Comprehensive analysis reveals key genes and environmental toxin exposures underlying treatment response in ulcerative colitis based on in-silico analysis and Mendelian randomization.

BACKGROUND: UC is increasingly prevalent worldwide and represents a significant global disease burden. Although medical therapeutics are employed, they often fall short of being optimal, leaving patients struggling with treatment non-responsiveness and many related complications. MATERIALS AND METHODS: The study utilized gene microarray data and clinical information from GEO. Gene enrichment and differential expression analyses were conducted using Metascape and Limma, respectively. Lasso Regression Algorithm was constructed using glmnet and heat maps were generated using pheatmap. ROC curves were used to assess diagnostic parameter capability, while XSum was employed to screen for small-molecule drugs exacerbating UC. Molecular docking was carried out using Autodock Vina. The study also performed Mendelian randomization analysis based on TwoSampleMR and used CTD to investigate the relationship between exposure to environmental chemical toxicants and UC therapy responsiveness. RESULTS: Six genes (ELL2, DAPP1, SAMD9L, CD38, IGSF6, and LYN) were found to be significantly overexpressed in UC patient samples that did not respond to multiple therapies. Lasso analysis identified ELL2 and DAPP1 as key genes influencing UC treatment response. Both genes accurately predicted intestinal inflammation in UC and impacted the immunological infiltration status. Clofibrate showed therapeutic potential for UC by binding to ELL2 and DAPP1 proteins. The study also reviews environmental toxins and drug exposures that could impact UC progression. CONCLUSIONS: We used microarray technology to identify DAPP1 and ELL2 as key genes that impact UC treatment response and inflammatory progression. Clofibrate was identified as a promising UC treatment. Our review also highlights the impact of environmental toxins on UC treatment response, providing valuable insights for personalized clinical management.

Clofibrate as an Adjunct to Phototherapy for Unconjugated Hyperbilirubinemia in Term Neonates.

OBJECTIVE: To evaluate the efficacy of oral clofibrate as an adjunct to phototherapy for unconjugated hyperbilirubinemia in term neonates. METHODS: This randomized controlled trial was done in the level III neonatal intensive care unit (NICU) of a tertiary care hospital. Ninety term neonates with unconjugated hyperbilirubinemia with serum bilirubin 15-25 mg/dl were randomized to either intervention group (single dose of clofibrate in a dose of 50 mg/kg prior to starting phototherapy) or standard care group (only phototherapy). Primary outcome was absolute fall in bilirubin by 48 h. Secondary outcomes were duration of phototherapy, absolute fall in bilirubin levels at 12, 24, 36, 48 h, need for exchange transfusion and incidence of side-effects. RESULTS: After 48 h of intervention, significantly lower bilirubin levels were noted in the intervention group compared to standard care group with a mean difference of 7 mg/dl (95% CI 6.7 mg/dl to 7.2 mg/dl). Duration of phototherapy required was less in the intervention group compared to standard care group with mean difference of 23.82 h (95% CI 30.46 h to 17.18 h). Exchange transfusion was needed for 4 neonates in the standard care group and none in the intervention group. No side-effects were noted with clofibrate. CONCLUSIONS: Single dose clofibrate prior to starting phototherapy in term neonates with uncomplicated unconjugated hyperbilirubinemia reduces the duration of phototherapy significantly.

Peroxisome proliferator-activated receptors (PPAR) downregulate the expression of pro-inflammatory molecules in an experimental model of myocardial infarction.

