Haim Shapiro

Curcumin ameliorates acute thioacetamide-induced hepatotoxicity.

Background and Aim:  Increased production of reactive oxygen species and nitric oxide and activation of nuclear factor κ B are implicated in the pathogenesis of various liver diseases, including fulminant hepatic failure. Curcumin is a naturally occurring anti‐oxidant that reduces oxidative stress and inhibits nuclear factor κ B and nitric oxide formation. The aim of the present study is to assess curcumins therapeutic potential in acute thioacetamide hepatotoxicity, a rat model of fulminant hepatic failure.

Polyphenols in the treatment of inflammatory bowel disease and acute pancreatitis

Polyphenols are phytochemicals that are abundant in food and beverages derived from plants. Although no deficiency state has been described for them, increased intake of polyphenols appears to protect against disease in virtue of their anti-inflammatory and vasculoprotective properties. This article focuses on four polyphenols with established anti-inflammatory properties: resveratrol, epigallocatechin gallate, curcumin and quercetin. In rodents, ingestion or systemic administration of these agents inhibits nuclear factor κ B-dependent gene expression and induces phase II antioxidant and detoxifying proteins. Conditions prevented and/or ameliorated by these polyphenols include inflammatory colitis and acute pancreatitis. Polyphenols also attenuate ischaemia-reperfusion injury and endotoxemic sepsis, which has a role in the development of multiple organ dysfunction in severe acute pancreatitis. Enteral nutrition has an important role in the management of inflammatory bowel disease (IBD)—mainly of Crohn’s disease, and of acute pancreatitis. Parenteral nutrition is reserved for refractory cases and disease-associated complications. Artificial nutrition attempts to safely administer the essential and otherwise beneficial constituents of food to patients with an impaired ability to ingest or digest food; yet, polyphenols are not included in the formulas. We suggest that the addition of polyphenols to artificial nutritional formulas would improve the outcome of patients with IBD and acute pancreatitis in need of enteral or parenteral nutrition. Plants, like other unicellular and multicellular organisms, contain ubiquitous organic molecules (eg, amino acids, carbohydrates and fatty acids) termed primary metabolites that are essential to cell structure and basic metabolism. These compounds also serve as substrates for the synthesis of an array of chemicals called secondary plant metabolites, which are accumulated at lower concentrations and are more variably distributed among different species. Once thought to be waste products, these agents are now considered to have a role in ecological interactions with friendly and hostile microorganisms and macroorganisms, and protection from environmental stressors. …

The therapeutic potential of long-chain omega-3 fatty acids in nonalcoholic fatty liver disease.

OBJECTIVES The pharmacologic approach to disease management has not (as of yet) demonstrated safety and efficacy in nonalcoholic fatty liver disease (NAFLD). The current article introduces the long-chain omega-3 polyunsaturated fatty acids (LC-ω3s), and reviews the evidence and mechanisms by which their increased intake or supplementation may ameliorate NAFLD. METHODS A literature search was performed through Ovid Medline, using such terms as NAFLD, NASH, nonalcoholic, steatosis, polyunsaturated fatty acids, fish oil and omega-3. RESULTS The LC-ω3s display pleiotropic properties that are of benefit in cardiovascular disease. Deficiency of omega-3 fatty acids results in hepatic steatosis, whereas fish oil displays powerful hypotriglyceridemic properties. Intake and/or metabolism of omega-3 fatty acids are commonly impaired in NAFLD patients. A number of pre-clinical and clinical studies have demonstrated an ameliorative effect of supplemental fish oil, seal oil and purified LC-ω3s in reducing hepatic lipid content in NAFLD. There is less evidence that hepatic inflammation and fibrosis are safely reduced by LC-ω3s. CONCLUSIONS Supplementation of LC-ω3s appears to safely reduce nutritional hepatic steatosis in adults. Whether other histopatholgic features of NAFLD also respond to LC-ω3s is being addressed by clinical trials. Any recommendation for omega-3 supplementation in NAFLD/NASH is contingent on these results.

