Purinergic signaling and energetic metabolism in bipolar disorder: From pathophysiology to precision therapeutics.

Introduction Bipolar affective disorder (BD) is a chronic psychiatric illness characterized by alternating manic and depressive episodes. Despite extensive research, its underlying mechanisms remain unclear. Recent studies suggest that purinergic signaling and inflammation may play key roles in BD pathophysiology. This study aimed to explore biomarkers related to these systems to improve understanding of BD and identify potential diagnostic and prognostic indicators. Methods The study included 76 BD patients and 20 healthy controls from the Department of Adult Psychiatry, Poznan University of Medical Sciences. Blood samples were collected during acute episodes and after symptom remission. Biomarkers analyzed included uric acid (UA), interleukin-6 (IL-6), NACHT, P2X7 receptor, adenosine deaminase (ADA), xanthine dehydrogenase (XDH), and adenosine (ADO), measured by ELISA. Results NACHT (p = 0.004) and P2X7 (p = 0.001) were significantly higher post-treatment. Age positively correlated with NACHT, and BMI with UA. P2X7 levels negatively correlated with depressive symptom improvement. Gender differences revealed higher pre-treatment ADA levels in women and greater post-treatment increases in NACHT, ADA, and XDH in men. IL-6 was elevated during depressive episodes, while NACHT and XDH were higher in manic states. ROC analysis indicated strong diagnostic potential for XDH (AUC=0.917) and ADA (AUC=0.903). Logistic regression identified post-treatment NACHT and P2X7 as significant BD predictors. Conclusions The study highlights the involvement of purinergic and inflammatory pathways in BD pathophysiology. Biomarkers such as NACHT, P2X7, ADA, and XDH may aid in diagnosing BD and monitoring treatment responses, offering potential for biologically informed therapies.

To the Editor: Recently, an update from the Framingham study could not find uric acid to be an independent risk factor for cardiovascular disease.1 While serum uric acid levels correlated significantly with the risk for cardiovascular events and mortality in women, this relationship became insignificant after factoring for 11 additional variables including hypertension, body mass index, and diuretic use.1 Both the authors1 and an accompanying editorial2 interpreted these findings as showing that uric acid is not a true risk factor for cardiovascular disease and that it should not be routinely measured to assess cardiovascular risk. The careful analysis of the Framingham study is to be commended, but one must be cautious in the interpretation of the findings. While some epidemiologic studies such as the current one have not been able to show uric acid to be an independent risk factor for cardiovascular disease, other studies using multivariate analyses3 4 5 6 came to an opposite conclusion. Another recently completed study, the Worksite,7 also found uric acid to be an independent risk factor for cardiovascular events and mortality, especially in women. One might look for subtle explanations to account for the differences in these various studies, as Culleton et al1 have attempted, but most of the studies examined the very same variables. A more central issue is whether one should interpret the finding that a risk factor is not statistically independent to mean that it should not be considered biologically important. We would argue that this is not true in several situations. First, if the risk factors are causally linked, then one may not be able to show that they are independent of each other. For example, although smoking is a risk factor for mortality, it might no longer be independent if it is …

BackgroundAssociation between vitamin D insufficiency and hyperuricemia has not been reported so far. We aimed to study the association of vitamin D insufficiency with elevated serum uric acid among middle-aged and elderly Chinese Han women.MethodsWe collected data from participants residing in Jinchang district of Suzhou from January to May, 2010. Serum uric acid, 25-hydroxy vitamin D and other traditional biomarkers including fasting plasma glucose and blood lipids were determined in 1726 women aged above 30 years. Association between vitamin D insufficiency and elevated uric acid was analyzed in premenopausal and postmenopausal women, respectively.ResultsAmong postmenopausal women, 25-hydroxy vitamin D level of participants with elevated uric acid was lower than that of those with normal uric acid (median [interquartile range]: 35[28–57] vs 40[32–58], µg/L; P = 0.006). Elevated uric acid was more prevalent in participants with vitamin D insufficiency compared to those without vitamin D insufficiency (16.50% vs 8.08%; P<0.001). Association between vitamin D insufficiency and elevated uric acid was not significant among premenopausal women. However, participants with vitamin D insufficiency were more likely to have elevated uric acid compared with those without vitamin D insufficiency among postmenopausal women (OR, 95% CI: 2.38, 1.47–3.87). Moreover, after excluding individuals with diabetes and/or hypertension, the association of vitamin D insufficiency with elevated uric acid was still significant (OR, 95% CI: 2.48, 1.17–5.44).ConclusionsVitamin D insufficiency was significantly associated with elevated uric acid among postmenopausal Chinese Han women. This study suggested that a clinical trial should be conducted to confirm the association of vitamin D insufficiency with hyperuricemia.