Myocardial infarction (MI) has been associated with an inflammatory response and a rise in TNF-α, interleukin (IL)-1ß, and IL-6. Peroxisome proliferator-activated receptors (PPARs) promote a decreased expression of inflammatory molecules. We aimed to study whether PPAR stimulation by clofibrate decreases inflammation and reduces infarct size in rats with MI. Male Wistar rats were randomized into 3 groups: control, MI + vehicle, and MI + clofibrate (100 mg/kg). Treatment was administered for 3 consecutive days, previous to 2 h of MI. MI induced an increase in protein expression, mRNA content, and enzymatic activity of inducible nitric oxide synthase (iNOS). Additionally, MI incited an increased expression of matrix metalloproteinase (MMP)-2 and MMP-9, intercellular adhesion molecule (ICAM)-1, and IL-6. MI also elevated the nuclear content of nuclear factor-κB (NF-κB) and decreased IκB, both in myocyte nuclei and cytosol. Clofibrate treatment prevented MI-induced changes in iNOS, MMP-2 and MMP-9, ICAM-1, IL-6, NF-κB, and IκB. Infarct size was smaller in clofibrate-treated rats compared to MI-vehicle animals. In silico analysis exhibited 3 motifs shared by genes from renin-angiotensin system, PPARα, iNOS, MMP-2 and MMP-9, ICAM-1, and VCAM-1, suggesting a cross regulation. In conclusion, PPARα-stimulation prevents overexpression of pro-inflammatory molecules and preserves viability in an experimental model of acute MI.

Up-regulation of Hnf1α gene expression in the liver of rats with experimentally induced chronic renal failure - A possible link between circulating PCSK9 and triacylglycerol concentrations.

BACKGROUND: The aim of this study was to verify if an increase in Hnf1α gene expression could be a possible link between circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) and TAGs concentrations in chronic renal failure (CRF). METHODS: Rats underwent 5/6 nephrectomy or a sham surgery. Liver expressions of Pcsk9, Mttp, ApoB-100, Hnf1α, Hnf4α, lipogenic enzymes and ß-actin genes were quantified by qPCR. Liver levels of proteins coding by these genes were analyzed by Western blotting. Serum apoB-100 and PCSK9 concentration were estimated with an immunoassay. RESULTS: CRF rats showed an increase in circulating concentrations of TAGs, VLDL, apoB-100 and PCSK9, along with an enhanced liver VLDL-TAG secretion rate and a coordinated liver up-regulation of genes coding: a) lipogenic enzymes; b) Mttp and ApoB-100; c) Pcsk9; d) Hnf1α and Hnf4α. Positive correlations were found between serum creatinine concentrations and: a) the liver levels of HNF1α mRNA (r = 0.79, p < 0.01) and HNF4α (r = 0.76, p < 0.01); b) the liver levels of PCSK9 mRNA (r = 0.88, p < 0.01) and serum PCSK9 concentrations (r = 0.73, p < 0.01); c) the liver levels of apoB-100 mRNA (r = 0.83, p < 0.01) and serum apoB-100 concentrations (r = 0.87, p < 0.01). Clofibrate treatment was shown to concomitantly decrease the liver levels of HNF1α, HNF4α and PCSK9 mRNA, as well as serum PCSK9, TAGs and total cholesterol concentrations in CRF rats. CONCLUSION: The results presented are consistent with a cause-effect relationship between the enhanced liver expression of Hnf1α gene and its target genes the products of which are involved in synthesis, assembly and secretion of VLDL, as well as Pcsk9 gene in CRF rats. This may at least in part explain an association between circulating PCSK9 and TAGs in CRF rats and possibly also in humans with chronic kidney disease (CKD).

Fibrates for secondary prevention of cardiovascular disease and stroke.

