Publications by authors named "Ernesto Germán Cardona-Muñoz"

37 Publications

Assessment of serum macrophage migration inhibitory factor (MIF), adiponectin, and other adipokines as potential markers of proteinuria and renal dysfunction in lupus nephritis: a cross-sectional study.

Biomark Res 2020 28;8:55. Epub 2020 Oct 28.

Programa de Doctorado en Farmacología del Departamento de Fisiología y Programa de Doctorado en Salud del Pública Depatamento de Salud Pública, Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud, Sierra Mojada 950, Colonia Independencia, 44340 Guadalajara, Jalisco Mexico.

Background: To date, the association of serum macrophage migration inhibitory factor (MIF) and serum adipokines with lupus nephritis is controversial.

Objective: To assess the utility of serum MIF, leptin, adiponectin and resistin levels as markers of proteinuria and renal dysfunction in lupus nephritis.

Methods: Cross-sectional study including 196 systemic lupus erythematosus (SLE) patients and 52 healthy controls (HCs). Disease activity was assessed by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Renal SLE involvement was investigated by renal-SLEDAI. MIF, adiponectin, leptin and resistin levels were quantified by ELISA. We assessed the correlations of quantitative variables by Spearman correlation (r). Multivariable linear regression adjusted the variables associated with the severity of proteinuria.

Results: SLE patients had higher MIF ( = 0.02) and adiponectin ( < 0.001) than HCs. Patients with renal SLE involvement ( = 43) had higher adiponectin (19.0 vs 13.3 μg/mL,  = 0.002) and resistin (10.7 vs 8.9 ng/mL,  = 0.01) than patients with non-renal SLE ( = 153). Proteinuria correlated with high adiponectin (  = 0.19,  < 0.009) and resistin (  = 0.26,  < 0.001). MIF (  = 0.27,  = 0.04). Resistin correlated with increased creatinine (  = 0.18,  = 0.02). High renal-SLEDAI correlated with adiponectin (  = 0.21,  = 0.004). Multiple linear regression showed that elevated adiponectin ( = 0.02), younger age ( = 0.04) and low MIF ( = 0.02) were associated with the severity of proteinuria. Low MIF and high adiponectin levels interacted to explain the association with the severity of proteinuria (R = 0.41).

Conclusions: High adiponectin combined with low MIF concentrations int+eract to explain the severity of proteinuria in renal SLE. These findings highlight the relevance of adiponectin, resistin and MIF as markers of LN.
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http://dx.doi.org/10.1186/s40364-020-00236-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594329PMC
October 2020

Importance of the Use of Oxidative Stress Biomarkers and Inflammatory Profile in Aqueous and Vitreous Humor in Diabetic Retinopathy.

Antioxidants (Basel) 2020 Sep 20;9(9). Epub 2020 Sep 20.

Department of Physiology, Health Sciences University Center, Institute of Clinical and Experimental Therapeutics, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico.

Diabetic retinopathy is one of the leading causes of visual impairment and morbidity worldwide, being the number one cause of blindness in people between 27 and 75 years old. It is estimated that ~191 million people will be diagnosed with this microvascular complication by 2030. Its pathogenesis is due to alterations in the retinal microvasculature as a result of a high concentration of glucose in the blood for a long time which generates numerous molecular changes like oxidative stress. Therefore, this narrative review aims to approach various biomarkers associated with the development of diabetic retinopathy. Focusing on the molecules showing promise as detection tools, among them we consider markers of oxidative stress (TAC, LPO, MDA, 4-HNE, SOD, GPx, and catalase), inflammation (IL-6, IL-1ß, IL-8, IL-10, IL-17A, TNF-α, and MMPs), apoptosis (NF-kB, , and caspases), and recently those that have to do with epigenetic modifications, their measurement in different biological matrices obtained from the eye, including importance, obtaining process, handling, and storage of these matrices in order to have the ability to detect the disease in its early stages.
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http://dx.doi.org/10.3390/antiox9090891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555116PMC
September 2020

Administration of Herbarium Mixture () on Metabolic Profile in Type 2 Diabetes Mellitus Patients: A Randomized, Double-Blind, Placebo-Controlled Trial.

J Med Food 2021 May 21;24(5):527-532. Epub 2020 Sep 21.

Department of Physiology, Health Science University Center, Institute of Experimental and Clinical Therapeutics, University of Guadalajara, Guadalajara, Mexico.

The use of herbarium mixture has been empirical, and the properties are not yet known. The aim of this study was to evaluate the effect of oral administration of herbarium mixture () on metabolic profile in patients with type 2 diabetes mellitus (T2DM). A randomized, double-blind, placebo-controlled, clinical trial was carried out in 40 patients with T2DM. They were between 40 and 65 years of age, with body mass index (BMI) between 25.0 and 34.9 kg/m and HbA1c >7.0%. BMI, waist circumference, fasting glucose, HbA1c, lipids, kidney, and liver function were measured. The patients were randomly assigned to receive the herbarium mixture () 400 mg before each meal, or placebo for 90 days. Herbarium mixture group showed decreased waist circumference (99 ± 14 vs. 98 ± 15 cm;  = .019), fasting glucose (12.0 ± 5.7 vs. 10.3 ± 5.1 mM;  = .019), and HbA1c (9.9% ± 2.7% vs. 8.9% ± 2.5%,  = .002). In conclusion, the administration of herbarium mixture () improved the glycemic profile in patients with T2DM. ClinicalTrial registration: NCT03313856 ClinicalTrials.gov.
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http://dx.doi.org/10.1089/jmf.2020.0082DOI Listing
May 2021

The Alteration of Pro-inflammatory Cytokines and Oxidative Stress Markers at Six-Month Post-living Kidney Donation.

Front Med (Lausanne) 2020 29;7:382. Epub 2020 Jul 29.

Department of Physiology, Institute of Experimental and Clinical Therapeutics, University Center of Health Sciences, University of Guadalajara, Guadalajara, Mexico.

