The metabolic syndrome refers to a constellation of signs including abdominal obesity, elevated serum triglycerides, low HDL-cholesterol, elevated blood pressure and insulin resistance. Today approximately one third of the adult population has the metabolic syndrome. While there is little doubt that the signs constituting the metabolic syndrome frequently cluster, much controversy exists over the definition, pathogenesis, or clinical utility. Here we present evidence from the field of comparative physiology that the metabolic syndrome is similar to the biological process that animals engage to store fat in preparation for periods of food shortage. We propose that the metabolic syndrome be changed to fat storage condition to more clearly align with its etiology. Obesity in humans is likely the consequences of both genetic predisposition (driven in part by thrifty genes) and environment. Recent studies suggest that the loss of the uricase gene may be one factor that predisposes humans to obesity today. Understanding the process animals engage to switch from a lean insulin-sensitive to an obese insulin-resistant state may provide novel insights into the cause of obesity and diabetes in humans, and unique opportunities for reversing their pathology.
hibernation; insulin resistance; metabolic syndrome; obesity
The brown bear (Ursus arctos) hibernates for 5 to 6 months each winter and during this time ingests no food or water and remains anuric and inactive. Despite these extreme conditions, bears do not develop azotemia and preserve their muscle and bone strength. To date most renal studies have been limited to small numbers of bears, often in captive environments. Sixteen free-ranging bears were darted and had blood drawn both during hibernation in winter and summer. Samples were collected for measurement of creatinine and urea, markers of inflammation, the calcium-phosphate axis, and nutritional parameters including amino acids. In winter the bear serum creatinine increased 2.5 fold despite a 2-fold decrease in urea, indicating a remarkable ability to recycle urea nitrogen during hibernation. During hibernation serum calcium remained constant despite a decrease in serum phosphate and a rise in FGF23 levels. Despite prolonged inactivity and reduced renal function, inflammation does not ensue and bears seem to have enhanced antioxidant defense mechanisms during hibernation. Nutrition parameters showed high fat stores, preserved amino acids and mild hyperglycemia during hibernation. While total, essential, non-essential and branched chain amino acids concentrations do not change during hibernation anorexia, changes in individual amino acids ornithine, citrulline and arginine indicate an active, although reduced urea cycle and nitrogen recycling to proteins. Serum uric acid and serum fructose levels were elevated in summer and changes between seasons were positively correlated. Further studies to understand how bears can prevent the development of uremia despite minimal renal function during hibernation could provide new therapeutic avenues for the treatment of human kidney disease.
Fructose consumption predicts increased hepatic fibrosis in those with nonalcoholic fatty liver disease (NAFLD). Due to its ability to lower hepatic adenosine triphosphate (ATP) levels, habitual fructose consumption could result in more hepatic ATP depletion and impaired ATP recovery. The degree of ATP depletion following an intravenous fructose challenge test in low versus high fructose consumers was assessed. We evaluated diabetic adults enrolled in the Look AHEAD Fatty Liver Ancillary Study (n=244) for whom dietary fructose consumption estimated by a 130-item Food Frequency questionnaire, hepatic ATP measured by phosphorus MRS (31P MRS) and uric acid (UA) levels were performed (n=105). In a subset of participants (n=25), an intravenous fructose challenge was utilized to assess change in hepatic ATP content. The relationships between dietary fructose, UA and hepatic ATP depletion at baseline and following intravenous fructose challenge was evaluated in low (<15 g/d) vs. high (≥15 g/d) fructose consumers. High dietary fructose consumers had slightly lower baseline hepatic ATP levels and a greater absolute change in hepatic α-ATP/Pi ratio (0.08 vs. 0.03, p=0.05) and γ-ATP /Pi ratio following an intravenous fructose challenge (0.03 vs. 0.06, p=0.06). Patients with high UA (≥5.5 mg/dl) showed a lower minimum liver ATP/Pi ratio post-fructose challenge (4.5 vs. 7.0, p = 0.04).
High fructose consumption depletes hepatic ATP and impairs recovery from ATP depletion following an intravenous fructose challenge. Subjects with high UA show a greater nadir in hepatic ATP in response to fructose. Both high dietary fructose intake and elevated UA level may predict more severe hepatic ATP depletion in response to fructose and hence may be risk factors for the development and progression of NAFLD.
