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Guanine was investigated as a potential green corrosion inhibitor to API 5L X65 carbon steel in HCl 0.1 mol.dm-3 solution, at pH = 2.0, under hydrodynamic conditions using electrochemical, weight loss and Raman spectroscopy experiments. Cyclic voltammetry and potentiodynamic polarization curves suggested that Guanine does not change the metal/solution interface appreciably and weight loss tests confirmed the low inhibition efficiency (IE) of Guanine in protecting the X65 steel in this corrosive medium. An IE = 22% was determined after 48 h of exposure, a value lower than that reported in the literature on the mild steel/Guanine/HCl system. Raman spectroscopy was employed to gain insight on the nature of the steel/Guanine interaction and the results pointed out to a weak physisorption of the molecule, thus explaining the very low IE values obtained.

Sodium‐glucose co-transporter 2 (SGLT2) inhibitors have recently emerg ed as an effective means to protect kidney function in people with type 2 diabetes and chronic kidney disease (CKD). In this review, we explore the role of SGLT2 inhibition in these individuals. SGLT2 inhibitors specifically act to inhibit sodium and glucose reabsorption in the early proximal tubule of the renal nephron. Although originally developed as glucose-lowering agents through their ability to induce glycosuria, it became apparent in cardiovascular outcome trials that the trajectory of kidney function decline w as significantly slowed and the incidence of serious falls in kidney function was reduced in participants receiving an SGLT2 inhibitor. These observations have recently led to spe cific outcome trials in participants with CKD, including DAPA-CKD, CREDENCE and EMPA-KIDNEY, and real-world studies, like CVD-REAL-3, that have confirmed the observation of kidney benefits in this setting. In response, recent KDIGO Guidelines have recommended the use of SGLT2 inhibitors as first-line therapy in patients with CKD, alongside statins, renin–angiotensin– aldosterone system inhibitors and multifactorial risk factor management as indicated. However, SGLT2 inhibitors remain significantly underutilized in the setting of CKD. Indeed, an inertia paradox exists, with patients with more severe disease less likely to receive an SGLT2 inhibitor. Concerns regarding safety appear unfounded, as acute kidney injury, hyperkalaemia, major acute cardiovascular events and cardiac death in patients with CKD appear to be lower following SGLT2 inhibition. The first-in-clas s indication of dapagliflozin for CKD may begin a new approach to managing kidney disease in type 2 diabetes.

Rationale & Objective: Kidney function progressively declines in most patients with type 2 diabetes (T2DM). Many develop progressive chronic kidney disease (CKD), but some experience a more rapid decline, with a greater risk of kidney failure and cardiovascular disease. In EMPA-REG OUTCOME, empagliflozin was associated with slower kidney disease progression. This post hoc analysis evaluated the effect of empagliflozin (pooled doses) on the prevalence of a “rapid decliner” phenotype, defined by an annual estimated glomerular filtration rate (eGFR) decline of >3 mL/min/1.73 m2. Study Design: This was an exploratory analysis of EMPA-REG OUTCOME, a large randomized, double-blind, placebo-controlled trial in adults with T2DM, established cardiovascular disease and an eGFR of ≥30 mL/min/1.73 m2. Setting & Participants: Analysis was undertaken on 6,967 participants (99.2%) in whom serial eGFR data was available. Interventions: Patients were randomized (1:1:1) to empagliflozin 10 mg, 25 mg, or placebo in addition to standard of care. Outcomes: Annual change in eGFR over the maintenance phase of treatment (week 4 to last value on treatment) was calculated using linear regression models. Logistic regression analysis was used to investigate differences in rapid decline between the treatment groups. Results: Over the study period, a rapid decliner phenotype was observed in 188 (9.5%) participants receiving placebo and 134 (3.4%) receiving empagliflozin. After adjusting for other risk factors, this equated to a two-third reduction in odds (OR, 0.32; 95% CI, 0.25-0.40; P 5 mL/min/1.73 m2/y (empagliflozin vs placebo, 43 [1.1%] vs 44 [2.2%] participants; OR, 0.47; 95% CI, 0.31-0.72; P