In the current issue of Circulation , Anker and colleagues1 report that elevated levels of uric acid (UA) predict mortality and the need for heart transplantation in patients with congestive heart failure (HF). Serum concentrations of UA added important prognostic information alone and when combined with measures of cardiac function (ejection fraction) and patient functional status (maximal oxygen consumption with exercise) and were independent of renal function, serum sodium, serum urea, diuretic usage, and patient age. Receiver operating curve analysis identified a cutoff of 585 μmol/L (9.8 mg/dL) as the best mortality predictor. This finding is not only potentially of value in patient management but also raises extremely interesting questions regarding the pathophysiological underpinnings of this finding. See p 1991 A consideration of the mechanism of UA production and metabolism offers insight into the relationship between UA levels and HF outcomes. Indeed, accumulating data support the idea that UA, in addition to being a potentially valuable prognostic marker, possesses specific toxic or other properties that could contribute to HF pathophysiology. Moreover, UA levels may reflect xanthine oxidase (XO) pathway activity, which has the potential to contribute to the progression of left ventricular dysfunction by interfering with myocardial energetics2 and myofilament calcium sensitivity.3 UA is a metabolic byproduct of purine metabolism (Figure). Serum UA may increase in the failing circulation because of increased generation, decreased excretion, or a combination of the 2 factors. There are several possible contributors to increased UA production in HF, including increased abundance and activity of XO,4 increased conversion of …

Low relative skeletal muscle mass indicative of sarcopenia is associated with elevations in serum uric acid levels: findings from NHANES III.

Uric acid and essential hypertension: the endothelial connection.

Elevated serum uric acid may be closely related to the occurrence of gestational diabetes mellitus (GDM). We aimed to elucidate the relationship between changes in serum uric acid before 24 weeks of gestation and the risk of GDM and associated adverse pregnancy outcomes and provide clinical epidemiological evidence for the involvement of uric acid in the etiology of GDM. We conducted a retrospective cohort study of 23 843 singleton pregnant women between February 2018 and June 2022. The exposure factor was serum uric acid before 24 weeks of gestation, primary outcome was gestational diabetes diagnosed at 24 to 28 weeks of gestation, and secondary outcomes were GDM A2 (GDM requiring pharmacotherapy), GDM combined with pre-eclampsia, preterm delivery, and large for gestational age infants. Adjusted risk ratios (RRs) were calculated using multivariate predictive marginal proportions from logistic regression models. Among 23 843 singleton pregnant women, 3204 (13.44%) were diagnosed with GDM at 24 to 28 weeks of gestation, and elevated uric acid before 24 weeks of gestation was strongly associated with the risk of GDM. Compared with uric acid <240 µmol/L, the RR for GDM was 1.43 (95% CI 1.29-1.56) when uric acid was between 240 and 300 µmol/L; when uric acid was >300 µmol/L, the RR for GDM was 1.82 (95% CI 1.55-2.15). In secondary outcomes uric acid had a similar relationship with GDM A2, preterm birth, and GDM combined with pre-eclampsia. Elevated uric acid levels before 24 weeks of gestation are associated with subsequent GDM; the best time to test for uric acid is before 18 weeks of gestation. Pregnant women with low and intermediate risk for GDM development may benefit more from serum uric acid measurements before 18 weeks of gestation.

