Serum Tumor Necrosis Factor-alpha Research Articles

Exercise-induced downregulation of serum interleukin-6 and tumor necrosis factor-alpha in Egyptian handball players.

Muscles of candidates work at various grades of intensity during handball exercises according to the pace of exercise. The movement pattern involves large number of contractions, feints, dodges and numerous changes in movements, all of which are highly responsible for changes in trainer's organs, including the immune system. In this study, inflammatory mediators involving interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in serum of 18 Egyptian male handball players, selected from Tanta club handball under 21 year’s old team, were analyzed. The analysis was established on samples collected just before and immediately after intermediate reasonable exercise via enzyme linked immunosorbent assay (ELISA). Moreover, white blood cells (WBCs) count and other hematological markers including hemoglobin %, hematocrit value, and platelet count were assessed. Our results demonstrated a significant decrease in the levels of IL-6 and TNF-α after exercise compared to those before exercise. This was coupled with an increase in WBCs and platelets count. It is also noteworthy that there was a significant positive correlation between serum levels of IL-6 and TNF-α in the study subjects coupled with a significant negative correlation between IL-6 and WBCs after the exercise. Therefore, it is concluded that intermediate reasonable exercises result in decreased levels of IL-6 and TNF-α, which result in decreasing of the inflammation and help in healing and rapid recovery of muscles of the candidates.

Effects of rhamnolipids on growth performance and intestinal health parameters in Linnan yellow broilers

This study determined the effects of dietary supplementation of rhamnolipids (RLS) on the growth performance, gut morphology, immune function, intestinal volatile fatty acid, and microflora community in Linnan yellow broilers. A total of 480 1-day-old broiler chicks were randomly assigned to groups for supplementation with one of the following for 56 d: no supplement (control), 30 mg/kg bacitracin (ANT), 500 mg/kg RLS, or 1,000 mg/kg RLS (RLS2). The RLS2 diet was found to improve the final BW and ADG on day 56. The RLS diet reduced jejunal crypt depth, increased jejunal villus length, and increased serum IgA, IgM, IgY, IL-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) levels. The RLS broilers had higher cecum concentrations of acetic acid, propionic acid, butyrate, isobutyric acid, valerate, and isovalerate. High-throughput sequencing indicated that RLS affected microbial quantity and diversity in the cecum. Bacterial richness was higher in the RLS broilers than the ANT broilers. The RLS broilers had higher relative abundances of Megasphaera hypermegale and Lachnospiraceae bacterium 19gly4 on day 28 and Clostridium spiroforme and Alistipes obesi on day 56. These results suggest that RLS supplementation improves growth performance, benefits the intestinal villus morphology, regulates host immune function, and raises intestinal volatile fatty acid content and the relative abundance of the gut microbiota in broiler chickens.

Clinical Immunological Correlations in Patients with Multiple Sclerosis Treated with Natalizumab.

Natalizumab (NAT) was the first disease modifying therapy used for the treatment of relapsing-remitting multiple sclerosis (MS) that was designed with a specific mechanism of action that targets an important step of the MS immunopathology, directly blocking the T lymphocyte intrusion in the central nervous system. Initially, it was considered that NAT carried no biological effects on the peripheral immune response. The purpose of our study was to assess the effects of NAT on the peripheral pro and anti-inflammatory cytokines and to reveal possible correlations between them and the clinical activity of the disease. We noticed a significant decrease in interleukin (IL)-17, tumor necrosis factor-alpha (TNF-α) and IL-31 serum levels in treated patients. The lack of relapses during the study was associated with low baseline IL-17 level. The patients that had an increase in the disability score during the study had significantly lower IL-17 and higher IL-1β baseline levels. IL-17 can be used as a biomarker for disease activity but also for progression assessment in NAT treated patients. NAT has a far more complex mechanism compared to what was initially believed, besides modulating lymphocyte trafficking through the blood–brain barrier, it also changes the peripheral levels of pro and anti-inflammatory cytokines in MS patients.

