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Main contributors to adverse outcomes in severely burned pediatric patients are profound and complex metabolic changes in response to the initial injury. It is currently unknown how long these conditions persist beyond the acute phase post-injury. The aim of the present study was to examine the persistence of abnormalities of various clinical parameters commonly utilized to assess the degree hypermetabolic and inflammatory alterations in severely burned children for up to three years post-burn to identify patient specific therapeutic needs and interventions. Nine-hundred seventy-seven severely burned pediatric patients with burns over 30% of the total body surface admitted to our institution between 1998 and 2008 were enrolled in this study and compared to a cohort non-burned, non-injured children. Demographics and clinical outcomes, hypermetabolism, body composition, organ function, inflammatory and acute phase responses were determined at admission and subsequent regular intervals for up to 36 months post-burn. Statistical analysis was performed using One-way ANOVA, Student's t-test with Bonferroni correction where appropriate with significance accepted at p<0.05. Resting energy expenditure, body composition, metabolic markers, cardiac and organ function clearly demonstrated that burn caused profound alterations for up to three years post-burn demonstrating marked and prolonged hypermetabolism, p<0.05. Along with increased hypermetabolism, significant elevation of cortisol, catecholamines, cytokines, and acute phase proteins indicate that burn patients are in a hyperinflammatory state for up to three years post-burn p<0.05. Severe burn injury leads to a much more profound and prolonged hypermetabolic and hyperinflammatory response than previously shown. Given the tremendous adverse events associated with the hypermetabolic and hyperinflamamtory responses, we now identified treatment needs for severely burned patients for a much more prolonged time.

Cachexia, or weight loss despite adequate nutrition, significantly impairs quality of life and response to therapy in cancer patients. In cancer patients, skeletal muscle wasting, weight loss and mortality are all positively associated with increased serum cytokines, particularly Interleukin-6 (IL-6), and the presence of the acute phase response. Acute phase proteins, including fibrinogen and serum amyloid A (SAA) are synthesized by hepatocytes in response to IL-6 as part of the innate immune response. To gain insight into the relationships among these observations, we studied mice with moderate and severe Colon-26 (C26)-carcinoma cachexia. Moderate and severe C26 cachexia was associated with high serum IL-6 and IL-6 family cytokines and highly similar patterns of skeletal muscle gene expression. The top canonical pathways up-regulated in both were the complement/coagulation cascade, proteasome, MAPK signaling, and the IL-6 and STAT3 pathways. Cachexia was associated with increased muscle pY705-STAT3 and increased STAT3 localization in myonuclei. STAT3 target genes, including SOCS3 mRNA and acute phase response proteins, were highly induced in cachectic muscle. IL-6 treatment and STAT3 activation both also induced fibrinogen in cultured C2C12 myotubes. Quantitation of muscle versus liver fibrinogen and SAA protein levels indicates that muscle contributes a large fraction of serum acute phase proteins in cancer. These results suggest that the STAT3 transcriptome is a major mechanism for wasting in cancer. Through IL-6/STAT3 activation, skeletal muscle is induced to synthesize acute phase proteins, thus establishing a molecular link between the observations of high IL-6, increased acute phase response proteins and muscle wasting in cancer. These results suggest a mechanism by which STAT3 might causally influence muscle wasting by altering the profile of genes expressed and translated in muscle such that amino acids liberated by increased proteolysis in cachexia are synthesized into acute phase proteins and exported into the blood.

