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Biomedical subjects

Gary P Zaloga

Publications and source records attributed to Gary P Zaloga.

At least 19 recordsLinked to original sources
PubMed2007

Diverse signaling pathways regulate fibroblast differentiation and transformation through Rho kinase activation.

This study examined the role of agonist-induced Rho kinase (ROCK) involvement in the morphological outcome of pulmonary-derived fibroblasts. Normal human lung fibroblasts (NHLF) spontaneously differentiate into network-like structures in a two-dimensional growth factor reduced Matrigel matrix-based assay. Sphingosine 1-phosphate (SPP), a bioactive phospholipid that regulates angiogenesis, inhibited fibroblast morphogenesis in a dose-dependent manner, virtually eliminating the presence of multi-cellular structures at 500 nM. Pretreatment with the Rho kinase-specific inhibitor, H1152, eradicated the high dose SPP-induced inhibition. Similarly, NHLFs transfected with Rho kinase siRNA prevented SPP-induced inhibition of the fibroblast morphogenesis. Alternatively, transforming growth factor-beta1 (TGF-beta1), a cytokine recognized as a key mediator of wound healing, terminally differentiates NHLF into myofibroblasts as evidenced by the expression of the smooth muscle cell isoform of alpha-actin (alpha-SMA). H1152 suppressed TGF-beta1-induced alpha-SMA expression in a dose-dependent manner. Similarly, treatment with Rho kinase siRNA reduced alpha-SMA expression by greater than 50%. SPP treatment had no effect on TGF-beta1-induced transformation into myofibroblasts, and TGF-beta1 treatment did not alter fibroblast morphogenesis. This study suggests a dual regulatory role for Rho kinase in cellular regulation of fibroblasts in which SPP-induced Rho kinase activation via a G-protein coupled receptor suppresses fibroblast morphogenesis while TGF-beta1-induced Rho kinase activation through a serine/threonine kinase receptor culminates in transformation into myofibroblasts.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2006

Parenteral nutrition in adult inpatients with functioning gastrointestinal tracts: assessment of outcomes.

Malnutrition is a common comorbidity that places inpatients at risk of complications, infections, long length of stay, higher costs, and increased mortality. Thus, nutrition support has become an important therapeutic adjunctive to the care of these patients. For patients unable to feed themselves, nutrition can be delivered via the parenteral or enteral routes. The formulations used to deliver nutrients and the route of nutrient delivery, absorption, and processing differ substantially between parenteral and enteral nutrition. Over the past two decades, many randomised clinical trials have assessed the effects of parenteral versus enteral nutrition on outcomes (ie, complications, infections, length of stay, costs, mortality) in diverse inpatient populations. From a search of medical publications, studies were selected that assessed important clinical outcomes of parenteral versus enteral feeding or intravenous fluids in patients with trauma/burn injuries, surgery, cancer, pancreatic disease, inflammatory bowel disease, critical illness, liver failure, acute renal failure, and organ transplantation. Our goal was to determine the optimum route of feeding in these patient groups. The available evidence lends support to the use of enteral over parenteral feeding in inpatients with functioning gastrointestinal tracts.

Adult↗
PubMed2006

(N-3) long-chain polyunsaturated fatty acids prolong survival following myocardial infarction in rats.

Many clinical studies report that (n-3) PUFAs decrease the incidence of sudden death in patients with coronary artery disease after myocardial infarction (MI). However, the mechanisms for the beneficial effects of (n-3) PUFAs are unknown. The objectives of the present study were to confirm the findings from clinical trials using an animal model of MI in which dietary intake could be closely controlled and to utilize the model to investigate molecular mechanisms for the beneficial effects of (n-3) PUFAs. Male rats were subjected to coronary ligation to induce MI and were randomly assigned to diets high in (n-6) (58% of lipid) or (n-3) (28% of lipid) PUFAs for 6 mo. A diet high in (n-3) PUFAs was associated with an improvement in 6-mo survival (89.2% vs. 64.9%, P = 0.013) compared with rats consuming a diet high in (n-6) PUFAs (n = 37/group). In a separate study (n = 5 rats/diet group), the (n-3) PUFA diet decreased the (n-6):(n-3) PUFA ratio in plasma (0.6 +/- 0.1 vs. 7.9 +/- 1.8, P < 0.05) and cardiac tissue (0.9 +/- 0.1 vs. 11.8 +/- 1.6, P < 0.05) of rats fed for 4 wk. The increased survival in the (n-3) diet group was associated with decreased cardiac activities of protein kinase A and calcium calmodulin-dependent kinase II by 33-38% (P < 0.05) and a 28% decrease (P < 0.05) in phosphorylation (activation) of the ryanodine receptor calcium release channel. Based upon our results, we speculate that decreased activities of protein kinases induced by diets high in (n-3) PUFAs are associated with a decrease in sudden death after MI in rats.

