Uric Acid Accumulation Research Articles

Influence of d-Amino Acids in Beer on Formation of Uric Acid.

SUMMARYExcessive intake of beer could increase serum uric acid levels, leading to high risk of gout, which was previously attributed to high purine content in beer. Recent reports that purine-rich vegetables and bean products do not cause higher uric acid levels do not support this theory. Why excessive intake of beer could increase a high risk of gout has been unclear. Other factors affecting the accumulation of uric acid in the blood have been explored. Beer contains relatively high levels of d-amino acids due to the racemization of l-amino acids induced by food processing. d-amino acid was catalyzed by d-amino acid oxidase to produce H2O2, which is further oxidized in the presence of Fe2+ to produce hydroxyl radicals, resulting in DNA damage and formation of a large amount of purine bases, which are oxidized to uric acid by a series of enzymes. Some food ingredients, such as vitamins and I–, prompt d-amino acids to form uric acid. d-amino acids in beer are one of the key factors responsible for the increase in uric acid levels. The biological response of d-amino acids could explain gout occurrence in beer drinkers.

Gout - asymptomatic hyperuricemia with/without asymptomatic monosodium urate crystal deposition: To be treated or not?

Elevation of serum uric acid level without clinically visible arthritis (known as asymptomatic hyperuricemia) is not traditionally considered to be gout disease, but only a possible cause of it, even though it may be accompanied by tissue uric acid crystal deposition. On the other hand, gout is traditionally recognized as recurrent, overt arthritis, visible only after a long period of time due to uric acid accumulation in joints. Advanced imaging techniques have substantially changed the perception of this problem, identifying gout as a low-grade chronic inflammatory disease from the very beginning, visible only by phases of acute arthritis attacks. According to ultrasonography, uric acid crystal hyperechoic aggregates (tophi) are seen not only in the symptomatic gout disease phase, but also in the preceding ? asymptomatic (latent) ? gout phase. New perception of the problem was approved by the recently described NETs (neutrophil extracellular traps) phenomenon. Also, hyperuricemia has recently been identified as a systemic disorder, responsible not only for the apparent gout arthritis, but also for the renal and cardiovascular disease occurrence and progression. Positive effect of urate-lowering therapy (xanthine oxidase inhibitors and uricosurics) on hypertension and chronic kidney disease indicates a possibility of its utility in asymptomatic hyperuricemia and asymptomatic gout therapy, apart from the use in clinically manifested gout treatment and for certain conditions, such as tumor lysis syndrome.

Lactobacillus brevis DM9218 ameliorates fructose-induced hyperuricemia through inosine degradation and manipulation of intestinal dysbiosis.

High fructose consumption exacerbates purine degradation and intestinal dysbiosis, which are closely related to the development of hyperuricemia. Probiotics are powerful weapons to combat metabolic disturbance and intestinal dysbiosis. Previously we isolated a Lactobacillus strain named DM9218 that could reduce the serum uric acid (UA) level by assimilating purine nucleosides. The present study aimed to evaluate the effects of DM9218 on high-fructose-induced hyperuricemia and to elucidate the underlying mechanisms. Mice were fed a normal diet, a high-fructose diet, or high-fructose diet with DM9218. Metabolic parameters, fructose- and UA-related metabolites, and fecal microbiota were investigated. Whole-genome sequencing of strain DM9218 was also conducted. In addition, an inosine hydrolase from DM9218 was heterologously expressed in Escherichia coli, and its inosine-degrading activity was detected. Our results indicated that DM9218 could decrease serum UA level and hepatic xanthine oxidase activity in fructose-fed mice. It could protect against high-fructose-induced liver damage and retard UA accumulation by degrading inosine. The modulation effect of DM9218 on high-fructose-induced intestinal dysbiosis resulted in enhancement of intestinal barrier function and reduction of liver lipopolysaccharide, which was closely correlated with the down-regulation of inflammatory cytokine-stimulated xanthine oxidase expression and activity. Lactobacillus brevis DM9218 is a probiotic strain with the potential to ameliorate fructose-induced hyperuricemia.

Accumulation of uric acid in the epidermis forms the white integument of Samia ricini larvae.