Recent studies on the tissue distribution and developmental regulation of adenosine deaminase (ADA) activity in mice show that very high ADA levels exist in the murine alimentary tract (tongue, esophagus, forestomach, proximal small intestine) and at the fetal-maternal interface. To understand the role of ADA in these tissues, we measured the levels of three other enzymes involved in purine catabolism, purine nucleoside phosphorylase (PNP), guanine deaminase (GDA), and xanthine dehydrogenase (XDH), to see how their levels correlated with ADA activity. Our results show that the highest level of PNP, GDA, and XDH is present in the proximal small intestine. Levels of these purine catabolic enzymes are much lower in the tongue, esophagus, forestomach, and fetal-maternal interface in marked contrast to ADA distribution. We also determined mRNA levels encoding PNP, XDH, and ADA in a variety of tissues. Tissue-specific differences in PNP, XDH, and ADA activity correlated with RNA abundance, indicating that the regulation of gene expression is at the level of mRNA production. Thus, ADA is part of a purine catabolic pathway leading to the production of uric acid that is present at the highest known level in the proximal small intestine. ADA may have additional roles in other tissues.

In a recent issue of this Journal, Montalcini and coworkers demonstrated that an increase in serum uric acid levels may be an independent risk factor for atherosclerosis in a series of healthy postmenopausal women [1]. The possible causative effect of modifications in uric acid metabolism in the pathogenesis of cardiovascular disease (CVD) was also reviewed by Manzato in the same issue of the journal [2], bringing to the attention of the scientific community the old concept of the possible role of uric acid as an additional player in the development of atherosclerosis and arterial thrombosis. Epidemiological studies showed that elevated serum uric acid may be a risk factor for CVD independent of other abnormalities commonly observed in patients with the metabolic syndrome, such as obesity, dyslipidaemia, hypertension, insulin resistance and glucose intolerance [3–5]. The study by Montalcini et al. [1] tested the pro-atherosclerotic effects of hyperuricaemia by using high-resolution ultrasound, a widely accepted technique able to noninvasively detect early atherosclerotic modifications of arterial wall in vivo, and specifically an increase in carotid intima-media thickness. It has been previously shown that this structural change correlates with future clinical events, therefore providing reliable information on the prognostic role of cardiovascular risk factors [6]. The mechanisms potentially involved in the pro-atherosclerotic effect of uric acid are still under investigation and, as mentioned by Manzato [2], several hypotheses have been made to explain this issue. One possible pathogenetic mechanism relates to the effect exerted by uric acid on vascular and inflammatory cells. It has been demonstrated that uric acid, in a range of concentration of 120–240 μmol/l (6–12 mg/dl), is able to upregulate Creactive protein (CRP) mRNA expression in human umbilical vein endothelial cells (HUVEC) in vitro, thus inducing CRP release into culture media [7]. In the same experiments uric acid was shown to stimulate human vascular smooth muscle cell (VSMC) proliferation and migration, and to inhibit endothelial cell proliferation and nitric oxide (NO) release. All these effects of uric acid could be blocked by incubation of vascular cells with anti-CRP antibodies [7]. Taken together these data suggest that uric acid may potentially contribute to vasoconstriction and platelet activation and to atherosclerotic plaque growth, and that these effects are mediated by locally produced CRP. Work by the same group showed that hyperuricaemia, obtained in rats by blocking uricase by oxonic acid, was also able to induce a decrease in serum NO levels together with an increase in systolic blood pressure, and that this effect was reversed after allopurinol treatment for 7 days. In additional experiments, uric acid was shown to dose dependently inhibit both basal and vascular endothelial growth factor (VEGF)-induced NO production by bovine endothelial cells in vitro, thus suggesting that exposure to uric acid may induce endothelial dysfunction and a pro-atherosclerotic phenotype in these cells [8]. Kanellis and coworkers also demonstrated that uric acid induced an increase in rat aortic VSMC monocyte chemoattractant protein-1 (MCP-1) expression in a timeand dose-dependent manner, with a peak at 24 h. Overexpression of MCP-1 mRNA and protein occurred as early as 3 h after the incubation of VSMC with uric acid and was associated with activation of the transcription factors NF-κB and activator protein-1 (AP-1), as well as with the activation of the mitogen-activated protein kinase (MAPK) extracellular signalling molecules ERK p44/42 and p38, and with an increase in cyclooxygenase-2 (COX2) mRNA expression [9]. Inhibition of ERK p44/42, p38 and COX-2 each suppressed uric acid-induced MCP-1 production [9]. These data clearly show that uric acid, in its soluble form, can elicit an inflammatory response in VSMC, thus providing further evidence of its potential role in monocyte recruitment, VSMC activation and finally in atherosclerotic plaque growth and rupture. A large body of experimental data demonstrated that inflammatory processes play a crucial role in all steps of atherosclerotic plaque formation and disruption and in its thrombotic complications, and that these processes are sustained by a variety of cells such as endothelial cells, VSMC and macrophages [10]. CRP is one of the most important inflammatory mediators. It is mainly produced by the liver in response to the proinflammatory cytokine IL-6 which, in turn, is syntheIntern Emerg Med (2007) 2:320–321 DOI 10.1007/s11739-007-0087-x