Animals↗
PubMed2006

Nutrition modulation of cachexia/proteolysis.

Cachexia represents progressive wasting of muscle and adipose tissue and is associated with increased morbidity and mortality. Although anorexia usually accompanies cachexia, cachexia rarely responds to increased food intake alone. Our knowledge of the underlying mechanisms responsible for cachexia remains incomplete. However, most states of cachexia are associated with underlying inflammatory processes and/or cancer. These processes activate protein degradation and lipolytic pathways, resulting in tissue loss. In this article, we briefly review the pathophysiology of cachexia and discuss the role of specific nutrient supplements for the treatment of cachexia. The branched chain amino acid leucine, the leucine metabolite beta-hydroxy-beta-methylbutyrate, arginine, glutamine, omega-3 long chain fatty acids, conjugated linoleic acid, and polyphenols have demonstrated some efficacy in animal and/or human studies. Optimal treatment for cachexia is likely aimed at maximizing muscle and adipose synthesis while minimizing degradation.

Adipose Tissue↗
PubMed2006

Trans fatty acids and coronary heart disease.

Epidemiologic evidence has linked trans fatty acids (TFAs) in the diet to coronary heart disease in human populations. It has been estimated that dietary TFAs from partially hydrogenated oils may be responsible for between 30,000 and 100,000 premature coronary deaths per year in the United States. Although it is known that TFAs increase low-density lipoprotein (LDL) cholesterol levels and decrease high-density lipoprotein (HDL) cholesterol levels (markers of coronary heart disease), there is little known about the mechanisms by which TFAs actually function at the cellular level. It is unknown what levels of TFAs are clinically significant and it is unclear how TFAs are associated with cardiac arrhythmias or sudden cardiac death. We hypothesize that TFAs affect membrane structure, thus altering enzymatic pathways that may subsequently induce cardiac arrhythmias and sudden death.

Cholesterol, LDL↗
PubMed2005

Omega-3 polyunsaturated fatty acids attenuate breast cancer growth through activation of a neutral sphingomyelinase-mediated pathway.

The effect of fish oils and their active omega-3 fatty acid constituents, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), were investigated on breast cancer growth. In in vivo experiments, mice were fed diets that were rich in either omega-3 (fish oil) or omega-6 (corn oil) fatty acids. Three weeks after implantation of MDA-MB-231 breast cancer cells, the tumor volume and weight were significantly lower (p < 0.05) for mice fed the omega-3 diets compared to those fed the omega-6 diets. Dietary fish oil also caused a 40% (p < 0.05) increase in neutral sphingomyelinase (N-SMYase) activity in the tumors. The tumor tissues from fish oil-fed animals expressed elevated p21 (waf1/cip1) mRNA, whereas tumor tissues from corn oil-fed animals exhibited undetectable levels of p21 expression. In in vitro experiments, at concentrations as low as 25 muM, DHA and EPA inhibited the growth of cultured MDA-MB-231 cells in a dose-dependent manner by 20-25% (p < 0.05). N-SMYase activity was also increased by 30-40% (p < 0.05) in the DHA- or EPA-treated cells in which an increase in ceramide formation was observed. DHA and EPA were both observed to enhance membrane bleb formation and also to induce the expression of p21. Omega-3 fatty acids-induced bleb formation and p21 expression were inhibited by the N-SMYase inhibitor GW4869, which also inhibited apoptosis by approximately 40% (p < 0.05). The results suggest that inhibition of breast cancer growth in nude mice by dietary fish oil and inhibition of breast cancer cell growth in culture by treatment with DHA and EPA is mediated by activation of N-SMYase.