Donors have a higher risk of developing chronic kidney disease than the general population. Some mechanisms mediated by pro-inflammatory cytokines and oxidative stress may be involved as risk factors. The objective of the study was to evaluate the behavior of pro-inflammatory cytokines and oxidative stress markers in living renal donors with a 6-month follow-up. A single prospective cohort was performed in 88 renal donors. At the end of the follow-up, the levels of lipoperoxides, 6.52 ± 1.12 mM, and 8-isoprostanes, 63.75 ± 13.28 pg/mL, were lower than before donation, 10.20 ± 3.95 mM ( < 0.001) and 67.54 ± 9.64 pg/mL ( = 0.026), respectively. Initial levels of nitric oxide (NO), 356.09 ± 59.38 μM increased at the end of the follow-up, 467.08 ± 38.74 μM ( < 0.001). It was observed in the final determination of donors decreased activity of antioxidant enzymes superoxide dismutase (SOD), 0.74 ± 0.57 U/L and glutathione peroxidase (GPx), 556.41 ± 80.37 nmol, in comparison with the levels obtained in the initial determination, 1.05 ± 0.57 U/L ( < 0.001) and 827.93 ± 162.78 nmol ( < 0.001), respectively. The pro-inflammatory cytokines, Tumor necrosis factor alpha and interleukin-6 showed no differences at 6 months after donation. The enzyme oxoguanine glycosylase (hOGG1) responsible for repairing oxidative damage to DNA, showed a decrease in its concentration at the end of the study in donor men, 0.40 ± 0.21 ng/mL compared to the initial levels, 0.55 ± 0.32 ng/mL ( = 0.025). The marker, 8-hydroxy-2-deoxyguanosine (8-OHdG) exhibited an increase in donor men at the final determination 2.28 ± 1.99 ng/mL, compared to the concentration before donation, 1.72 ± 1.96 ng/mL ( < 0.001). We found significant changes in the markers of the oxidative state with increased NO and 8-OHdG, as well as a significant decrease in the antioxidant defenses SOD, GPx, and in the DNA repair enzyme in living renal donors after 6 months of follow-up.
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http://dx.doi.org/10.3389/fmed.2020.00382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403208PMC
July 2020

Foods with Potential Prooxidant and Antioxidant Effects Involved in Parkinson's Disease.

Oxid Med Cell Longev 2020 3;2020:6281454. Epub 2020 Aug 3.

Department of Physiology, University Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico.

Oxidative stress plays a fundamental role in the pathogenesis of Parkinson's disease (PD). Oxidative stress appears to be responsible for the gradual dysfunction that manifests via numerous cellular pathways throughout PD progression. This review will describe the prooxidant effect of excessive consumption of processed food. Processed meat can affect health due to its high sodium content, advanced lipid oxidation end-products, cholesterol, and free fatty acids. During cooking, lipids can react with proteins to form advanced end-products of lipid oxidation. Excessive consumption of different types of carbohydrates is a risk factor for PD. The antioxidant effects of some foods in the regular diet provide an inconclusive interpretation of the environment's mechanisms with the modulation of oxidation stress-induced PD. Some antioxidant molecules are known whose primary mechanism is the neuroprotective effect. The melatonin mechanism consists of neutralizing reactive oxygen species (ROS) and inducing antioxidant enzyme's expression and activity. N-acetylcysteine protects against the development of PD by restoring levels of brain glutathione. The balanced administration of vitamin B3, ascorbic acid, vitamin D and the intake of caffeine every day seem beneficial for brain health in PD. Excessive chocolate intake could have adverse effects in PD patients. The findings reported to date do not provide clear benefits for a possible efficient therapeutic intervention by consuming the nutrients that are consumed regularly.
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http://dx.doi.org/10.1155/2020/6281454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424374PMC
June 2021

The Role of Oxidative Stress in Physiopathology and Pharmacological Treatment with Pro- and Antioxidant Properties in Chronic Diseases.

Oxid Med Cell Longev 2020 23;2020:2082145. Epub 2020 Jul 23.

Department of Physiology, University Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico.

Oxidative stress (OS) has the ability to damage different molecules and cellular structures, altering the correct function of organs and systems. OS accumulates in the body by endogenous and exogenous mechanisms. Increasing evidence points to the involvement of OS in the physiopathology of various chronic diseases that require prolonged periods of pharmacological treatment. Long-term treatments may contribute to changes in systemic OS. In this review, we discuss the involvement of OS in the pathological mechanisms of some chronic diseases, the pro- or antioxidant effects of their pharmacological treatments, and possible adjuvant antioxidant alternatives. Diseases such as high blood pressure, arteriosclerosis, and diabetes mellitus contribute to the increased risk of cardiovascular disease. Antihypertensive, lipid-lowering, and hypoglycemic treatments help reduce the risk with an additional antioxidant benefit. Treatment with methotrexate in autoimmune systemic inflammatory diseases, such as rheumatoid arthritis, has a dual role in stimulating the production of OS and producing mitochondrial dysfunction. However, it can also help indirectly decrease the systemic OS induced by inflammation. Medicaments used to treat neurodegenerative diseases tend to decrease the mechanisms related to the production of reactive oxygen species (ROS) and balance OS. On the other hand, immunosuppressive treatments used in cancer or human immunodeficiency virus infection increase the production of ROS, causing significant oxidative damage in different organs and systems without widely documented exogenous antioxidant administration alternatives.
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http://dx.doi.org/10.1155/2020/2082145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396016PMC
May 2021

The Effect of Visceral Abdominal Fat Volume on Oxidative Stress and Proinflammatory Cytokines in Subjects with Normal Weight, Overweight and Obesity.

Diabetes Metab Syndr Obes 2020 8;13:1077-1087. Epub 2020 Apr 8.

Department of Physiology, University Health Sciences Centre, University of Guadalajara, Guadalajara, Jalisco, Mexico.

Purpose: The increase of visceral abdominal fat (VAF) and oxidative stress (OS) are independent predictors for cardiovascular risk. This study aimed to determine the association of VAF with proinflammatory cytokines, oxidants, antioxidants, and oxidative damage to DNA in subjects with normal weight, overweight, and obesity.

Patients and methods: A cross-sectional study that included 21 men and 71 women who attended for a medical check-up was conducted. Dual-energy X-ray absorptiometry (DXA) was used to measure the VAF volume. ELISA and colorimetric techniques were used for chemical analysis.

Results: Low activity of superoxide dismutase (SOD) was found in overweight and obese subjects compared to the normal weight group (=0.005). In contrast, the activity of glutathione peroxidase (GPx) was higher in the overweight and obesity groups compared to the normal weight subjects (=0.017). The total antioxidant capacity (TAC) was also increased in the overweight group compared to the normal weight group (=0.04). According to the volume of VAF, the levels of tumor necrosis factor alfa and interleukin 6 showed no differences between subjects with normal and high VAF. Subjects with high VAF show higher levels of 8-isoprostans compared to normal VAF group (=0.039). Less concentration of 8-oxoguanine-DNA-N-glycosylase-1 (hOGG1) was found in the high VAF group (=0.032) compared to the normal VAF subjects. VAF was positively correlated with lipoperoxides (LPO) (r=0.27, <0.05) and 8-isoprostanes (r=0.25, <0.05). We also found correlations between oxidative stress markers and anthropometric ratios for intra-abdominal fat. The waist-hip ratio was positively correlated with LPO (r=0.30, <0.05) and TAC (r=0.24, <0.05).

Conclusion: These findings suggest that the predominantly oxidative damage associated with VAF in overweight or obesity is lipoperoxidation and oxidative DNA damage. Alterations in endogenous antioxidant defenses may not be linked to the amount of VAF.
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http://dx.doi.org/10.2147/DMSO.S245494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152535PMC
April 2020

Adjuvant Therapies in Diabetic Retinopathy as an Early Approach to Delay Its Progression: The Importance of Oxidative Stress and Inflammation.