The white color in the larval integument of the silkworm Bombyx mori is considered the result of uric acid accumulation in its epidermal cells. Larvae of the eri silkworm Samia ricini (Lepidoptera; Saturniidae) also have a white and opaque integument, but little is known about its coloration mechanism. In this study, we first performed a feeding assay of S. ricini larvae using allopurinol, an inhibitor of xanthine oxidase, which catalyzes the degradation of xanthine to uric acid. This treatment induced a clear translucent integument phenotype, indicating that the larval color of S. ricini is also determined by uric acid accumulation. Next, to investigate the genetic basis that controls uric acid accumulation in S. ricini larvae, we isolated and characterized the S. ricini homolog of mammalian biogenesis of lysosome-related organelles complex 1, subunit 2 (BLOS2), which is known to play a crucial role in urate granule biosynthesis. We created a transcription activator-like effector nuclease (TALEN)-mediated gene knockout of S. ricini BLOS2 (SrBLOS2) and succeeded in establishing SrBLOS2 knockout strains (SrBLOS2KO). SrBLOS2KO mutants exhibited a translucent larval integument phenotype and lacked uric acid in the epidermis, as also observed in allopurinol-fed larvae. In addition, electron microscopy revealed that urate granules were rarely observed in the epidermis of SrBLOS2KO larvae, whereas abundant granules were found in the epidermis of wild-type larvae. These results clearly demonstrated that larval S. ricini accumulates uric acid as urate granules in the epidermis and that the genetic basis that controls uric acid accumulation is evolutionarily conserved in S. ricini and B. mori.

CXCR1/CXCR2 antagonist G31P inhibits nephritis in a mouse model of uric acid nephropathy

The prevalence of gout is relatively high worldwide, and many gout patients suffer from uric acid nephropathy (UAN) concomitantly. ELR-CXC chemokines such as CXCL8 and CXCL1 have a elevated expression in UAN. In this research, a mouse UAN model was established for a 12 week duration, and uric acid-related crystals were observed. CXCL8(3-72)K11R/G31P (G31P) is a mutant protein of CXCL8/interleukin 8 (IL-8), which has been reported to have therapeutic efficacy in both inflammatory diseases and malignancies for it acts as a selective antagonist towards CXCR1/CXCR2. In this study, G31P-treated mice showed declined production of the blood urea nitrogen (BUN) level and urine volume in UAN mice compared with G31P-untreated UAN counterparts. In addition, G31P effectively improved renal fibrosis, and reduced uric acid accumulation and leukocyte infiltration in UAN kidneys. Furthermore, the expressions of CXCL1 and CXCL2 were reduced and the activation of NOD-like receptors protein 3 (NLRP3) was inhibited by G31P treatment. This study has demonstrated that G31P attenuates inflammatory progression in chronic UAN, and plays a renoprotective function.

Probiotic supplements prevented oxonic acid-induced hyperuricemia and renal damage.

Hyperuricemia is highly prevalent and especially common in subjects with metabolic, cardiovascular and renal diseases. In chronic kidney disease, hyperuricemia is extremely common, and uric acid (UA) excretion relies on gut uricolysis by gut microbiota. Current therapy for lowering serum UA includes drugs that may produce undesired secondary effects. Therefore, this pilot study was designed to evaluate the potential of two probiotic supplements to reduce systemic uric acid concentrations. Secondary objectives were to assess whether the hypouricemic effect related to a therapeutic benefit on the hyperuricemia-induced renal damage and hypertension. Analysis of fecal microbiota was also performed. Groups of 6 rats each were followed for 5 weeks and allocated in the following treatment groups: C = Control; HU-ND = Oxonic acid-induced hyperuricemia (HU) +regular diet; HU-P = HU+placebo; HU-F1 = HU+ probiotics formula 1 and HU-F2 = HU+ probiotics formula 2. We confirmed that oxonic acid-induced hyperuricemia produced hypertension and renal functional and structural changes, along with modest changes in the overall composition of fecal microbiota. Both probiotic-containing diets prevented HU, elevated UA urinary excretion and intrarenal UA accumulation induced by oxonic acid. The hypouricemic effect conferred by probiotic supplementation also prevented the renal changes and hypertension caused by hyperuricemia. However, probiotic treatment did not restore the fecal microbiota. In conclusion, we demonstrated for the first time the ability of probiotics containing uricolytic bacteria to lower serum uric acid in hyperuricemic animals with beneficial consequences on blood pressure and renal disease. As probiotics supplements are innocuous for human health, we recommend clinical studies to test if probiotic supplements could benefit hyperuricemic individuals.

