Urinary biomarkers of inflammation and tissue remodeling may predict bladder dysfunction in patients with benign prostatic hyperplasia.

PURPOSE: To evaluate the expression of urinary biomarkers of inflammation and tissue remodeling in patients with BPH undergoing surgery and evaluate the association of biomarkers with postoperative urodynamic outcomes MATERIALS AND METHODS: We analyzed urine samples from 71 patients treated with TURP from 2011 to 2017. Urinary levels of epidermal growth factor (EGF), matrix-metalloproteinase-1 (MMP-1), interleukin-6 (IL-6), nerve growth factor (NGF) and monocyte-chemoattractant protein-1 (MCP-1) (by commercial ELISA kit) were measured, adjusted by urinary creatinine (Cr) and analyzed according to patients clinical and urodynamic characteristics (baseline and 12-month postoperative urodynamic) RESULTS: MMP-1/Cr levels were significantly higher among subjects with higher detrusor pressure on preoprative urodynamic. MCP-1/Cr levels were significantly higher amongs subjects with preoperative DO. Preoperative levels of NGF/Cr (0.13 vs 0.08, p = 0.005) and MMP-1/Cr (0.11 vs 0.04, p = 0.021) were predictors of persistent DO 12 months after surgery. The following factors were shown to be useful for predicting the persistence of DO in the postoperative period: NGF/Cr, with an AUC of 0.77 (95% CI 0.62-0.92) (p = 0.006), and MMP-1/Cr, with an AUC of 0.72 (95% CI 0.56-0.88) (p = 0.022). CONCLUSIONS: MMP-1/Cr was associated with higher detrusor pressure and MCP-1/CR with DO. NGF/Cr and MMP-1/Cr were shown to be predictors of persistent postoperative DO.

Urinary metabolomics analysis reveals the effect of volatile oil from Angelica sinensis on LPS-induced inflammation rats.

Lipopolysaccharide (LPS)-induced inflammation occurs commonly and volatile oil from Angelica sinensis (VOAS) can be used as an anti-inflammatory agent. The molecular mechanisms that allow the anti-inflammatory factors to be expressed are still unknown. In this paper, we applied gas chromatography-mass spectrometry (GC-MS) and high-performance liquid chromatography-time-of-flight mass spectrometry (LC-Q/TOF-MS) based on a metabolomics platform coupled with a network approach to analyze urine samples in three groups of rats: one with LPS-induced inflammation (MI); one with intervention with VOAS; and normal controls (NC). Our study found definite metabolic footprints of inflammation and showed that all three groups of rats, MI, intervention with VOAS and NC have distinct metabolic profiles in urine. The concentrations of 48 metabolites differed significantly among the three groups. The metabolites in urine were screened by the GC-MS and LC-Q/TOF-MS methods. The significantly changed metabolites (p < 0.05, variable importance in projection > 1.5) between MI, NC and VOAS were included in the metabolic networks. Finally, hub metabolites were screened, including glycine, arachidonic acid, l-glutamate, pyruvate and succinate, which have high values of degree (k). the Results suggest that disorders of glycine, arachidonic acid, l-glutamate, pyruvate and succinate metabolism might play an important part in the predisposition and development of LPS-induced inflammation. By applying metabolomics with network methods, the mechanisms of diseases are clearly elucidated.

Efficacy and safety of a hexanic extract of Serenoa repens (Permixon® ) for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH): systematic review and meta-analysis of randomised controlled trials and observational studies.

OBJECTIVES: To comprehensively evaluate the efficacy and safety of the hexanic extract of Serenoa repens (HESr, Permixon® ; Pierre Fabre Médicament, Castres, France), at a dose of 320 mg daily, as monotherapy for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). MATERIALS AND METHODS: We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) and prospective observational studies in patients with LUTS/BPH identified through searches in Medline, Web of Knowledge (Institute for Scientific Information), Scopus, the Cochrane Library, and bibliographic references up to March 2017. Articles studying S. repens extracts other than Permixon were excluded. Data were collected on International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax ), nocturia, quality of life, prostate volume, sexual function, and adverse drug reactions (ADRs). Data obtained from RCTs and observational studies were analysed jointly and separately using a random effects model. A sub-group analysis was performed of studies that included patients on longer-term treatment (≥1 year). RESULTS: Data from 27 studies (15 RCTs and 12 observational studies) were included for meta-analysis (total N = 5 800). Compared with placebo, the HESr was associated with 0.64 (95% confidence interval [CI] -0.98 to -0.31) fewer voids/night (P < 0.001) and an additional mean increase in Qmax of 2.75 mL/s (95% CI 0.57 to 4.93; P = 0.01). When compared with α-blockers, the HESr showed similar improvements on IPSS (weighted mean difference [WMD] 0.57, 95% CI -0.27 to 1.42; P = 0.18) and a comparable increase in Qmax to tamsulosin (WMD -0.02, 95% CI -0.71 to 0.66; P = 0.95). Efficacy assessed using the IPSS was similar after 6 months of treatment between the HESr and 5α-reductase inhibitors (5ARIs). Analysis of all available published data for the HESr showed a mean improvement in IPSS from baseline of -5.73 points (95% CI -6.91 to -4.54; P < 0.001). HESr did not negatively affect sexual function and no clinically relevant effect was observed on prostate-specific antigen. Prostate volume decreased slightly. Similar efficacy results were seen in patients treated for ≥1 year (n = 447). The HESr had a favourable safety profile, with gastrointestinal disorders being the most frequent ADR (mean incidence of 3.8%). CONCLUSION: The present meta-analysis, which includes all available RCTs and observational studies, shows that the HESr (Permixon) reduced nocturia and improved Qmax compared with placebo and had a similar efficacy to tamsulosin and short-term 5-ARI in relieving LUTS. HESr (Permixon) appears to be an efficacious and well-tolerated therapeutic option for the long-term medical treatment of LUTS/BPH.

