Acute Phase Proteins and Vitamin D Seasonal Variation in End-Stage Renal Disease Patients.

End-stage renal disease (ESRD) patients are vulnerable to vitamin D deficiency due to impaired renal hydroxylation, low dietary intake and inadequate sun exposure. Vitamin D plays a role in innate and adaptive immunity and its seasonal variation has been linked to mortality. ESRD is associated with inadequate removal of pro-inflammatory cytokines regulating acute phase protein (APP) synthesis. Our aim was to look for associations between lifestyle factors, diet, and vitamin D seasonal variation and their relationship with selected APPs and calcium-phosphate metabolism. The study included 59 ESRD patients treated with maintenance hemodialysis. A 24-hour dietary recall was conducted in the post-summer (November 2018, PS) and post-winter (February/March 2019, PW) period, and blood was collected for the measurements of serum total vitamin D, α1-acid glycoprotein (AGP), C-reactive protein (CRP), albumin, prealbumin (PRE), parathormone, calcium and phosphate. A self-constructed questionnaire gathered information on vitamin D supplementation, sun exposure and physical activity. Higher caloric intake was observed PW compared PS. Less than 15% of participants met the dietary recommendations for energy, protein, fiber, vitamin D and magnesium intake. Vitamin D supplementation was associated with higher serum vitamin D regardless of season. AGP, PRE, albumin, and vitamin D presented seasonal changes (higher values PS). In patients with serum vitamin D below 25 ng/mL, vitamin D seasonal change correlated with CRP and prealbumin change. Phosphate and Ca × P correlated positively with AGP. A low vitamin D serum level could impact the inflammatory process; however, more studies are needed to confirm the relationship.

Capsaicin-Sensitive Sensory Nerves Are Necessary for the Protective Effect of Ghrelin in Cerulein-Induced Acute Pancreatitis in Rats.

Ghrelin was shown to exhibit protective and therapeutic effect in the gut. Aim of the study was to investigate the role of sensory nerves (SN) in the protective effect of ghrelin in acute pancreatitis (AP). Studies were performed on male Wistar rats or isolated pancreatic acinar cells. After capsaicin deactivation of sensory nerves (CDSN) or treatment with saline, rats were pretreated intraperitoneally with ghrelin or saline. In those rats, AP was induced by cerulein or pancreases were used for isolation of pancreatic acinar cells. Pancreatic acinar cells were incubated in cerulein-free or cerulein containing solution. In rats with intact SN, pretreatment with ghrelin led to a reversal of the cerulein-induced increase in pancreatic weight, plasma activity of lipase and plasma concentration of tumor necrosis factor-α (TNF-α). These effects were associated with an increase in plasma interleukin-4 concentration and reduction in histological signs of pancreatic damage. CDSN tended to increase the severity of AP and abolished the protective effect of ghrelin. Exposure of pancreatic acinar cells to cerulein led to increase in cellular expression of mRNA for TNF-α and cellular synthesis of this cytokine. Pretreatment with ghrelin reduced this alteration, but this effect was only observed in acinar cells obtained from rats with intact SN. Moreover, CDSN inhibited the cerulein- and ghrelin-induced increase in gene expression and synthesis of heat shock protein 70 (HSP70) in those cells. Ghrelin exhibits the protective effect in cerulein-induced AP on the organ and pancreatic acinar cell level. Sensory nerves ablation abolishes this effect.

Essential Role of Growth Hormone and IGF-1 in Therapeutic Effect of Ghrelin in the Course of Acetic Acid-Induced Colitis.

Previous studies have shown that ghrelin exhibits a protective and therapeutic effect in the gut. The aim of the present study was to examine whether administration of ghrelin affects the course of acetic acid-induced colitis and to determine what is the role of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in this effect. In sham-operated or hypophysectomized male Wistar rats, colitis was induced by enema with 1 mL of 3% solution of acetic acid. Saline or ghrelin (given at the dose of 8 nmol/kg/dose) was administered intraperitoneally twice a day. Seven days after colitis induction, rats were anesthetized and the severity of the colitis was assessed. Treatment with ghrelin reduced the area of colonic mucosa damage in pituitary-intact rat. This effect was associated with increase in serum levels of GH and IGF-1. Moreover, administration of ghrelin improved blood flow in colonic mucosa and mucosal cell proliferation, as well as reduced mucosal concentration of proinflammatory interleukin-1ß (IL-1ß) and activity of myeloperoxidase. Hypophysectomy reduced serum levels of GH and IGF-1 and increased the area of colonic damage in rats with colitis. These effects were associated with additional reduction in mucosal blood follow and DNA synthesis when compared to pituitary-intact rats. Mucosal concentration of IL-1ß and mucosal activity of myeloperoxidase were maximally increased. Moreover, in hypophysectomized rats, administration of ghrelin failed to affect serum levels of GH or IGF-1, as well as the healing rate of colitis, mucosal cell proliferation, and mucosal concentration of IL-1ß, or activity of myeloperoxidase. We conclude that administration of ghrelin accelerates the healing of the acetic acid-induced colitis. Therapeutic effect of ghrelin in experimental colitis is mainly mediated by the release of endogenous growth hormone and IGF-1.