BACKGROUND: Fibrates are a class of drugs characterised by mainly lowering high triglyceride, raising high-density lipoprotein (HDL) cholesterol, and lowering the small dense fraction of low-density lipoprotein (LDL) cholesterol. Their efficacy for secondary prevention of serious vascular events is unclear, and to date no systematic review focusing on secondary prevention has been undertaken. OBJECTIVES: To assess the efficacy and safety of fibrates for the prevention of serious vascular events in people with previous cardiovascular disease (CVD), including coronary heart disease and stroke. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 9, 2014) on the Cochrane Library, MEDLINE (OVID, 1946 to October week 1 2014), EMBASE (OVID, 1980 to 2014 week 41), the China Biological Medicine Database (CBM) (1978 to 2014), the Chinese National Knowledge Infrastructure (CNKI) (1979 to 2014), Chinese Science and Technique Journals Database (VIP) (1989 to 2014). We also searched other resources, such as ongoing trials registers and databases of conference abstracts, to identify further published, unpublished, and ongoing studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in which a fibrate (for example gemfibrozil, fenofibrate) was compared with placebo or no treatment. We excluded RCTs with only laboratory outcomes. We also excluded trials comparing two different fibrates without a placebo or no-treatment control. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed risk of bias, and extracted the data. We contacted authors of trials for missing data. MAIN RESULTS: We included 13 trials involving a total of 16,112 participants. Eleven trials recruited participants with history of coronary heart disease, two trials recruited participants with history of stroke, and one trial recruited participants with a mix of people with CVD. We judged overall risk of bias to be moderate. The meta-analysis (including all fibrate trials) showed evidence for a protective effect of fibrates primarily compared to placebo for the primary composite outcome of non-fatal stroke, non-fatal myocardial infarction (MI), and vascular death (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.83 to 0.94; participants = 16,064; studies = 12; I(2) = 45%, fixed effect). Fibrates were moderately effective for preventing MI occurrence (RR 0.86, 95% CI 0.80 to 0.93; participants = 13,942; studies = 10; I(2) = 24%, fixed effect). Fibrates were not effective against all-cause mortality (RR 0.98, 95% CI 0.91 to 1.06; participants = 13,653; studies = 10; I(2) = 23%), death from vascular causes (RR 0.95, 95% CI 0.86 to 1.05; participants = 13,653; studies = 10; I(2) = 11%, fixed effect), and stroke events (RR 1.03, 95% CI 0.91 to 1.16; participants = 11,719; studies = 6; I(2) = 11%, fixed effect). Excluding clofibrate trials, as the use of clofibrate was discontinued in 2012 due to safety concerns, the remaining class of fibrates were no longer effective in preventing the primary composite outcome (RR 0.90, 95% CI 0.79 to 1.03; participants = 10,320; studies = 7; I(2) = 50%, random effects). However, without clofibrate data, fibrates remained effective in preventing MI (RR 0.85, 95% CI 0.76 to 0.94; participants = 8304; studies = 6; I(2) = 47%, fixed effect). There was no increase in adverse events with fibrates compared to control. Subgroup analyses showed the benefit of fibrates on the primary composite outcome to be consistent irrespective of age, gender, and diabetes mellitus. AUTHORS' CONCLUSIONS: Moderate evidence showed that the fibrate class can be effective in the secondary prevention of composite outcome of non-fatal stroke, non-fatal MI, and vascular death. However, this beneficial effect relies on the inclusion of clofibrate data, a drug that was discontinued in 2002 due to its unacceptably large adverse effects. Further trials of the use of fibrates in populations with previous stroke and also against a background treatment with statins (standard of care) are required.

Nonstatin therapies for management of dyslipidemia: a review.