Animal Feed↗
PubMed2005

Anticancer properties of propofol-docosahexaenoate and propofol-eicosapentaenoate on breast cancer cells.

INTRODUCTION: Epidemiological evidence strongly links fish oil, which is rich in docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), with low incidences of several types of cancer. The inhibitory effects of omega-3 polyunsaturated fatty acids on cancer development and progression are supported by studies with cultured cells and animal models. Propofol (2,6-diisopropylphenol) is the most extensively used general anesthetic-sedative agent employed today and is nontoxic to humans at high levels (50 microg/ml). Clinically relevant concentrations of propofol (3 to 8 microg/ml; 20 to 50 microM) have also been reported to have anticancer activities. The present study describes the synthesis, purification, characterization and evaluation of two novel anticancer conjugates, propofol-docosahexaenoate (propofol-DHA) and propofol-eicosapentaenoate (propofol-EPA). METHODS: The conjugates linking an omega-3 fatty acid, either DHA or EPA, with propofol were synthesized and tested for their effects on migration, adhesion and apoptosis on MDA-MB-231 breast cancer cells. RESULTS: At low concentrations (25 microM), DHA, EPA or propofol alone or in combination had minimal effect on cell adhesion to vitronectin, cell migration against serum and the induction of apoptosis (only 5 to 15% of the cells became apoptotic). In contrast, the propofol-DHA or propofol-EPA conjugates significantly inhibited cell adhesion (15 to 30%) and migration (about 50%) and induced apoptosis (about 40%) in breast cancer cells. CONCLUSION: These results suggest that the novel propofol-DHA and propofol-EPA conjugates reported here may be useful for the treatment of breast cancer.

Antineoplastic Agents↗
PubMed2005

Short-chain fatty acids modulate gene expression for vascular endothelial cell adhesion molecules.

OBJECTIVE: Leukocyte infiltration into the intestinal wall is central to the pathogenesis of tissue injury that occurs in patients with a variety of inflammatory bowel diseases. Migration of leukocytes from the intestinal circulation into bowel tissues is mediated by chemotactic substances and adhesion molecules (i.e., intercellular adhesion molecule-1 [ICAM-1] and E-selectin) on the surface of endothelial cells lining blood vessels. Short-chain fatty acids (SCFAs) derived from dietary fiber decrease inflammatory responses in colon cells. However, the effect of SCFAs on vascular adhesion molecules is unknown. We investigated the effects of SCFAs on vascular endothelial cell adhesion molecule expression. METHODS: We assessed the effect of physiologically relevant concentrations of butyrate on expression of ICAM-1 protein and mRNA in cultures of human umbilical vein endothelial cells. We also assessed the effect of butyrate on levels of HLA-DR, E-selectin, vascular cell adhesion molecule-1, and endoglin. In additional experiments, we evaluated the effect of butyrate on ICAM-1 mRNA stability and the effect of valerate, isobutyrate, and propionate on ICAM-1 expression. The effect of butyrate on ICAM-1 expression was compared with that of trichostatin A, a specific inhibitor of histone deacetylase. Data were evaluated with Student's t tests or Tukey's multiple comparison tests, with P < 0.05 considered statistically significant. RESULTS: Butyrate concentrations of 2.5 to 5 mM significantly increased endothelial expressions of ICAM-1 protein and mRNA. The effect of butyrate (5 mM) on ICAM-1 expression was time dependent, with significant increases in levels occurring after 16 h of incubation. Butyrate (5 mM) also increased expression of E-selectin but not of HLA-DR, vascular cell adhesion molecule-1, or endoglin. Isobutyrate had little effect on ICAM-1 expression, whereas valerate and propionate significantly increased expression of ICAM-1 but were weaker stimulants compared with butyrate. Butyrate (5 mM) did not alter stability of ICAM-1 mRNA. The effect of butyrate (5 mM) was comparable to that of trichostatin A. The stimulatory effect of butyrate on ICAM-1 expression was reversed after 48 h of butyrate withdrawal. CONCLUSIONS: Butyrate increases vascular endothelial expressions of ICAM-1 and E-selectin. We speculate that butyrate-induced effects on vascular adhesion molecules modulate gut inflammation. The role of SCFAs and fiber in the pathogenesis and modulation of gut inflammation in vivo requires further study.