Nonalcoholic steatohepatitis; Diabetes mellitus; Obesity; Fructose metabolism; Uric acid; Fructose consumption
Hyperuricemia is associated with obesity and the metabolic syndrome. URAT1 is a urate transporter, and we tested the association of URAT1 transporter gene (SLC22A12) polymorphisms with obesity and the metabolic syndrome in hypertensive subjects.
Patients with essential hypertension (n = 414) from a randomized controlled study were genotyped for SLC22A12 SNPs rs11602903, rs505802 and rs11231825.
In Caucasians, SLC22A12 SNPs were associated with the body mass index (BMI). rs11602903 was associated with BMI (p < 0.0001), waist circumference (p = 0.003), HDL cholesterol (p = 0.018) and the metabolic syndrome (p = 0.033), and accounted for 7% of the variation of BMI in Caucasians. In African Americans, SLC22A12 SNP rs11602903 was not associated with BMI, waist circumference, HDL cholesterol or triglycerides.
The URAT1 gene SLC22A12 polymorphism may play a role in obesity and the metabolic syndrome in Caucasian hypertensive subjects.
Hypertension; Metabolic syndrome; Obesity; SLC22A12 polymorphisms; URAT1; Uric acid
The mechanisms that drive the development of diabetic nephropathy remain undetermined. Only 30–40% of patients with diabetes mellitus develop overt nephropathy, which suggests that other contributing factors besides the diabetic state are required for the progression of diabetic nephropathy. Endothelial dysfunction is associated with human diabetic nephropathy and retinopathy, and advanced diabetic glomerulopathy often exhibits thrombotic microangiopathy, including glomerular capillary microaneurysms and mesangiolysis, which are typical manifestations of endothelial dysfunction in the glomerulus. Likewise, diabetic mice with severe endothelial dysfunction owing to deficiency of endothelial nitric oxide synthase develop progressive nephropathy and retinopathy similar to the advanced lesions observed in humans with diabetes mellitus. Additionally, inhibitors of the renin–angiotensin system fail to be renoprotective in some individuals with diabetic nephropathy (due in part to aldosterone breakthrough) and in some mouse models of the disease. In this Review, we discuss the clinical and experimental evidence that supports a role for endothelial nitric oxide deficiency and subsequent endothelial dysfunction in the progression of diabetic nephropathy and retinopathy. If endothelial dysfunction is the key factor required for diabetic nephropathy, then agents that improve endothelial function or raise intraglomerular nitric oxide level could be beneficial in the treatment of diabetic nephropathy.
It is unclear whether high fructose corn syrup (HFCS), which contains a higher amount of fructose and provides an immediate source of free fructose, induces greater systemic concentrations of fructose as compared to sucrose. It is also unclear whether exposure to higher levels of fructose leads to increased fructose-induced adverse effects. The objective was to prospectively compare the effects of HFCS- versus sucrose-sweetened soft drinks on acute metabolic and hemodynamic effects.
Forty men and women consumed 24 oz of HFCS- or sucrose-sweetened beverages in a randomized crossover design study. Blood and urine samples were collected over 6 hr. Blood pressure, heart rate, fructose, and a variety of other metabolic biomarkers were measured.
Fructose area under the curve and maximum concentration, dose normalized glucose area under the curve and maximum concentration, relative bioavailability of glucose, changes in postprandial concentrations of serum uric acid, and systolic blood pressure maximum levels were higher when HFCS-sweetened beverages were consumed as compared to sucrose-sweetened beverages.
Compared to sucrose, HFCS leads to greater fructose systemic exposure and significantly different acute metabolic effects.
soft drinks; sweetened beverages; adverse metabolic effects; carbohydrate metabolism
Hyperuricemia is an independent risk factor for renal progression in IgA nephropathy (IgAN). However, no study has evaluated the effect of allopurinol on the clinical outcome in hyperuricemic IgAN.
First,a retrospective cohort study of 353 IgAN patients was conducted to explore the relationship between uric acid (UA) and the progression of renal disease over a mean period of 5 years. Then, 40 hyperuricemic IgAN patients were randomized to receive allopurinol (100–300 mg/day) or usual therapy for 6 months. The study outcomes were renal disease progression and/or blood pressure.