CoTOL is a traditional Chinese medicine (TCM) formula in clinics for treating gout and hyperuricemia, especially in obese patients with recurrent attacks. However, fewer studies have investigated how CoTOL impacts the intestinal flora in reducing uric acid. In the present, we analyze the bacteria targeted by ingredients of CoTOL and evaluate the effects of CoTOL on uric acid and intestinal flora in a mice model of obese hyperuricemia inoculated with xanthine dehydrogenase- (XOD-) producing bacteria, Streptococcus faecalis. Firstly, ingredients of herbs in CoTOL and gene target by these ingredients were retrieved from TCMID 2.0, and these genes were screened by DAVID Bioinformatics Resources 6.8, deciphered to retrieve the bacteria. Then, 3-4-week-old male C57bl/6j mice were randomly divided into 6 groups and fed with high fat diet for 8 weeks up to obesity standard. The mice were inoculated intragastrically with 5 × 109 CFU Streptococcus faecalis 3 times at the 5th, 6th, and 7th week and intragastrically administrated with uricase inhibitor, potassium-oxonate (PO, 250 mg/kg), to induce hyperuricemia at the 8th week, once a day for 7 consecutive days, respectively (IB model). IB model plus CoTOL (0.4 ml/20g) and allopurinol (40 mg/kg) were administrated by gavage at the 5th week, once a day for 4 weeks. The feces and blood in each group were sampled at the 4th and 8th week. With no bacteria inoculation, CoTOL, allopurinol, and blank group were treated with CoTOL and allopurinol or water, respectively. 44 species of bacteria (i.e., Enterococcus faecalis, Streptococcus, etc.) genes were targeted by 6 ingredients of 6 herbs in CoTOL. Inoculation with Streptococcus faecalis significantly caused the elevation of uric acid and the change of intestinal flora structure, whereas treatment with CoTOL significantly increased the abundance of Akkermansia and those of Bacteroides and Alloprevotella decreased. Furthermore, CoTOL exhibited a unique effect on reducing weight unobserved in allopurinol intervention. The present study, for the first time, demonstrated that CoTOL has beneficial effects on hyperuricemia and overweight, which may be attributed to regulating material metabolism and improving the structure or function of intestinal flora. Thus, CoTOL may be a promising therapy for hyperuricemia and overweight in chronic gout management and can be integrated with conventional treatments.

