Taurine treatment reverses protein malnutrition-induced endothelial dysfunction of the pancreatic vasculature: The role of hydrogen sulfide.

BACKGROUND: Protein malnutrition in childhood predisposes individuals to vascular and pancreatic endocrine dysfunction, thus increasing the risk of diabetes and hypertension. Because taurine may reduce cardiometabolic risk, we hypothesized that taurine treatment has a beneficial effect on the pancreatic vasculature during protein restriction. METHODS AND RESULTS: Weaned mice were fed a normal or a low-protein diet and were treated with or without taurine for 3 months. The lieno-pancreatic artery (LPA) from low-protein diet-treated mice exhibited impaired endothelium-dependent relaxation to acetylcholine that was associated with decreased endothelium-derived hyperpolarization (EDH), hydrogen sulfide (H2S) production, and H2S-synthesizing CBS expression and impaired vasorelaxation to an H2S-donor, NaHS. These changes were prevented by taurine treatment. We compared the effects of taurine with the effects of the direct vasodilator hydralazine and found that both normalized blood pressure and the endothelial vasodilator function of the LPA in the mice fed a protein-restricted diet. However, only taurine restored the CBS expression in the LPA and insulin secretion in response to high glucose. The LPA supplies the pancreas and shares morphometry with the mesenteric resistance artery (MRA). However, in the MRA, low-protein diet-induced endothelial dysfunction is driven by impaired NOS-derived NO with no changes in H2S signaling. CONCLUSIONS: The results suggest that taurine protects against protein malnutrition-induced endothelial dysfunction in the LPA by upregulating the CBS-H2S pathway. Considering the importance of the pancreatic vasculature for endocrine islet activity, taurine may be a potential therapy for the vascular and metabolic dysfunction associated with malnutrition and comorbidities.

Unusual Late-onset Enteropathy in a Patient With Lipopolysaccharide-responsive Beige-like Anchor Protein Deficiency.

In recent years, monogenic causes of immune dysregulation syndromes, with variable phenotypes, have been documented. Mutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) protein are associated with common variable immunodeficiency, autoimmunity, chronic enteropathy, and immune dysregulation disorders. The LRBA protein prevents degradation of cytotoxic T-lymphocyte antigen 4 (CTLA4) protein, thus inhibiting immune responses. Both LRBA and CTLA4 deficiencies usually present with immune dysregulation, mostly characterized by autoimmunity and lymphoproliferation. In this report, we describe a patient with an atypical clinical onset of LRBA deficiency and the patient's response to abatacept, a fusion protein-drug that mimics the action of CTLA4.

Hydroalcoholic extract of Brazilian green propolis modulates inflammatory process in mice submitted to a low protein diet.

The occurrence of inflammation and protein malnutrition is an aggravating risk factor for morbidity and mortality in the clinical setting. The green propolis, a natural product made by Apis mellifera bees from Baccharis dracunculifolia resin, has therapeutic potential to modulate chronic inflammation. However, its effect on inflammation in an impaired nutritional status is not known. The aim of this study was to characterize the effects of the administration of the hydroalcoholic extract of the green propolis in the chronic inflammatory process of mice submitted to a low-protein diet. For this, we used the subcutaneous implantation of sponge disks as an inflammatory model and the animals were distributed in the following groups: standard protein diet (12% protein content), control treatment; standard protein diet, propolis treatment; low-protein diet (3% protein content), control treatment; low-protein diet, propolis treatment. Propolis was given daily at a dose of 500 mg/kg (p.o.) during a period of 7 or 15 days. Our main findings show that animals fed with standard protein diet and treated with propolis had low levels of red blood cells, hemoglobin, and hematocrit, with the subsequent reestablishment of these levels, in addition to monocyte count elevation and higher TNF levels after one week of treatment. In the low-protein diet group, the propolis treatment provided a significant recovery in weight and maintenance of total serum protein levels at the end of two weeks of treatment. Histological analysis showed propolis reduced the inflammatory infiltrate in the sponges of both standard and low-protein diet groups. In addition, the propolis extract presented antiangiogenic effect in both groups. Therefore, our data suggests that the hydroalcoholic extract of the green propolis promotes weight recovery and avoid the reduction of protein levels, in addition to inhibit inflammation and angiogenesis in animals fed with a low-protein diet.