Diabetic nephropathy (DN) is a polygenic disorder with few risk variants showing robust replication in large-scale genome-wide association studies. To understand the role of DNA methylation, it is important to have the prevailing genomic view to distinguish key sequence elements that influence gene expression. This is particularly challenging for DN because genome-wide methylation patterns are poorly defined. While methylation is known to alter gene expression, the importance of this causal relationship is obscured by array-based technologies since coverage outside promoter regions is low. To overcome these challenges, we performed methylation sequencing using leukocytes derived from participants of the Finnish Diabetic Nephropathy (FinnDiane) type 1 diabetes (T1D) study (n = 39) that was subsequently replicated in a larger validation cohort (n = 296). Gene body–related regions made up more than 60% of the methylation differences and emphasized the importance of methylation sequencing. We observed differentially methylated genes associated with DN in 3 independent T1D registries originating from Denmark (n = 445), Hong Kong (n = 107), and Thailand (n = 130). Reduced DNA methylation at CTCF and Pol2B sites was tightly connected with DN pathways that include insulin signaling, lipid metabolism, and fibrosis. To define the pathophysiological significance of these population findings, methylation indices were assessed in human renal cells such as podocytes and proximal convoluted tubule cells. The expression of core genes was associated with reduced methylation, elevated CTCF and Pol2B binding, and the activation of insulin-signaling phosphoproteins in hyperglycemic cells. These experimental observations also closely parallel methylation-mediated regulation in human macrophages and vascular endothelial cells.

Abstract We investigated the association between diet and risk of hospitalisation for diabetic ketoacidosis (DKA) or hypoglycaemia in type 1 diabetes. Food records were used to assess dietary intake. Data on DKA and hypoglycaemia hospitalisations, within two years of dietary assessments, were obtained from registries. Analyses were conducted with and without macronutrient substitution. Data were available from 1391 participants, 28 (2.0%) and 55 (4.0%) of whom were hospitalised due to DKA or hypoglycaemia, respectively. In the adjusted model, self-reported alcohol intake was associated with increased (per 10 g: B = 1.463, 95% CI = 1.114–1.922, p = 0.006; per E%: B = 1.113, 95% CI = 1.027–1.206, p = 0.009), and fibre intake with reduced (per g/MJ: B = 0.934, 95% CI = 0.878–0.995, p = 0.034) risk of DKA hospitalisation. Substituting carbohydrates for fats was associated with increased risk for hypoglycaemia hospitalisation (B = 1.361, 95% CI = 1.031–1.795, p = 0.029), while substituting alcohol for carbohydrates (B = 1.644, 95% CI = 1.006–2.685, p = 0.047) or proteins (B = 2.278, 95% CI = 1.038–4.999, p = 0.040) increased the risk for DKA hospitalisation. In conclusion, refraining from alcohol intake is a preventable risk factor for DKA, while higher fibre intake seems rather protective. Increasing carbohydrate intake while decreasing that of fats, is associated with higher hypoglycaemia risk. Whether this is a cause or effect of hypoglycaemia remains to be established.

Circulating levels of soluble ACE2 are increased by diabetes. Although this increase is associated with the presence and severity of cardiovascular disease, the specific role of soluble ACE2 in atherogenesis is unclear. Previous studies suggested that, like circulating ACE, soluble ACE2 plays a limited role in vascular homeostasis. To challenge this hypothesis, we aimed to selectively increase circulating ACE2 and measure its effects on angiotensin II dependent atherogenesis. Firstly, in Ace2/ApoE DKO mice, restoration of circulating ACE2 with recombinant murine soluble (rmACE219-613; 1 mg/kg/alternate day IP) reduced plaque accumulation in the aortic arch, suggesting that the phenotype may be driven as much by loss of soluble ACE2 as the reduction in local ACE2. Secondly, in diabetic ApoE KO mice, where activation of the renin angiotensin system drives accelerated atherosclerosis, rmACE219-613 also reduced plaque accumulation in the aorta after 6 weeks. Thirdly, to ensure consistent long-term delivery of soluble ACE2, an intramuscular injection was used to deliver a DNA minicircle encoding ACE219-613. This strategy efficiently increased circulating soluble ACE2 and reduced atherogenesis and albuminuria in diabetic ApoE KO mice followed for 10 weeks. We propose that soluble ACE2 has independent vasculoprotective effects. Future strategies that increase soluble ACE2 may reduce accelerated atherosclerosis in diabetes and other states in which the renin angiotensin system is upregulated.