Polyphenols in the prevention and treatment of sepsis syndromes: Rationale and pre-clinical evidence

Sepsis is the overwhelming systemic response to infection of a normally sterile body compartment. Despite advances in elucidating its pathophysiology, severe sepsis remains a leading cause of death in the critically ill. Polyphenols are a family of chemicals found in food and beverages derived from plants, such as cocoa, green tea, turmeric, and soya, as well as in medicinal herbs. These phytochemicals exhibit anti-inflammatory and vasculoprotective properties in clinical and preclinical studies. The oral or systemic administration of polyphenols protects rodents from endotoxinemia and microbial sepsis. Under these circumstances, polyphenols reproducibly attenuate microvascular hyperpermeability, tissue infiltration by leukocytes, oxidative and nitrosative stress, tissue injury, organ dysfunction, shock and vasoplegia, lactate production, and mortality. Importantly, efficacy is maintained in some cases even when treatment is initiated hours after the onset of sepsis. The inhibition of nuclear factor-kappaB activation and subsequent expression of inducible nitric oxide synthase, adhesion molecules, and tumor necrosis factor-alpha by polyphenols is operative in ameliorating the sequelae of sepsis. Enhancement of the endogenous antioxidant capacity probably also contributes to the effectiveness of the polyphenols. Because several of the polyphenols reviewed in this article appear to be safe and to exert anti-inflammatory effects in humans, clinical trials assessing their efficacy in the critically ill are indicated. Whether delivered alone or in combination with nutritional formulas, polyphenols may help to prevent and treat sepsis.

Effects of polyunsaturated fatty acid consumption in diabetic nephropathy

The complex metabolic, vascular and inflammatory perturbations that characterize diabetes mellitus often lead to progressive albuminuria, renal injury and dysfunction (diabetic nephropathy [DN]), and diabetes is the leading cause of end-stage renal disease in the US and Europe. Diet has an important role in cardiometabolic disorders and its potential influence on DN is of interest. Fatty acids are a major source of energy, but in excess, fatty acids (particularly saturated fatty acids) can induce lipotoxicity. Omega-3 polyunsaturated fatty acids (PUFAs) confer protection against cardiovascular disease—the major cause of death in patients with DN—by virtue of their antihyperlipidemic, antihypertensive, anti-inflammatory and other properties. Omega-6 PUFAs are also cardioprotective. However, a significant proportion of adults consume insufficient quantities of these essential nutrients. This Review describes the role of omega-3 and omega-6 PUFAs in nutrition and metabolism, with a focus on experimental, epidemiologic and clinical studies that have investigated their renoprotective effect in patients with diabetes. Results from a number of studies suggest, but do not firmly establish, that long-chain omega-3 PUFAs (found in fish oil) reduce albuminuria in the setting of DN. Intake of omega-6 fatty acids is associated with reduced albuminuria in experimental settings and in epidemiologic studies of DN. Although PUFAs do not seem to attenuate glomerular dysfunction, insufficient evidence exists to rule out such an effect. We feel that further research is needed into the potential of PUFA consumption and supplementation in DN.

Enteral omega-3 in acute respiratory distress syndrome.

Purpose of reviewThe acute respiratory distress syndrome (ARDS) is a severe illness that is often the cause of death in ICU patients. A safe and effective intervention for this condition is lacking. Fish oil-based enteral nutrition [rich in n-3 polyunsaturated fatty acids (PUFAs) and antioxidants] improved clinical outcomes in a previous trial on ARDS patients but was ineffective, or even harmful in other studies utilizing different fish oil formulae (rich in n-3 PUFAs and arginine) in severely ill ICU patients. Until most recently, consistent evidence that enteral n-3 PUFA is therapeutic in ARDS was lacking. Recent findingsIn ARDS, an overwhelming inflammatory response damages the endothelial–alveolar units, reducing oxygen diffusion and increasing pulmonary workload. n-3 PUFA targets this inflammatory response. In two recent randomized, controlled studies, the fish oil formula that was previously shown to be effective was administered to patients with ARDS/acute lung injury (in which hypoxia is less severe) and to patients with severe sepsis and hypoxia, respectively. n-3 PUFA feeding improved oxygenation, and a meta-analysis of the three studies demonstrated that enteral fish oil reduces mortality, complications and length of ICU stay. SummaryEnteral administration of fish oil, antioxidants and physiologic amounts of arginine improve oxygenation and clinical outcomes in ICU patients with impaired oxygenation. Whether n-3 PUFA per se produces such benefit is the subject of an ongoing clinical study.

Inhaled Aerosolized Insulin: A “Topical” Anti-inflammatory Treatment for Acute Lung Injury and Respiratory Distress Syndrome?

Acute lung injury (ALI) and the more severe acute respiratory distress syndrome (ARDS) are forms of pulmonary edema that result from robust local and systemic inflammatory states, such as sepsis. The morbidity and mortality associated with ALI and ARDS are significant and the treatment of these conditions presents a formidable challenge. Controlling hyperglycemia with insulin is a core component of patient management in the critically ill. Insulin treatment also exerts beneficial metabolic effects beyond glucose control, as well as non-metabolic effects, in insulin-resistant states. For instance, insulin inhibits NF-κB—dependent synthesis of pro-inflammatory factors and attenuates production of ROS. Indeed, intravenous administration of insulin ameliorates pulmonary injury and dysfunction in the LPS model of ALI. Most recently, an inhalable insulin formulation was shown to effectively reduce glucose concentrations with minimal impact on long-term pulmonary function. We propose that administering inhalable insulin to hyperglycemic ALI/ARDS patients could directly reduce alveolar inflammation while reducing circulating glucose levels.