Nicorandil and atorvastatin attenuate carbon tetrachloride – induced liver fibrosis in rats

Purpose The present study aimed to evaluate the possible hepatoprotective effects of nicorandil and atorvastatin against experimentally induced liver fibrosis. Materials and methods Wistar male rats wereassigned tofivegroups; control group, fibrosis group, the remaining three groups received in addition to CCl4, N-acetyl cysteine (300 mg/kg), nicorandil(15 mg/kg) and atorvastatin (20 mg/kg), respectively. Liver fibrosis was induced by intraperitoneal injection of rats with CCl4 (2 ml/kg), twice weekly for five consecutive weeks. All treatments were administered daily starting from the first day of fibrosis induction for five consecutive weeks. By the end of the experiment, fibrosis biomarkers [hepatic transforming growth factor β1 (TGF-β1) and hydroxyproline (HYP)], liver function [serum alanine transaminase (ALT), aspartate transaminase (AST), albumin and total bilirubin] were assessed. Moreover, lipid profile [total cholesterol, serum triglycerides, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)], inflammatory biomarkers [hepatic myeloperoxidase (MPO), serum tumor necrosis factor alpha (TNF-α)], relative liver weight] and oxidative stress biomarkers [malondialdehyde (MDA), glutathione (GSH) and catalase (CAT)] were evaluated. In support, histopathological and immunohistochemical examination of liver alpha smooth muscle actin (α-SMA) were performed. Results Nicorandil and atorvastatin effectively reduced fibrosis and liver function biomarkers. They both restored serum lipid profile, TNF-α, MPO, relative liver weight, and hepatic MDA content. Alternatively, they markedly elevated albumin, HDL-C and hepatic content of GSH and CAT. Additionally, a marked histopathological and immunohistochemical improvement of α-SMA was observed. Conclusion Nicorandil and atorvastatin might be promising protective agents against liver fibrosis through amelioration of liver function, modulation of fibrous formation, anti-inflammatory and antioxidant potentials.

Impact of tissue macrophage proliferation on peripheral and systemic insulin resistance in obese mice with diabetes

IntroductionObesity-related insulin resistance is a widely accepted pathophysiological feature in type 2 diabetes. Systemic metabolism and immunity are closely related, and obesity represents impaired immune function that predisposes individuals to...

Effect of Zhongyi paste on inflammatory pain in mice by regulation of the extracellular regulated protein kinases 1/2-cyclooxygenase-2-prostaglandin E2 pathway.

BackgroundZhongyi paste is a traditional Chinese medicine herbal paste that is externally applied to reduce inflammation and relieve pain.MethodsAn acute foot swelling inflammation model in C57BL/6J mice was established by carrageenan-induced pathogenesis. Zhongyi paste raised the pain threshold and also reduced the degree of swelling in mice with carrageenan-induced foot swelling.ResultsAnalysis indicated that serum tumor necrosis factor-alpha, interleukin-1 beta, and prostaglandin E2 (PGE2) cytokine levels and PGE2 levels in the paw tissue of the mice were decreased by Zhongyi paste treatment. The quantitative polymerase chain reaction and western blot results showed that Zhongyi paste downregulated the mRNA and protein expression of extracellular signal-regulated kinase 1/2 (ERK1/2), and cyclooxygenase-2 (COX-2), and also downregulated the mRNA expression of PGE2. At the same time, the Zhongyi paste exerted a stronger effect as an external drug than that of indomethacin, which is an oral drug, and voltaren, which is an externally applied drug.ConclusionsOur results indicated that Zhongyi paste is a very effective drug to reduce inflammatory swelling of the foot, and its mechanism of action is related to regulation of the ERK1/2–COX-2–PGE2 pathway.