A reexamination on the deficiency of riboflavin accumulation in Malpighian tubules in larval translucent mutants of the silkworm, Bombyx mori.

A variety of insects accumulate high contents of riboflavin (vitamin B2) in their Malpighian tubules (MTs). Although this process is known to be genetically controlled, the mechanism is not known. In the 1940s and the 1950s, several studies showed that riboflavin contents were low in the MTs of some Bombyx mori (silkworm) mutants with translucent larval skin mutations (e.g., w-3, od, oa, and otm) and that genes responsible for these translucent mutations also affected riboflavin accumulation in the MTs. Since the 2000s, it has been shown that the w-3 gene encodes an ABC transporter, whereas genes responsible for od, oa, and otm mutations encode for the biogenesis of lysosome-related organelles. These findings suggest that some genes of ABC transporters and biogenesis of lysosome-related organelles may control the accumulation of riboflavin in MTs. Therefore, we reexamined the effects that translucent mutations have on the accumulation of riboflavin in MTs by using the translucent and wild-type segregants in mutant strains to measure the specific effect that each gene has on riboflavin accumulation (independent of genomic background). We used nine translucent mutations (w-3oe, oa, od, otm, Obs, oy, or, oh, and obt) even though the genes responsible for some of these mutations (Obs, oy, or, oh, and obt) have not yet been isolated. Through observation of larval MTs and measurements of riboflavin content using high-performance liquid chromatography, we found that the oa, od, otm, and or mutations were responsible for low contents of riboflavin in MTs, whereas the Obs and oy mutations did not affect riboflavin accumulation. This indicates that the molecular mechanism for riboflavin accumulation is similar but somewhat different than the mechanism responsible for uric acid accumulation in epidermal cells. We found that the genes responsible for oa, od, and otm mutations were consistent with those already established for uric acid accumulation in larval epidermis. This suggests that these three genes control riboflavin accumulation in MTs through a mechanism similar to that of uric acid accumulation, although we do not yet know why the or mutation also controls riboflavin accumulation.

Different Catabolism Pathways Triggered by Various Methylxanthines in Caffeine-Tolerant Bacterium Pseudomonas putida CT25 Isolated from Tea Garden Soil.

The degradation efficiency and catabolism pathways of the different methylxanthines (MXs) in isolated caffeine-tolerant strain Pseudomonas putida CT25 were comprehensively studied. The results showed that the degradation efficiency of various MXs varied with the number and position of the methyl groups on the molecule (i.e., xanthine > 7-methylxanthine ≈ theobromine > caffeine > theophylline > 1-methylxanthine). Multiple MX catabolism pathways coexisted in strain CT25, and a different pathway would be triggered by various MXs. Demethylation dominated in the degradation of N-7-methylated MXs (such as 7-methylxanthine, theobromine, and caffeine), where C-8 oxidation was the major pathway in the catabolism of 1-methylxanthine, whereas demethylation and C-8 oxidation are likely both involved in the degradation of theophylline. Enzymes responsible for MX degradation were located inside the cell. Both cell culture and cell-free enzyme assays revealed that N-1 demethylation might be a rate-limiting step for the catabolism of the MXs. Surprisingly, accumulation of uric acid was observed in a cell-free reaction system, which might be attributed to the lack of activity of uricase, a cytochrome c-coupled membrane integral enzyme.

Dietary and lifestyle recommendations for urolithiasis prevention: A systematic literature review

What are the dietary, fluid intake and lifestyle indications for the disease management and recurrences prevention in patients with urolithiasis? Despite the progress in urolithiasis diagnosis and treatment, its incidence has increased in the last decades and a high rate of recurrence is still a real problem. Dietary and lifestyle modifications represent the most effective preventive measures. Recommendations and evidence available in literature are not always accurate and consistent, negatively affecting patients’ education. A systematic review was conducted starting from a research in electronic databases; the study selection process was based on PRISMA indications. Methodological quality and risk of bias were assessed. Data were analysed in three phases: (1) critical review of articles; (2) data extraction; (3) evidence synthesis. Thirty‐six studies were included: researchers used prevalently non‐probabilistic sampling methods and data from several studies derived from small samples, mainly from Western countries. Despite these limitations, the below listed themes for urolithiasis prevention arose: (1) the importance of a prevalently vegetarian regime with a reduced intake of meats and fats, decreasing the risk of stones formation from the accumulation of uric acid; (2) water intake greater than two litres per day is proven to prevent recurrences and drinking beverages, such as decaffeinated coffee, tea, beer and wine, also seems to be associated with a decrease in risk; (3) being physically active and having a healthy lifestyle can help to prevent recurrences. Various dietary and lifestyle modifications have a potential to prevent urolithiasis and recurrences. Clinicians should advise patients to reduce animal proteins and fats, increase fruits and vegetables, and increase water intake, as well as having a healthy lifestyle. Further rigorous methodological studies are needed.