Hyperuricemia independently predicted renal survival at 1, 3, and 5 years after adjustment for different baseline estimated glomerular filtration rates. In the randomized controlled trial, allopurinol did not significantly alter renal progression or proteinuria. The antihypertensive drug dosage was reduced in 7 of 9 cases with hypertension in the allopurinol group compared to 0 of 9 cases in the control group (p < 0.01). UA levels correlated with mean arterial pressure in normotensive patients (r = 0.388, p < 0.001).
Hyperuricemia predicts the progression of IgAN independently of baseline estimated glomerular filtration rate. Allopurinol may improve the control of blood pressure. Further studies are required to explore the effects of lowering UA on renal protection in IgAN.
Hyperuricemia; IgA nephropathy; Prognosis; Outcome
Attention-deficit/hyperactivity disorder (ADHD) affects nearly 10% of children in the United States, and the prevalence of this disorder has increased steadily over the past decades. The cause of ADHD is unknown, although recent studies suggest that it may be associated with a disruption in dopamine signaling whereby dopamine D2 receptors are reduced in reward-related brain regions. This same pattern of reduced dopamine-mediated signaling is observed in various reward-deficiency syndromes associated with food or drug addiction, as well as in obesity. While genetic mechanisms are likely contributory to cases of ADHD, the marked frequency of the disorder suggests that other factors are involved in the etiology. In this article, we revisit the hypothesis that excessive sugar intake may have an underlying role in ADHD. We review preclinical and clinical data suggesting overlaps among ADHD, sugar and drug addiction, and obesity. Further, we present the hypothesis that the chronic effects of excessive sugar intake may lead to alterations in mesolimbic dopamine signaling, which could contribute to the symptoms associated with ADHD. We recommend further studies to investigate the possible relationship between chronic sugar intake and ADHD.
ADHD; sucrose; fructose; high-fructose corn syrup; reward-deficiency syndrome; dopamine; D2 receptor; obesity
Hyperuricemia frequently complicates cyclosporine (CsA) therapy. Previous studies have shown that hyperuricemia exacerbates interstitial and vascular lesions in the cyclosporine model. We tested the hypothesis that normalization of uric acid could prevent the development of cyclosporine toxicity.
CsA nephropathy was induced by administering CsA (15 mg/kg/day) for 7 weeks to rats on a low salt diet (CsA group). The effect of preventing hyperuricemia was determined by concomitant treatment with a xanthine oxidase inhibitor, allopurinol (CsAALP), or with a uricosuric, benzbromarone (CsABENZ), in drinking water. Control groups included vehicle-treated rats.
CsA-treated rats developed mild hyperuricemia with arteriolar hyalinosis, tubular atrophy, striped interstitial fibrosis, increased cell proliferation and decreased VEGF expression. Treatment with allopurinol or benzbromarone limited renal disease, with reduced interstitial fibrosis, cell proliferation, macrophage infiltration, osteopontin expression and arteriolar hyalinosis, in association with restoration of VEGF expression. Both drugs provided comparable protection.
An increase in uric acid exacerbates CsA nephropathy in the rat. Concomitant treatment with allopurinol or benzbromarone reduced the severity of renal disease. The similar protection observed with both drugs suggests that the effect is associated more with lowering uric acid levels than the antioxidant effect of allopurinol.
Cyclosporine; Uric acid; Arteriolar hyalinosis; Tubulointerstitial fibrosis
Cardiovascular disease (CVD) is increasingly recognised as a complication of childhood chronic kidney disease (CKD) even in the absence of diabetes and hypertension. We hypothesized that an alteration in angiopoietin-1 and -2, growth factors which regulate endothelial and vascular function could be involved. We report that the endothelial survival factor, angiopoietin-1 is low in children with pre-dialysis CKD whereas the pro-inflammatory angiopoietin-2 is elevated in children on dialysis. In dialysis patients, angiopoietin-2 positively correlated with time on dialysis, systolic blood pressure, and carotid artery intima media thickness. Elevated angiopoietin-2 levels in dialysis versus pre-dialysis CKD patients were also associated with an anti-angiogenic (high soluble VEGFR-1 and low VEGF-A) and pro-inflammatory (high urate, E-selectin, P-selectin and VCAM-1) milieu. Ang-2 was immunodetected in arterial biopsy samples whilst the expression of VEGF-A was significantly downregulated in dialysis patients. Serum urate correlated with angiopoietin-2 levels in dialysis patients and addition of uric acid was able to induce rapid release of angiopoietin-2 from cultured endothelial cells. Thus, angiopoietin-2 is a marker for cardiovascular disease in children on chronic dialysis and may act as an anti-angiogenic and pro-inflammatory effector in this context. The possibility that the release of angiopoietin-2 from endothelia is mediated by urate should be explored further.