Oxid Med Cell Longev 2020 11;2020:3096470. Epub 2020 Mar 11.

Institute of Clinical and Experimental Therapeutics, Department of Physiology, Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco, Mexico.

Diabetes mellitus (DM) is a progressive disease induced by a sustained state of chronic hyperglycemia that can lead to several complications targeting highly metabolic cells. Diabetic retinopathy (DR) is a multifactorial microvascular complication of DM, with high prevalence, which can ultimately lead to visual impairment. The genesis of DR involves a complex variety of pathways such as oxidative stress, inflammation, apoptosis, neurodegeneration, angiogenesis, lipid peroxidation, and endoplasmic reticulum (ER) stress, each possessing potential therapeutic biomarkers. A specific treatment has yet to be developed for early stages of DR since no management is given other than glycemic control until the proliferative stage develops, offering a poor visual prognosis to the patient. In this narrative review article, we evaluate different dietary regimens, such as the Mediterranean diet, Dietary Pattern to Stop Hypertension (DASH) and their functional foods, and low-calorie diets (LCDs). Nutraceuticals have also been assessed in DR on account of their antioxidant, anti-inflammatory, and antiangiogenic properties, which may have an important impact on the physiopathology of DR. These nutraceuticals have shown to lower reactive oxygen species (ROS), important inflammatory factors, cytokines, and endothelial damage biomarkers either as monotherapies or combined therapies or concomitantly with established diabetes management or nonconventional adjuvant drugs like topical nonsteroidal anti-inflammatory drugs (NSAIDs).
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http://dx.doi.org/10.1155/2020/3096470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086452PMC
December 2020

The effect of dulaglutide on stroke: an exploratory analysis of the REWIND trial.

Lancet Diabetes Endocrinol 2020 02 7;8(2):106-114. Epub 2020 Jan 7.

Robert Koch Medical Center, Sofia, Bulgaria.

Background: Cardiovascular outcome trials have suggested that glucagon-like peptide 1 (GLP-1) receptor agonists might reduce strokes. We analysed the effect of dulaglutide on stroke within the researching cardiovascular events with a weekly incretin in diabetes (REWIND) trial.

Methods: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial done at 371 sites in 24 countries. Men and women (aged ≥50 years) with established or newly detected type 2 diabetes whose HbA was 9·5% or less (with no lower limit) on stable doses of up to two oral glucose-lowering drugs with or without basal insulin therapy were eligible if their body-mass index was at least 23 kg/m. Participants were randomly assigned (1:1) to weekly subcutaneous injections of either masked dulaglutide 1·5 mg or the same volume of masked placebo (containing the same excipients but without dulaglutide). Randomisation was done by a computer-generated random code with an interactive web response system with stratification by site. Participants, investigators, the trial leadership, and all other personnel were masked to treatment allocation until the trial was completed and the database was locked. During the treatment period, participants in both groups were instructed to inject study drug on the same day at around the same time, each week. Strokes were categorised as fatal or non-fatal, and as either ischaemic, haemorrhagic, or undetermined. Stroke severity was assessed using the modified Rankin scale. Participants were seen at 2 weeks, 3 months, 6 months, and then every 3 months for drug dispensing and every 6 months for detailed assessments, until 1200 confirmed primary outcomes accrued. The primary endpoint was the first occurrence of any component of the composite outcome, which comprised non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular or unknown causes. All analyses were done according to an intention-to-treat strategy that included all randomly assigned participants, irrespective of adherence. The trial is registered with ClinicalTrials.gov, number NCT01394952.

Findings: Between Aug 18, 2011, and Aug 14, 2013, we screened 12 133 patients, of whom 9901 with type 2 diabetes and additional cardiovascular risk factors were randomly assigned to either dulaglutide (n=4949) or an equal volume of placebo (n=4952). During a median follow-up of 5·4 years, cerebrovascular and other cardiovascular outcomes were ascertained and adjudicated. 158 (3·2%) of 4949 participants assigned to dulaglutide and 205 (4·1%) of 4952 participants assigned to placebo had a stroke during follow-up (hazard ratio [HR] 0·76, 95% CI 0·62-0·94; p=0·010). Dulaglutide reduced ischaemic stroke (0·75, 0·59-0·94, p=0·012) but had no effect on haemorrhagic stroke (1·05, 0·55-1·99; p=0·89). Dulaglutide also reduced the composite of non-fatal stroke or all-cause death (0·88, 0·79-0·98; p=0·017) and disabling stroke (0·74, 0·56-0·99; p=0·042). The degree of disability after stroke did not differ by treatment group.

Interpretation: Long-term dulaglutide use might reduce clinically relevant ischaemic stroke in people with type 2 diabetes but does not affect stroke severity.

Funding: Eli Lilly and Company.
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http://dx.doi.org/10.1016/S2213-8587(19)30423-1DOI Listing
February 2020

The Role of Cardiolipin and Mitochondrial Damage in Kidney Transplant.

Oxid Med Cell Longev 2019 25;2019:3836186. Epub 2019 Nov 25.

Departamento de Química del Centro Universitario de Ciencias Exactas e Ingenierías, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico.

Chronic kidney disease (CKD) is highly incident and prevalent in the world. The death of patients with CKD is primarily due to cardiovascular disease. Renal transplantation (RT) emerges as the best management alternative for patients with CKD. However, the incidence of acute renal graft dysfunction is 11.8% of the related living donor and 17.4% of the cadaveric donor. Anticardiolipin antibodies (ACAs) or antiphospholipid antibodies (APAs) are important risk factors for acute renal graft dysfunction. The determination of ACA or APA to candidates for RT could serve as prognostic markers of early graft failure and would indicate which patients could benefit from anticoagulant therapy. Cardiolipin is a fundamental molecule that plays an important role in the adequate conformation of the mitochondrial cristae and the correct assembly of the mitochondrial respiratory supercomplexes and other proteins essential for proper mitochondrial function. Cardiolipin undergoes a nonrandom oxidation process by having pronounced specificity unrelated to the polyunsaturation pattern of its acyl groups. Accumulation of hydroxyl derivatives and cardiolipin hydroperoxides has been observed in the affected tissues, and recent studies showed that oxidation of cardiolipin is carried out by a cardiolipin-specific peroxidase activity of cardiolipin-bound cytochrome c. Cardiolipin could be responsible for the proapoptotic production of death signals. Cardiolipin modulates the production of energy and participates in inflammation, mitophagy, and cellular apoptosis. The determination of cardiolipin or its antibodies is an attractive therapeutic, diagnostic target in RT and kidney diseases.
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http://dx.doi.org/10.1155/2019/3836186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899302PMC
May 2020

Oxidative Stress as the Main Target in Diabetic Retinopathy Pathophysiology.