Abstract 4477: Downregulation of ABCG2 expression in colitis and colon cancer: Relevance to iron overload, hemochromatosis and p53, and therapeutic use of carbidopa to reverse the downregulation

Abstract The efflux pump ABCG2 is a part of cellular defense. In intestine it is located at the luminal side, and effluxes exogenous/endogenous dysplasia-promoting agents. Since cancer cells exposed to chemotherapeutics overexpress ABCG2 to remove these drugs, ABCG2 is considered a multidrug-resistance protein. However, its physiologic protective role in cancer initiation/progression has not received much attention. In numerous studies, ABCG2 is present in colon at lower levels in patients with colitis and chemotherapy-naïve colon cancer than in controls. We therefore hypothesized that the physiologic role of ABCG2 is to suppress colonic inflammation and colon cancer. To test this, we monitored Abcg2 expression in the intestinal tract in experimental and genetic mouse models of colon cancer and colitis. In normal mice, Abcg2 was expressed throughout the intestinal tract, jejunum being the site with maximal expression. Colon was positive for expression, but the expression was lower than in jejunum. Compared to control colon, Abcg2 was present at lower levels in colonic polyps from experimental and genetic models of colon cancer; the same trend was seen in normal and cancer cell lines of colonic origin. In line with human colitis studies, colons from colitis mouse models had lower expression of Abcg2 compared to control colon. The association of excess iron to colon cancer is well known, but it is not known if excess iron has any role in tumor-associated downregulation of ABCG2 in colon. We used Hfe-/- mice as a model for hemochromatosis, a genetic iron-overload disease, and exploited the ability of Abcg2 to export uric acid as a measure of Abcg2 function. Colons from Hfe-/- mice had lower expression of Abcg2 and higher accumulation of uric acid. This decrease in Abcg2 function indicated that excess iron, directly or indirectly, dictates Abcg2 expression in colon. To better understand this phenomenon, colon cells were treated with ferric ammonium citrate as an iron source. This in vitro iron-overload model demonstrated nuclear depletion of the tumor suppressor p53, and at the same time a decrease in Abcg2 expression. In addition, Abcg2 mRNA was undetectable in p53-null mouse embryonic mouse fibroblasts, suggesting that Abcg2 is a p53 target. Additional in vitro studies included treatment of normal and cancer colon cells with Carbidopa, a drug which was recently shown as an aryl hydrocarbon receptor agonist. Our studies showed that Carbidopa is a potent iron chelator and an inducer of ABCG2 expression. In summary, ABCG2 is silenced in colon cancer and colitis, and the decreased expression of p53 under these conditions might be responsible for the decreased ABCG2 expression. Carbidopa could be used to reduce cellular levels of iron and to reverse iron-induced downregulation of ABCG2 as a prevention/treatment strategy for colitis and colon cancer. Citation Format: Bojana Ristic, Sathish Sivaprakasam, Jiro Ogura, Vadivel Ganapathy. Downregulation of ABCG2 expression in colitis and colon cancer: Relevance to iron overload, hemochromatosis and p53, and therapeutic use of carbidopa to reverse the downregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4477.

Proinflammatory mediators and gene polymorphism of ММР1 and ММР12 in post-traumatic knee osteoarthritis.