New Insights into the Pathogenesis of Non-Alcoholic Fatty Liver Disease: Gut-Derived Lipopolysaccharides and Oxidative Stress.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. The intricate NAFLD pathogenesis is summarized by the multiple-hits hypothesis, which combines all the environmental and genetic factors that promote the development of NAFLD into a single scenario. Among these, bacterial lipopolysaccharides (LPS) are derived from the overgrowth of Gram-negative bacteria and translocated mainly as a consequence of enhanced intestinal permeability. Furthermore, oxidative stress is increased in NAFLD as a consequence of reactive oxygen species (ROS) overproduction and a shortage of endogenous antioxidant molecules, and it is promoted by the interaction between LPS and the Toll-like receptor 4 system. Interestingly, oxidative stress, which has previously been described as being overexpressed in cardiovascular disease, could represent the link between LPS and the increased cardiovascular risk in NAFLD subjects. To date, the only effective strategy for the treatment of NAFLD and non-alcoholic steatohepatitis (NASH) is the loss of at least 5% body weight in overweight and/or obese subjects. However, the dose-dependent effects of multispecies probiotic supplementation on the serum LPS level and cardiometabolic profile in obese postmenopausal women were demonstrated. In addition, many antibiotics have regulatory effects on intestinal microbiota and were able to reduce serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and tumor necrosis factor alpha (TNF-α) in NASH animal models. Regarding the oxidant status, a Mediterranean diet has been reported to reduce oxidant stress, while vitamin E at high daily dosages induced the resolution of NASH in 36% of treated patients. Silymarin had the positive effect of reducing transaminase levels in NAFLD patients and long-term treatment may also decrease fibrosis and slow liver disease progression in NASH. Finally, the influence of nutraceuticals on gut microbiota and oxidant stress in NAFLD patients has not yet been well elucidated and there are insufficient data either to support or refuse their use in these subjects.

Icariin enhances AMP-activated protein kinase and prevents high fructose and high salt-induced metabolic syndrome in rats

Metabolic syndrome (MetS) is an increasing health threat and often leads to cardiovascular complications. The aim of this study was to evaluate icariin’s ability to combat MetS induced in rats and outline the involved mechanisms of action. Rats were grouped in four batches. The controls received a regular diet and water. MetS was induced in the remaining three groups using a high-salt high-fructose diet. Groups 1 and 2 were given daily doses of saline, while Groups 3 and 4 received 25 and 50 mg/kg icariin, respectively, for 12 weeks in total. The experimental protocol was carried out for 12 weeks consecutively. Icariin significantly decreased body mass index (BMI), adiposity index and body weight. Further, icariin protected against dyslipidemia, hyperglycemia, and hyperinsulinemia and improved insulin resistance as given by the homeostatic model assessment of insulin resistance (HOMA-IR) values. Icariin guarded against the rise in serum interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). In addition, it significantly inhibited the decrease in mRNA expression of glucose transporter type 4 (GLUT4) and liver kinase B1 (LKB1). These effects were accompanied by decreased liver content of nuclear factor kappa B (NFκB) and enhanced serum levels of phosphorylated 5ʹ-adenosine monophosphate-activated protein kinase (p-AMPK). Further, icariin significantly increased p-AMPK/AMPK ratio in liver tissues. Conclusively, icariin offers protection in experimentally induced MetS, partially due to AMPK activation.

Immunomodulatory and Antioxidant Effects of Polysaccharides from the Parasitic Fungus Cordyceps kyushuensis.