J Diabetes Res 2019 14;2019:8562408. Epub 2019 Aug 14.

Institute of Clinical and Experimental Therapeutics, Department of Physiology, Health Sciences University Center, University of Guadalajara, Mexico.

Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus (DM) causing vision impairment even at young ages. There are numerous mechanisms involved in its development such as inflammation and cellular degeneration leading to endothelial and neural damage. These mechanisms are interlinked thus worsening the diabetic retinopathy outcome. In this review, we propose oxidative stress as the focus point of this complication onset.
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http://dx.doi.org/10.1155/2019/8562408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710812PMC
March 2020

Effect of Telmisartan in the Oxidative Stress Components Induced by Ischemia Reperfusion in Rats.

Oxid Med Cell Longev 2019 2;2019:1302985. Epub 2019 Jul 2.

Instituto de Terapéutica Experimental y Clínica, Departamento de Fisiología, CUCS, Universidad de Guadalajara, Calle Sierra Mojada 950, Colonia Independencia, CP 44340 Guadalajara, Jalisco, Mexico.

The therapeutic effects of telmisartan, an angiotensin II receptor antagonist and a peroxisome proliferator-activated receptor- (PPAR-) agonist, have been demonstrated in several disorders. It has antioxidant and immune response modulator properties and has shown promising results in the treatment of an ischemia/reperfusion (I/R) lesion. In this study, a skeletal muscle (right gastrocnemius muscle) I/R lesion was induced in rats and different reperfusion times (1 h, 24 h, 72 h, 7-day, and 14-day subgroups) were assessed. Furthermore, levels of oxidative markers such as enzymatic scavengers (catalase (CAT) and superoxide dismutase (SOD)) and metabolites (nitrates and 8-oxo-deoxyguanosine) were determined. The degree of tissue injury (total lesioned fibers and inflammatory cell count) was also evaluated. We observed an increase in CAT and SOD expression levels under telmisartan treatment, with a decrease in injury and oxidative biomarker levels in the 72 h, 7-day, and 14-day subgroups. Telmisartan reduced oxidative stress and decreased the damage of the I/R lesion.
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http://dx.doi.org/10.1155/2019/1302985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636510PMC
February 2020

Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.

Lancet 2019 07 9;394(10193):121-130. Epub 2019 Jun 9.

Research Institute, FOSCAL and Medical School, Universidad de Santander UDES, Bucaramanga, Colombia.

Background: Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A (HbA) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control.

Methods: This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952.

Findings: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA 7·2% [IQR 6·6-8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1-5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79-0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80-1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001).

Interpretation: Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors.

Funding: Eli Lilly and Company.
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http://dx.doi.org/10.1016/S0140-6736(19)31149-3DOI Listing
July 2019

Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial.

Lancet 2019 07 9;394(10193):131-138. Epub 2019 Jun 9.

Research Institute, FOSCAL and Medical School, Universidad de Santander UDES, Bucaramanga, Colombia.

Background: Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease.

Methods: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952.

Findings: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p<0·0001), with HRs of 0·89 (0·78-1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39-1·44; p=0·39) for chronic renal replacement therapy.

Interpretation: Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes.

Funding: Eli Lilly and Company.
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http://dx.doi.org/10.1016/S0140-6736(19)31150-XDOI Listing
July 2019

Effect of statins on oxidative DNA damage in diabetic polyneuropathy.

J Circ Biomark 2018 Jan-Dec;7:1849454418804099. Epub 2018 Oct 3.

Department of Health-Disease Sciences as an Individual Process, Tonala University Centre, University of Guadalajara, Jalisco, México.

Oxidative stress induces nerve damage in type 2 diabetes mellitus and leads to diabetic polyneuropathy (DPN) and can affect the DNA and antioxidant status. Statins have pleiotropic, protective effects on the peripheral nerves of patients with diabetes. The aim of this study was to determine the effects of ezetimibe/simvastatin and rosuvastatin on DNA damage in patients with DPN. This randomized, double-blind, placebo-controlled, clinical trial comprised outpatients from Guadalajara, Mexico. The inclusion criteria were either gender, age 35-80 years, type 2 diabetes, glycated hemoglobin ≤10%, diabetic polyneuropathy stage 1/2, and signed informed consent. Patients who were taking antioxidant therapy or statins, had hypersensitivity to drugs, experienced organ failure, were pregnant or breastfeeding, or had other types of neuropathy were excluded. We assigned patients to placebo, ezetimibe/simvastatin 10/20 mg, or rosuvastatin 20 mg, and the primary outcomes were 8-hydroxy-2'-deoxyguanosine (8-OHdG) for DNA damage, 8-oxoguanine-DNA--glycosilase (hOGG1) for DNA repair, and superoxide dismutase (SOD). Seventy-four patients were recruited. Nine patients were included as negative controls. There were no differences in 8-OHdG between the healthy subjects (4.68 [3.53-6.38] ng/mL) and the DPN patients (4.51 [1.22-9.84] ng/mL), whereas the hOGG1 level was 0.39 (0.37-0.42) ng/mL in the healthy subjects and 0.41 (0.38-0.54) ng/mL in patients with DPN at baseline ( = 0.01). SOD decreased significantly in patients with DPN (5.35 [0.01-17.90] U/mL) compared with the healthy subjects (9.81 [8.66-12.61] U/mL) at baseline ( < 0.001). No significant changes in DNA biomarkers were observed in any group between baseline and final levels. We noted a rise in hOGG1 in patients with DPN, without modifications after treatment. There was a slight, albeit insignificant, increase in SOD in patients who were on statins.
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http://dx.doi.org/10.1177/1849454418804099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170961PMC
October 2018

Efficacy and safety of the combination of isosorbide dinitrate spray and chitosan gel for the treatment of diabetic foot ulcers: A double-blind, randomized, clinical trial.

Diab Vasc Dis Res 2018 07 23;15(4):348-351. Epub 2018 Apr 23.

1 Instituto de terapéutica experimental y clínica, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico.

Aim: To evaluate whether a combination of isosorbide dinitrate spray and chitosan gel (10%) topically applied can have additive benefits for management of diabetic foot ulcers.

Methods: In a randomized, placebo-controlled, double-blinded clinical trial, 68 patients were divided into four groups: Group 1: treated with chitosan gel; Group 2: isosorbide dinitrate spray; Group 3: combination of isosorbide dinitrate spray and chitosan gel; Group 4: placebo.

Results: Histological analyses showed a significant regeneration in all groups ( p < 0.001). On the final assessment of the ulcer, using the combination was found a wound closure percentage of 71 ± 30, 70 ± 27 using isosorbide dinitrate, 58 ± 30 with chitosan and 50 ± 16 with placebo. The number of patients who achieved complete ulcer closure was six using the combination, four with isosorbide dinitrate, three with chitosan and one with placebo. The progression in the healing process of the ulcer showed marked inmunohistochemical differences of Von Willebrand Factor, desmin, vascular endothelial growth factor-A and α-smooth muscle actin in all groups ( p < 0.001), but without notable differences between them.