Butyrates↗
PubMed2004

C-reactive protein: from innocent bystander to pivotal mediator of atherosclerosis.

There is compelling evidence that C-reactive protein is a sensitive marker for the development of cardiovascular disease in the general population. Recent studies suggest that C-reactive protein is not only a biomarker but also an active mediator in the pathogenesis of atherosclerosis. We review the evidence and suggest mechanisms by which C-reactive protein can damage arterial endothelium and promote the development of atherosclerotic lesions, including the effects of C-reactive protein on arterial endothelial activation, macrophage recruitment, and foam cell generation. The direct role of C-reactive protein in sustaining a proinflammatory and procoagulant milieu within the arterial neointima is emphasized. We also discuss the evidence that C-reactive protein can injure arterial endothelium. Finally, we review therapies that target C-reactive protein for primary prevention and for the treatment of atherosclerotic diseases.

Acute-Phase Reaction↗
PubMed2004

Meta-analysis of parenteral nutrition versus enteral nutrition in patients with acute pancreatitis.

OBJECTIVE: To compare the safety and clinical outcomes of enteral and parenteral nutrition in patients with acute pancreatitis. DATA SOURCES: Medline, Embase, Cochrane controlled trials register, and citation review of relevant primary and review articles. STUDY SELECTION: Randomised controlled studies that compared enteral nutrition with parenteral nutrition in patients with acute pancreatitis. From 117 articles screened, six were identified as randomised controlled trials and were included for data extraction. DATA EXTRACTION: Six studies with 263 participants were analysed. Descriptive and outcome data were extracted. Main outcome measures were infections, complications other than infections, operative interventions, length of hospital stay, and mortality. The meta-analysis was performed with the random effects model. DATA SYNTHESIS: Enteral nutrition was associated with a significantly lower incidence of infections (relative risk 0.45; 95% confidence interval 0.26 to 0.78, P = 0.004), reduced surgical interventions to control pancreatitis (0.48, 0.22 to 1.0, P = 0.05), and a reduced length of hospital stay (mean reduction 2.9 days, 1.6 days to 4.3 days, P < 0.001). There were no significant differences in mortality (relative risk 0.66, 0.32 to 1.37, P = 0.3) or non-infectious complications (0.61, 0.31 to 1.22, P = 0.16) between the two groups of patients. CONCLUSIONS: Enteral nutrition should be the preferred route of nutritional support in patients with acute pancreatitis.

Acute Disease↗
PubMed2004

Arginine: mediator or modulator of sepsis?

Arginine is a conditionally essential amino acid that plays pivotal roles in maintaining body homeostasis. Arginine is a substrate for protein synthesis but can also be metabolized to various bioactive compounds that include nitric oxide, ornithine, polyamines, creatine phosphate, agmatine, and dimethylarginines. Arginine produces physiologic effects via nitric oxide dependent and independent pathways. Nitric oxide is important for the modulation of vascular tone, inflammation, immune function, endothelial function, platelet and leukocyte adherence, and neurotransmission. Nitric oxide modulates many biochemical processes important for the response to sepsis. Arginine, independent of nitric oxide, is important for growth, wound healing, cardiovascular function, immune function, inflammatory responses, energy metabolism, urea cycle function, and other metabolic processes. Arginine supplementation improves outcomes in animals with sepsis, wounds, ischemia-reperfusion injury, and following thermal injury. Enteral administration of arginine improves endothelial function but has little effect upon hemodynamics during human sepsis. An analysis of clinical studies using enteral formulas with supplemental arginine suggests benefits upon outcome, with no evidence of significant detrimental effects.