Synergic Interaction of Rifaximin and Mutaflor (Escherichia coli Nissle 1917) in the Treatment of Acetic Acid-Induced Colitis in Rats.

Background. Inflammatory bowel disease results from the dysregulation of immune response to environmental and microbial agents in genetically susceptible individuals. The aim of the present study was to examine the effect of rifaximin and/or Mutaflor (Escherichia coli Nissle 1917, EcN) administration on the healing of acetic acid-induced colitis. Methods. Colitis was induced in male Wistar rats by rectal enema with 3.5% acetic acid solution. Rifaximin (50 mg/kg/dose) and/or Mutaflor (10(9) CFU/dose) were given intragastrically once a day. The severity of colitis was assessed at the 8th day after induction of inflammation. Results. Treatment with rifaximin significantly accelerated the healing of colonic damage. This effect was associated with significant reversion of the acetic acid-evoked decrease in mucosal blood flow and DNA synthesis. Moreover, administration of rifaximin significantly reduced concentration of proinflammatory TNF-α and activity of myeloperoxidase in colonic mucosa. Mutaflor given alone was without significant effect on activity of colitis. In contrast, Mutaflor given in combination with rifaximin significantly enhanced therapeutic effect of rifaximin. Moreover, Mutaflor led to settle of the colon by EcN and this effect was augmented by pretreatment with rifaximin. Conclusion. Rifaximin and Mutaflor exhibit synergic anti-inflammatory and therapeutic effect in acetic acid-induced colitis in rats.

Seasonal effect of vitamin D deficiency in patients with acute myocardial infarction.

BACKGROUND: Vitamin D is a major regulator of mineral bone metabolism. The lower vitamin D levels in patients with acute myocardial infarction (AMI) and the seasonal variation of vitamin D levels are proposed. AIM: The evaluation of the seasonal relationship of 25(OH)D levels in patients with AMI and analysis of confounding factors (gender or diabetes mellitus) affecting the levels of vitamin D in AMI patients. METHODS: Fifty-nine consecutive patients with mean age 58 ± 9.4 years were admitted to the Department of Invasive Cardiology. Subjects had diagnosed uncomplicated myocardial infarction. Blood samples for analysis were collected on patient admission to the cardiac unit after heparin treatment. Samples for routine laboratory tests were immediately processed. For 25(OH)D, the 25-hydroxycholecalciferol test, which measures total vitamin D levels in serum (DRG Instruments GmbH, Marburg, Germany), was applied. RESULTS: Median serum 25(OH)D concentration in AMI patients was below the recommended optimal values 7.1 (2.3-13.3) ng/mL. Fifty-three (89.8%) patients had vitamin D deficiency (VDD) below 20 ng/mL, six (10.2%) patients had suboptimal 25(OH)D levels (between 20 ng/mL and 30 ng/mL), and no one had the recommended reference range. The seasonal effect of 25(OH)D variations among AMI patients was observed with the lowest levels in the beginning of the year (January-March) and the highest levels at the end of the year (September-December) (p = 0.007). Patients with normoglycaemia had significantly higher (9.2 [2.3-16.8] ng/mL) vitamin D levels compared to patients with impaired glucose tolerance (2.3 [2.3-3.9] ng/mL) or diabetes mellitus (8.5 [2.5-13.3] ng/mL) (p = 0.01). CONCLUSIONS: A high prevalence of VDD in AMI patients has been confirmed. Supplementation of vitamin D in AMI patients with hyperglycaemia can bring greater benefits.

Obestatin Accelerates the Healing of Acetic Acid-Induced Colitis in Rats.

Obestatin, a 23-amino acid peptide derived from the proghrelin, has been shown to exhibit some protective and therapeutic effects in the gut. The aim of present study was to determine the effect of obestatin administration on the course of acetic acid-induced colitis in rats. Materials and Methods. Studies have been performed on male Wistar rats. Colitis was induced by a rectal enema with 3.5% acetic acid solution. Obestatin was administered intraperitoneally twice a day at a dose of 8 nmol/kg, starting 24 h after the induction of colitis. Seven or 14 days after the induction of colitis, the healing rate of the colon was evaluated. Results. Treatment with obestatin after induction of colitis accelerated the healing of colonic wall damage and this effect was associated with a decrease in the colitis-evoked increase in mucosal activity of myeloperoxidase and content of interleukin-1ß. Moreover, obestatin administration significantly reversed the colitis-evoked decrease in mucosal blood flow and DNA synthesis. Conclusion. Administration of exogenous obestatin exhibits therapeutic effects in the course of acetic acid-induced colitis and this effect is related, at least in part, to the obestatin-evoked anti-inflammatory effect, an improvement of local blood flow, and an increase in cell proliferation in colonic mucosa.

Obestatin Accelerates the Recovery in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats.