Conclusion: The combination was better than placebo to reduce the dimensions of the ulcer, accelerate healing and increase the number of patients who achieved complete closure of the ulcer, but the combination was not better than chitosan or isosorbide dinitrate used separately.
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http://dx.doi.org/10.1177/1479164118769528DOI Listing
July 2018

Effect of Alpha-Lipoic Acid on Clinical and Neurophysiologic Recovery of Carpal Tunnel Syndrome: A Double-Blind, Randomized Clinical Trial.

J Med Food 2018 May 22;21(5):521-526. Epub 2018 Jan 22.

1 Institute of Experimental and Clinical Therapeutics, Health Science University Center, University of Guadalajara , Guadalajara, Jalisco, México .

The objective of our study was to examine the effect of alpha-lipoic acid (ALA) on clinical and neurophysiologic outcomes after surgery for idiopathic carpal tunnel syndrome (CTS). We conducted a randomized, double-blind, placebo-controlled clinical trial in 20 adults diagnosed with idiopathic CTS after clinical and neurophysiologic assessment. Eligible participants took 600 mg ALA or placebo per day for 1 month before surgery, and for 2 months afterward. Further clinical and neurophysiologic assessments were undertaken immediately before surgical decompression, and at 12 weeks postoperatively with additional clinical assessments at the 4th and 8th week after surgery. Clinical outcome measures were taken by Boston Questionnaire score, the presence or absence of Tinel's sign, and Phalen's test findings. Median nerve conduction studies were also undertaken and interpreted according to Dumitru's reference values. Nineteen patients completed the study; one member of the placebo group was lost during follow-up. There were significant improvements in clinical and neurophysiologic variables in the ALA treatment group, present even before surgery. Boston Questionnaire scores had improved significantly in both groups. In the ALA group, none of the participants had positive Phalen's or Tinel's signs at 12 weeks, and motor and sensory fiber latency and amplitude had significantly improved; in the placebo group, only the sensory distal latency had improved significantly. In conclusion, ALA administered 1 month before open decompression and for 2 months afterward improves the clinical and neurophysiologic outcomes after surgery.
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http://dx.doi.org/10.1089/jmf.2017.0056DOI Listing
May 2018

Identification of beta-Lactamases and beta-Lactam-Related Proteins in Human Pathogenic Bacteria using a Computational Search Approach.

Curr Microbiol 2017 Aug 16;74(8):915-920. Epub 2017 May 16.

Departamento de Fisiología, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Sierra Mojada #950, colonia Independencia, C.P. 44340, Guadalajara, Jalisco, Mexico.

A systematic analysis of beta-lactamases based on comparative proteomics has not been performed thus far. In this report, we searched for the presence of beta-lactam-related proteins in 591 bacterial proteomes belonging to 52 species that are pathogenic to humans. The amino acid sequences for 19 different types of beta-lactamases (ACT, CARB, CifA, CMY, CTX, FOX, GES, GOB, IMP, IND, KPC, LEN, OKP, OXA, OXY, SHV, TEM, NDM, and VIM) were obtained from the ARG-ANNOT database and were used to construct 19 HMM profiles, which were used to identify potential beta-lactamases in the completely sequenced bacterial proteomes. A total of 2877 matches that included the word "beta-lactamase" and/or "penicillin" in the functional annotation and/or in any of its regions were obtained. These enzymes were mainly described as "penicillin-binding proteins," "beta-lactamases," and "metallo-beta-lactamases" and were observed in 47 of the 52 species studied. In addition, proteins classified as "beta-lactamases" were observed in 39 of the species included. A positive correlation between the number of beta-lactam-related proteins per species and the proteome size was observed (R 0.78, P < 0.00001). This correlation partially explains the high presence of beta-lactam-related proteins in large proteomes, such as Nocardia brasiliensis, Bacillus anthracis, and Mycobacterium tuberculosis, along with their absence in small proteomes, such as Chlamydia spp. and Mycoplasma spp. We detected only five types of beta-lactamases (TEM, SHV, CTX, IMP, and OXA) and other related proteins in particular species that corresponded with those reported in the literature. We additionally detected other potential species-specific beta-lactamases that have not yet been reported. In the future, better results will be achieved due to more accurate sequence annotations and a greater number of sequenced genomes.
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http://dx.doi.org/10.1007/s00284-017-1265-3DOI Listing
August 2017

Serum levels of P-glycoprotein and persistence of disease activity despite treatment in patients with systemic lupus erythematosus.

Clin Exp Med 2018 Feb 27;18(1):109-117. Epub 2017 Feb 27.

Programa de Doctorado en Farmacologia, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Sierra Mojada 950, Col. Independencia, 44340, Guadalajara, Jalisco, Mexico.

Around 25% of patients with systemic lupus erythematosus (SLE) could be refractory to conventional therapies. P-glycoprotein expression on cell surface has been implied on drug resistance, however, to date, it is unknown if P-gp serum levels are associated with SLE disease activity. Evaluate the association of serum P-gp levels and SLE with disease activity despite treatment. A cross-sectional study was conducted on 93 female SLE patients, all receiving glucocorticoids at stable doses for the previous 6 months before to baseline. SLE patients were classified into two groups: (a) patients with active disease [SLE disease activity index (SLEDAI) ≥ 3] despite treatment, and (b) patients with inactive disease (SLEDAI < 3) after treatment. Forty-three healthy females comprised the control group. Serum P-gp, anti-DNA, and both anti-nucleosome antibody levels were measured using ELISA. Active-SLE patients despite treatment had higher P-gp levels compared with inactive-SLE after treatment (78.02 ng/mL ± 114.11 vs. 33.75 ng/mL ± 41.11; p = 0.018) or versus reference group subjects (30.56 ng/mL ± 28.92; p = 0.011). P-gp levels correlated with the scores of SLEDAI (r = 0.26; p = 0.01), Mexican-SLEDAI (MEX-SLEDAI) (r = 0.32; p = 0.002), SLICC/ACR damage index (r = 0.47; p < 0.001), and with prednisone doses (r = 0.33; p = 0.001). In the multivariate model, the high P-gp levels were associated with SLICC/ACR score (p = 0.001), and SLEDAI score (p = 0.014). Our findings support a relationship between serum P-gp levels and SLE with disease activity despite treatment, but it requires further validation in longitudinal studies.
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http://dx.doi.org/10.1007/s10238-017-0459-0DOI Listing
February 2018

Alternative Interventions to Prevent Oxidative Damage following Ischemia/Reperfusion.

Oxid Med Cell Longev 2016 28;2016:7190943. Epub 2016 Dec 28.

Instituto de Terapéutica Experimental y Clínica, Departamento de Fisiología, CUCS, Universidad de Guadalajara, Calle Sierra Mojada 950, Colonia Independencia, 44340 Guadalajara, Jal, Mexico.