Mastitis is the most prevalent disease in dairy cattle worldwide and not only causes huge economic losses in the dairy industry but also threatens public health. To evaluate the therapeutic potential of melatonin in mastitis, we examined the ability of melatonin to protect bovine mammary epithelial cells (bMECs) from the harmful effects of lipopolysaccharide (LPS). We found that melatonin inhibited the LPS-binding protein-CD14-TLR4 signaling pathway in bMECs, which had opposing effects on pro-inflammatory and anti-inflammatory mediators. Melatonin decreased LPS-induced expression of pro-inflammatory cytokines, chemokines, and positive acute-phase proteins (APPs), including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, granulocyte-monocyte colony-stimulating factor, chemokine CC motif ligand (CCL)2, CCL5, serum amyloid A, haptoglobin, C-reactive protein, ceruloplasmin, and α-1 antitrypsin, and increased expression of the anti-inflammatory cytokine IL-1Ra and the negative APP fibrinogen. In addition, melatonin increased dityrosine levels but suppressed nitrite levels by upregulating the expression of Nrf2 and heme oxygenase-1 in the Nrf2 antioxidant defense pathway. Finally, melatonin administration increased the viability of LPS-stimulated bMECs. These results suggest that melatonin protects bMECs from LPS-induced inflammatory and oxidant stress damage and provide evidence that melatonin might have therapeutic utility in mastitis.

The potential contribution of chronic inflammation to the development of neuropsychiatric disorders such as major depression has received increasing attention. Elevated biomarkers of inflammation, including inflammatory cytokines and acute-phase proteins, have been found in depressed patients, and administration of inflammatory stimuli has been associated with the development of depressive symptoms. Data also have demonstrated that inflammatory cytokines can interact with multiple pathways known to be involved in the development of depression, including monoamine metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits relevant to mood regulation. Further understanding of mechanisms by which cytokines alter behavior have revealed a host of pharmacologic targets that may be unique to the impact of inflammation on behavior and may be especially relevant to the treatment and prevention of depression in patients with evidence of increased inflammation. Such targets include the inflammatory signaling pathways cyclooxygenase, p38 mitogen-activated protein kinase, and nuclear factor-κB, as well as the metabolic enzyme, indoleamine-2,3-dioxygenase, which breaks down tryptophan into kynurenine. Other targets include the cytokines themselves in addition to chemokines, which attract inflammatory cells from the periphery to the brain. Psychosocial stress, diet, obesity, a leaky gut, and an imbalance between regulatory and pro-inflammatory T cells also contribute to inflammation and may serve as a focus for preventative strategies relevant to both the development of depression and its recurrence. Taken together, identification of mechanisms by which cytokines influence behavior may reveal a panoply of personalized treatment options that target the unique contributions of the immune system to depression.

The pre-weaning period is critical for calf health and growth, and intensive milk feeding programs may assist postnatal development by improving body growth and organ maturation. The aim of the present work was to study the effects of ad libitum milk replacer (MR) feeding on the growth, metabolic adaptation, health, and immune status of newborn calves. Twenty-eight newborn Holstein and Holstein x Charolais crossbred calves were fed ad libitum (ADLIB) or in restricted amounts (6 liters per day; RES) during the first five weeks of life. The MR intake in the ADLIB treatment was gradually reduced at weeks 6 and 7, and all calves then received 6 liters of MR per day until day 60. Blood samples were collected to measure the plasma concentrations of metabolites, insulin, insulin-like growth factor (IGF)-I and IGF binding proteins (IGFBP), immunoglobulins, and acute phase proteins. The expression of mRNA associated with both the somatotropic axis and gluconeogenic enzymes was measured in the liver on day 60. Intensive feeding improved MR intake and growth in ADLIB without influencing concentrate intake. Carcass weight, perirenal fat, and muscle mass were greater in ADLIB. Plasma concentrations of glucose, triglycerides, insulin, and IGF-I were greater, whereas plasma concentrations of β-hydroxybutyrate, total protein, albumin, urea, IGFBP-2 and -4, and fibrinogen were lower at distinct time points in ADLIB. The hepatic mRNA expression of cytosolic phosphoenolpyruvate carboxykinase was greater in ADLIB. Most metabolic and endocrine differences occurred during the MR feeding period, but a slightly greater concentrate intake was associated with increased plasma IGF-I and insulin at the end of the study. The immune and health status of the calves were not affected by MR feeding. However, increased plasma fibrinogen in the RES group suggested differences in the acute phase response.