Joint injury is a well-established risk factor for development of post-traumatic knee osteoarthritis (PTOA) and may lead to joint inflammation. The aims of the study were: the investigation of proinflammatory mediators - the levels of IL-1β and uric acid (UA), the activity of xanthine oxidoreductase (XOR) - in the plasma and synovial fluid (SF) of patients with PTOA; the search for putative predictors of progression and predisposition to the PTOA development among these mediators and polymorphic gene loci of matrix metalloproteinases (MMP) - rs1799750 ММР1 and rs2276109 ММР12. Patients with a radiographically diagnosed PTOA (Kellgren-Lawrence, K/L grades I-III, N = 71) and 44 healthy controls were enrolled in the study of the levels of proinflammatory mediators. The XOR activity was measured by quantitation of uric acid accumulation at 293 nm as a result of xanthine oxidation. The uric acid level was determined using a commercially available kit (“Vital”, Russia) and spectrophotometer. The level of IL-1β was measured using commercially available enzyme-linked immunosorbent assay (ELISA) kit (“Vector-Best”, Russia) according to the manufacturers’ instructions. We used PCR followed by agarose gel electrophoresis (“SNP-Express” kits, “Lytech”, Russia) for SNP-genotyping. The XOR activity, the levels of proinflammatory mediators uric acid and IL-1β were determined to be significantly increased in the plasma of PTOA patients - by 20% (p = 0,03), 49% (p = 0,009) and 41% (p = 0,044), respectively. Multiple regression adjusted for age, gender, BMI of patients showed that xanthine oxidase activity was a significant predictor of radiographic knee osteoarthritis (β = 0,373, p < 0,01). Genetic analyses of 184 patients with PTOA and 113 healthy controls demonstrated that G-allele of polymorphic locus A-82G ММР-12 was associated with higher risk of post-traumatic knee osteoarthritis development (OR = 1,803, p = 0,028). The -82G-allele of ММР-12 may abrogate angiostatic effect of MMP-12 by decreasing its expression and promote activated macrophage recruitment and degradation of the cartilage.

Hyperuricemia enhances intracellular urate accumulation via down-regulation of cell-surface BCRP/ABCG2 expression in vascular endothelial cells

Hyperuricemia has been recognized as an independent risk factor for cardiovascular disease. Urate stimulates NADPH oxidase and induces production of reactive oxygen species (ROS); consequently, intracellular urate accumulation can induce oxidative stress leading to endothelial dysfunction. Here, we studied the mechanism involved, using human umbilical vascular endothelial cells (HUVEC) as a model. Pretreatment with 15 mg/dL unlabeled uric acid (corresponding to hyperuricemia) resulted in increased uptake of [14C]uric acid at steady-state by HUVEC, whereas pretreatment with 5 mg/dL uric acid (in the normal serum concentration range) did not. However, the initial uptake rate of [14C]uric acid was not affected by uric acid at either concentration. These results suggest that efflux transport of uric acid is decreased under hyperuricemic conditions. We observed a concomitant decrease of phosphorylated endothelial nitric oxide synthase. Plasma membrane expression of breast cancer resistance protein (BCRP), a uric acid efflux transporter, was decreased under hyperuricemia, though the total cellular expression of BCRP remained constant. Uric acid did not affect expression of another uric acid efflux transporter, multidrug resistance associated protein 4 (MRP4). Moreover, phosphorylation of Akt, which regulates plasma membrane localization of BCRP, was decreased. These uric acid-induced changes of BCRP and Akt were reversed in the presence of the antioxidant N-acetylcysteine. These results suggest that in hyperuricemia, uric acid-induced ROS generation inhibits Akt phosphorylation, causing a decrease in plasma membrane localization of BCRP, and the resulting decrease of BCRP-mediated efflux leads to increased uric acid accumulation and dysregulation of endothelial function.

Bisphenol A promotes hyperuricemia via activating xanthine oxidase

The prevalence of hyperuricemia has increased rapidly over the past decades. Bisphenol A (BPA) is an environmental endocrine disruptor. We investigated the effects of BPA on uric acid metabolism and its potential mechanisms. Experiments were performed in different animal models, cell cultures, and humans. In 3 different animal models, BPA exposure increased serum and hepatic uric acid with enhanced activity of xanthine oxidase (XO) in liver, whereas the excretion of uric acid was unchanged. Both in vivo and in vitro, BPA-induced uric acid production was decreased after treatment with allopurinol, which is a XO inhibitor. XO led to the accumulation of uric acid after xanthine was added, with the enzyme-catalyzed reaction, which was enhanced by BPA. Altered secondary structures of XO were found by circular dichroism analysis in the conditions of different BPA concentrations. Molecular docking portrayed Asp360 and Lys422 of XO to be the preferred binding sites for BPA. Mutation of both sites significantly blocked the effect of BPA on XO activity. In humans, patients with hyperuricemia exhibited higher levels of serum BPA than subjects without hyperuricemia. These findings demonstrate BPA promotes hyperuricemia by increasing hepatic uric acid synthesis via the activation of XO, probably through direct binding.-Ma, L., Hu, J., Li, J., Yang, Y., Zhang, L., Zou, L., Gao, R., Peng, C., Wang, Y., Luo, T., Xiang, X., Qing, H., Xiao, X., Wu, C., Wang, Z., He, J. C., Li, Q., Yang, S. Bisphenol A promotes hyperuricemia via activating xanthine oxidase.