Combined oral contraceptive (COC) treatment has been shown to be associated with glucose deregulation and increased triglyceride levels, but the mechanisms are elusive. Soluble dipeptidyl peptidase-4 (sDPP-4) and adenosine deaminase (ADA) are involved in the initiation and/or progression of cardiometabolic disorders. We therefore, hypothesized that increased DPP-4 and ADA activities are involved in glucose deregulation and hepatic triglyceride accumulation induced by COC treatment. This study also investigated whether short-chain fatty acid, acetate, would protect against COC-induced dysmetabolic effects. Female Wistar rats received (p.o.) vehicle and COC (1.0μg ethinylestradiol plus 5.0μg levonorgestrel) with or without sodium acetate (ACE; 200mg) for 8weeks. Treatment with COC led to increased plasma triglyceride-glucose index, 1-h postload glucose response, insulin, free fatty acid, insulin resistance, and impaired glucose tolerance. COC treatment also resulted in increased plasma and hepatic triglycerides (TG), TG/HDL-cholesterol ratio, malondialdehyde, uric acid, lactate dehydrogenase, DPP-4, ADA, and xanthine oxidase (XO) activities. On the other hand, COC led to reduction in nitric oxide level. However, ACE significantly ameliorated the alterations induced by COC treatment, but XO activity remains elevated during COC treatment. This result also demonstrates that increased DPP-4 and ADA activities are at least in part involved in glucose deregulation and hepatic TG accumulation induced by COC treatment. Therefore, sodium acetate would impact positively on cardiometabolic disorders, at least in part, by inhibition of DPP-4 and ADA activities.

Purinergic signaling is linked to neurodegenerative and proinflammatory damage during pathological conditions such as hypoxia, but involvement of this pathway in brain damage in fish exposed to environmental hypoxia remains unknown, and we propose dietary supplementation with caffeine in order to improve the immune response. Therefore, the aim of the study was to evaluate whether the enzymatic purinergic signaling pathway is associated with inflammatory brain damage in Nile tilapia (Oreochromis niloticus) exposed to environmental hypoxia and whether dietary supplementation with caffeine (5% and 8%) can prevent these changes in purinergic signaling. Animals were randomly divided into six groups (A-F, n = 6 per group, in triplicate), as follows: groups A-C were submitted to normoxia, while groups D-F were submitted to hypoxia. Groups A and D received the basal diet, while groups B and D and groups C and F received a diet containing 5% and 8% caffeine, respectively, and fed with their respective diets for 21days. After 21days, aeration was disconnected (groups D-F) and the dissolved oxygen levels were maintained as follows: group A (6.55 ± 0.23mg/L), group B (6.51 ± 0.24mg/L), group C (6.58 ± 0.22mg/L), group D (1.23 ± 0.11mg/L), group E (1.20 ± 0.15mg/L), and group F (1.18 ± 0.13mg/L). Cerebral triphosphate diphosphohydrolase (NTPDase) using adenosine triphosphate (ATP) as a substrate and 5'-nucleotidase activities decreased in fish exposed to 72h of hypoxia compared with the normoxia group, while adenosine deaminase (ADA) activity and levels of nitric oxide (NOx) metabolites were higher. Dietary supplementation with 5% and 8% caffeine prevented all alterations elicited by hypoxia, with the exception of ADA activity in the case of 5% caffeine. Based on this evidence, our findings reveal that nucleotide/nucleoside hydrolysis is modified in the brains of fish exposed to 72h of hypoxia, contributing to inflammatory damage, which apparently is mediated by excessive ATP content in the extracellular medium and by excessive NOx production. Also, the use of a diet containing 5% and 8% caffeine prevented these alterations (except 5% of dietary caffeine on ADA activity) and can be considered an interesting approach to preventing the impairment of immune and inflammatory responses elicited by hypoxia, principally the inclusion of 8% caffeine.