Journal Article↗
PubMed2004

Omega 3-fatty acids: health benefits and cellular mechanisms of action.

Epidemiological evidence has established that ingestion of long-chain polyunsaturated omega-3 fatty acids (omega-3 PUFAs), abundant in fish oils, have profound effects on many human disorders and diseases, including cardiovascular disease and cancer. Here we briefly review the dietary recommendations and the food sources that are naturally enriched by these fatty acids. There are also a number of products including eggs, bread, and cereals available to supplement omega-3 fatty acid dietary intake. Some of these supplements are proposed to aid different pathological conditions. While the beneficial effects of omega-3 fatty acids can no longer be doubted, their molecular mechanism of action remains elusive. Without question, the action of omega-3 fatty acids is complex and involves a number of integrated signaling pathways. This review focuses on one of the possible cellular mechanisms by which the omega-3 PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may function. Studies with cancer cells suggest that DHA induces cell cycle arrest and apoptosis by activating protein phosphatases, leading to dephosphorylation of retinoblastoma protein (pRB). Protein phosphatases are also involved with the protein Bcl2, which regulates the release of cytochrome c from mitochondria, and eventually, activation of the apoptotic enzyme caspase 3.

Apoptosis↗
PubMed2004

Biologically active dietary peptides.

A large variety of peptides are generated in the gut lumen during normal digestion of dietary proteins. Large quantities of small peptides (ie. dipeptides and tripeptides) are absorbed through the gut mucosa and represent the primary mechanism for absorption of dietary nitrogen. However, larger peptide fragments are also absorbed with absorption decreasing with increasing chain length. Many of these dietary peptides have been shown to have biologic activity and many are active in microgram quantities. These peptides may modulate neural, endocrine, and immune function. In this report, we review normal protein digestion and absorption. We then discuss the biological actions of the amino acids arginine and glutamine and the biologic actions of a variety of dietary derived peptides. We concentrate on the immune effects of these peptides. We illustrate the potency of dietary peptides with a discussion of the cardiovascular effects of carnosine. We also review biologic effects of different protein sources, which generate different peptide profiles during digestion. The implications of dietary peptides for modulation of disease are discussed.

Amino Acids↗
PubMed2003

Gastric versus post-pyloric feeding: a systematic review.

BACKGROUND: Our objective was to evaluate the impact of gastric versus post-pyloric feeding on the incidence of pneumonia, caloric intake, intensive care unit (ICU) length of stay (LOS), and mortality in critically ill and injured ICU patients. METHOD: Data sources were Medline, Embase, Healthstar, citation review of relevant primary and review articles, personal files, and contact with expert informants. From 122 articles screened, nine were identified as prospective randomized controlled trials (including a total of 522 patients) that compared gastric with post-pyloric feeding, and were included for data extraction. Descriptive and outcomes data were extracted from the papers by the two reviewers independently. Main outcome measures were the incidence of nosocomial pneumonia, average caloric goal achieved, average daily caloric intake, time to the initiation of tube feeds, time to goal, ICU LOS, and mortality. The meta-analysis was performed using the random effects model. RESULTS: Only medical, neurosurgical and trauma patents were enrolled in the studies analyzed. There were no significant differences in the incidence of pneumonia, percentage of caloric goal achieved, mean total caloric intake, ICU LOS, or mortality between gastric and post-pyloric feeding groups. The time to initiation of enteral nutrition was significantly less in those patients randomized to gastric feeding. However, time to reach caloric goal did not differ between groups. CONCLUSION: In this meta-analysis we were unable to demonstrate a clinical benefit from post-pyloric versus gastric tube feeding in a mixed group of critically ill patients, including medical, neurosurgical, and trauma ICU patients. The incidences of pneumonia, ICU LOS, and mortality were similar between groups. Because of the delay in achieving post-pyloric intubation, gastric feeding was initiated significantly sooner than was post-pyloric feeding. The present study, while providing the best current evidence regarding routes of enteral nutrition, is limited by the small total sample size.

Critical Care↗