Effects of hexanic extract of Serenoa repens (Permixon® 160 mg) on inflammation biomarkers in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia.

BACKGROUND: Chronic prostatic inflammation (CPI) could be a cause of symptomatic or complicated benign prostatic hyperplasia (BPH). In previous in vitro and in vivo studies, Hexanic Extract of Serenoa repens (HESr) namely Permixon(®) has demonstrated potent anti-inflammatory properties. With the aim to provide new insight onto HESr anti-inflammatory properties in human we explore its effect on CPI biomarkers in men with lower urinary tract symptoms (LUTS) related to BPH using a non-invasive method and investigate links between biomarkers and clinical symptoms. METHODS: An international, randomized, double-blind, parallel-group, tamsulosin-controlled study was carried out in 206 men with BPH-related LUTS. Patients received oral daily HESr 320mg or tamsulosin 0.4 mg during 3 months. The first urine stream after digital rectal examination (DRE) was collected at Day 1 and Day 90 and mRNA was extracted from prostatic epithelial cells desquaming in the lumen of the glands and seminal plasma fluid after DRE. mRNA quantification of the 29 most significant published inflammation markers in BPH and protein detection in urine was performed. RESULTS: At D90, a decrease in mean gene expression was observed for 65.4% of the markers detected in the HESr group versus 46.2% in the tamsulosin group. In the 15 most frequently expressed genes, this difference was higher (80% vs. 33% respectively). Three proteins (MCP-1/CCL2, IP-10/CXCL10, and MIF) were detected. At D90, a decrease in the number of patients who expressed MCP-1/CCL2 and IP-10/CXCL10 was observed only in the HESr group. Moreover, MIF expression was significantly reduced by HESr compared with tamsulosin (P = 0.007). Finally, in contrast to tamsulosin, the subgroup of patients treated by HESr and who over expressed MIF at baseline, had a higher response to the International Prostate Symptom Score (I-PSS) than those who did not over express this protein (mean I-PSS change: -6.4 vs. -4.5 respectively). As the study is exploratory, results should be confirmed in a powered clinical study. CONCLUSIONS: These results showed for the first time at clinical level the anti-inflammatory properties of HESr, already indicated in BPH-related LUTS. Thus, HESr could be of interest to prevent unfavourable evolution in patients with CPI.

Oxidative stress and inflammation in mucopolysaccharidosis type IVA patients treated with enzyme replacement therapy.

Mucopolysaccharidosis type IVA (MPS IVA) is an inborn error of glycosaminoglycan (GAG) catabolism due to the deficient activity of N-acetylgalactosamine-6-sulfate sulfatase that leads to accumulation of the keratan sulfate and chondroitin 6-sulfate in body fluids and in lysosomes. The pathophysiology of this lysosomal storage disorder is not completely understood. The aim of this study was to investigate oxidative stress parameters, pro-inflammatory cytokine and GAG levels in MPS IVA patients. We analyzed urine and blood samples from patients under ERT (n=17) and healthy age-matched controls (n=10-15). Patients presented a reduction of antioxidant defense levels, assessed by a decrease in glutathione content and by an increase in superoxide dismutase activity in erythrocytes. Concerning lipid and protein damage, it was verified increased urine isoprostanes and di-tyrosine levels and decreased plasma sulfhydryl groups in MPS IVA patients compared to controls. MPS IVA patients showed higher DNA damage than control group and this damage had an oxidative origin in both pyrimidine and purine bases. Interleukin 6 was increased in patients and presented an inverse correlation with GSH levels, showing a possible link between inflammation and oxidative stress in MPS IVA disease. The data presented suggest that pro-inflammatory and pro-oxidant states occur in MPS IVA patients even under ERT. Taking these results into account, supplementation of antioxidants in combination with ERT can be a tentative therapeutic approach with the purpose of improving the patient's quality of life. To the best of our knowledge, this is the first study relating MPS IVA patients with oxidative stress.

