Renal Denervation: A Potential Novel Treatment for Type 2 Diabetes Mellitus?

Type 2 diabetes mellitus (T2DM) is a group of metabolic diseases of multiple etiologies. Although great progress has been made, researchers are still working on the pathogenesis of T2DM and how to best use the treatments available. Aside from several novel pharmacological approaches, catheter-based sympathetic renal denervation (RDN) has gained a significant role in resistant hypertension, as well as improvements in glycemic control in T2DM.In this article, we will summarize herein the role sympathetic activation plays in the progression of T2DM and review the recent clinical RDN experience in glucose metabolism.We performed systematic review in online databases, including PubMed, EmBase, and Web of Science, from inception until 2015.Studies were included if a statistical relationship was investigated between RDN and T2DM.The quality of each included study was assessed by Newcastle–Ottawa scale score. To synthesize these studies, a random-effects model or a fixed-effects model was applied as appropriate. Then, we calculated heterogeneity, performed sensitivity analysis, tested publication bias, and did meta-regression analysis. Finally, we identified 4 eligible articles.In most studies, RDN achieved via novel catheter-based approach using radiofrequency energy has gained a significant role in resistant hypertension, as well as improvements in glycemic control in T2DM. But the DREAMS-Study showed that RDN did not change median insulin sensitivity nor systemic sympathetic activity.Firstly, the current published studies lacked a proper control group, along with the sample capacity was small. Also, data obtained in the subgroups of diabetic patients were not separately analyzed and the follow-up period was very short. In addition, a reduction in blood pressure accounts for the improvements in glucose metabolism and insulin resistance cannot be excluded.If the favorable result of better glucose metabolism is confirmed in large-scale, randomized studies, RDN may emerge as a novel therapeutic option for patients with T2DM.     

Lysophospholipid Receptors,as Novel Conditional Danger Receptors and Homeostatic Receptors Modulate Inflammation—Novel Paradigm and Therapeutic Potential

There are limitations in the current classification of danger-associated molecular patterns (DAMP) receptors. To overcome these limitations, we propose a new paradigm by using endogenous metabolites lysophospholipids (LPLs) as a prototype. By utilizing a data mining method we pioneered, we made the following findings: (1) endogenous metabolites such as LPLs at basal level have physiological functions; (2) under sterile inflammation, expression of some LPLs is elevated. These LPLs act as conditional DAMPs or anti-inflammatory homeostasis-associated molecular pattern molecules (HAMPs) for regulating the progression of inflammation or inhibition of inflammation, respectively; (3) receptors for conditional DAMPs and HAMPs are differentially expressed in human and mouse tissues; and (4) complex signaling mechanism exists between pro-inflammatory mediators and classical DAMPs that regulate the expression of conditional DAMPs and HAMPs. This novel insight will facilitate identification of novel conditional DAMPs and HAMPs, thus promote development of new therapeutic targets to treat inflammatory disorders.     

Biomarkers of β-Cell Stress and Death in Type 1 Diabetes

The hallmark of type 1 diabetes (T1D) is a decline in functional β-cell mass arising as a result of autoimmunity. Immunomodulatory interventions at disease onset have resulted in partial stabilization of β-cell function, but full recovery of insulin secretion has remained elusive. Revised efforts have focused on disease prevention through interventions administered at earlier disease stages. To support this paradigm, there is a parallel effort ongoing to identify circulating biomarkers that have the potential to identify stress and death of the islet β-cells. Whereas no definitive biomarker(s) have been fully validated, several approaches hold promise that T1D can be reliably identified in the pre-symptomatic phase, such that either β-cell preservation or immunomodulatory agents might be employed in at-risk populations. This review summarizes the most promising protein- and nucleic acid-based biomarkers discovered to date and reviews the context in which they have been studied.     

Effects of the Thiazolidinedione Medications on Micro- and Macrovascular Complications in Patients with Diabetes—Update 2008

Introduction

The thiazolidinedione (TZD) drugs, including pioglitazone (Actos®) and rosiglitazone (Avandia®), are commonly prescribed in patients with type 2 diabetes mellitus (T2DM), largely due to their favorable effects on hyperglycemia, insulin sensitivity, and cardiometabolic profile. However, the data are sparse assessing the effects of TZDs on micro- and macrovascular disease risk.