Ischemia/reperfusion (I/R) lesions are a phenomenon that occurs in multiple pathological states and results in a series of events that end in irreparable damage that severely affects the recovery and health of patients. The principal therapeutic approaches include preconditioning, postconditioning, and remote ischemic preconditioning, which when used separately do not have a great impact on patient mortality or prognosis. Oxidative stress is known to contribute to the damage caused by I/R; however, there are no pharmacological approaches to limit or prevent this. Here, we explain the relationship between I/R and the oxidative stress process and describe some pharmacological options that may target oxidative stress-states.
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http://dx.doi.org/10.1155/2016/7190943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225393PMC
March 2017

Diabetic Polyneuropathy in Type 2 Diabetes Mellitus: Inflammation, Oxidative Stress, and Mitochondrial Function.

J Diabetes Res 2016 12;2016:3425617. Epub 2016 Dec 12.

Instituto de Terapéutica Experimental y Clínica, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, JAL, Mexico.

Diabetic polyneuropathy (DPN) is defined as peripheral nerve dysfunction. There are three main alterations involved in the pathologic changes of DPN: inflammation, oxidative stress, and mitochondrial dysfunction. Inflammation induces activation of nuclear factor kappa B, activator protein 1, and mitogen-activated protein kinases. Oxidative stress induced by hyperglycemia is mediated by several identified pathways: polyol, hexosamine, protein kinase C, advanced glycosylation end-products, and glycolysis. In addition, mitochondrial dysfunction accounts for most of the production of reactive oxygen and nitrosative species. These free radicals cause lipid peroxidation, protein modification, and nucleic acid damage, to finally induce axonal degeneration and segmental demyelination. The prevalence of DPN ranges from 2.4% to 78.8% worldwide, depending on the diagnostic method and the population assessed (hospital-based or outpatients). Risk factors include age, male gender, duration of diabetes, uncontrolled glycaemia, height, overweight and obesity, and insulin treatment. Several diagnostic methods have been developed, and composite scores combined with nerve conduction studies are the most reliable to identify early DPN. Treatment should be directed to improve etiologic factors besides reducing symptoms; several approaches have been evaluated to reduce neuropathic impairments and improve nerve conduction, such as oral antidiabetics, statins, and antioxidants (alpha-lipoic acid, ubiquinone, and flavonoids).
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http://dx.doi.org/10.1155/2016/3425617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5183791PMC
May 2017

The Oxidative and Inflammatory State in Patients with Acute Renal Graft Dysfunction Treated with Tacrolimus.

Oxid Med Cell Longev 2016 30;2016:5405847. Epub 2016 Oct 30.

Institute of Experimental and Clinical Therapeutics, Department of Physiology, University Health Sciences Centre, University of Guadalajara, Guadalajara, JAL, Mexico.

To determine the oxidative stress/inflammation behavior in patients with/without acute graft dysfunction (AGD) with Tacrolimus. Cross-sectional study, in renal transplant (RT) recipients (1-yr follow-up). Patients with AGD and without AGD were included. Serum IL-6, TNF-, 8-isoprostanes (8-IP), and Nitric Oxide (NO) were determined by ELISA; C-reactive protein (CRP) was determined by nephelometry; lipid peroxidation products (LPO) and superoxide dismutase (SOD) were determined by colorimetry. The AGD presentation was at 5.09 ± 3.07 versus 8.27 ± 3.78 months ( < 0.001); CRP >3.19 mg/L was found in 21 versus 19 in the N-AGD group ( = 0.83); TNF- 145.53 ± 18.87 pg/mL versus 125.54 ± 15.92 pg/mL in N-AGD ( = 0.64); IL-6 2110.69 ± 350.97 pg/mL versus 1933.42 ± 235.38 pg/mL in N-AGD ( = 0.13). The LPO were higher in AGD ( = 0.014): 4.10 ± 0.69 M versus 2.41 ± 0.29 M; also levels of 8-IP were higher in AGD 27.47 ± 9.28 pg/mL versus 8.64 ± 1.54 pg/mL ( = 0.01). Serum levels of NO in AGD were lower 138.44 ± 19.20 mol/L versus 190.57 ± 22.04 mol/L in N-AGD ( = 0.042); antioxidant enzyme SOD activity was significantly diminished in AGD with 9.75 ± 0.52 U/mL versus 11.69 ± 0.55 U/mL in N-AGD ( = 0.012). Patients with RT present with a similar state of the proinflammatory cytokines whether or not they have AGD. The patients with AGD showed deregulation of the oxidative state with increased LPO and 8-IP and decreased NO and SOD.
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http://dx.doi.org/10.1155/2016/5405847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107219PMC
March 2017

Effects of Ezetimibe/Simvastatin and Rosuvastatin on Oxidative Stress in Diabetic Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Oxid Med Cell Longev 2015 28;2015:756294. Epub 2015 Jul 28.

Instituto de Terapéutica Experimental y Clínica, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, 44340 Guadalajara, JAL, Mexico.

Objective: To evaluate the effects of ezetimibe/simvastatin (EZE/SIMV) and rosuvastatin (ROSUV) on oxidative stress (OS) markers in patients with diabetic polyneuropathy (DPN).

Methods: We performed a randomized, double-blind, placebo-controlled phase III clinical trial in adult patients with Type 2 Diabetes Mellitus (T2DM) and DPN, as evaluated by composite scores and nerve conduction studies (NCS). Seventy-four subjects with T2DM were allocated 1 : 1 : 1 to placebo, EZE/SIMV 10/20 mg, or ROSUV 20 mg for 16 weeks. All patients were assessed before and after treatment: primary outcomes were lipid peroxidation (LPO), and nitric oxide (NO) surrogate levels in plasma; secondary outcomes included NCS, neuropathic symptom scores, and metabolic parameters. Data were expressed as mean ± SD or SEM, frequencies, and percentages; we used nonparametric analysis.

Results: LPO levels were reduced in both statin arms after 16 weeks of treatment (p < 0.05 versus baseline), without changes in the placebo group. NO levels were not significantly affected by statin treatment, although a trend towards significance concerning increased NO levels was noted in both statin arms. No significant changes were observed for the NCS or composite scores.

Discussion: EZE/SIMV and ROSUV are superior to placebo in reducing LPO in subjects with T2DM suffering from polyneuropathy. This trial is registered with NCT02129231.
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http://dx.doi.org/10.1155/2015/756294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531178PMC
May 2016

Anti-Cyclic Citrullinated Peptide Antibodies and Severity of Interstitial Lung Disease in Women with Rheumatoid Arthritis.

J Immunol Res 2015 19;2015:151626. Epub 2015 May 19.

Programa de Doctorado en Salud Pública, CUCS, U de G, 44340 Guadalajara, JAL, Mexico ; Departamento de Medicina Interna-Reumatología y Departamento de Medicina Interna-Neumología, HGR-110, IMSS, 44700 Guadalajara, JAL, Mexico.