Transient enalapril attenuates the reduction in glomerular filtration rate in prenatally programmed rats.

A maternal low-protein diet has been shown to program hypertension and a reduction in glomerular filtration rate in adult offspring. This study examined the effect of continuous administration of enalapril in the drinking water and transient administration of enalapril administered from 21 to 42 days of age on blood pressure and glomerular filtration rate (GFR) in male rats whose mothers were fed a 20% protein diet (control) or a 6% protein diet (programmed) during the last half of pregnancy. After birth all rats were fed a 20% protein diet. Programmed rats (maternal 6% protein diet) were hypertensive at 15 months of age compared to control rats and both continuous and transient administration of enalapril had no effect on blood pressure on control offspring, but normalized the blood pressure of programmed offspring. GFR was 3.2 ± 0.1 mL/min in the control group and 1.7 ± 0.1 mL/min in the programmed rats at 17 months of age (P < 0.001). The GFR was 3.0 ± 0.1 mL/min in the control and 2.7 ± 0.1 mL/min in the programmed group that received continuous enalapril in their drinking water showing that enalapril can prevent the decrease in GFR in programmed rats. Transient administration of enalapril had no effect on GFR in the control group (3.2 ± 0.1 mL/min) and prevented the decrease in GFR in the programmed group (2.9 ± 0.1 mL/min). In conclusion, transient exposure to enalapril for 3 weeks after weaning can prevent the hypertension and decrease in GFR in prenatal programmed rats.

Thrombotic microangiopathy due to acquired ADAMTS13 deficiency in a patient receiving interferon-beta treatment for multiple sclerosis.

Thrombotic microangiopathies (TMAs) can be due to inherited or acquired ADAMTS13 deficiency. Acquired deficiency is mainly associated with autoantibodies directed to ADAMTS13, including drug-induced forms. A few cases of TMA have been reported in association with interferon-alpha treatment and more rarely with interferon-beta. We report the case of a 52-year-old male with TMA-associated severe renal failure secondary to severe ADAMTS13 deficiency due to an anti-ADAMTS13 IgG antibody which developed after interferon-beta treatment for multiple sclerosis. Treatment included interferon-beta discontinuation, immediate plasma exchange therapy, corticosteroids, and hemodialysis. After an initial hematologic improvement, early hemolysis relapse led us to introduce rituximab allowing durable hematologic recovery. This is the first reported case of interferon-beta-induced TMA due to acquired ADAMTS13 deficiency that was treated by rituximab.

Antenatal taurine supplementation for improving brain ultrastructure in fetal rats with intrauterine growth restriction.

Changes in brain ultrastructure of fetal rats with intrauterine growth restriction (IUGR) were explored and the effects of antenatal taurine supplementation on their brain ultrastructure were determined. Fifteen pregnant rats were randomly divided into three groups: control group, IUGR model group and IUGR group given antenatal taurine supplements. Taurine was added to the diet of the taurine group at a dose of 300 mg/kg/d from 12 days after conception until natural delivery. Transmission electron microscopy was used to observe ultrastructural changes in the brains of the newborn rats. At the same time, brain cellular apoptosis was detected using TUNEL, and the changes in protein expression of neuron specific enolase and glial fibrillary acidic protein were analyzed using immunohistochemistry. The results showed that: 1) The average body weight and cerebral weight were significantly lower in the IUGR group than in the control group (p<0.01) and both of them were less so after taurine was supplemented (p<0.01). 2) Transmission electron microscopy revealed that brain cortex structures were sparse IUGR rats, showing many scattered apoptotic cells, decreased numbers of synapses, lower glial cell proliferation, and fewer neurons, more sparsely arranged, while these factors were significantly improved with taurine supplementation. 3) The results of TUNEL showed that the counts of apoptotic brain cells in IUGR groups were significantly increased from those in control groups and that taurine could significantly decrease brain cell apoptosis (p<0.001). 4) The results of immunohistochemistry showed that antenatal taurine-supplementation could significantly increase the counts of neuron specific enolase and glial fibrillary acidic protein immunoreactive cells in fetal rats with IUGR (p<0.001). It can be concluded that it IUGR has a significant detrimental influence on the development of fetal rat brains, and antenatal supplement of taurine can significantly improve the IUGR fetal brain development.