To elucidate whether uric acid changes in early pregnancy are associated with the development of preeclampsia and their association with preeclampsia-related adverse pregnancy outcomes. We conducted a retrospective cohort study of 4725 singleton pregnant women between January 2017 and July 2019 using propensity score matching. The primary outcome of the cohort was preeclampsia, and the secondary outcomes were preterm delivery, preterm preeclampsia and low birth weight infants. Multivariable predicted marginal proportions from logistic regression models were used to compute adjusted risk ratios. The quantitative-effect relationship between serum uric acid and preeclampsia development was observed by a dose‒response graph, and the effect of serum uric acid on the week of gestation at delivery was assessed using the Kaplan‒Meier method and the log-rank test. The risk of preeclampsia development increased with higher serum uric acid levels. After adjusting for confounders, the risk ratio for the development of preeclampsia with uric acid levels ≥240 µmol/l was 1.25 (95% CI: 0.96-1.65) compared with the group with uric acid levels <240 µmol/l. In the subgroup analysis of KM (Kaplan-Meier) curves, the gestational week at delivery was earlier when uric acid levels ≥240 µmol/l occurred at 8-12 weeks of gestation. Elevated serum uric acid levels before 20 weeks of gestation are associated with the development of preeclampsia, especially in the first 8-12 weeks of gestation, and the effect is attenuated with increasing gestational weeks, which suggests that elevated uric acid levels in early pregnancy may be a causative factor in preeclampsia. Elevated serum uric acid levels before 20 weeks of gestation are associated with the development of preeclampsia, especially in the early 8-12 weeks of gestation, and the effect attenuates with increasing gestational weeks, which suggest that elevated uric acid in early pregnancy may be a causative factor in preeclampsia.

The association of elevated serum uric acid with the development of hypertension is established outside of pregnancy. We investigated whether first trimester uric acid was associated with the development of the following: gestational hypertension or pre eclampsia, these outcomes stratified by presence of hyperuricemia at delivery since this denotes more severe disease, preterm birth, or small for gestational age (SGA). Uric acid was measured in 1,541 banked maternal plasma samples from a prior prospective cohort study that were collected at a mean gestational age of 9.0 (± 2.5) weeks. Polytomous regressions were performed and adjusted for parity and prepregnancy body mass index (BMI). First trimester uric acid in the highest quartile (>3.56 mg/dl) compared to lowest three quartiles was associated with an increased risk of developing pre-eclampsia (adjusted odds ratio (OR) = 1.82; 95% confidence interval (CI), 1.03-3.21) but not gestational hypertension. In women with hypertensive disease complicated by hyperuricemia at delivery, high first trimester uric acid was associated with a 3.22-fold increased risk of hyperuricemic gestational hypertension (HU) and a 3.65-fold increased risk of hyperuricemic pre-eclampsia (HPU). High first trimester uric acid was not associated with gestational hypertension or pre-eclampsia without hyperuricemia (H or HP) at delivery, preterm birth, or SGA. In women who developed hypertensive disease, elevated uric acid at delivery was only partly explained by elevated uric acid in the first trimester (r(2) = 0.23). First trimester elevated uric acid was associated with later pre-eclampsia and more strongly with pre-eclampsia and gestational hypertension with hyperuricemia.

Serum uric acid may serve as a marker for the activation of oxidative stress and may therefore be a marker for subsequent cardiovascular events. Our goal was to assess the association of serum uric acid levels and the outcomes of patients who have undergone percutaneous coronary intervention (PCI). We performed a retrospective cohort study of patients who underwent PCI between 1/1/2000 and 12/31/2007. Data were retrieved from the Cardiac Lab Interventional Clinical Database as well as the medical records. Outcomes of mortality as well as major adverse cardiac events (MACE) that include death, myocardial infarction (MI), and target vessel revascularization were obtained. There were 10,632 unique patients who had a PCI at the Mayo Clinic in Rochester and allowed use of their records for research. During this time, 1,916 had a uric acid measure within 2 years prior to the day of PCI. Of the 1,916 patients in our cohort, 1,353 had normal uric acid levels and 563 had elevated uric acid. After multivariable analysis, there was a strong trend in association with follow-up mortality in patients with elevated uric acid (HR = 1.25, 95% CI 0.98-1.59, P = 0.07). The association with mortality or MI (HR = 1.15, 95% CI 0.93-1.43, P = 0.20) and the association with MACE (HR = 1.04, CI 0.86- 1.25, P = 0.71) were not significant. In a large single-center database with complete follow-up, elevated serum uric acid was associated with increased mortality in PCI patients. These data show a trend for uric acid in the pathophysiology of atherosclerotic coronary artery disease and highlight the need for further research.