PURPOSE: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Recently published cholesterol treatment guidelines emphasize the use of statins as the preferred treatment strategy for both primary and secondary prevention of CVD. However, the optimal treatment strategy for patients who cannot tolerate statin therapy or those who need additional lipid-lowering therapy is unclear in light of recent evidence that demonstrates a lack of improved cardiovascular outcomes with combination therapy. The purpose of this review is to summarize and interpret evidence that evaluates nonstatin drug classes in reducing cardiovascular outcomes, to provide recommendations for use of nonstatin therapies in clinical practice, and to review emerging nonstatin therapies for management of dyslipidemia. METHODS: Relevant articles were identified through searches of PubMed, International Pharmaceutical Abstracts, and the Cochrane Database of Systematic Reviews by using the terms niacin, omega-3 fatty acids (FAs), clofibrate, fibrate, fenofibrate, fenofibric acid, gemfibrozil, cholestyramine, colestipol, colesevelam, ezetimibe, proprotein convertase subtilisin/kexin 9 (PCSK9), cholesteryl ester transfer protein (CETP), and cardiovascular outcomes. Only English language, human clinical trials, meta-analyses, and systematic reviews were included. Additional references were identified from citations of published articles. FINDINGS: Niacin may reduce cardiovascular events as monotherapy; however, recent trials in combination with statins have failed to show a benefit. Trials with omega-3 FAs have failed to demonstrate significant reductions in cardiovascular outcomes. Fibrates may improve cardiovascular outcomes as monotherapy; however, trials in combination with statins have failed to show a benefit, except in those with elevated triglycerides (>200 mg/dL) or low HDL-C (<40 mg/dL). There is a lack of data that evaluates bile acid sequestrant in combination with statin therapy on reducing cardiovascular events. Ezetimibe-statin combination therapy can reduce cardiovascular outcomes in those with chronic kidney disease and following vascular surgery or acute coronary syndrome. Long-term effects of emerging nonstatin therapies (CETP and PCSK9 inhibitors) are currently being evaluated in ongoing Phase III trials. IMPLICATIONS: Nonstatin therapies have a limited role in reducing cardiovascular events in those maintained on guideline-directed statin therapy. In certain clinical situations, such as patients who are unable to tolerate statin therapy or recommended intensities of statin therapy, those with persistent severe elevations in triglycerides, or patients with high cardiovascular risk, some nonstatin therapies may be useful in reducing cardiovascular events. Future research is needed to evaluate the role of nonstatin therapies in those who are unable to tolerate guideline-directed statin doses.

Topical clofibrate improves symptoms in patients with atopic dermatitis and reduces serum TARC levels: a randomized, double-blind, placebo-controlled pilot study.

BACKGROUND: Though topical corticosteroids (TC) are used for treating atopic dermatitis (AD) as a standard, there exist several problems including topical steroid addiction (TSA) or Red skin syndrome. Moreover, the number of patients, who refrain from using TC because of steroid-phobia, is increasing. Recently, topical PPAR alpha ligand application has been reported to improve experimental allergic dermatitis. The purpose of this study was to investigate the short-term efficacy and safety of topical clofibrate, one of PPAR alpha ligand, in such steroid-phobic patients with AD. METHODS: This study was conducted as a double-blind design to investigate the effects of random administration of topical clofibrate and base (placebo) on skin manifestation and blood parameters of patients for 2 weeks. Severity was digitized using severity scoring systems for atopic dermatitis by the Japanese Dermatological Association (SSS-JDA) before and after two weeks. Subjective severity of patients was evaluated using visual analog scale (Pt-VAS). Serum thymus and activation-regulated chemokine (TARC) and immunoglobulin E (IgE) were also investigated. RESULTS: Twenty patients were enrolled, and 19 of 20 patients completed the study. In 19 patients, the value of severity score using SSS-JDA was decreased significantly after administration of topical clofibrate (P=0.001). Subjective evaluation using Pt-VAS (P=0.008) and serum TARC levels (P=0.03) were also significantly decreased after two weeks of topical clofibrate. There was not a significant difference in serum IgE levels. No adverse effect was observed. CONCLUSIONS: Topical clofibrate is useful for patients with AD especially who are reluctant to use topical steroids.

Clofibrate in combination with phototherapy for unconjugated neonatal hyperbilirubinaemia.

