Pyruvate Protects Against Intestinal Injury by Inhibiting the JAK/STAT Signaling Pathway in Rats With Hemorrhagic Shock.

BACKGROUND: This study aimed to investigate the role of Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway in protection by peritoneal resuscitation (PR) using pyruvate-peritoneal dialysis solution (PY-PDS) against intestinal injury from hemorrhagic shock (HS) in rats. MATERIALS AND METHODS: Sixty-four rats were assigned to eight groups: group SHAM; group intravenous resuscitation (VR); groups NS, LA, and PY in which the rats were subjected to HS and PR with normal saline (NS), lactate-peritoneal dialysis solution (LA-PDS), and PY-PDS, respectively, combined with VR; and groups DMSO, RPM, and AG490 in which the rats were subjected to HS and VR with pretreatment of dimethyl sulfoxide (DMSO), rapamycin (RPM), and tyrphostin B42 (AG490). RESULTS: At 2 h after HS and resuscitation, the levels of diamine oxidase, 15-F2t-isoprostane, thromboxane B2, and endothelin-1, in the blood and the intestinal mucosal apoptotic index and caspase-3 were lower in groups PY, RPM, and AG490 than in groups VR, NS, LA, and DMSO. Group PY showed lower levels of malondialdehyde and myeloperoxidase and a higher level of superoxide dismutase than groups VR, NS, and LA. Phosphorylated JAK2 and phosphorylated STAT3 levels were lower in groups PY, RPM, AG490, and LA than in groups VR, NS, and DMSO. CONCLUSIONS: The protection mechanism of PR with PY-PDS combined with VR was related to the inhibition of the JAK/STAT signaling pathway during HS and resuscitation. The process might include suppression of oxidative stress, reduction of neutrophil infiltration, regulation of microcirculation, and inhibition of apoptosis.

Cytokine and radical inhibition in septic intestinal barrier failure.

BACKGROUND: Breakdown of the intestinal barrier is a driving force of sepsis and multiple organ failure. Radical scavengers or cytokine inhibitors may have a therapeutic impact on intestinal failure. Therapeutic effects on different sites of small intestine and colon have not been compared. Therefore, we investigated time-dependent intestinal permeability changes and their therapeutic inhibition in colon and small intestine with an ex vivo model. METHODS: Male Sprague-Dawley rats were either pretreated for 24 h with lipopolysaccharide (LPS) intraperitoneally alone or in combination with a radical scavenger (pyruvate or Tempol) or a cytokine inhibitor (parecoxib or vasoactive intestinal peptide). The gastrointestinal permeability was measured by time-dependent fluorescein isothiocyanate inulin diffusion using washed and everted tube-like gut segments. Blood and tissue samples were taken to investigate the development of inflammatory cytokine level (interleukin 6) in the context of cytokine inhibition and reactive oxygen species level via nicotinamide adenine dinucleotide phosphate oxidase activity in radical scavenger groups. RESULTS: After LPS treatment, mucosal permeability was enhanced up to 170% in small intestine and colon. In the small intestine the most significant reduction in permeability was found for pyruvate and parecoxib. Treatment with vasoactive intestinal peptide and parecoxib resulted in the most pronounced reduction of permeability in the colon. CONCLUSIONS: Our data suggest that cytokine inhibitors and radical scavengers have pronounced effects in LPS-induced disrupted intestinal barrier of the colon and small intestine. Our novel model comparing different anatomic sites and different points in time after the onset of sepsis may contribute to gain new insight into mechanisms and treatment options of sepsis-related gut mucosal breakdown.

Protection against intestinal injury from hemorrhagic shock by direct peritoneal resuscitation with pyruvate in rats.

OBJECTIVE: We explored the effects of direct peritoneal resuscitation with pyruvate-peritoneal dialysis solution (PDS) following intravenous resuscitation (VR) on intestinal ischemia-reperfusion injury in rats with hemorrhagic shock (HS). METHODS: Fifty rats were randomly assigned equally to five groups. In group sham, a surgical operation was performed on rats without shock or resuscitation. In group VR, rats were subjected only to VR. In groups NS, LA, and PY, direct peritoneal resuscitation was performed with normal saline (NS), lactate-based PDS (Lac-PDS), and pyruvate-based PDS (Pyr-PDS), respectively, after VR. Mean arterial pressure was monitored in the right common carotid artery. Two hours after resuscitation, the lactate level in arterial blood and the wet weight/dry weight ratio of the intestine were determined. The intestinal mucosal damage index was estimated, and ultrastructural changes in the intestinal mucosa were observed. Malondialdehyde, myeloperoxidase, nitric oxide, and tumor necrosis factor α levels were also measured. RESULTS: Two hours after HS and resuscitation, the increase in arterial blood lactate and intestinal wet weight/dry weight ratio declined significantly in rats from Groups LA and PY compared with groups VR and NS, whereas group PY was more advantageous in the changes of these parameters. The intestinal mucosal damage index and ultrastructural changes were also improved in groups LA and PY when compared with groups VR and NS. Protection was more apparent with Pyr-PDS than Lac-PDS. Hemorrhagic shock resulted in a significant increase in malondialdehyde levels and myeloperoxidase activity and was accompanied by overexpression of tumor necrosis factor α and a reduction in nitric oxide levels. These changes were significantly attenuated by Lac-PDS and Pyr-PDS at 2 h after resuscitation, and Pyr-PDS showed more effective protection for the intestine than Lac-PDS. CONCLUSIONS: Direct peritoneal resuscitation with Lac-PDS and Pyr-PDS after VR alleviated intestinal injury from HS in rats, and Pyr-PDS was superior to Lac-PDS in its protective effect. Mechanisms of action might include the elimination of free oxygen radicals, reduction of neutrophil infiltration, inhibition of the inflammatory response, and regulation of intestinal mucosal blood flow and barrier function.