The atypical chemokine receptor D6 controls macrophage efferocytosis and cytokine secretion during the resolution of inflammation

The resolution of acute inflammation is hallmarked by the apoptotic death of inflammatory polymorphonuclear (PMN) cells, followed by their clearance by macrophages. In turn, resolution‐phase macrophages exert reduced proinflammatory cytokine production, termed immune silencing. In this study, we found that the atypical chemokine receptor D6 plays an important and chemokine scavenging‐independent role in promoting macrophage‐mediated resolution. D6–/– mice displayed increased numbers of macrophages (2.2‐fold increase), but not neutrophils, in their peritonea during the resolution of murine zymosan A‐initiated peritonitis, in comparison to D6+/+ animals. Moreover, D6‐deficient macrophages engulfed higher numbers of apoptotic PMN cells in vivo (1.6‐fold increase), and secreted higher amounts of TNF‐α, CCL3, and CCL5 ex vivo than their wild‐type (WT) counterparts. In addition, D6 was found to be expressed on apoptotic neutrophils from healthy humans and rodents. Moreover, the immune silencing of LPS‐stimulated macrophages following their incubation with senescent PMN cells ex vivo (in terms of TNF‐α, IL‐1β, and CCL5 secretion) was diminished (50–65% decrease) when D6–/– PMN cells were applied. Accordingly, the adhesive responses induced by macrophage interactions with senescent PMN cells were reduced with D6‐deficient PMN cells. Thus, our results indicate a novel mode of action for D6 during the resolution of inflammation that is instrumental to the shaping of resolving macrophage phenotypes and the completion of resolution.—Pashover‐Schallinger, E., Aswad, M., Schif‐Zuck, S., Shapiro, H., Singer, P., Ariel, A. The atypical chemokine receptor D6 controls macrophage efferocytosis and cytokine secretion during the resolution of inflammation. FASEB J. 26, 3891–3900 (2012). www.fasebj.org

Impact of a Nutritional Formula Enriched in Fish Oil and Micronutrients on Pressure Ulcers in Critical Care Patients

BACKGROUND Pressure ulcers are an important source of morbidity and suffering for patients and a formidable burden on caregivers. OBJECTIVES To assess the impact of a feeding formula enriched with fish oil on healing of preexisting pressure ulcers and serum levels of C-reactive protein in critical care patients. METHODS Adult patients with pressure ulcers grade II or higher were randomly allocated to receive either a formula enriched with fish oil or an isocaloric control formula. Wound healing was assessed by using the Pressure Ulcer Scale for Healing tool on days 7, 14, and 28. Blood levels of C-reactive protein were measured on days 0, 7, and 14. RESULTS Baseline demographics did not differ between the study (n = 20) and the control (n = 20) groups. The mean score on the ulcer healing tool increased significantly (P = .02) from day 0 to day 28 in the control group (from 9.25 [SD, 2.12] to 10.75 [SD, 3.41]) compared with the study group (from 9.10 [SD, 2.84] to 9.40 [SD, 3.72]). Mean levels of C-reactive protein decreased significantly (P= .02) from day 0 to day 14 in the study group (from 191 [SD, 104.4] mg/L to 111.7 [SD, 97.8] mg/L) compared with the control group (from 145 [SD, 90] mg/L to 139 [SD, 62] mg/L). CONCLUSION Administration of a feeding formula enriched with fish oil was associated with decreased progression of pressure ulcers and a decrease in blood concentrations of C-reactive protein.

Brain death and organ damage: the modulating effects of nutrition.

Severe brain injury that progresses to brain death may result in a series of insults, including hemodynamic instability, endocrine disturbances, and the release of chemokines and cytokines, which may have a deleterious effect on the quality of donor organs so that many are lost for transplantation. In addition, during the harvesting, preservation, and reperfusion stages, organs are subject to ischemia-reperfusion injury, which may impair the functioning of harvested organs. These processes also result in marked alterations in the nutritional status of the brain-dead organ donor. Because organ energy and redox status are closely related to nutritional status, organ dysfunction may be further compromised. Appropriate nutritional support can prevent depletion of micro- and macronutrients. In addition, experimental evidence suggests that the use of antioxidants may decrease the oxidative stress as well as the effects of ischemia reperfusion injury. We review the effects of nutritional depletion and discuss the potential modulating role of nutritional support using nutraceuticals, in particular polyphenols, fish oil, and glutamine, in preventing organ dysfunction.