BACKGROUND: There are many pathological conditions leading to an elevated unconjugated bilirubin level (hyperbilirubinaemia) in neonates. Currently the standard therapies for unconjugated hyperbilirubinaemia include phototherapy and exchange transfusion. In addition to phototherapy, clofibrate has been studied as a treatment for hyperbilirubinaemia in several countries. OBJECTIVES: To determine the efficacy and safety of clofibrate in combination with phototherapy versus phototherapy alone in unconjugated neonatal hyperbilirubinaemia. SEARCH METHODS: Randomised controlled trials were identified by searching MEDLINE (1950 to April 2012) before being translated for use in The Cochrane Library, EMBASE 1980 to April 2012 and CINAHL databases. All searches were re-run on 2 April 2012. SELECTION CRITERIA: We included trials where neonates with hyperbilirubinaemia received either clofibrate in combination with phototherapy or phototherapy alone or placebo in combination with phototherapy. DATA COLLECTION AND ANALYSIS: Data were extracted and analysed independently by two review authors (MG and HM). Treatment effects on the following outcomes were determined: mean change in bilirubin levels, mean duration of treatment with phototherapy, number of exchange transfusions needed, adverse effects of clofibrate, bilirubin encephalopathy and neonatal mortality. Study authors were contacted for additional information. Studies were analysed for methodological quality in a 'Risk of bias' table. MAIN RESULTS: Fifteen studies (two including preterm neonates and 13 including term neonates) were included in this review. All but one of the included studies were conducted in Iran. For preterm neonates, there was a significantly lower bilirubin level in the 100 mg/kg clofibrate group compared to the control group with a mean difference of -1.37 mg/dL (95% CI -2.19 mg/dL to -0.55 mg/dL) (-23 µmol/L; 95% CI -36 µmol/L to -9 µmol/L) after 48 hours. For the term neonates, there were significantly lower bilirubin levels in the clofibrate group compared to the control group after both 24 and 48 hours of treatment with a weighted mean difference of -2.14 mg/dL (95% CI -2.53 mg/dL to -1.75 mg/dL) (-37 µmol/L; 95% CI -43 µmol/L to -30 µmol/L] and -1.82 mg/dL (95% CI -2.25 mg/dL to -1.38 mg/dL) (-31 µmol/L; 95% CI -38 µmol/L to -24 µmol/L), respectively.There was a significantly lower duration of phototherapy in the clofibrate group compared to the control group for both preterm and term neonates with a weighted mean difference of -23.82 hours (95% CI -30.46 hours to -17.18 hours) and -25.40 hours (95% CI -28.94 hours to -21.86 hours), respectively.None of the studies reported on bilirubin encephalopathy rates, neonatal mortality rates, or the levels of parental or staff satisfactions with the interventions. AUTHORS' CONCLUSIONS: There are insufficient data from different countries on the use of clofibrate in combination with phototherapy for hyperbilirubinaemia to make recommendations for practice. There is a need for larger trials to determine how effective clofibrate is in reducing the need for, and duration of, phototherapy in term and preterm infants with hyperbilirubinaemia.

Novel use of a lipid-lowering fibrate medication to prevent nicotine reward and relapse: preclinical findings.

Experimental drugs that activate α-type peroxisome proliferator-activated receptors (PPARα) have recently been shown to reduce the rewarding effects of nicotine in animals, but these drugs have not been approved for human use. The fibrates are a class of PPARα-activating medications that are widely prescribed to improve lipid profiles and prevent cardiovascular disease, but these drugs have not been tested in animal models of nicotine reward. Here, we examine the effects of clofibrate, a representative of the fibrate class, on reward-related behavioral, electrophysiological, and neurochemical effects of nicotine in rats and squirrel monkeys. Clofibrate prevented the acquisition of nicotine-taking behavior in naive animals, substantially decreased nicotine taking in experienced animals, and counteracted the relapse-inducing effects of re-exposure to nicotine or nicotine-associated cues after a period of abstinence. In the central nervous system, clofibrate blocked nicotine's effects on neuronal firing in the ventral tegmental area and on dopamine release in the nucleus accumbens shell. All of these results suggest that fibrate medications might promote smoking cessation. The fact that fibrates are already approved for human use could expedite clinical trials and subsequent implementation of fibrates as a treatment for tobacco dependence, especially in smokers with abnormal lipid profiles.

Clofibrate for unconjugated hyperbilirubinemia in neonates: a systematic review.