Beneficial effect of pyruvate therapy on Leigh syndrome due to a novel mutation in PDH E1α gene.

Leigh syndrome (LS) is a progressive untreatable degenerating mitochondrial disorder caused by either mitochondrial or nuclear DNA mutations. A patient was a second child of unconsanguineous parents. On the third day of birth, he was transferred to neonatal intensive care units because of severe lactic acidosis. Since he was showing continuous lactic acidosis, the oral supplementation of dichloroacetate (DCA) was introduced on 31st day of birth at initial dose of 50 mg/kg, followed by maintenance dose of 25 mg/kg/every 12 h. The patient was diagnosed with LS due to a point mutation of an A-C at nucleotide 599 in exon 6 in the pyruvate dehydrogenase E1α gene, resulting in the substitution of aspartate for threonine at position 200 (N200T). Although the concentrations of lactate and pyruvate in blood were slightly decreased, his clinical conditions were deteriorating progressively. In order to overcome the mitochondrial or cytosolic energy crisis indicated by lactic acidosis as well as clinical symptoms, we terminated the DCA and administered 0.5 g/kg/day TID of sodium pyruvate orally. We analyzed the therapeutic effects of DCA or sodium pyruvate in the patient, and found that pyruvate therapy significantly decreased lactate, pyruvate and alanine levels, showed no adverse effects such as severe neuropathy seen in DCA, and had better clinical response on development and epilepsy. Though the efficacy of pyruvate on LS will be evaluated by randomized double-blind placebo-controlled study design in future, pyruvate therapy is a possible candidate for therapeutic choice for currently incurable mitochondrial disorders such as LS.

Antioxidant strategies based on tomato-enriched food or pyruvate do not affect disease onset and survival in an animal model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder which is mostly sporadic, although about 5-10% of the cases are inherited. About 15-20% of patients with familial ALS (FALS) carry mutations in the gene encoding the free radical scavenging enzyme Cu/Zn superoxide dismutase (SOD1). In this study, we explored the potential neuroprotective effects of antioxidant strategies based on either a tomato-enriched diet, or pyruvate administration, in an animal model of ALS. To that aim, transgenic mice expressing a mutant form of SOD1 [the gly(93) --> ala (G93A) substitution; G93A SOD1] were fed on either tomato-enriched food pellets or the Altromin diet in which milk serum and proteins substitute for soy and fish flours. In both cases, treatments were started at the 29th day of age. In a second set of experiments, G93A SOD1 mice were treated with pyruvate intraperitoneally (500 mg/kg, i.p; starting at the 70th day of age) and compared with control mice receiving i.p. saline injections. Our results indicate that neither the tomato-enriched diet nor pyruvate administration caused any significant effect on the overall survival time and disease onset in G93A SOD1 mice. Thus, despite the wealth of data indicating the relevant role of oxidative stress and defective energy homeostasis both in patients and animal models of ALS, antioxidant strategies based on tomato-enriched food or pyruvate seem to be not sufficient to promote a disease modifying effect in an animal model of ALS.

A perspective on the current strategies for the treatment of obesity.

The prevalence in obesity has increased dramatically over the past 30 years, more than double in the United States alone. Obesity is associated with an increased risk for type 2 diabetes mellitus, dyslipidemia, hypertension, biliary disease, obstructive sleep apnea, and certain types of cancer. The pathophysiology of obesity is complex, involving behavioral, environmental, and genetic factors. Current treatment options include behavior modification and lifestyle changes which incorporate weight-reducing diets and physical activity, FDA approved long-term anti-obesity pharmacological agents sibutramine and orlistat, non-FDA approved over-the-counter (OTC) supplements and nutriceuticals, and, when appropriate, bariatric surgery. Without adequate prevention and treatment of obesity, government agencies have suggested that the direct and indirect costs associated with obesity may overwhelm the healthcare system. This brief review explores the current data available on treatments for the obese patient including the relative merits of different types of macronutrient composition (e.g., low carbohydrate vs. high carbohydrate diets) of weight-reducing diets, the value of resistance/ strength training in physical activity programs designed for the obese patient, the safety and efficacy associated with OTC supplements and nutriceuticals for weight reduction (e.g., Ephedra, conjugated linoleic acid (CLA), Garcinia cambogia/ hydroxycitric acid (HCA), chromium, pyruvate), the safety and efficacy of FDA-approved long-term obesity treatments sibutramine and orlistat, and bariatric surgery.