Fructose has been strongly linked with hypertension, hyperuricemia and inflammation in experimental models and humans. However, the effect of low-fructose diet on inflammation, hyperuricemia and the progression of renal disease has not yet been evaluated in patients with chronic kidney disease (CKD).
Twenty-eight patients (age 59 ± 15 years, 17 males/11 females) with Stages 2 and 3 CKD were switched from a regular (basal) (60.0 g/24 h) to a low (12.0 g/24 h) fructose diet for 6 weeks, followed by a resumption of their regular diet for another 6 weeks. Diet was monitored by a dietician. At the baseline, low- and regular-fructose diet ambulatory blood pressure (BP) was measured and blood sampled for renal function (creatinine), inflammatory markers, fasting glucose and insulin and serum uric acid. Twenty-four-hour urine collections were also obtained for creatinine, uric acid, monocyte chemotatic protein-1, transforming growth factor-beta and N-acetyl-beta-D-glucosaminidase.
The low-fructose diet tended to improve BP for the whole group (n = 28), while significant reduction of BP was only seen in dippers (n = 20) but not in non-dippers (n = 8). No effects on estimated glomerular filtration rate (eGFR) or proteinuria were observed. Serum uric acid was lowered non-significantly with low-fructose diet (7.1 ± 1.3 versus 6.6 ± 1.0 mg/dL, P < 0.1), whereas a significant decrease in fasting serum insulin was observed (11.2 ± 6.1 versus 8.2 ± 2.9 mIU/mL, P < 0.05) and the reduction persisted after return to the regular diet. A slight but not significant reduction in urinary uric acid and fractional uric acid excretion was observed while the patients were on the low fructose diet. The low-fructose diet also decreased high sensitivity C-reactive protein (hsCRP) (4.3 ± 4.9 versus 3.3 ± 4.5 mg/L; P < 0.01) and soluble intercellular adhesion molecule (sICAM) (250.9 ± 59.4 versus 227 ± 50.5 ng/mL; P < 0.05). The hsCRP returned to baseline with resumption of the regular diet, whereas the reduction in sICAM persisted.
Low-fructose diet in subjects with CKD can reduce inflammation with some potential benefits on BP. This pilot study needs to be confirmed by a larger clinical trial to determine the long-term benefit of a low-fructose diet compared to other diets in subjects with CKD.
blood pressure; chronic kidney disease; inflammation; low-fructose diet; uric acid
This article reviews the role of immune competent cells infiltrating the kidney and their association with oxidative stress and renal angiotensin activity in the development of salt-sensitive hypertension.We discuss the alteration of the pressure-natriuresis relationship resulting from renal inflammation and its improvement resulting from immunosuppressive treatment.The potential role of T cell-driven reactivity in sustaining the renal inflammation is examined in the light of accumulating evidence of autoimmune mechanisms in experimental and clinical hypertension.
Heat Shock proteins; lymphocytes; macrophages; pressure natriuresis; T cells
Fructose induces metabolic syndrome in rats but studies have been criticized for using high concentrations of fructose that are not physiologic, for using only pure fructose, and for not controlling for energy intake. We tested the hypothesis that a 40% sucrose diet (containing 20% fructose) might induce features of metabolic syndrome in male breeder rats independent of excess energy intake.
Male Sprague-Dawley breeder rats were pair fed 40% sucrose or isocaloric starch diet for 4 months and evaluated for metabolic syndrome and diabetes. In vitro studies were performed in rat insulinoma cells (RIN-m5F) exposed to uric acid and markers of inflammation were assessed.
Rats fed a 40% sucrose diet developed accelerated features of metabolic syndrome with upregulation of fructose-dependent transporter Glut 5 and fructokinase. Fatty liver and low grade pancreatic inflammation also occurred. Uric acid was found to stimulate inflammatory mediators and oxidative stress in islet cells in vitro.
Sucrose, at concentrations ingested by a subset of Americans, can accelerate metabolic syndrome, fatty liver and type 2 diabetes in male breeder rats, and the effects are independent of excess energy intake.