OBJECTIVE: To evaluate the effect of clofibrate for unconjugated hyperbilirubinemia in neonates. METHODS: A systematic review with meta-analysis of randomized controlled trials or quasi-randomized controlled trials was conducted to evaluate the clofibrate treatment in neonates with unconjugated hyperbilirubinemia. We followed the guidelines from the Cochrane review group and the PRISMA statement. RESULTS: Of 148 studies identified, a total of 13 studies on 867 infants were included. A single oral administration of clofibrate was associated with decreased need of phototherapy (RR:.38, 95% CI: 0.21 to 0.68), shortened duration of phototherapy (mean duration: 23.88 h, 95% CI: 33.03 to -14.72 h) and reduced peak total serum bilirubin (mean duration: -1.62 mg/dL, 95% CI: 2.13 to -1.11 mg/dL). These effects were especially obvious in term infants and infants without hemolytic diseases. Data regarding mortality or kernicterus were not available from included studies. CONCLUSIONS: Clofibrate may have short-term benefits for the infants with hyperbilirubinaemia, especially for population of term infants and infants without hemolytic diseases. Large RCTs with long-term followup are required to verify the safety of clofibrate and assess its long-term effects.

The effect of clofibrate on hyperbilirubinemia of term neonates.

Clofibrate is a glucuronosyl transferase inducer that has been proposed to increase the elimination of bilirubin in neonates with hyperbilirubinemia. This study was conducted to determine the therapeutic effect of clofibrate in term neonates with non-hemolytic jaundice. This study was conducted on 52 newborns with pathologic unconjugated jaundice in Qazvin children hospital. Newborns divided randomly in two groups. Case group treated with clofibrate and intensive phototherapy, while control group treated only with intensive phototherapy. Serum bilirubin level was measured before and 6, 12, 24 and 48 hours after treatment. Results were compared and analyzed. The mean serum level of bilirubin before treatment in the case and control groups were 20.78 ± 2.38 and 20.52 ± 2.44 mg/dl, respectively (P=0.69). The mean serum level of bilirubin in 6, 12, 24 and 48 hours after treatment in the case group were 18.20 ± 2.20, 14.70 ± 2.06, 10.72 ± 2.40 and 8.90 ± 0.83 mg/dl , respectively. These values in control group were 18.26 ± 2.42, 15.36 ± 2.59, 12.29 ± 2.28 and 10.23 ± 1.50 mg/dl, respectively. There was significant difference between two groups regarding mean serum level of bilirubin 24 hours (P=0.019) and 48 hours after treatment (P=0.005). In conclusion, clofibrate was effective in reducing neonatal jaundice and its effect appeared 24 hours after treatment.

Effects of clofibrate on salt loading-induced hypertension in rats.

The effects of clofibrate on the hemodynamic and renal manifestations of increased saline intake were analyzed. Four groups of male Wistar rats were treated for five weeks: control, clofibrate (240 mg/kg/day), salt (2% via drinking water), and salt + clofibrate. Body weight, systolic blood pressure (SBP), and heart rate (HR) were recorded weekly. Finally, SBP, HR, and morphologic, metabolic, plasma, and renal variables were measured. Salt increased SBP, HR, urinary isoprostanes, NOx, ET, vasopressin and proteinuria and reduced plasma free T(4) (FT(4)) and tissue FT(4) and FT(3) versus control rats. Clofibrate prevented the increase in SBP produced by salt administration, reduced the sodium balance, and further reduced plasma and tissue thyroid hormone levels. However, clofibrate did not modify the relative cardiac mass, NOx, urinary ET, and vasopressin of saline-loaded rats. In conclusion, chronic clofibrate administration prevented the blood pressure elevation of salt-loaded rats by decreasing sodium balance and reducing thyroid hormone levels.

Effect of clofibrate on vascular reactivity in a model of high blood pressure secondary to aortic coarctation.