Discussion

Although no studies have been published on microvascular clinical outcomes, both TZDs significantly reduce the urine albumin-to-creatinine ratio. TZDs have consistently been associated with favorable effects on atherosclerosis and cardiovascular disease (CVD) risk. Only one study has been published to date specifically designed to assess the effects of a TZD (pioglitazone) on macrovascular outcomes, the PROactive trial. In this trial, pioglitazone versus placebo was associated with a non-significant 10% reduction in the combined primary endpoint of mortality, coronary and peripheral vascular events, and revascularizations. No individual trial has been published specifically assessing the CVD effects of rosiglitazone, but several meta-analyses and a published interim report from an ongoing trial (RECORD) point to safety concerns regarding rosiglitazone use and the risk of myocardial infarctions (MI), leading to amplified warnings in the product labeling for rosiglitazone to reflect these concerns.

Conclusion

All published trials and meta-analyses of TZDs have consistently shown increased risk of heart failure (HF) with both TZDs, though the actual placebo-subtracted incidence of HF is low (<0.5% per year). The initiation of either TZD is contraindicated in patients with NHYA class III or IV HF, and cautions exist for their use in any patient with heart failure. Much uncertainty remains regarding the aggregate CVD effects of the TZDs, and several trials are presently underway to further address these issues.     

Emerging Roles of Viroporins Encoded by DNA Viruses: Novel Targets for Antivirals?

Studies have highlighted the essential nature of a group of small, highly hydrophobic, membrane embedded, channel-forming proteins in the life cycles of a growing number of RNA viruses. These viroporins mediate the flow of ions and a range of solutes across cellular membranes and are necessary for manipulating a myriad of host processes. As such they contribute to all stages of the virus life cycle. Recent discoveries have identified proteins encoded by the small DNA tumor viruses that display a number of viroporin like properties. This review article summarizes the recent developments in our understanding of these novel viroporins; describes their roles in the virus life cycles and in pathogenesis and speculates on their potential as targets for anti-viral therapeutic intervention.     

Recombinant Platelet-Activating Factor–Acetylhydrolase Attenuates Paracetamol-Induced Liver Oxidative Stress,Injury, and Regeneration

The aim of this study was to investigate the effects of platelet-activating factor (PAF) inactivator, recombinant PAF-acetylhydrolase (rPAF-AH), on post–paracetamol treatment functional outcome of the liver in the rat. Fifty male Wistar rats were divided into two groups: the control group received a toxic dose of paracetamol (3.5 g/kg body weight [BW]) by gastric tube and the rPAF-AH-treated group received the same dose of paracetamol followed by a dose of rPAF-AH (10 mg/kg BW) intraperitoneally. The animals were sacrificed at time points of 56, 66, 72, 84, and 96 hr after paracetamol treatment. Hepatic injury was evaluated by determination of AST, ALT, and ALP activities and degree of necrosis and apoptosis. Liver regeneration was estimated by [³H]thymidine incorporation into hepatic DNA, liver thymidine kinase activity, and hepatocyte mitotic index. Hepatic levels of malondialdehyde (MDA) and serum cholesterol/high-density lipoprotein cholesterol fraction were also measured as parameters of oxidant–antioxidant balance. The positive effects of rPAF-AH were expressed by (1) reduction of oxidative stress, (2) large decrease in hepatic injury, and (3) diminution of regenerating activity. These results indicate that the use of PAF inactivator enhances the liver’s recovery from paracetamol intoxication and attenuates the severity of experimental liver injury, providing important means of improving liver function following paracetamol intoxication.     

