript written by Dr. Steinau et al. [1] recently published in your journal. The author proposed their approach for the management of abdominal compartment syndrome (ACS) in childhood presenting a wide case mix of pathology ranging from neonates to school children. We agree that the gold standard for the indirect intrabdominal preassure (IAP) measurement both in adults and children is the intra-bladder pressure monitoring with an intermittent saline bolus. In accordance with the adult guidelines, intrabdominal hypertension (IAH) in children is firstly managed with a conservative therapy, while in the presence of ACS (low abdominal perfusion pressure associated to a new onset of organ dysfunction) early abdominal decompression remains a mandatory approach in order to reduce the high mortality rate associated with this condition [2, 3]. Unfortunately, the ‘‘numbers’’ used in the adult population to perform an abdominal decompression are not applicable in children since the variable abdomen compliance especially in neonates and infants [2]. Many authors [1, 2, 4] suggested proper cut-off values for IAH, to establish the ‘‘critical pressure number’’ at which regularly a switch from IAH to ACS in pediatric patients can be observed. In his work, Dr. Steinau et al. used the criteria proposed by Dr. Eijke [4] to define the pediatric ACS [3]. He considered the pediatric ACS as a lasting IAH higher than 12 mmHg combined with at least one organ dysfunction. We believe that a fixed ‘‘critical’’ number is not suitable for all pediatric patients and that the values proposed by Dr. Stainau are just indicative of an evolving process that could lead or not to a multiple organ dysfunction. Both in adults and children, clinical examination and laboratory testing (base deficit, lactate, unpaired dieresis) are sensitive in detecting abnormalities of tissue perfusion during ACS only after sustained periods of inadequate perfusion, furthermore the early changes in organ metabolism are not easily identified with the traditional monitoring systems. We believe that the outcome of ACS would improve if an earlier detection of regional tissue hypoperfusion would be provided to these patients. Differently from adults, in both neonates and infants, abdominal organs perfusion (kidney) can be monitored using the near infrared spectroscopy (NIRS). This device enables the detection of the states of organ hypoperfusion, allowing a rapid intervention to limit the cascade of multiple organs dysfunction and the development of shock [5–7]. NIRS uses nonpulsatile oximetry to determine venous-weighted oxy-hemoglobin saturation of the underlying regional tissue (rSO2) studied. In pediatrics generally two-site NIRS (brain–kidney) is used for the non invasive assessment of the cardiac output and of its autoregulation in the case of shock [6]. Normally tissue beds with high oxygen consumption (brain) have lower baseline rSO2, where tissue with little metabolic demand (kidney) have a higher baseline rSO2. Figure 1 shows a case of primary ACS for a Clostridium difficilis enterocolitis in a 6-month-old child (7 kg body weight) in which two-site NIRS (brain–kidney) was continuously used to manage the relation between cardiac output and IAP. This patient presented a pathologic change in brain and kidney saturation (dotted arrow) when IAP was *10 mmHg and diuresis was still 1.5 ml/kg/h. This state was not controlled with the medical therapy (deep sedation, neuromuscular M. Di Nardo (&) C. Cecchetti F. Stoppa N. Pirozzi S. Picardo Pediatric Intensive Care Unit, Children’s Hospital Bambino Gesu, Rome, Italy e-mail: matteo.dinardo@tin.it

The effect of testosterone on water distribution on secondary sex glands of male rats.

Alterations of water distribution have been reported as one of the earliest demonstrable effects of estrogens on the uterus (Talbot, Lowry and Astwood, 1940; Roberts and Szego, 1947) and androgens on the seminal vesicles (Rudolph and Samuels, 1949). The latter reported an increased intracellular water of the seminal vesicles, estimated by chloride space, as early as ten hours after androgen administration to castrated rats. Other changes occurring at this time were increases in Qo2, weight, and fructose content. It was also suggested that changes in organic metabolism preceded the shifts in water and electrolytes and cell growth. In the present study extracellular water was estimated with isotopic sodium in the seminal vesicles and prostates of uncastrated rats and of castrated rats with and without the administration of testosterone. METHODS Male albino rats from Sprague-Dawley Inc. were used in these experiments. When 92 clays of age the animals were castrated and twenty-eight days after castration a si...