One major interest in soil systems ecology is to maintain ecosystem functions. As soil is exposed to disturbances of different spatial configurations, identifying disturbance characteristics that still allow for maintaining functions is crucial. In macro-ecology, the influence of fragmentation on ecosystems is continuously debated, especially in terms of extinction thresholds on the landscape scale. Whether this influence is positive or negative depends on the considered type of fragmentation: habitat fragmentation often promotes population extinction, whereas spatially fragmented disturbances reduce extinction probability in many cases. In this study, we make use of these concepts to analyze how spatial disturbance characteristics determine functional resilience on the microscale. We used the numerical model eColony considering bacterial growth, substrate consumption, and dispersal for analyzing the dynamic response of biodegradation as an exemplary important microbial ecosystem function to disturbance events. We systematically varied the frequency of the disturbance events, and the size and fragmentation of the disturbed area. We found that the influence of the disturbance size on functional recovery depends on the spatial fragmentation of the disturbance, indicating that to some extent disturbance size can be compensated for by the spatial configuration of the disturbed area. In general, biodegradation performance decreases as the disturbed area increases in size, and becomes more contiguous. However, if a disturbance is highly fragmented, an increase in disturbance size has no influence on biodegradation performance unless the disturbance is critically large. In this case, the functional performance decreases dramatically. Under recurrent disturbances, this critical disturbance size is shifted toward lower values depending on the disturbance frequency. Our results indicate the importance of spatial disturbance characteristics for functional resilience of soil microbial ecosystems. Critical values for disturbance size and degree of fragmentation emerge from an interplay between both characteristics. Consequently, these characteristics which are widely discussed on the landscape scale need to be equally considered on smaller scales when assessing functional resilience of soil ecosystems.

Background 8‐Oxo‐2′‐deoxyguanosine (8‐oxo‐2′‐dG) is a biomarker of oxidative DNA damage that is associated with cardiovascular disease and premature mortality in the general population. Although oxidative stress has a proven role in cardiovascular complications in diabetes mellitus, evidence for a relationship between plasma 8‐oxo‐2′‐dG and major cardiovascular outcomes in diabetes mellitus is weak. Methods and Results A case‐cohort study was performed in 3766 participants with prevalent diabetes mellitus in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial (ClinicalTrials.gov number NCT00145925). The hazard ratios for mortality and major acute cardiovascular events were derived using Cox regression models. During a median of 5 years of follow‐up, 695 (18.4%) participants in this enriched cohort died (including 354 deaths from cardiovascular disease). Individuals with higher levels of 8‐oxo‐2′‐dG were more likely to die. After adjusting for cardiovascular disease risk factors, the hazard ratio for a 1‐SD increase in plasma 8‐oxo‐2′‐dG was 1.10 (95% confidence interval, 1.01–1.20; P=0.03). This was driven by an independent association between plasma 8‐oxo‐2′‐dG and cardiovascular death (hazard ratio, 1.23; 95% confidence interval, 1.10–1.37 [P

Heart failure is a leading cause for hospitalisation and for readmission, especially in patients over the age of 65. Diabetes is an increasingly common companion to heart failure. The presence of diabetes and its associated comorbidity increases the risk of adverse outcomes and premature mortality in patients with heart failure. In particular, patients with diabetes are more likely to be readmitted to hospital soon after discharge. This may partly reflect the greater severity of heart disease in these patients. In addition, agents that reduce the chances of readmission such as β-blockers, renin-angiotensin-aldosterone system blockers, and mineralocorticoid receptor antagonists are underutilised because of the perceived increased risks of adverse drug reactions and other limitations. In some cases, readmission to hospital is precipitated by acute decompensation of heart failure (re-exacerbation) leading to pulmonary congestion and/or refractory oedema. However, it appears that for most of the patients admitted and then discharged with a primary diagnosis of heart failure, most readmissions are not due to heart failure, but rather due to comorbidity including arrhythmia, infection, adverse drug reactions, and renal impairment/reduced hydration. All of these are more common in patients who also have diabetes, and all may be partly preventable. The many different reasons for readmission underline the critical value of multidisciplinary comprehensive care in patients admitted with heart failure, especially those with diabetes. A number of new strategies are also being developed to address this area of need, including the use of SGLT2 inhibitors, novel nonsteroidal mineralocorticoid antagonists, and neprilysin inhibitors.