Objective: To evaluate whether serum titers of second-generation anticyclic citrullinated peptide antibodies (anti-CCP2) are associated with the severity and extent of interstitial lung disease in rheumatoid arthritis (RA-ILD).

Methods: In across-sectional study, 39 RA-ILD patients confirmed by high-resolution computed tomography (HRCT) were compared with 42 RA without lung involvement (RA only). Characteristics related to RA-ILD were assessed in all of the patients and serum anti-CCP2 titers quantified.

Results: Higher anti-CCP2 titers were found in RA-ILD compared with RA only (medians 77.9 versus 30.2 U/mL, P < 0.001). In the logistic regression analysis after adjustment for age, disease duration (DD), smoke exposure, disease activity, functioning, erythrocyte sedimentation rate, and methotrexate (MTX) treatment duration, the characteristics associated with RA-ILD were higher anti-CCP2 titers (P = 0.003) and + RF (P = 0.002). In multivariate linear regression, the variables associated with severity of ground-glass score were anti-CCP2 titers (P = 0.02) and with fibrosis score DD (P = 0.01), anti-CCP2 titers (P < 0.001), and MTX treatment duration (P < 0.001).

Conclusions: Anti-CCP2 antibodies are markers of severity and extent of RA-ILD in HRCT. Further longitudinal studies are required to identify if higher anti-CCP2 titers are associated with worst prognosis in RA-ILD.
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http://dx.doi.org/10.1155/2015/151626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452340PMC
March 2016

Influence of Anti-TNF and Disease Modifying Antirheumatic Drugs Therapy on Pulmonary Forced Vital Capacity Associated to Ankylosing Spondylitis: A 2-Year Follow-Up Observational Study.

J Immunol Res 2015 19;2015:980147. Epub 2015 May 19.

Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, 44340 Guadalajara, JAL, Mexico ; Hospital General Regional No. 110, Instituto Mexicano del Seguro Social (IMSS), 44716 Guadalajara, JAL, Mexico ; Departamento de Fisiologia, CUCS, Universidad de Guadalajara, 44340 Guadalajara, JAL, Mexico.

Objective: To evaluate the effect of anti-TNF agents plus synthetic disease modifying antirheumatic drugs (DMARDs) versus DMARDs alone for ankylosing spondylitis (AS) with reduced pulmonary function vital capacity (FVC%).

Methods: In an observational study, we included AS who had FVC% <80% at baseline. Twenty patients were taking DMARDs and 16 received anti-TNF + DMARDs.

Outcome Measures: changes in FVC%, BASDAI, BASFI, 6-minute walk test (6MWT), Borg scale after 6MWT, and St. George's Respiratory Questionnaire at 24 months.

Results: Both DMARDs and anti-TNF + DMARDs groups had similar baseline values in FVC%. Significant improvement was achieved with anti-TNF + DMARDs in FVC%, at 24 months, when compared to DMARDs alone (P = 0.04). Similarly, patients in anti-TNF + DMARDs group had greater improvement in BASDAI, BASFI, Borg scale, and 6MWT when compared to DMARDs alone. After 2 years of follow-up, 14/16 (87.5%) in the anti-TNF + DMARDs group achieved the primary outcome: FVC% ≥80%, compared with 11/20 (55%) in the DMARDs group (P = 0.04).

Conclusions: Patients with anti-TNF + DMARDs had a greater improvement in FVC% and cardiopulmonary scales at 24 months compared with DMARDs. This preliminary study supports the fact that anti-TNF agents may offer additional benefits compared to DMARDs in patients with AS who have reduced FVC%.
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http://dx.doi.org/10.1155/2015/980147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452441PMC
March 2016

Toll-like receptor-1 and receptor-2 and Beta-defensin in postcholecystectomy bile duct injury.

Gastroenterol Res Pract 2015 8;2015:216129. Epub 2015 Feb 8.

University Health Sciences Centre, University of Guadalajara, Avenida La Paz No. 2758, Colonia Arcos Sur, 44150 Guadalajara, JAL, Mexico.

Postcholecystectomy bile duct injuries (BDI) produce hepatic cholestasis and cause infection of the biliary tract. The biliary cells participate in secreting cytokines and in expression of immune response receptors. Toll-like receptors (TLRs) conduct signalling and activate the innate and adaptive inflammatory response. The objective was to determine the serum levels of TLR-2 and the expression of TLR-1 and TLR-2 and β-defensin in liver biopsies of postcholecystectomy BDI patients. A transverse, analytical study with 2 groups was done. One group included healthy volunteers (control group) and other included 25 postcholecystectomy BDI patients with complete biliary obstruction. Using the Enzyme-linked Immunosorbent Assay (ELISA) technique, serum levels of TLR-2 were determined, and with immunofluorescence the morphologic analysis of TLR-1 and TLR-2 and β-defensin in liver biopsies of postcholecystectomy BDI patients was performed. The average TLR-2 serum level in the control group was 0.0 pg/mL and in the BDI group, 0.023 ± 0.0045 pg/mL (P < 0.0001, bilateral Mann Whitney U). Immunofluorescence was used to determine the expression in liver biopsies, blood vessels, bile ducts, and hepatic parenchyma where 12 hepatic biopsies were positive for TLR-1 with average of 3213057.74 ± 1071019.25 μm(2); and 7 biopsies were positive for β-defensin with an average of 730364.33 ± 210838.02 μm(2); and 6 biopsies positive for TLR-2, obtaining an average of 3354364.24 ± 838591.06 μm(2). In conclusion, TLR-1 and TLR-2 and β-defensin play an important role in the innate antimicrobial defense of the hepatobiliary system.
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http://dx.doi.org/10.1155/2015/216129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337755PMC
March 2015

Effect of necrosectomy and vacuum-assisted closure (VAC) on mitochondrial function and oxidative stress markers in severe acute pancreatitis.

Rev Esp Enferm Dig 2014 Dec;106(8):505-14

Background: Severe acute pancreatitis (SAP) is associated with high morbidity and mortality.

Objective: To evaluate whether necrosectomy, alone or combined with vacuum-assisted closure (VAC), has any additional beneficial effects on mitochondrial function and/or oxidative stress markers in SAP.

Methods: Patients with SAP, APACHE II score > 8, and inadequate response to management in an intensive care unit were included in a prospective observational study. Sixteen underwent necrosectomy and 24 underwent necrosectomy plus VAC every 48 h. Patients were then categorized as survivors or deceased. Submitochondrial membrane fluidity of platelets and F0F1-ATPase hydrolysis were measured to represent mitochondrial function. Oxidative/nitrosative stress was measured using lipoperoxides (LPOs), nitric oxide (NO), erythrocyte membrane fluidity, and total antioxidant capacity (TAC).