Hepcidin—A Potential Novel Biomarker for Iron Status in Chronic Kidney Disease

Background and objectives: Hepcidin is a key regulator of iron homeostasis, but its study in the setting of chronic kidney disease (CKD) has been hampered by the lack of validated serum assays.Design, setting, participants, & measurements: This study reports the first measurements of bioactive serum hepcidin using a novel competitive ELISA in 48 pediatric (PCKD2–4) and 32 adult (ACKD2–4) patients with stages 2 to 4 CKD along with 26 pediatric patients with stage 5 CKD (PCKD5D) on peritoneal dialysis.Results: When compared with their respective controls (pediatric median = 25.3 ng/ml, adult = 72.9 ng/ml), hepcidin was significantly increased in PCKD2–4 (127.3 ng/ml), ACKD2–4 (269.9 ng/ml), and PCKD5D (652.4 ng/ml). Multivariate regression analysis was used to assess the relationship between hepcidin and indicators of anemia, iron status, inflammation, and renal function. In PCKD2–4 (R² = 0.57), only ferritin correlated with hepcidin. In ACKD2–4 (R² = 0.78), ferritin and soluble transferrin receptor were associated with hepcidin, whereas GFR was inversely correlated. In PCKD5D (R² = 0.52), percent iron saturation and ferritin were predictors of hepcidin. In a multivariate analysis that incorporated all three groups (R² = 0.6), hepcidin was predicted by ferritin, C-reactive protein, and whether the patient had stage 5D versus stages 2 to 4 CKD.Conclusions: These findings suggest that increased hepcidin across the spectrum of CKD may contribute to abnormal iron regulation and erythropoiesis and may be a novel biomarker of iron status and erythropoietin resistance.Recombinant erythropoietin (rhEPO) has transformed anemia therapy in patients with chronic kidney disease (CKD). However, rhEPO resistance, often associated with iron deficiency and inflammation, remains a challenging problem (1–4). Current available iron indices do not reliably identify iron-restricted erythropoiesis, often a sequela of inflammation, or those patients who would likely benefit from parenteral iron therapy (5–7). To address these issues, it is crucial to understand the molecular mechanisms that link inflammation, iron balance, and erythropoiesis.Hepcidin, an acute phase reactant protein produced in the liver, is a recently discovered key regulator of iron homeostasis. Hepcidin inhibits intestinal iron absorption and iron release from macrophages and hepatocytes (8). Because hepcidin production is increased by inflammation, and high hepcidin concentrations limit iron availability for erythropoiesis, hepcidin likely plays a major role in the anemia of inflammation and rhEPO resistance.Due to the previous absence of an accurate serum assay, most studies of hepcidin in humans have been performed using a urinary assay. Because such an assay may not reliably reflect serum hepcidin levels in patients with CKD, previous studies have instead attempted to measure the serum levels of prohepcidin, the peptide precursor of hepcidin (9–11). However, these studies have been difficult to interpret because the relationship between prohepcidin, hepcidin, and iron parameters remains unclear (12–16). Mass spectrometry is capable of measuring serum hepcidin and was used to detect a positive correlation between serum hepcidin and ferritin levels in CKD (10,17), but this technique is limited by its semiquantitative nature and requirement for equipment that is not widely available.Because of its renal elimination (18,19) and regulation by inflammation (20–23), it is possible that progressive renal insufficiency leads to altered hepcidin metabolism, subsequently affecting enteric absorption of iron and the availability of iron stores. In this study, using a novel assay, we present the first quantitative measurements of bioactive serum hepcidin in both pediatric and adult patients across the spectrum of CKD.     

Follow-Ups of Metabolic,Inflammatory and Oxidative Stress Markers,and Brachial–Ankle Pulse Wave Velocity in Middle-Aged Subjects without Metabolic Syndrome

This study investigates the association among metabolic risk factors, inflammatory and oxidative stress markers, and brachial–ankle pulse wave velocity (ba-PWV). We conducted a 3-year longitudinal, observational study of 288 middle-aged adults not meeting the criteria for metabolic syndrome (MetS) at the initial screening. We measured metabolic risk factors, inflammatory and oxidative stress markers, and ba-PWV. Within the 3-year study period, 15.6% (45 out of 288) of participants developed MetS. At the 3-year follow-up, patients were categorized as those with MetS (n = 45) and those without MetS (n = 243). Patients with MetS had significantly unfavorable initial measurements of baseline body mass index (BMI), waist circumference (WC), blood pressure (BP), triglyceride (TG), high-density lipoprotein (HDL)-cholesterol, glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR) index, and ba-PWV. After 3 years, participants without MetS showed significant increases in WC, diastolic BP (DBP), total- and low-density lipoprotein (LDL)-cholesterol, malondialdehyde (MDA), oxidized-LDL (ox-LDL), and ba-PWV and a significant decrease in HDL-cholesterol and free fatty acids (FFA). Subjects who developed MetS showed significant increases in BMI, WC, BP, TG, glucose, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), MDA, ox-LDL, and ba-PWV and a significant decrease in HDL-cholesterol. Changes in BMI, WC, BP, TG, HDL-cholesterol, glucose, HOMA-IR index, FFA, C-reactive protein (P = .022), IL-6 (P = .004), leukocyte count (P < .001), MDA (P = .002), ox-LDL (P = .015), and ba-PWV (P = .001) differed significantly between the two groups after adjustment for baseline values. Changes in ba-PWV were positively correlated with the changes in systolic and DBP, total-cholesterol, glucose, leukocyte count, and MDA. The age-related increase in arterial stiffness is greater in the presence of MetS with higher levels of inflammatory and oxidative stress markers.     

Oxidative Stress and Pathogenesis of Inflammatory Bowel Disease: An Epiphenomenon or the Cause?