Hot water extracts of Chlorella vulgaris improve immune function in protein-deficient weanling mice and immune cells.

The objective of this study was to investigate the effects of hot water extracts of Chlorella vulgaris (CVE) on a deteriorated immune function through utilization of a protein-energy malnutrition (PEM) diet. Unicellular algae, C. vulgaris, were used as biological response modifier. PEM is associated with decreased host immune defense. Male C57BL/6J mice, initially four weeks old, were fed for 8 days with standard diet or a PEM diet. Mice in the PEM diet group were orally administered 0.1 g/kg and 0.15 g/kg of CVE for the following week. Nutritional parameters such as the total protein, albumin, glucose, and interferon γ (IFN-γ) were increased in blood serum of the CVE-treated group compared with the non-treated group. The mononuclear cell numbers from spleen, superficial, and mesenteric lymph node were reduced in mice fed with PEM diet, but numbers from the spleen and superficial lymph node were increased by the CVE (0.1 and 0.15 g/kg) treatment. We also investigated the effect of CVE on the production of cytokines in human T-cell line, MOLT-4 cells, and primary cultured splenocytes. The CVE treatment significantly increased the production of both interleukin (IL)-2 and IL-4 compared with the media control, but did not affect the production of IFN-γ. These results suggest that CVE may be useful in improving the immune function.

Protein therapeutics: a summary and pharmacological classification.

Once a rarely used subset of medical treatments, protein therapeutics have increased dramatically in number and frequency of use since the introduction of the first recombinant protein therapeutic--human insulin--25 years ago. Protein therapeutics already have a significant role in almost every field of medicine, but this role is still only in its infancy. This article overviews some of the key characteristics of protein therapeutics, summarizes the more than 130 protein therapeutics used currently and suggests a new classification of these proteins according to their pharmacological action.

Protective effect of selenium on protein-undernutrition-induced brain damage in rats.

The effect of ad libitum ingestion of selenium (Se) in drinking water (0.15 mg SeO2/L) for 3 wk on the brain weight, total brain protein, glutathione (GSH) level, catalase activity, and lipid peroxidation in the brain of protein-undernourished (PU) rats was investigated, in an attempt to determine whether antioxidants alone can reverse some of the neuropathological changes associated with protein undernutrition in rats. Feeding on a normal diet (16% casein) by well-fed rats or a low-protein diet (5% casein) by PU rats and Se-treated PU rats lasted 14 wk. Se-treated PU rats were given Se in drinking water during the last 3 wk of the experiment. Results show that protein undernutrition induced significant reductions (p < 0.001) in brain weight, total brain protein, and catalase activity (p < 0.05) while it induced a significant increase (p < 0.05) in lipid peroxidation when compared with well-nourished rats; but no significant effect was observed for the GSH level. However, the ingestion of Se in drinking water by PU rats for 3 wk resulted in significant increases (p < 0.05) in brain weight, catalase activity, and total brain protein but induced a significant reduction (p < 0.05) in lipid peroxidation when compared with PU rats given water. The values obtained for Se-treated PU rats are comparable with those obtained for well-nourished rats. The GSH level was, however, not affected by Se ingestion. We suggest that Se, by inducing increases in the concentration of certain proteins, including catalase, in the brain, abolished some of the pathological changes associated with protein undernutrition in the brain, and appears as a promising antioxidant in the prevention and management of pro-oxidant-induced brain damage.

Hepatoprotective role of zinc in lead-treated, protein-deficient rats.