During liver injury, hepatic stellate cells (HSCs) can undergo activation and transform into alpha-smooth muscle actin (αSMA)-expressing contractile myofibroblast-like cells, leading to deposition of excessive scar matrix. We have recently demonstrated that depletion of adenosine deaminase acting on double-stranded RNA (ADAR1) from mouse hepatocytes leads to HSC activation and induction of inflammation and hepatic fibrosis that is mediated by interleukin 6 (IL-6). Our aim was to identify and characterize the molecular pathways involved in the direct, inflammation-independent activation of HSCs by IL-6. Primary HSCs were isolated from mouse livers. mRNA levels of αSMA and Col1a were analyzed using qRT-PCR. Protein levels of αSMA, MAPK, p-MAPK, p38, p-p38, STAT3 and p-STAT3 were assessed by Western Blot analysis. The effect of specific signal transduction pathway inhibitors (i.e., SB203580 (P-38 inhibitor), U0126 (MAPK inhibitor), S3I-201 (STAT3 inhibitor) and Ruxolitinib (Jak1/2 inhibitor)) was also studied. Primary HSCs treated with IL-6 demonstrated upregulation of αSMA and Col1a mRNA levels as well as increased αSMA protein levels. Moreover, the phenotypic transition of quiescent HSCs toward myofibroblast-like cells was noted upon administration of IL-6 and not in untreated samples. In addition, the phosphorylation levels of p38, MAPK and STAT3 increased 30 minutes after treatment, and was followed by a decline in the phosphorylation levels 2-4 hours post-treatment. However, addition of specific signal transduction pathway inhibitors curbed this effect, and resulted in αSMA and Col1a expression levels similar to those measured in untreated control samples. IL-6 can directly induce the transition of HSCs toward myofibroblast-like cells. The effect is mediated by the activation of both MAPK and JAK/STAT signaling pathways. Elimination of either MAPK or JAK/STAT signaling pathways inhibits HSC stimulation. These results might pave the road toward the development of potential therapeutic interventions for hepatic fibrosis.

Introduction: Serum amyloid A (SAA), secreted group IIA phospholipase A sub(2) (sPLA sub(2)-IIA), and C-reactive protein (CRP) are acute-phase proteins whose serum concentrations increase not only during inflammatory disorders, but also in the course of malignant diseases. Materials and methods: In this study we analyzed serum levels of these inflammatory markers along with prostate-specific antigens (PSA) in patients with benign prostatic hyperplasia (BPH, n = 55), localized prostate cancers (PCa, n = 55), and metastatic prostate cancers (mPCa, n = 27) using immunological assays. Results: We found that in comparison to healthy individuals (n = 55), patients with BPH, PCa and mPCa have elevated serum levels of SAA, sPLA sub(2)-IIA, and CRP, in addition to elevated levels of PSA. Significant differences with respect to inflammatory biomarkers were found between localized and metastatic PCa (p < 0.001), suggesting a prognostic value of these parameters. In addition, serum concentrations of SAA and sPLA sub(2)-IIA positively correlate with CRP in BPH patients (p < 0.05) and in patients with PCa and mPCa (p < 0.001), but not with PSA levels, Gleason score, or tumor stage, emphasizing a role of SAA and sPLA sub(2)-IIA as circulating biomarkers of inflammation rather than of neoplastic transformation. In contrast to PSA, which differed significantly between BPH and localized PCa patients (p < 0.01), such a difference was not found for SAA, sPLA sub(2)-IIA, and CRP. In order to elucidate whether the elevated levels of SAA and sPLA sub(2)-IIA can be caused by cancer cell-associated synthesis, in vitro studies were performed. These analyses demonstrated the expression of SAA and sPLA sub(2)-IIA in LNCaP and PC-3 prostate cell lines, which can be further upregulated by pro-inflammatory cytokines in a cell type-dependent manner. This might suggest that, in addition to the hepatic origin, SAA and sPLA sub(2)-IIA can also be synthesized and secreted by prostatic cancer tissue itself. Conclusion: The results of the present study emphasize the utility of SAA, sPLA sub(2)-IIA, and CRP as circulating biomarkers of inflammation during BPH development and PCa progression.