Sucrose; Fructose; Insulin Resistance; Uric acid; Nonalcoholic Fatty Liver Disease
All humans are uricase knockouts; we lost the uricase gene due to a mutation that occurred in the mid Miocene approximately 15 million years ago. The consequence of being a uricase knockout is that we have higher serum uric acid levels that are less regulatable and can be readily influenced by diet. This increases our risk for gout and kidney stones, but there is also increasing evidence that uric acid increases our risk for hypertension, kidney disease, obesity and diabetes. This raises the question of why this mutation occurred. In this paper we review current hypotheses. We suggest that uric acid is a danger and survival signal carried over from the RNA world. The mutation of uricase that occurred during the food shortage and global cooling that occurred in the Miocene resulted in a survival advantage for early primates, particularly in Europe. Today, the loss of uricase functions as a thrifty gene, increasing our risk for obesity and cardiorenal disease.
uricase; fructose; thrifty gene; anti-oxidant; oxidant; RNA world
Two risk factors for the development and progression of cancers that are amenable to life style modification are chronic inflammation and the metabolic syndrome. This review proposes two new targets that may mechanistically integrate inflammation and metabolic syndrome, have been largely ignored, and are known to be druggable. Recent evidence has demonstrated that elevated serum uric acid (hyperuricemia) is associated with excess cancer risk, recurrence, and mortality. Although uric acid (UA) can function as a systemic antioxidant, its pro-inflammatory properties have been postulated to play an important role in the pathogenesis of cancer. Furthermore, obesity, Type 2 Diabetes Mellitus (T2DM), and the metabolic syndrome (MetS) are also associated with excess cancer, chronic inflammation, and with hyperuricemia, suggesting that UA may represent an important link between these disorders and the development of cancer. While pharmacological modulation of hyperuricemia could in principal augment anti-cancer therapeutic strategies, some cancer cells express low intracellular levels of the enzyme Xanthine Oxidoreductase (XOR) that are associated with increased cancer aggressiveness and poor clinical outcome. Thus, systemic pharmacological inhibition of XOR may worsen clinical outcome, and specific strategies that target serum uric acid (SUA) without inhibiting tumor cell XOR may create new therapeutic opportunities for cancer associated with hyperuricemia. This review will summarize the evidence that elevated SUA may be a true risk factor for cancer incidence and mortality, and mechanisms by which UA may contribute to cancer pathogenesis will be discussed in the hope that these will identify new opportunities for cancer management.
Cancer; Obesity; T2DM; Metabolic syndrome; Uric acid
Elevated serum uric acid has been associated with cognitive dysfunction and vascular cognitive impairment in the elderly. Serum uric acid is also commonly elevated in chronic kidney disease (CKD), but its relationship with cognitive function in these patients has not been addressed.
Subjects with CKD (defined as eGFR <60/ml/min/1.73 m2) were evaluated for cognitive dysfunction using the validated Standardized Mini-Mental State Examination (SMMSE). Individuals with dementia, depression or other psychiatric disorders were excluded, as were subjects on uric acid-lowering therapy or with serious illnesses such as severe anemia or active or ongoing cardiovascular or cerebrovascular disease.
247 subjects were enrolled. SMMSE scores showed stepwise deterioration with increasing quartile of serum uric acid (26.4; 26.1; 25.5; 25.3, score range 20–30, p = 0.019). Post-hoc analysis demonstrated that there was no linear trend and only groups 1 and 4 were different with respect to SMMSE scores (p = 0.025). Stepwise multivariate linear regression revealed that age, educational status, presence of cerebrovascular disease, and serum uric acid were independently related to SMMSE scores.
Serum uric acid levels are independently and inversely associated with mild cognitive dysfunction in subjects with CKD.
Cognitive function; Chronic kidney disease; Uric acid
Uric acid, despite being a major antioxidant in the human plasma, both correlates and predicts development of obesity, hypertension, and cardiovascular disease, conditions associated with oxidative stress. While one explanation for this paradox could be that a rise in uric acid represents an attempted protective response by the host, we review the evidence that uric acid may function either as an antioxidant (primarily in plasma) or pro-oxidant (primarily within the cell). We suggest that it is the pro-oxidative effects of uric acid that occur in cardiovascular disease and may have a contributory role in the pathogenesis of these conditions.
Uric acid; redox homeostasis; metabolic syndrome; cardiovascular disease
An elevated serum uric acid level is strongly associated with endothelial dysfunction and inflammation, both of which are common in chronic kidney disease (CKD). We hypothesized that endothelial dysfunction in subjects with CKD would correlate with uric acid levels.