Results: Membrane fluidity in submitochondrial particles of platelets remained significantly increased throughout the study, and then eventually rised in deceased patients managed with necrosectomy + VAC vs. survivors (p < 0.041). Hydrolysis was significantly increased from baseline to endpoint in all patients, predominating in those who died after management with necrosectomy (p < 0.03). LPO increased in all patients, and necrosectomy was more efficient for the eventual decrease in survivors (p < 0.039). NO was found to be increased for the baseline-endpoint result among both survivors and deceased patients with both management options. Erythrocyte membrane fluidity was increased in survivors managed with necrosectomy + VAC, and eventually returned to normal (p < 0.045). TAC was found to be consumed in all patients for the duration of the study.

Conclusions: Mitochondrial dysfunction and oxidative/ nitrosative stress with significant systemic antioxidant consumption were found. Necrosectomy was more efficient and better cleared LPOs. Necrosectomy + VAC improved erythrocyte membrane fluidity and increased survival.
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December 2014

Dietary flavonoids added to pharmacological antihypertensive therapy are effective in improving blood pressure.

Basic Clin Pharmacol Toxicol 2015 Jul 29;117(1):57-64. Epub 2014 Dec 29.

Clinical Analysis Laboratory, IMSS Merida, Yucatan, Mexico.

Epidemiological studies have suggested that the daily intake of flavonoids is associated with a decreased risk of developing cardiovascular disease. Our purpose was to evaluate the effect of the addition of dietary flavonoids (DF) to antihypertensive treatment (AHT), based on telmisartan (Tms) or captopril (Cpr), on blood pressure (BP), body mass index (BMI), waist/hip ratio, leptin, lipid profile and inflammation in hypertensive young patients. An open-label, randomized, controlled trial was performed among 79 patients aged 20-55 years with grade I or grade II systemic arterial hypertension. The subjects were assigned to one of four groups for AHT plus DF during 6 months: Cpr (n = 14), Cpr + DF (n = 19), Tms (n = 25) and Tms + DF (n = 21). DF consisted of dark chocolate, dehydrated red apple and green tea in an infusion to obtain a daily dose of 425.8 ± 13.9 mg epicatechin equivalents. The BP and anthropometric parameters were measured every 2 weeks. Lipid profile, leptin and hsCRP were determined by standard methods. The combination AHT-DF produced an additional and significant reduction in (i) SBP/DBP of -5/-4 mmHg, being -7/-5 for Cpr + DF and -4/-3 for Tms + DF; (ii) triglyceride levels (-30.6%) versus AHT alone (-9.6%); and (iii) leptin: Cpr + DF versus Tms + DF (p < 0.005). Finally, C-reactive protein plasma levels were reduced significantly in all groups independently of the applied treatment. We conclude that the addition of flavonoids to pharmacological antihypertensive therapy shows additional benefits on BP, lipid profile, leptin, obesity and inflammation.
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http://dx.doi.org/10.1111/bcpt.12360DOI Listing
July 2015

Modifications in lipid levels are independent of serum TNF-α in rheumatoid arthritis: results of an observational 24-week cohort study comparing patients receiving etanercept plus methotrexate or methotrexate as monotherapy.

Biomed Res Int 2014 27;2014:510305. Epub 2014 Aug 27.

Departamento de Medicina Interna-Reumatologia, Hospital General Regional 110, IMSS, 44716 Guadalajara, JAL, Mexico ; Programa de Doctorado en Salud Publica, CUCS, U de G, 44340 Guadalajara, JAL, Mexico.

Objective: To compare the modifications in lipids between patients with rheumatoid arthritis (RA) receiving etanercept plus methotrexate (ETA + MTX) versus methotrexate (MTX) and their relationship with serum levels of tumor necrosis factor-alpha (TNF-α).

Methods: In an observational cohort study, we compared changes in lipid levels in patients receiving ETA + MTX versus MTX in RA. These groups were assessed at baseline and at 4 and 24 weeks, measuring clinical outcomes, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, and TNF-α.

Results: Baseline values for lipid levels were similar in both groups. HDL-C levels increased significantly only in the ETA + MTX group (from 45.5 to 50.0 mg/dL at 4 weeks, a 10.2% increase, P < 0.001, and to 56.0 mg/dL at 24 weeks, a 25.1% increase, P < 0.001), while other lipids underwent no significant changes. ETA + MTX also exhibited a significant increase in TNF-α (44.8 pg/mL at baseline versus 281.4 pg/mL at 24 weeks, P < 0.001). The MTX group had no significant changes in lipids or TNF-α. Significant differences in HDL-C between groups were observed at 24 weeks (P = 0.04) and also in TNF-α  (P = 0.01).

Conclusion: HDL-C levels increased significantly following treatment with ETA + MTX, without a relationship with decrease of TNF-α.
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http://dx.doi.org/10.1155/2014/510305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160615PMC
June 2015

Effect of rosuvastatin on diabetic polyneuropathy: a randomized, double-blind, placebo-controlled Phase IIa study.

Diabetes Metab Syndr Obes 2014 4;7:401-7. Epub 2014 Sep 4.

Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Jalisco, México.

Background: Diabetic neuropathy affects 50%-66% of patients with diabetes mellitus. Oxidative stress generates nerve dysfunction by causing segmental demyelinization and axonal degeneration. Antioxidants are considered to be the only etiologic management for diabetic polyneuropathy, and statins such as rosuvastatin increase nitric oxide bioavailability and reduce lipid peroxidation. The aim of this study was to evaluate the antioxidant effect of rosuvastatin in diabetic polyneuropathy.

Methods: We conducted a randomized, double-blind, placebo-controlled Phase IIa clinical trial in patients with type 2 diabetes and diabetic polyneuropathy (DPN) stage ≥1b. We allocated subjects to two parallel groups (1:1) that received rosuvastatin 20 mg or placebo for 12 weeks. Primary outcomes were neuropathic symptom score, disability score, and nerve conduction studies, and secondary outcomes were glycemic control, lipid and hepatic profile, lipid peroxidation, and nerve growth factor beta (NGF-β) levels.

Results: Both groups were of similar age and duration since diagnosis of diabetes and DPN. We observed improvement of DPN in the rosuvastatin group from stage 2a (88.2%) to stage 1b (41.2%), improvement of neuropathic symptom score from 4.5±2 to 2.4±1.8, and significant (P=0.001) reductions of peroneal nerve conduction velocity (from 40.8±2.2 to 42.1±1.6 seconds) and lipid peroxidation (from 25.4±2 to 12.2±4.0 nmol/mL), with no significant change in glycemic control or β-NGF.

Conclusion: The severity, symptoms, and nerve conduction parameters of DPN improved after 12 weeks of treatment with rosuvastatin. These beneficial effects appear to be attributable to reductions in lipid peroxidation and oxidative stress.
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http://dx.doi.org/10.2147/DMSO.S65500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159311PMC
September 2014