The aims of this study were to identify the effect of clofibrate administration in the development of high blood pressure secondary to aortic coarctation (AoCo) and to assess its effect on vascular reactivity. Three experimental groups of rats were used: sham-operated, aortic coarctated vehicle-treated (AoCo-V), and aortic coarctated clofibrate-treated (AoCo-C100). The rats were treated for seven days. Blood pressure was measured, and the vascular response to angiotensin II (AngII), norepinephrine (NE), and acetylcholine (ACh) were evaluated in aortic rings. The activity and expression of endothelial nitric oxide synthase (eNOS) was also evaluated. The major findings of this study include the following: AoCo induced a rise in blood pressure, and this effect was attenuated by clofibrate. The vascular response to AngII was higher in aortic rings from the AoCo-V group compared to the Sham-V or AoCo-C100 groups. ACh-elicited vasorelaxation was lower in the arteries of AoCo-V rats than Sham-V or AoCo-C100, while it was comparable between the Sham-V and AoCo-C100 groups. In every case, vasorelaxation was dependent on NO. However, the ACh-induced release of NO as well as NOS activity and expression were reduced in the arteries of AoCo-V rats. Clofibrate maintained normal NOS activity and increased eNOS expression. In conclusion, clofibrate administration attenuated the AoCo-induced rise in blood pressure by a mechanism that involves the participation of the NO system at both the NO synthesis and the eNOS protein expression levels. These events improved endothelial function, preserved normal vascular responses to both vasorelaxants and vasoconstrictors, and led to better blood pressure control.

Peroxisome proliferator-activated receptor {alpha} agonism prevents renal damage and the oxidative stress and inflammatory processes affecting the brains of stroke-prone rats.

A growing body of evidence suggests that chronic kidney disease is a significant risk for cardiovascular events and stroke regardless of traditional risk factors. The aim of this study was to examine the effects of peroxisome proliferator-activated receptor (PPAR) agonists on the tissue damage affecting salt-loaded spontaneously hypertensive stroke-prone rats ( SHRSPs), an animal model that develops a complex pathology characterized by systemic inflammation, hypertension, and proteinuria and leads to end-organ injury (initially renal and subsequently cerebral). Compared with the PPARγ agonist rosiglitazone, the PPARα ligands fenofibrate and clofibrate significantly increased survival (p < 0.001) by delaying the occurrence of brain lesions monitored by magnetic resonance imaging (p < 0.001) and delaying increased proteinuria (p < 0.001). Fenofibrate completely prevented the renal disorder characterized by severe vascular lesions, tubular damage, and glomerular sclerosis, reduced the number of ED-1-positive cells and collagen accumulation, and decreased the renal expression of interleukin-1ß, transforming growth factor ß, and monocyte chemoattractant protein 1. It also prevented the plasma and urine accumulation of acute-phase and oxidized proteins, suggesting that the protection induced by PPARα agonists was at least partially caused by their anti-inflammatory and antioxidative properties. The results of this study demonstrate that PPAR agonism has beneficial effects on spontaneous brain and renal damage in SHRSPs by inhibiting systemic inflammation and oxidative stress, and they support carrying out future studies aimed at evaluating the effect of PPARα agonists on proteinuria and clinical outcomes in hypertensive patients with renal disease at increased risk of stroke.

Mitochondrial HMG-CoA synthase partially contributes to antioxidant protection in the kidney of stroke-prone spontaneously hypertensive rats.

OBJECTIVE: Increased oxidative stress plays an important role in cardiovascular diseases including hypertension and stroke. Evidence has indicated that ketone bodies could exert antioxidative effects. We explored the role of renal mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase (HMGCS2) expression, a key control site of ketogenesis, in stroke-prone spontaneously hypertensive rats (SHRSPs) and their ancestral hypertensive but stroke-resistant spontaneously hypertensive rats (SHRs). METHODS: Two groups of SHRSPs were fed a standard chow or standard chow supplemented with clofibrate (an agonist of HMGCS2 promoter), respectively, and SHRs fed with a standard chow were used as controls. The renal levels of HMGCS2, Akt, and phosphorylated protein kinase B (Akt) were measured by western blotting. Malondialdehyde, catalase, superoxide dismutase, and glutathione peroxidase were detected by assay kits. RESULTS: Compared with SHRs, lower HMGCS2 protein expression, enhanced phosphorylated Akt signal, higher malondialdehyde levels, and higher catalase activity were observed in kidney tissues in SHRSPs (P < 0.05). No differences in superoxide dismutase and glutathione peroxidase activities were observed between SHRSPs and SHRs. Clofibrate treatment significantly upregulated renal HMGCS2 expressions, inhibited phosphorylation of Akt, and decreased malondialdehyde levels and catalase activities in SHRSP kidney tissues (P < 0.05). CONCLUSION: These results demonstrated the difference in HMGCS2 expression and oxidative stress in kidney tissues between SHRSPs and their SHR controls. The enhanced oxidative stress was partly due to the lower HMGCS2 expression regulated possibly by the Akt signaling pathway.