Materials and Methods
We evaluated the association between serum uric acid level and ultrasonographic flow-mediated dilatation (FMD) in 263 of 486 patients with recently diagnosed CKD (stage 3–5) (48% male, age 52 ± 12 years). To minimize confounding, 233 patients were excluded because they were diabetic, had established cardiovascular complications or were taking drugs (renin-angiotensin system blockers, statins) interfering with vascular function.
Serum uric acid level was significantly increased in all stages of CKD and strongly correlated with estimated glomerular filtration rate (eGFR-MDRD); FMD was inversely associated with serum uric acid (r = −0.49, p < 0.001). The association of serum uric acid with FMD remained after adjustment for age, gender, smoking, LDL cholesterol, eGFR, high-sensitivity C-reactive protein, systolic blood pressure, proteinuria, and homeostatic model assessment index (β = −0.27, p < 0.001).
Increased serum uric acid is an independent predictor of endothelial dysfunction in subjects with CKD.
Chronic kidney disease; Uric acid; Endothelial dysfunction
Hyperuricemia is strongly associated with obesity and metabolic syndrome and can predict visceral obesity and insulin resistance. Previously, we showed that soluble uric acid directly stimulated the redox-dependent proinflammatory signaling in adipocytes. In this study we demonstrate the role of hyperuricemia in the production of key adipokines.
RESEARCH DESIGN AND METHODS
We used mouse 3T3-L1 adipocytes, human primary adipocytes, and a mouse model of metabolic syndrome and hyperuricemia.
Uric acid induced in vitro an increase in the production (mRNA and secreted protein) of monocyte chemotactic protein-1 (MCP-1), an adipokine playing an essential role in inducing the proinflammatory state in adipocytes in obesity. In addition, uric acid caused a decrease in the production of adiponectin, an adipocyte-specific insulin sensitizer and anti-inflammatory agent. Uric acid–induced increase in MCP-1 production was blocked by scavenging superoxide or by inhibiting NADPH oxidase and by stimulating peroxisome-proliferator–activated receptor-γ with rosiglitazone. Downregulation of the adiponectin production was prevented by rosiglitazone but not by antioxidants. In obese mice with metabolic syndrome, we observed hyperuricemia. Lowering uric acid in these mice by inhibiting xanthine oxidoreductase with allopurinol could improve the proinflammatory endocrine imbalance in the adipose tissue by reducing production of MCP-1 and increasing production of adiponectin. In addition, lowering uric acid in obese mice decreased macrophage infiltration in the adipose tissue and reduced insulin resistance.
Hyperuricemia might be partially responsible for the proinflammatory endocrine imbalance in the adipose tissue, which is an underlying mechanism of the low-grade inflammation and insulin resistance in subjects with the metabolic syndrome.
Since its first identification in the late 1800s, a variety of etiologies for essential hypertension have been proposed. In this paper we review the primary proposed hypotheses in the context of both the time in which they were proposed as well as the subsequent studies performed over the years. From these various insights, we propose a current paradigm to explain the renal mechanisms underlying the hypertension epidemic today. Specifically, we propose that hypertension is initiated by agents that cause systemic and intrarenal vasoconstriction. Over time intrarenal injury develops with microvascular disease, interstitial T cell and macrophage recruitment with the induction of an autoimmune response, with local angiotensin II formation and oxidant generation. These changes maintain intrarenal vasoconstriction and hypoxia with a change in local vasoconstrictor-vasodilator balance favoring sodium retention. Both genetic and congenital (nephron number) mechanisms have profound influence on this pathway. As blood pressure rises, renal ischemia is ameliorated and sodium balance restored completely (in salt-resistant) or partially (in salt-sensitive) hypertension, but at the expense of a rightward shift in the pressure natriuresis curve and persistent hypertension.