The ascomycete Cordyceps genus has been used as valued traditional Chinese medicine. Cordyceps kyushuensis is a unique species of Cordyceps, which parasitizes on the larvae of Clanis bilineata Walker, and its major component cordycepin and aqueous extract are known to have many pharmacological effects. However, the physiological function of water-soluble polysaccharides has not been explored in detail. In this study, to resolve these doubts, we extracted and separated Cordyceps-derived polysaccharides and then evaluated the immunomodulatory and antioxidant activities. Four polysaccharide fractions were purified from Cordyceps-cultured stroma by DEAE-cellulose 23 and Sephadex G-150 column chromatography. Basic structural information was elucidated on the basis of physicochemical property and spectroscopic evidences. The antioxidant activities were evaluated by a 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical method and protective effect of DNA damage. The qualified immunologic activities were also determined in vivo and in vitro. The polysaccharides could stimulate the proliferation of mouse splenocytes whether concanavalin A (ConA) and lipopolysaccharide (LPS) existed or not, strengthen peritoneal macrophages to devour neutral red, and increase the content of interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-α) in serum. The research provides the corresponding evidence for Cordyceps polysaccharides as a potential candidate for functional foods and therapeutic agents.

Resveratrol Nanoemulsion; A Promising Inhibitor against Mitogen-Activated Protein Kinase - Dependent Inflammation and Ameliorates Nicotine induced-lung Toxicity in Rats

Background: Nicotine, a major component of cigarette smoke, plays an important role in the development of cardiovascular disease and lung cancer in smokers. The aim of the present article was to investigate protective activity of resveratrol nanoemulsion (RENE) against lung toxicity induced by nicotine in adult rats as compared to basic resveratrol. Materials and Methods: RENE was prepared using bovine serum albumin method, then characterized for their particle size and zeta potential. Furthermore, Adult albino rats weighing around 150 ±10 g were used for the evaluation of lung protective activity of RENE (50 mg/k.b.w.) against nicotine-induced lung toxicity in rats. Results: The mean particle size of RENE was 49.5 ± 0.05 nm and zeta potential of +15.75 with the observed shapes of nanoparticle was spherical. The daily oral administration of the RENE at a concentration of 39.75 mg/kg body weight for 30 days to rats treated with nicotine (2.5 mg/kg.b.w.) resulted in a significant improve plasma cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol as well as serum tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and growth factor (TGF)-β1 in nicotine treated groups rats. On the other hand, oral administration of RENE elevated the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx) and total protein kinase-1 (Akt-1) as well as reduced the level malondialdehyde (MDA) in lung rats treated with nicotine. In addition, RENE reduced the expression of lung inducible nitric oxide synthase (iNOS) and mitogen-activated protein kinase (p38-MAPK) levels as compared to nicotine treated control group. Also, RENE and resveratrol almost normalized these effects in the histoarchitecture of the lung. Conclusion: The obtained biochemical, molecular biology and histological results of our study proved the lung protective activity of RENE against nicotine induced lung toxicity in rats.

Role of inflammation in childhood epilepsy and ADHD comorbidity

Epilepsy is a heterogeneous disorder that is not limited to experiencing seizures but also includes multiple neuropsychiatric squeal (i.e. attention-deficit/hyperactivity disorder (ADHD), depression and anxiety) that adversely impact a child quality of life. However, the underlying mechanism linking both disorders is not yet thoroughly explored. Our objective was to assess pro-inflammatory cytokines levels in children with seizure controlled epilepsy and explore the association between pro-inflammatory cytokines and the co-occurrence of ADHD in such children. A cross-sectional study included 50 children with controlled epilepsy for at least one year, in addition to 30 neurotypical children as controls. All children were assessed by the Conner parent scale for ADHD. Serum interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels were measured and correlated to clinical data. In the present study, 23 out of 50 children with epilepsy also had ADHD (46%). Children with ADHD have been found to have a significantly lower age of onset, longer duration of epilepsy, and a higher serum level of IL-6 and TNF-α than those without ADHD. The Conner's parent rating scale overall total score yielded significant negative correlations with the age of onset of epilepsy and a significant positive correlation with the duration of epilepsy and pro-inflammatory cytokine levels. In addition to active seizures, the presence of elevated circulating inflammation markers may be associated with increased frequency of ADHD in children with epilepsy aged 6-14 years.