Semi-arid ecosystems made up of patterned vegetation, for instance, are thought to be highly sensitive. This highlights the importance of understanding the dynamics of the formation of vegetation patterns. The most renowned mathematical model describing such pattern formation consists of two partial differential equations and is often referred to as the Klausmeier model. This paper provides analytical and numerical investigations regarding the influence of different parameters, including the so-far not contemplated evaporation, on the long-term model results. Another focus is set on the influence of different initial conditions and on environmental noise, which has been added to the model. It is shown that patterning is beneficial for semi-arid ecosystems, that is, vegetation is present for a broader parameter range. Both parameter variability and environmental noise have only minor impacts on the model results. Increasing mortality has a high, nonlinear impact underlining the importance of further studies in order to gain a sufficient understanding allowing for suitable management strategies of this natural phenomenon.

Diabetes mellitus was originally conceived as a renal disorder. In the last decade, however, there has been renewed interest in role of the kidney in the development and maintenance of high glucose levels. This has led to the development of novel agents to inhibit sodium glucose transporter-2 (SGLT 2 ) as a means to better control glucose levels and at the same time augment calorie wasting and lower insulin, blood pressure and uric acid levels. Such actions, indirectly, may also have benefits for the prevention of diabetic complications including renal disease. However, there are also data to support the potential for direct renoprotective actions arising from inhibition of SGLT 2 , including actions to attenuate diabetes-associated hyperfiltration and tubular hypertrophy, as well as reduce the tubular toxicity of glucose. Some studies have demonstrated significant reductions in albumin excretion in various experimental models, independent of its effects on blood pressure or glucose control. Although promising, such actions remain to be established by comprehensive clinical trials with a renal focus, many of which are currently in progress. This article reviews the clinical and experimental data pertaining to the renal effects of SGLT 2 inhibition with a particular focus on dapaglifozin.

It has been hypothesized that a reduced nephron endowment exacerbates the hypertensive and renal effects of obesity. We therefore examined the impact of diet-induced obesity on renal structure and function, and arterial pressure in a genetic model of reduced nephron endowment, the GDNF Heterozygous (HET) mouse. 6 wk-old male GDNF WT and HET mice were placed on control or high fat (HFF) diet for 20 weeks. 24 hr arterial pressure, heart rate and activity (radiotelemetry), creatinine clearance and albumin excretion were measured, and kidneys collected (histopathology, collagen content). Bodyweights of HFF WT (50.6 ± 1.2 g) and HET (48.8 ± 1.4 g) mice were ∼14 g greater than control mice (37.3 ± 1.3 g, 36.4 ± 1.1 g respectively; Pdiet

Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPAR𝛼 agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPAR𝛾 agonists, and more recently dual PPAR𝛼/𝛾 coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPAR𝛾 receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease.

IntroductionBlockade of the renin-angiotensin aldosterone system (RAAS) is one of the most prescribed treatments in all of medicine. The pleiotropic benefits of RAAS blockade on inflammation (1-3), atherogenesis (4, 5), [...], Activation of the type 1 angiotensin II receptor ([AT.sub.1]) triggers proinflammatory signaling through pathways independent of classical Gq signaling that regulate vascular homeostasis. Here, we report that the [AT.sub.1] receptor preformed a heteromeric complex with the receptor for advanced glycation endproducts (RAGE). Activation of the [AT.sub.1] receptor by angiotensin II (Ang II) triggered transactivation of the cytosolic tail of RAGE and NF-[kappa]B-driven proinflammatory gene expression independently of the liberation of RAGE ligands or the ligand-binding ectodomain of RAGE. The importance of this transactivation pathway was demonstrated by our finding that adverse proinflammatory signaling events induced by [AT.sub.1] receptor activation were attenuated when RAGE was deleted or transactivation of its cytosolic tail was inhibited. At the same time, classical homeostatic Gq signaling pathways were unaffected by RAGE deletion or inhibition. These data position RAGE transactivation by the [AT.sub.1] receptor as a target for vasculoprotective interventions. As proof of concept, we showed that treatment with the mutant RAGE peptide S391A-[RAGE.sub.362-404] was able to inhibit transactivation of RAGE and attenuate Ang II-dependent inflammation and atherogenesis. Furthermore, treatment with WT [RAGE.sub.362-404] restored Ang II-dependent atherogenesis in Ager/Apoe-KO mice, without restoring ligand-mediated signaling via RAGE, suggesting that the major effector of RAGE activation was its transactivation.