The current study was designed to evaluate the hepatoprotective role of zinc after lead (Pb) treatment of protein-deficient (PD) rats. The animals were subjected to seven different treatment groups: G-1 (normal control, 18% protein), G-2 (protein-deficient, 8% protein), G-3 (Pb-treated, 100 mg/kg body weight of lead acetate), G-4 (Zn-treated, zinc sulfate at a dose level of 227 mg/L drinking water), G-5 (PD + Pb-treated), G-6 (PD + Zn-treated), and G-7 (PD + Pb + Zn-treated). Serum albumin levels and total serum protein contents were estimated to assess the severity of protein deficiency at the end of 8 weeks in all the treatment groups. Also, the study explored the role of zinc on antioxidative defense system enzymes in liver of protein-deficient rats subjected to lead toxicity treatment. Further, the study was extended to elucidate the levels of zinc and lead in liver tissue after different treatments of rats using positron-induced X-ray emission technique (PIXE). The current study indicated a significant change in the levels of various antioxidative enzymes and serum albumin as well as total protein contents of protein-deficient rats subjected to lead treatment. A significant increase in the levels of malondialdehyde (MDA), catalase, and glutathione peroxidase (GPx) was seen after 8 weeks of lead treatment of protein-deficient rats. On the contrary, levels of albumin, total protein content, superoxide dismutase (SOD), GSH, were found to be decreased. Interestingly, zinc supplementation has tended to normalize the altered levels of these enzymes to a significant extent. The levels of zinc in liver tissue was found to be decreased significantly in protein-deficient as well as lead-treated rats. However, hepatic zinc concentration was increased to a significant extent in protein-deficient rats supplemented with zinc when compared with protein-deficient rats. Further, the presence of lead was also observed in livers of lead-treated animals. In conclusion, the study revealed the antioxidative role of zinc in hepatotoxic conditions induced by subjecting the rats to protein-deficient diet and lead treatment.

Supplementation of N-acetylcysteine normalizes lipopolysaccharide-induced nuclear factor kappaB activation and proinflammatory cytokine production during early rehabilitation of protein malnourished mice.

Increased sensitivity to septic shock has been reported in protein malnourished patients. In this study, we used an animal septic shock model to investigate effects of glutathione (GSH) levels on nuclear factor kappaB (NFkappaB) activation and proinflammatory cytokine production in protein malnutrition. We further investigated molecular mechanisms by which protein malnutrition influenced inflammatory responses. CD-1 mice were fed for 3 wk a normal protein (150 g/kg) diet or a protein-deficient (5 g/kg) diet, or for 2 wk a protein-deficient diet followed by 1 wk of N-acetylcysteine (NAC) supplementation. Lipopolysaccharide (LPS) was injected intravenously, and liver was collected at 0, 15 min, 1, 4, 24 and 48 h after LPS administration. Protein malnutrition significantly increased the activation of NFkappaB and transcription levels of its downstream genes interleukin-1beta and tumor necrosis factor-alpha. Peak NFkappaB activation was inversely associated with GSH levels (r = -0.939, P < 0.0001) but positively correlated with the GSH disulfide/2GSH reduction potential (r = 0.944 P < 0.0001). We noted unusual NFkappaB p50/p50 homodimer translocation that was significantly elevated in tissue from protein malnourished mice, along with decreased peak levels of normal p65/p50 heterodimer translocation. Interestingly, mRNA levels of IkappaB-alpha were not affected by protein malnutrition. However, early supplementation of NAC to protein malnourished mice without replenishing with dietary protein restored GSH levels and reduction potential, and normalized NFkappaB activation and proinflammatory cytokine production. Taken together, these findings provide evidence supporting the role of GSH in NFkappaB activation and inflammatory response in protein malnutrition, and the use of NAC in early rehabilitation of protein malnutrition without a high protein diet.

IgA B and T cells in the intestinal Villi of immunodeficient rats orally treated with thymomodulin.

Previous studies on the effect of the oral administration of bacterial immunomodulators (1M-104 and RN-301) during the protein free diet period, have shown an increase on B and T cell gut repopulation, accompanied by IgA antibody production. The usefulness of oral administration of the immunomodulator thymomodulin (TmB) during the protein refeeding period was investigated. TmB allowed the recovery of a normal repopulation of gut lamina propria with IgA B and CD5 T cells and decreases to control values the number of activated intraepithelial lymphocytes (CD25+ T cell subset). Therefore, the oral administration of TmB may be useful as a therapeutic agent as it seems to improve the repopulation of intestinal villi with immunocompetent cells. Also, it seems to regulate the immunosurveillance at the epithelium level as it increases the CD5+ T cells but decreases the activated ones.

Replacement of amino acid and protein losses with 1.1% amino acid peritoneal dialysis solution.