Combined NMR and GC-MS analyses revealed dynamic metabolic changes associated with the carrageenan-induced rat pleurisy.

Inflammation is closely associated with pathogenesis of various metabolic disorders, cardiovascular diseases, and cancers. To understand the systems responses to localized inflammation, we analyzed the dynamic metabolic changes in rat plasma and urine associated with the carrageenan-induced self-limiting pleurisy using NMR spectroscopy in conjunction with multivariate data analysis. Fatty acids in plasma were also analyzed using GC-FID/MS with the data from clinical chemistry and histopathology as complementary information. We found that in the acute phase of inflammation rats with pleurisy had significantly lower levels in serum albumin, fatty acids, and lipoproteins but higher globulin level and larger quantity of pleural exudate than controls. The carrageenan-induced inflammation was accompanied by significant metabolic alterations involving TCA cycle, glycolysis, biosyntheses of acute phase proteins, and metabolisms of amino acids, fatty acids, ketone bodies, and choline in acute phase. The resolution process of pleurisy was heterogeneous, and two subgroups were observed for the inflammatory rats at day-6 post treatment with different metabolic features together with the quantity of pleural exudate and weights of thymus and spleen. The metabolic differences between these subgroups were reflected in the levels of albumin and acute-phase proteins, the degree of returning to normality for multiple metabolic pathways including glycolysis, TCA cycle, gut microbiota functions, and metabolisms of lipids, choline and vitamin B3. These findings provided some essential details for the dynamic metabolic changes associated with the carrageenan-induced self-limiting inflammation and demonstrated the combined NMR and GC-FID/MS analysis as a powerful approach for understanding biochemical aspects of inflammation.

[Experience in the use of mineral water "Naftusya" of Zbruchansk field in the treatment of patients with uroliths].

The study has evaluated the effect of combined treatment including slightly mineralized hydrocarbonate-magnesium-calcium mineral water "Naftusya" of Zbruchansk field on the urinary system of 47 adult patients with urolithiasis and chronic pyelonephritis aged 24 to 76 years and 3 children of different age groups. 14 patients dropped out of the study group after 1-3 days after the start of treatment due to the negative reaction of the gastrointestinal tract to the reception of water; thus, study group consisted of 36 patients. At baseline, kidney or ureteral stones were diagnosed in all patients. For adult patients, water was administered at a dose 200 ml 3 times a day, for children--50-150 ml 3 times a day, 30-40 minutes before meals for 7-20 days. Examination of patients was performed using laboratory, ultrasound and radiographic methods. It was revealed that against the background of complex treatment, discharge of small stones, their fragments and urinary sand have occurred 1-3 days earlier than with standard treatment. There was no effect on calcium and inorganic phosphate metabolism. The trend to uric acid crystalluria and reducing the pH of urine was revealed. Statistically significant reduction of leukocyturia and erythrocyturia was identified. 60% of patients had a disappearance of bacteriuria or reduction of the titer of bacteria. The results led to the conclusion of advisability of use of mineral water "Naftusya" of Zbruchansk field in the complex treatment of inflammatory processes in the urinary system and for stimulation of discharge of ureteral stones with sizes enabaling to presume their independent discharge.

Effect of acupuncture on rats with acute gouty arthritis inflammation: a metabonomic method for profiling of both urine and plasma metabolic perturbation.

Acute gouty arthritis is a common inflammation model with multiple pathogenic mechanisms seen in clinical practice, for which acupuncture may potentially be an alternative therapy. To investigate the effect of acupuncture on acute gouty arthritis and search for its mechanism, a metabonomic method was developed in this investigation. Acute gouty arthritis model rats were induced by monosodium urate (MSU) crystals. The urine and plasma samples were collected at several time points and the endogenous metabolites were analyzed by an ultra-performance liquid chromatography coupled with a mass spectrometry (UPLC-MS). Data were analyzed using principal components analysis (PCA) and partial least squares (PLS) analysis to compare metabolic profiles of MSU crystal-induced acute gouty arthritis rats with MSU crystal-induced acute gouty arthritis, treated with acupuncture rats. The results showed that acupuncture could restore the metabolite network that disturbed by MSU administration. Our study indicates that UPLC-MS-based metabonomics can be used as a potential tool for the investigation of biological effect of acupuncture on acute gouty arthritis.