Association between adipokines and thyroid carcinoma: a meta-analysis of case-control studies

BackgroundThe incidence of thyroid carcinoma is increasing all over the world. Some studies have suggested that the change of adipokines expression can induce thyroid carcinoma. However, other studies have come to the opposite conclusion. Therefore, we studied the relationship between adipokines and thyroid carcinoma.MethodsDatabases—PubMed, Cochrane Library, SinoMed, CNKI, Wanfang, and clinical trial registries were searched. A meta-analysis was then performed through a fixed or random-effects model to calculate I values for heterogeneity analysis.ResultsTwenty-nine articles were finally included for analysis. The level of serum tumor necrosis factor-alpha (TNF-α) [standardized mean difference (SMD) =1.31, 95% confidence interval (95% CI): 0.35 to 2.28, I2 = 98%, P = 0.008] and the ratio of TNF-α immunoreactivity in tissues [odds ratios (OR) =6.36, 95% CI: 1.92 to 21.05, I2 = 66%, P = 0.002] in thyroid carcinoma are significantly higher than those in control. The serum interleukin-6 (IL-6) in patients with thyroid carcinoma is higher than that in control (SMD = 1.04, 95% CI: 0.40 to 1.67, I2 = 96%, P = 0.001). There is no significant difference of the ratio of IL-6 immunoreactivity in tissues between carcinoma and control (OR = 1.23, 95% CI: 0.62 to 2.43, I2 = 86%, P = 0.55). The ratio of leptin immunoreactivity in tissues is significantly associated with the risk of thyroid carcinoma (OR = 12.21, 95% CI: 3.36 to 44.40, I2 = 85%, P < 0.00001). However, after analyzing the expression level of serum adiponectin in three studies, no significant difference is found between thyroid carcinoma and the control (P = 0.81).ConclusionsAdipokines (TNF-α, IL-6 and leptin) show a strong relationship between elevated concentrations (in serum and/or tissue) and thyroid carcinoma. However, the association between adiponectin and thyroid carcinoma needs further research.

Association between TNFA, IL10 and IL18 promoter gene variants and cognitive functions in patients with relapsing-remitting multiple sclerosis

ObjectivesTo investigate the relationship between TNFA-308G > A, IL10–1082A > G, IL18-607C > A, and cognitive functioning in relapsing-remitting multiple sclerosis (RRMS). ResultsIn the patients' group: AG genotype of TNFA-308G > A was associated with higher serum tumor necrosis factor-alpha (TNF-alpha) than GG genotype, and higher TNF-alpha levels correlated with poorer results on Symbol Digit Modalities Test; CC genotype of IL18-607C > A was related to lower score on Isaacs test, compared to AC variant; AA genotype of IL10–1082A > G was associated with abnormally low results on Paced Auditory Series Addition Test. ConclusionsTNFA-308G > A, IL10–1082A > G and IL18-607C > A gene variants may be associated with impaired cognitive functions in RRMS patients.

Mesenchymal Stem Cells Decrease M1/M2 Ratio and Alleviate Inflammation to Improve Limb Ischemia in Mice.