OBJECTIVE: Losses of nutrients into dialysate may contribute to malnutrition. Peritoneal dialysis (PD) patients are reported to lose 3-4 g/day of amino acids (AAs) and 4-15 g/day of proteins. The extent to which one exchange with a 1.1% AA dialysis solution (Nutrineal, Baxter, Deerfield, IL, U.S.A.) offsets these losses was investigated in a 3-day inpatient study in 20 PD patients. DESIGN: Simple, open-label, cross-over study on consecutive days in a clinical research unit. On day 1 all patients were given a peritoneal equilibration test (PET). On day 2 they received 1.5% dextrose Dianeal (Baxter) as the first exchange of the day and their usual regimen thereafter. On day 3, the first exchange of the day was the 1.1% AA solution in place of 1.5% Dianeal and the usual PD regimen thereafter. On days 2 and 3 all dialysate effluent was collected and analyzed for AAs and proteins. Patients were maintained on a constant diet. RESULTS: Losses of AAs and total proteins on day 2 were 3.4 +/- 0.9 g and 5.8 +/- 2.4 g, respectively, totaling 9.2 +/- 2.7 g. The net uptake of AAs on day 3 was 17.6 +/- 2.6 g (80 +/- 12% of the 22 g infused). Mean gains of AAs on day 3 exceeded losses of proteins and AAs on day 2, p < 0.001. Losses of total proteins, but not losses of AAs, and the net absorption of AAs from the dialysis solution were correlated directly with peritoneal membrane transport characteristics, obtained from the PET. CONCLUSION: Daily losses of AAs and proteins into dialysate are more than offset by gains of AAs absorbed from one exchange with 1.1% AA-based dialysis solution. Net gains of AAs exceeded losses of proteins and AAs in all patients studied. The difference was relatively constant across a wide range of membrane transport types. Net AA gains were approximately two times the total AA and protein losses.

IgA B and T cells in the intestinal villi of immunodeficient rats orailly treated with thymomodulin

Previous studies on the effect of the oral administration of bacterial immunomodulators (IM-104 and RN-301) during the protein free diet period, have shown an increase on B and T cell gut repopulation, accompanied by IgA antibody production. The usefulness of oral administration of the immunomodulator thymomodulin (TmB) during the protein refeeding period was investigated. TmB allowed the recovery of a normal repopulation of gut lamina propria with IgA B and CD5 T cells and decreases to control values the number of activated intraepithelial lymphocytes (CD25+T cell subset). Therefore, the oral administration of TmB may be useful as a therapeutic agent as it seems to improve the repopulation of intestinal villi with immunocompetent cells. Also, it seems to regulate the immunosurveillance at the epithelium level as it increases the CD5+T cells but decreases the activated ones.

Hormona de crecimiento: su uso en la asistencia nutricional del paciente crítico / Growth hormone: its use in nutritional support of critically patient

Se revisan los cambios metabólicos que se producen en el individuo en situación de ayuno sin y con estress; condición esta última propia del paciente crítico que requiere apoyo nutricional. Se analizan los métodos de evaluación clínica y de laboratorio del estado de desnutrición proteica. Sobre bases fisiopatológicas se presentan los usos de la hormona de crecimiento en el paciente crítico, llamando la atención sus efectos directos e indirectos mediados por la IGF1. Las principales indicaciones del empleo de GH en la actualidad son: sujetos sometidos a cirugía mayor, pacientes con quemaduras extensas, enfermos sépticos, individuos con enfermedad bronquial obstructiva crónica y pacientes con intestino corto. Las dosis de GH utilizadas van de 0.1 a 0.2 mg/kg/día por vía subcutánea, intramuscular o endovenosa. Existen métodos para mejorar las acciones de la GH, entre ellos: optimizar el aporte nutricional y el uso simultáneo de insulina y/o IGF1. Finalmente, se anotan las contraindicaciones y los efectos adversos que puede provocar la GH, los que deben ser considerados para el mejor éxito terapéutico

[Mineral balance during nutritional recuperation of infants with protein deficiency]. / Balance de minerales durante la recuperación nutricional en lactantes con desnutrición energético-proteica.