Taraxerol, a pentacyclic triterpenoid, from Abroma augusta leaf attenuates diabetic nephropathy in type 2 diabetic rats

Persistent hyperglycaemia coupled with inflammation plays an important role in the pathogenesis of diabetic nephropathy (DN). Present study examined the therapeutic potential of taraxerol isolated from the methanol extract of Abroma augusta leaf against DN using rodent model of type 2 diabetes (T2D). T2D was experimentally induced by high fat diet and a single low-single dose of streptozotocin (35mg/kg, i.p.). Accumulation of serum creatinine, urea, and uric acid, activation of lactate dehydrogenase and creatinin kinase, and release of urinary albumin represented the glomerular damage and the progression of nephropathy in T2D rats. Taraxerol (20mg/kg, p.o.) treatment significantly reinstated the aforementioned changes in biochemical parameters near to normalcy. Molecular mechanism studies demonstrated an impaired signaling cascade, IRS1/PI3K/Akt/AMPK/GLUT4/GSK3β, of glucose metabolism in the skeletal muscle and increase in serum levels of pro-inflammatory cytokines, CRP and MCP1 in T2D rats. Activation of polyol pathway, enhanced production of AGEs, up-regulation of NF-κB/PKCs/PARP signaling, and renal fibrosis was also observed in T2D rats. Taraxerol (20mg/kg, p.o.) treatment stimulated glucose metabolism in skeletal muscle, regulated blood glycaemic status and lipid profile in the sera, reduced the secretion of pro-inflammatory cytokines, and restored the renal physiology in T2D rats. Histological assessments were also in agreement with the above findings. Molecular docking study again supported the probable interactions of taraxerol with PKCβ, PKCδ, NF-κB, PARP, PI3K, IRS, Akt and AMPK. In silico ADME study predicted the drug-likeness character of taraxerol. Results suggest a possibility of taraxerol to be a new therapeutic agent for DN in future.

Uric acid, an important antioxidant contributing to survival in termites.

Reactive oxygen species (ROS) are generated spontaneously in all organisms and cause oxidative damage to biomolecules when present in excess. Accumulated oxidative damage accelerates aging; enhanced antioxidant capacity may be a positive factor for longevity. Recently, numerous studies of aging and longevity have been performed using short-lived animals, however, longevity mechanisms remain unknown. Here we show that a termite Reticulitermes speratus that is thought to be long-lived eusocial insect than other solitary insects uses large quantities of uric acid as an antioxidant against ROS. We demonstrated that the accumulation of uric acid considerably increases the free radical-scavenging activity and resistance against ultraviolet-induced oxidative stress in laboratory-maintained termites. In addition, we found that externally administered uric acid aided termite survival under highly oxidative conditions. The present data demonstrates that in addition to nutritional and metabolic roles, uric acid is an essential antioxidant for survival and contributes significantly to longevity. Uric acid also plays important roles in primates but causes gout when present in excess in humans. Further longevity studies of long-lived organisms may provide important breakthroughs with human health applications.

Diagnosis and Treatment of Inflammatory Joint Disease.

Arthritis damages the cartilage within joints, resulting in degenerative changes, including loss of function and joint instability. Ankylosing spondylitis (AS) is a chronic inflammatory condition affecting the spine and bone-to-tendon attachment area within the sacroiliac joint leading to back pain and progressive spinal stiffness. In the final stages, AS causes hyperkyphosis-a condition closely tied to the human leukocyte antigen-B27 gene. Rheumatoid arthritis is a chronic, systemic autoimmune disease characterized by the simultaneous inflammation of the synovium of multiple joints, leading to joint damage (e.g., destruction, deformation and disability). In the past, nonsteroidal anti-inflammatory drugs or conventional disease-modifying antirheumatic drug (DMARDs) have been used for the treatment of these autoimmune diseases, but biologic DMARDs have recently been introduced with excellent results. Gout is a chronic inflammatory disease that causes an alteration of joints resulting in severe pain. Specifically, gout is associated with an accumulation of uric acid within the body resulting from dysregulated purine metabolism, causing recurrent paroxysmal inflammation in the joints. Allopurinol and febuxostat are the primary treatment options for individuals with gout. It is necessary to have an accurate understanding of the pathogenesis, pathological ecology and treatment of AS, rheumatoid arthritis, and gouty arthritis, which are the representative diseases that may cause inflammatory arthritis.