The effect of a lignan complex isolated from flaxseed on inflammation markers in healthy postmenopausal women.

BACKGROUND AND AIM: Plant lignans are metabolised by the colonic micro-flora to the mammalian lignans enterodiol and enterolactone, which are hypothesized to be cardioprotective. The aim of this study was to investigate the effects of a plant lignan complex isolated from flaxseed, providing 500 mg/d of secoisolariciresinol diglucoside, on inflammatory markers. METHODS AND RESULTS: Healthy postmenopausal women (n=22) completed a randomised double-blind, placebo-controlled crossover study. Women consumed daily a low-fat muffin, with or without a lignan complex, for 6 weeks, separated by a 6-week washout period. A significant difference of approximately 15% (P=0.028) was observed for C-reactive protein (CRP) concentration between the lignan complex intervention period and placebo period. CRP concentrations (median; 25th, 75th percentiles) were 0.88 (0.63, 2.05) mg/L at baseline and 0.92 (0.59, 1.49) mg/L after the lignan complex intervention period compared with 0.80 (0.62, 1.62) mg/L at baseline and 1.10 (0.72, 1.62) mg/L after placebo. No significant differences in interleukin-6, tumor necrosis factor-alpha, soluble intracellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1 were found between the lignan complex intervention period and placebo period. CONCLUSION: Daily consumption for 6 week of a low-fat muffin enriched with a lignan complex may reduce CRP concentrations compared to a low-fat muffin with no lignans added.

Serum amino acid profile in patients with acute pancreatitis.

Patients in the early phase of acute pancreatitis (AP) have reduced serum levels of arginine and citrulline. This may be of patho-biological importance, since arginine is the substrate for nitric oxide, which in turn is involved in normal pancreatic physiology and in the inflammatory process. Serum amino acid spectrum was measured daily for five days and after recovery six weeks later in 19 patients admitted to the hospital for acute pancreatitis. These patients had abnormal levels of most amino acids including arginine, citrulline, glutamine and glutamate. Phenylalanine and glutamate were increased, while arginine, citrulline, ornithine and glutamine were decreased compared to levels after recovery. NO(2)/NO(3) concentration in the urine, but not serum arginase activity, was significantly increased day 1 compared to day 5 after admission. Acute pancreatitis causes a disturbance of the serum amino acid spectrum, with possible implications for the inflammatory process and organ function both in the pancreas and the gut. Supplementation of selected amino acids could possibly be of value in this severe condition.

Effect of eicosapentaenoic acid and docosahexaenoic acid on oxidative stress and inflammatory markers in treated-hypertensive type 2 diabetic subjects.

n-3 fatty acids reduce the risk of cardiovascular disease via a number of possible mechanisms. Despite this, there has been concern that these fatty acids may increase lipid peroxidation. The data in vivo are inconclusive, due in part to limitations in the methodologies. In this regard, the measurement of F2-isoprostanes provides a reliable assessment of in vivo lipid peroxidation and oxidant stress. This study aimed to assess the effects of supplementation with purified eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), the two major n-3 fatty acids, on urinary F2-isoprostanes and markers of inflammation, in type 2 diabetic patients. In a double-blind, placebo controlled trial of parallel design, 59 nonsmoking, treated-hypertensive, type 2 diabetic subjects, were randomized to 4 g daily of purified EPA, DHA, or olive oil for 6 weeks, while maintaining their usual diet. F2-isoprostanes, measured using gas chromatography-mass spectrometry in 24 h urines and C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), were measured before and after intervention. Thirty-nine men and 12 women aged 61.2 +/- 1.2 years, with body mass index (BMI), 29.5 +/- 0.5 kg/m2; 24 h blood pressure, 138/73 mmHg; HbA1c, 7.3 +/- 0.1% and fasting glucose, 7.9 +/- 0.2 mmol/l completed the intervention. Baseline urinary F2-isoprostanes were positively associated with HbA1c (p=.011) and fasting glucose (p=.032). Relative to the olive oil group, postintervention urinary F2-isoprostanes were decreased 19% by EPA (p=.017) and 20% by DHA (p=.014). There were no significant changes in CRP, IL-6, and TNF-alpha following EPA or DHA supplementation. In regression analysis, Delta F2-isoprostanes were positively associated with Delta HbA1c (p=.007) independent of treatment group; and with Delta TNF-alpha (p=.034) independent of age, gender, BMI, and treatment group. There were no associations with Delta CRP or Delta IL-6. This study is the first report demonstrating that either EPA or DHA reduce in vivo oxidant stress without changing markers of inflammation, in treated hypertensive, type 2 diabetic subjects.