Crohn’s disease (CD) and ulcerative colitis (UC), known as inflammatory bowel disease (IBD), are fairly common chronic inflammatory conditions of the gastrointestinal tract. Although the exact etiology of IBD remains uncertain, dysfunctional immunoregulation of the gut is believed to be the main culprit. Amongst the immunoregulatory factors, reactive oxygen species are produced in abnormally high levels in IBD. Their destructive effects may contribute to the initiation and/or propagation of the disease. We provided an extensive overview on the evidences from animal and human literature linking oxidative stress to IBD and its activity. Moreover, the effects of antioxidant therapy on IBD patients in randomized, controlled trials were reviewed and the need for further studies elaborated. We also summarized the evidence in support for causality of oxidative stress in IBD.     

Chronic Alcohol Consumption and Cerebral Indices of Oxidative Stress: Is There a Link?

BACKGROUND: It is still difficult to define the biochemical mechanisms that cause alterations in neuronal function and plasticity and neuronal cell loss in the brains of alcohol-dependent patients. METHODS: To evaluate the extent of cerebral alcohol-induced oxidative stress ex vivo, we investigated the levels of glutathione (GSH), its oxidation product glutathione disulfide (GSSG, produced by GSH-peroxidases), and the activities of catalase and superoxide dismutases (SOD). In addition, selected brain regions from up to 22 subjects (versus controls) were studied post mortem to compare the amount of oxidized DNA-base 8-hydroxy-2'-deoxyguanosine (8-OHdG) with levels of deoxyguanosine (dG) in mitochondrial and nuclear DNA. RESULTS: The most prominent findings showed significantly decreased GSH/(GSH+2GSSG) molar redox (oxidation-reduction) ratios in the corpus mamillare and cerebellum, which appeared due to an increase in GSSG caused by chronic alcohol intake. Catalase activity was increased in only the frontal cortex, whereas decreased catalase activity was found in the corpus callosum. In contrast, neither copper-zinc-superoxide dismutase (CuZnSOD) and manganese-superoxide dismutase (MnSOD) activities nor 8-OHdG/dG molar ratios were altered, although a tendency toward higher OHdG/dG ratios in temporal and parietal cortex from alcohol-dependent patients could be detected when mitochondrial DNA was analyzed selectively. CONCLUSIONS: We propose that decreased brain GSH/(GSH+2GSSG) molar redox (oxidation-reduction) ratios in alcohol-dependent patients may reflect neural impairment due to increased peroxide production after chronic alcohol consumption. However, future experiments, investigating the activities of enzymes and cofactors involved in GSH synthesis and metabolism in the human brain, will have to validate the specificity of these results for oxidative stress.     

Antifibrotic Mechanism of Pinocembrin: Impact on Oxidative Stress,Inflammation and TGF-β /Smad Inhibition in Rats

Introduction. The present study aimed to elucidate the potential antifibrotic effects of pinocembrin (PIN), a flavanone found abundantly in honey and propolis, by studying its effect on different oxidative stress, inflammatory and fibrosis markers in an experimental model of CCl₄-induced liver fibrosis.Material and methods. PIN (20 mg/kg) was given orally 3 times/week for 6 consecutive weeks alternating with CCl₄ (0.5 mL/kg, 1:1 mixture with corn oil, i. p.) twice weekly. Different hepatotoxicity indices, oxidative stress, inflammatory and liver fibrosis markers were assessed.Results. PIN significantly restored liver transaminases and total cholesterol to normal levels. Also, PIN ameliorated oxidative stress injury evoked by CCl₄ as evidenced by inhibition of reduced glutathione depletion and lipid peroxidation as well as elevation of antioxidant enzyme superoxide dismutase (SOD). Further, PIN up-regulated the nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), thereby inducing the expression and activity of the cytoprotective enzyme hemeoxygenase-1 (HO-1). Moreover, PIN alleviated pro-inflammatory cytokines such as TNF-α via inhibiting nuclear factor-KB (nF-kB) activation. As markers of fibrosis, collagen and α-SMA expression increased markedly in the CCl₄ group and PIN prevented these alterations. In addition, PIN down-regulated TGFβ1 and p-Smad2/3, thereby inhibiting TGFβ1/Smad signaling pathway.Conclusion. These results suggest that PIN possess potent antifibrotic effects that can be explained on its antioxidant properties. It ameliorates oxidative stress and inflammation during induction of fibrogenesis via its ability to augment cellular antioxidant defenses, activating Nrf2-mediated HO-1 expression and modulating NF-KB and TGF-β1/Smad signaling pathway.