Assessment of Serum Prostate Specific Antigen, Some Renal Indices and Uric Acid Levels in Subjects with Benign Prostatic Hyperplasia at Lokoja, Nigeria

Background: Prostate disorders (prostatitis, BPH and Pca) can contribute to renal impairment. Benign prostatic hyperplasia (BPH) and renal impairment (RI) such as chronic kidney disease are important public health problems in older men. The present study aimed to assess serum levels of prostate specific antigen, urea, creatinine, protein and uric acids in subjects with BPH at Federal Medical Center, Lokoja, Kogi State, Nigeria. A population-based sample of one hundred and ten (110) men aged (51-70) years were conveniently recruited and divided into three groups designation A= BPH with RI, (n=35) B=BPH without RI, (n=35) and C=Control, (n=40). Methods: Blood samples were collected from all the participants and serum separated and stored at -20˚C until analyzed for prostate specific antigen using Enzyme Linked Immunosorbent Assay (ELISA) and colorimetric assay method for creatinine, urea, protein and uric acid. Data were analyzed using SPSS software application (version 17.0). Pearson correlation and Receiving Operating Characteristics of the groups were done. Results: The result showed that urea and creatinine levels were significantly higher in BPH subjects with or without renal impairment when compared with controls (p<0.05 respectively). Similarly, total prostate specific antigen (tPSA), free prostate specific antigen (fPSA), complex prostate specific antigen (cPSA) and percent free prostate specific antigen (%fPSA) were significantly higher in BPH subjects with or without RI when compared with controls (p<0.05 respectively). Urea, creatinine and uric acid were significantly higher while total protein was significantly lower in BPH with RI when compared with BPH without RI (p<0.05 respectively). Conclusion: The significantly higher urea, creatinine and uric acid levels in BPH subjects showed that BPH subjects with RI may have decrease excretion and accumulation of uric acid by the kidney suggesting possible risk of progression to CKD while BPH subjects without RI tends to be more prone to developing renal dysfunction. The significant correlation between %fPSA, creatinine and urea shows an association between BPH and renal diseases. Using receiving operating characteristic (ROC) curves to assess diagnostic performance of various parameters in various groups for the prediction of BPH with or without renal disease, there was evidence that fPSA and %fPSA have higher predictive value in the diagnosis of BPH while uric acid, urea, creatinine and protein have higher predictive value in the diagnosis of renal disease. It is therefore, recommended that people with prostate disorders should be screened for renal diseases and vice versa.

Dual-energy computed tomography as a diagnostic tool for gout during intercritical periods.

The aim of this study is to evaluate the diagnostic yield of dual-energy computed tomography (DECT) in detection of uric acid accumulation in joints or periarticular structures in patients suspected of having gout, in their intercritical period. Patients with a history of recurrent, short-lived mono- or oligo-arthralgia or arthritis, referred to the rheumatology clinic for diagnosis of their condition, were included in this retrospective evaluation. DECT confirmed the diagnosis of gout in 30 of 50 patients (60%). A positive DECT was present in 12 of 16 cases (75%) with serum uric acid > 8.5 mg/dL, compared to seven of 13 cases (54%) and two of five cases (40%) with levels of 6.1-8.5 mg/dL and ≤ 6 mg/dL, respectively. The diagnostic impact of screening hands and feet were highest (78% and 56%, respectively). Follow-up data were available for 24 of the 30 patients with urate deposits identified by DECT. Twenty-one were treated with urate-lowering agents, all responded with lowering of serum uric acid and cessation of flares. Follow-up data were available for 16 of the 20 patients with no urate deposits identified by DECT. Gout was diagnosed in two of them by synovial fluid examination during subsequent flares. Both positive and negative predictive values of DECT for diagnosing gout in this patient population were 87%. Following DECT, treatment regimen was modified to gout-specific therapy in 52% of the patients. The ability to make a definite diagnosis of gout by DECT imaging in a substantial number of asymptomatic patients in the intercritical period should help in treatment decision-making and improve patient adherence to long-term urate-lowering therapy.