During infection, cellular resources are allocated toward the metabolically-demanding processes of synthesizing and secreting effector proteins that neutralize and kill invading pathogens. In Drosophila , these effectors are antimicrobial peptides (AMPs) that are produced in the fat body, an organ that also serves as a major lipid storage depot. Here we asked how activation of Toll signaling in the larval fat body perturbs lipid homeostasis to understand how cells meet the metabolic demands of the immune response. We find that genetic or physiological activation of fat body Toll signaling leads to a tissue-autonomous reduction in triglyceride storage that is paralleled by decreased transcript levels of the DGAT homolog midway , which carries out the final step of triglyceride synthesis. In contrast, Kennedy pathway enzymes that synthesize membrane phospholipids are induced. Mass spectrometry analysis revealed elevated levels of major phosphatidylcholine and phosphatidylethanolamine species in fat bodies with active Toll signaling. The ER stress mediator Xbp1 contributed to the Toll-dependent induction of Kennedy pathway enzymes, which was blunted by deleting AMP genes, thereby reducing secretory demand elicited by Toll activation. Consistent with ER stress induction, ER volume is expanded in fat body cells with active Toll signaling, as determined by transmission electron microscopy. A major functional consequence of reduced Kennedy pathway induction is an impaired immune response to bacterial infection. Our results establish that Toll signaling induces a shift in anabolic lipid metabolism to favor phospholipid synthesis and ER expansion that may serve the immediate demand for AMP synthesis and secretion but with the long-term consequence of insufficient nutrient storage.

Intestinal epithelial cells are multi-tasked cells that participate in digestion and absorption as well as in protection of the digestive tract. While information on the physiology and immune functions of intestinal epithelial cells in mammals is abundant, little is known of their immune function in birds and other species. Our main objectives were to study the development of anti-bacterial innate immune functions in the rapidly developing gut of the pre- and post-hatch chick and to determine the functional diversity of epithelial cells. After establishing primary intestinal epithelial cell cultures, we demonstrated their capacity to uptake and process bacteria. The response to bacterial products, LPS and LTA, induced expression of pro-inflammatory cytokine genes (IL-6, IL-18) as well as the expression of the acute phase proteins avidin, lysozyme and the secretory component derived from the polymeric immunoglobulin receptor. These proteins were then localized in gut sections, and the goblet cell was shown to store avidin, lysozyme as well as secretory component. Lysozyme staining was also located in a novel rod-shaped intestinal cell, situated at different loci along the villus, thus deviating from the classical Paneth cell in the mammal, that is restricted to crypts. Thus, in the chicken, the intestinal epithelium, and particularly goblet cells, are committed to innate immune protection. The unique role of the goblet cell in chicken intestinal immunity, as well as the unique distribution of lysozyme-positive cells highlight alternative solutions of gut protection in the bird.

Protein electrophoresis (PEP) is an important tool in supporting the analytical characterization of protein status in diseases related to monoclonal components, inflammation, and antibody deficiency. Here, we developed a deep learning-based PEP classification algorithm to supplement the labor-intensive PEP interpretation and enhance inter-observer reliability. A total of 2,578 gel images and densitogram PEP images from January 2018 to July 2019 were split into training (80%), validation (10%), and test (10.0%) sets. The PEP images were assessed based on six major findings (acute-phase protein, monoclonal gammopathy, polyclonal gammopathy, hypoproteinemia, nephrotic syndrome, and normal). The images underwent processing, including color-to-grayscale and histogram equalization, and were input into neural networks. Using densitogram PEP images, the area under the receiver operating characteristic curve (AUROC) for each diagnosis ranged from 0.873 to 0.989, and the accuracy for classifying all the findings ranged from 85.2% to 96.9%. For gel images, the AUROC ranged from 0.763 to 0.965, and the accuracy ranged from 82.0% to 94.5%. The deep learning algorithm demonstrated good performance in classifying PEP images. It is expected to be useful as an auxiliary tool for screening the results and helpful in environments where specialists are scarce.