Fructose; hypertension; inflammation; microvascular disease; oxidative stress; salt; uric acid
Naphthenic acids (NAs) occur naturally in oil sands and enter the environment through natural and anthropogenic processes. NAs comprise toxic carboxylic acids that are difficult to degrade. Information on NA biodegradation mechanisms is limited, and there are no studies on alkyl branched aromatic alkanoic acid biodegradation, despite their contribution to NA toxicity and recalcitrance. Increased alkyl side chain branching has been proposed to explain NA recalcitrance. Using soil enrichments, we examined the biodegradation of four aromatic alkanoic acid isomers that differed in alkyl side chain branching: (4′-n-butylphenyl)-4-butanoic acid (n-BPBA, least branched); (4′-iso-butylphenyl)-4-butanoic acid (iso-BPBA); (4′-sec-butylphenyl)-4-butanoic acid (sec-BPBA) and (4′-tert-butylphenyl)-4-butanoic acid (tert-BPBA, most branched). n-BPBA was completely metabolized within 49 days. Mass spectral analysis confirmed that the more branched isomers iso-, sec- and tert-BPBA were transformed to their butylphenylethanoic acid (BPEA) counterparts at 14 days. The BPEA metabolites were generally less toxic than BPBAs as determined by Microtox assay. n-BPEA was further transformed to a diacid, showing that carboxylation of the alkyl side chain occurred. In each case, biodegradation of the carboxyl side chain proceeded through beta-oxidation, which depended on the degree of alkyl side chain branching, and a BPBA degradation pathway is proposed. Comparison of 16S rRNA gene sequences at days 0 and 49 showed an increase and high abundance at day 49 of Pseudomonas (sec-BPBA), Burkholderia (n-, iso-, tert-BPBA) and Sphingomonas (n-, sec-BPBA).
beta-oxidation; butyl phenylbutyric acid biodegradation; naphthenic acids; oil sands; bioremediation
Humans have relatively low plasma ascorbate levels and high serum uric acid levels compared to most mammals due to the presence of genetic mutations in L-gulonolactone oxidase and uricase, respectively. We review the major hypotheses for why these mutations may have occurred. In particular, we suggest that both mutations may have provided a survival advantage to early primates by helping maintain blood pressure during periods of dietary change and environmental stress. We further propose that these mutations have the inadvertent disadvantage of increasing our risk for hypertension and cardiovascular disease in today’s society characterized by Western diet and increasing physical inactivity. Finally, we suggest that a “planetary biology” approach in which genetic changes are analyzed in relation to their biologic action and historical context may provide the ideal approach towards understanding the biology of the past, present and future.
To examine uric acid (UA) as a possible predictor of the progression of coronary artery calcification (CAC) using data from the prospective Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study.
RESEARCH DESIGN AND METHODS
CAC was measured by electron beam tomography at the baseline and at a follow-up 6.0 ± 0.5 years later. The study population included 443 participants with type 1 diabetes and 526 control subjects who were free of diagnosed coronary artery disease at baseline. The presence of renal disease was defined by the presence of albuminuria and/or low glomerular filtration rate.
In subjects without renal disease, serum UA predicted CAC progression (odds ratio 1.30 [95% CI 1.07–1.58], P = 0.007) independent of conventional cardiovascular risk factors including diabetes and the presence of metabolic syndrome.
Serum UA levels predict the progression of coronary atherosclerosis and may be useful in identifying who is at risk for vascular disease in the absence of significant chronic kidney disease.
Thrombotic microangiopathy (TMA) refers to a clinical and pathological syndrome in which endothelial injury results in the manifestations of thrombocytopenia, microangiopathic hemolytic anemia, and renal injury. A host of etiologies may induce endothelial injury and TMA, including enteric bacterial toxins, deficiency or dysfunction of complement regulatory proteins, deficiency or inhibition of von Willebrand factor cleaving proteases, and factors that inhibit endothelial cell proliferation and turnover. This has led specialists to concentrate on these specific inciting factors in terms of designing treatment and management. However, a key and less recognized factor is the underlying level of endothelial health. Indeed, many subjects with hereditary etiologies may remain disease free for years, and may never develop disease. Others with acute inciting events such as E coli O157 enteritis never manifest TMA. Experimental studies document the importance of specific factors such as endothelial nitric oxide levels in helping to protect animals from TMA. This suggests that one might approach the management of TMA not simply with specific treatments aimed at the underlying hereditary cause or inciting event, but rather also at general measures that may improve overall endothelial health. We propose studies to determine if interventions known to improve endothelial health, such as the administration of ACE inhibitors, statins, vitamin C, allopurinol, or nitric oxide-producing drugs may be able to prevent TMA even in subjects with underlying hereditary conditions that would otherwise predispose them to these diseases.
hemolytic uremic syndrome; nitric oxide; endothelial cell; vascular endothelial growth factor