GC×GC-TOFMS for the Analysis of Metabolites Produced by Termites (Reticulitermes flavipes) Bred on Different Carbon Sources

More and more studies are dedicated to termites and their symbionts, to better understand how they efficiently produce energy from lignocellulose. In that context, a powerful analytical method was developed to perform the detection, separation and identification of compounds in the 1 µL fluid volume of the gut of the termite Reticulitermes flavipes. Comprehensive two-dimensional gas chromatography (GC×GC) coupled to time-of-flight mass spectrometry (TOFMS) was tested with three different column combinations: (1) low-polar/mid-polar; (2) polar/low-polar and (3) mid-polar/low-polar. The column set (3) offered the best separation and was chosen for further analysis and comparison study. Metabolites were detected in the samples, including amino acids, sugars, amines and organic acids. Samples collected from termites fed for 30 days on Avicel cellulose or xylan powder diets were analyzed and compared with the wood diet. Principal component analysis (PCA) of metabolite profiles demonstrated a separation of different clusters corresponding to the three different diets, with a similar trend for diets containing cellulose. The Analysis of variance (ANOVA) (one way-ANOVA and Tukey’s test) was used to compare compound levels between these three different diets. Significant differences were observed, including higher levels of aromatic derivatives in the wood diet and higher levels of sugar alcohols in the xylan diet. A higher accumulation of uric acid was observed with the artificial diets (cellulose and xylan), likely to be related to the nitrogen deficiency. The present study highlighted the capability of adaptation of the termite system to non-optimal carbon sources and the subsequent modification of the metabolite profile. These results demonstrate the potential interest to investigate metabolite profiling with state-of-the-art separation science tools, in order to extract information that could be integrated with other omics data to provide more insight into the termite-symbiont digestion system.

A de novo transcriptome of the Malpighian tubules in non-blood-fed and blood-fed Asian tiger mosquitoes Aedes albopictus: insights into diuresis, detoxification, and blood meal processing.

Background. In adult female mosquitoes, the renal (Malpighian) tubules play an important role in the post-prandial diuresis, which removes excess ions and water from the hemolymph of mosquitoes following a blood meal. After the post-prandial diuresis, the roles that Malpighian tubules play in the processing of blood meals are not well described.Methods. We used a combination of next-generation sequencing (paired-end RNA sequencing) and physiological/biochemical assays in adult female Asian tiger mosquitoes (Aedes albopictus) to generate molecular and functional insights into the Malpighian tubules and how they may contribute to blood meal processing (3–24 h after blood ingestion).Results/Discussion. Using RNA sequencing, we sequenced and assembled the first de novo transcriptome of Malpighian tubules from non-blood-fed (NBF) and blood-fed (BF) mosquitoes. We identified a total of 8,232 non-redundant transcripts. The Malpighian tubules of NBF mosquitoes were characterized by the expression of transcripts associated with active transepithelial fluid secretion/diuresis (e.g., ion transporters, water channels, V-type H+-ATPase subunits), xenobiotic detoxification (e.g., cytochrome P450 monoxygenases, glutathione S-transferases, ATP-binding cassette transporters), and purine metabolism (e.g., xanthine dehydrogenase). We also detected the expression of transcripts encoding sodium calcium exchangers, G protein coupled-receptors, and septate junctional proteins not previously described in mosquito Malpighian tubules. Within 24 h after a blood meal, transcripts associated with active transepithelial fluid secretion/diuresis exhibited a general downregulation, whereas those associated with xenobiotic detoxification and purine catabolism exhibited a general upregulation, suggesting a reinvestment of the Malpighian tubules’ molecular resources from diuresis to detoxification. Physiological and biochemical assays were conducted in mosquitoes and isolated Malpighian tubules, respectively, to confirm that the transcriptomic changes were associated with functional consequences. In particular, in vivo diuresis assays demonstrated that adult female mosquitoes have a reduced diuretic capacity within 24 h after a blood meal. Moreover, biochemical assays in isolated Malpighian tubules showed an increase in glutathione S-transferase activity and the accumulation of uric acid (an end product of purine catabolism) within 24 h after a blood meal. Our data provide new insights into the molecular physiology of Malpighian tubules in culicine mosquitoes and reveal potentially important molecular targets for the development of chemical and/or gene-silencing insecticides that would disrupt renal function in mosquitoes.