Mineral requirements of normal infants change according to growth velocity. They are directly associated to needs for obtaining an adequate composition of new tissue, assure an optimal bone mineralization and for maintaining normal plasma mineral levels. Nutritional rehabilitation of malnourished infants determines increased mineral requirements, which may be not satisfied with usual infant formulas. We studied mineral retention (Ca, P, Mg, Zn and Cu) during nutritional recovery of 9 malnourished male infants (age: 2-7 mo; weight/age < 70%), fed two formulas, both with 85 Kcal/dL (356 KJoule/dL): the first based on whole cow's milk (LP) and the second on a modified cow's milk containing mineral recommendations for normal infants (LPM); balances were compared to normal for age and for length. Infants received each formula for 6 days, with the last 3 days on a metabolic balance Ca, Mg, and P showed high intakes and very low urinary excretions, calcium retention (68.5 +/- 22.7 and 61.4 +/- 16.7 mg/kg/d, for LP and LPM, respectively) were 3 times over normal mean for age (130 mg/d) and 2.5 times over the normal for length (155 mg/d). Mg retention (7.4 +/- 2.0 and 3.4 +/- 1.2 mg/kg/d)), for LP and LPM) were higher than normal for age (2.7 mg/d) or length (3.3 mg/d) and also those of P (LP: 74.8 +/- 7.1; LPM: 52.2 +/- 9.3 mg/kg/d), compared to a mean of 66 mg/d for the same age, or 79 mg/d for length. Zn retentions were comparable with both formulas (LP: 0.14 +/- 0.07 vs LPM: 0.18 +/- 0.06 mg/kg/d) and over normal requirements for age (0.3 mg/d) or length (0.5 mg/d). Copper retentions were significantly lower with LP than LPM (13.8 +/- 14.0 vs 40.0 +/- 13.2 micrograms/kg/d; p < 0.01), due to low intake with LP. We conclude that a high mineral retention is observed in infants recovering from malnutrition, when they are fed formulas with mineral content over its normal recommendations.

[The pharmacological properties of coenzyme A disulfide]. / Farmakologicheskie svoistva kofermenta A-disulfida.

Coenzyme A disulfide (CoA disulfide) was pharmacologically studied. It has been found to normalize lipid and carbohydrate metabolism when given in a dose of 2 mg/kg, i.m., in diverse liver dysfunctions. It possesses an antihypoxic action under hemic and histotoxic hypoxia. When given in small doses (80-160 micrograms/kg, i.v.), CoA disulfide depresses the function of cellular hemostasis.

[Effect of danazol on heterozygous c protein coagulation deficiency exacerbated by Salmonella typhi sepsis]. / Efecto del danazol en deficiencia heterocigota de la proteína C de coagulación agravada por sepsis por Salmonella typhi.

The case of an 8-month-old male with heterozygous coagulation protein C deficiency is presented. Sepsis due to Salmonella typhi aggravated the protein C deficiency and resulted in arterial thrombosis of the distal third of the lower right limb. The patient was treated with both heparin and danazol, the levels of functional protein C increasing and the necrotic phenomenon resolving, thus making unnecessary amputation of the limb. The observation is discussed with the evidences of danazol being useful in the treatment of patients with protein C deficiency.

Homozygous protein C deficiency: early treatment with warfarin.

We present a case of homozygous protein C deficiency with neonatal purpura fulminans and disseminated intravascular coagulopathy (DIC) starting shortly after birth. In addition, the infant had vitreal eye hemorrhages and intraparenchymal brain infarction, apparently as intrauterine events. Within 15 hours of institution of fresh frozen plasma (FFP) infusions the DIC resolved and the progression of purpura fulminans reversed. Warfarin (0.4 mg/kg/day) was started on the fifth day of life, followed by gradual tapering of the FFP infusions. There were no recurrences of purpura, areas of skin necrosis healed without the need for skin grafting, and the areas of brain infarction resolved without apparent sequelae. The eye and brain lesions may be intrauterine events and appear to be a regular feature of this syndrome. Family studies are essential to establish the diagnosis, although there may be no family history of thromboembolic events, as in this case. Homozygous protein C deficiency is a rare disorder, but one in which early recognition and intervention may be lifesaving. Ours is the youngest patient yet reported to be treated with warfarin anticoagulation. We were thus able to avoid the complications of long-term plasma therapy as well as the potential thrombotic complications of central venous catheter placement.