OBJECTIVE: Several previous studies have shown that obestatin exhibits protective and regenerative effects in some organs including the stomach, kidney, and the brain. In the pancreas, pretreatment with obestatin inhibits the development of cerulein-induced acute pancreatitis, and promotes survival of pancreatic beta cells and human islets. However, no studies investigated the effect of obestatin administration following the onset of experimental acute pancreatitis. AIM: The aim of this study was to evaluate the impact of obestatin therapy in the course of ischemia/reperfusion-induced pancreatitis. Moreover, we tested the influence of ischemia/reperfusion-induced acute pancreatitis and administration of obestatin on daily food intake and pancreatic exocrine secretion. METHODS: Acute pancreatitis was induced by pancreatic ischemia followed by reperfusion of the pancreas. Obestatin (8 nmol/kg/dose) was administered intraperitoneally twice a day, starting 24 hours after the beginning of reperfusion. The effect of obestatin in the course of necrotizing pancreatitis was assessed between 2 and 14 days, and included histological, functional, and biochemical analyses. Secretory studies were performed on the third day after sham-operation or induction of acute pancreatitis in conscious rats equipped with chronic pancreatic fistula. RESULTS: Treatment with obestatin ameliorated morphological signs of pancreatic damage including edema, vacuolization of acinar cells, hemorrhages, acinar necrosis, and leukocyte infiltration of the gland, and led to earlier pancreatic regeneration. Structural changes were accompanied by biochemical and functional improvements manifested by accelerated normalization of interleukin-1ß level and activity of myeloperoxidase and lipase, attenuation of the decrease in pancreatic DNA synthesis, and by an improvement of pancreatic blood flow. Induction of acute pancreatitis by pancreatic ischemia followed by reperfusion significantly decreased daily food intake and pancreatic exocrine secretion. Administration of obestatin at doses used was without significant effect with regard to daily food intake or pancreatic exocrine secretion in sham-operated rats, as well as in rats with acute pancreatitis. On the other hand, obestatin abolished a statistical significance of difference in food intake between animals with AP and control animals without pancreatic fistula and induction of AP. CONCLUSION: Treatment with the exogenous obestatin reduces severity of ischemia/reperfusion-induced acute pancreatitis and accelerates recovery in this disease. The involved mechanisms are likely to be multifactorial, and are mediated, at least in part, by anti-inflammatory properties of obestatin.

Serum matrix Gla protein concentrations in patients with mild and severe acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) causes an increase in proinflammatory cytokine and acute phase protein levels. Our previous studies in AP showed the role of fetuin A as a negative acute phase protein. Matrix Gla protein (MGP), beside fetuin A, is one of the main inhibitors of extraosseous calcification. In the present preliminary study we evaluated the relationship between MGP, lipase, and inflammation in AP patients. METHODS: The study included 40 patients with AP of diverse severity (28 mild, 12 severe), assessed during the early phase of AP (day 1 - day 7 of hospitalization). The concentration of MGP, fetuin A, polymorphonuclear elastase (PMN-elastase), interleukin 6 (IL-6), interleukin 18 (IL-18), hepatocyte growth factor (HGF), high sensitivity tumor necrosis factor alpha (hs TNFalpha), soluble receptor of tumor necrosis factor II (sTNFRII), and neopterin were measured by ELISA kits; albumin, lipase and amylase were measured on a Modular P Chemistry Analyser (Roche Diagnostica, Germany); procalcitonin (PCT) was measured using the LUMItest PCT (Brahms, Germany), and serum amyloid A (SAA) and high sensitivity C-reactive protein (hs CRP) were measured using an immunonephelometric method on a Nephelometer BNII (Siemens Healthcare, Germany). RESULTS: MGP positively correlated with lipase activity (R = 0.64; p < 0.05) on day 1 after admission to hospital. Lower MGP levels were consistent with higher intensity of inflammation, as MGP significantly (p < 0.05) inversely correlated with IL-6 (R = -0.48 on day 3; R = -0.46 on day 5 and R = -0.52 on day 7 after admission), IL-18 (R = - 0.55; R = -0.60; R = -0.48 on day 1, day 3, and day 5, respectively), HGF (R = -0.58 on day 3), hs TNFalpha (R = -0.45 on day 1 and R = -0.64 on day 5), its soluble receptor sTNFRII (R = -0.63; R = -0.61; R = -0.59 on day 3, day 5, and day 7, respectively), hs CRP (R = -0.76 on day 1 and R = -0.83 on day 5), PCT (R = -0.62 on day 1 and R = -0.59 on day 7), SAA (R = -0.45 on day 5) as well as with neopterin (R = -0.52 on day 1 after admission). MGP levels dropped simultaneously with fetuin A (R = 0.50 on day 3; R = 0.60 on day 5 and R = 0.63 on day 7) and albumin concentrations (R = 0.51; R = 0.70; R = 0.94 on day 1, day 5, and day 7 day after admission, respectively). There was a relationship between lipase activity and MGP concentration on day 1 of hospitalization (R = 0.64; p < 0.05). CONCLUSIONS: Our preliminary results indicate that the MGP level correlated negatively with all of the proinflammatory cytokines and acute phase proteins studied in patients with AP, and positively with lipase, fetuin A, and albumin measurements. These findings may indicate the role of MGP in calcium and phosphate metabolism disturbances in the course of AP.