Bounds on causal effects in randomized trials with noncompliance under monotonicity assumptions about covariates.

In randomized trials with nonrandom noncompliance, the causal effects of a treatment among the entire population cannot be estimated in an unbiased manner. Therefore, several authors have considered the bounds on the causal effects. Here, we propose bounds by applying an idea of VanderWeele (Biometrics 2008; 64:702-706), who showed that the sign of the unmeasured confounding bias can be determined under monotonicity assumptions about covariates in the framework of observational studies. In randomized trials with noncompliance by switching the treatment, we show that the lower or upper bound on the expectation of the potential outcome becomes the expectation from the per-protocol analysis under monotonicity assumptions similar to those of VanderWeele. In particular, the monotonicity assumptions can yield both the lower and the upper bounds on causal effects when the monotonic relationship between the covariates and the treatment actually received depends on the treatment assigned. The results are extended to cases of noncompliance by subjects not receiving any treatment. Although the monotonicity assumptions are not themselves identifiable, they are nonetheless reasonable in some situations.

The effect of clofibrate with phototherapy in late pre-term newborns with non-hemolytic jaundice.

BACKGROUND: Despite an understanding of the enzymatic pathways leading to bilirubin production and degradation, very few pharmacologic interventions are utilized and the mainstay of treatment remains phototherapy. AIMS: To evaluate the efficacy of clofibrate in reducing total serum bilirubin levels in late pre-term neonates with non-hemolytic jaundice. DESIGN AND SETTING: Double-blind, placebo-controlled, randomized trial; tertiary level neonatal unit. MATERIALS AND METHODS: A randomized controlled study was carried out in the neonatal ward of Children's Hospital, Tabriz, Iran, over a 1-year period. Sixty-eight healthy late pre-term infants readmitted with non-hemolytic hyperbilirubinemia were randomized to receive phototherapy and clofibrate (n= 35) or phototherapy and placebo (n= 33). STATISTICAL ANALYSIS USED: Chi-square test and independent sample 't' test. RESULTS: There were no significant differences in the weight, gender, modes of delivery and age of neonates between the two groups. Similarly the mean total serum bilirubin (TSB) level at the time of admission was not significantly different between the two groups [mean+/- SD: 19.72 +/- 1.79 (95% confidence interval: 19.12-20.54 mg/dL) vs. 20.05 +/- 2.82 (95% confidence interval, 19.54-22.04 mg/dL), P= 0.57]. The mean TSB 48 hours after phototherapy [mean+/- SD: 8.06+/- 1.34 (95% confidence interval: 7.94-10.18 mg/dL) vs.10.94 +/- 2.87 (95% confidence interval: 9.92-12.16 mg/dL), P= 0.02] and the mean duration of phototherapy [mean+/- SD: 64.32 +/- 12.48 (95% confidence interval: 60-81.6 hours) vs. 87.84 +/- 29.76 (95% confidence interval: 79.2-108 hours), P< 0.001] were significantly lower in the clofibrate-treated group. CONCLUSIONS: Clofibrate is an effective adjunctive drug in neonatal hyperbilirubinemia, which results in decreased TSB level and reduced duration of phototherapy in late pre-term newborns.