BackgroundLimb ischemia (LI) is the underlying pathology of peripheral artery disease (PAD). Macrophages play a critical role in inflammation and can contribute to the exacerbation or reduction of inflammation. Transplantation of mesenchymal stem cells (MSCs) is an emerging therapeutic strategy for PAD. However, the mechanism by which human placenta-derived mesenchymal stem cells (PMSCs) regulate macrophage differentiation in ischemic tissue remains unclear.Material/MethodsPlacentas were obtained from healthy donors with normal 38- to 40-week gestation, and PMSCs were isolated from the placentas and cultured. A mouse model of hind-limb ischemia was established. Ischemic limbs were injected intramuscularly with about 5×106 PMSCs in the PMSCs group or a placebo solution (phosphate-buffered saline) in the control group at 4 different sites 1 day after the procedure. The blood perfusion of hind-limbs and the histological morphology were observed at day 1, 7, and 14 after the surgical procedure. Macrophages were detected by flow cytometry. The expression of serum tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-10 were detected by enzyme-linked immunosorbent assay (ELISA). The expression of CD31 and smooth muscle α-actin (α-SMA) in frozen muscle samples were detected by immunofluorescence staining.ResultsIn the PMSCs group, blood perfusion was gradually recovered and ischemic injury was markedly alleviated. The percentage of M2-like macrophages was increased dramatically, while the M1/M2 macrophage ratio was reduced. The expression of TNF-α and IL-6 was reduced, while the IL-10 level was elevated. The expression and density of CD31- and α-SMA-positive vessels were both significantly increased.ConclusionsTransplanted PMSCs alleviated inflammation, promoted neovascularization, and improved hind limb ischemia through regulating macrophage differentiation toward the M2 phenotype and cytokine secretion. Cytokine manipulation of macrophage phenotypes may have potential therapeutic benefits in injured ischemic limbs.

Serum and Plasma Tumor Necrosis Factor Alpha Levels in Individuals with Obstructive Sleep Apnea Syndrome: A Meta-Analysis and Meta-Regression.

Background: Obstructive sleep apnea syndrome (OSAS) is associated with a variety of inflammatory factors. Specifically, proinflammatory cytokines appear to be associated with the pathogenesis of OSAS. Methods: For the present meta-analysis and meta-regression on serum and plasma tumor necrosis factor alpha (TNF-α) levels in individuals with and without OSAS, we performed a systematic search without any restrictions of the PubMed/Medline, Scopus, Cochrane Library, and Web of Science databases to find relevant articles published up to 1 February 2020. Results: Fifty-five (adults: 29 studies on serum and 17 studies on plasma; children: 4 studies on serum and 5 studies on plasma) were included and analyzed. Always compared to age-matched healthy controls, the pooled MDs were as follows: adults, serum: 10.22 pg/mL (95% CI = 8.86, 11.58; p < 0.00001); adults, plasma: 5.90 pg/mL (95% CI = 4.00, 7.80; p < 0.00001); children, serum: 0.21 pg/mL (95% CI = 0.05, 0.37; p = 0.01); children, plasma: 5.90 pg/mL (95% CI = 4.00, 7.80; p < 0.00001). Conclusions: Compared to healthy and age-matched controls, adult individuals with OSAS had significantly higher serum/plasma TNF-α levels. For children with OSAS, significantly higher levels were observed for TNF-α in serum but not in plasma.

Hepatoprotective effects and mechanisms of Ixeris denticulate water extract on liver cirrhosis in experimental rat

BackgroundTo explore the protective effect and mechanisms of Ixeris denticulate water extract (IDWE) in the development of liver cirrhosis in experimental rat.MethodsSixty rats were randomly divided into five groups: control group, model group and IDWE (2, 4 and 8 g/kg) treatment groups. Alanine transferase (ALT), aspartate transaminase (AST), albumin (ALB), tumor necrosis factor-alpha (TNF-α), Interleukin (IL)-6 and IL-8 in serum and superoxide dismutase (SOD), malondialdehyde (MDA) in liver tissue were evaluated, respectively. The liver index, liver morphology and liver histopathological analysis were detected as a supportive data. The liver protein expression of Bcl-2 and Bax were assessed by western blot, and NF-κB p65 protein expression was determined by immunohistochemistry analysis.ResultsThe result showed that a significantly decrease in the levels of serum AST, ALT and serum inflammatory factors TNF-α, IL-6 and IL-8 in IDWE-treated rats. The levels of serum ALB and SOD in liver tissue were markedly increased after IDWE treated, compared with model rats. Furthermore, IDWE-treated group also exhibited a down-regulated protein expression of NF-κB p65 and Bax, up-regulated Bcl-2 protein expression.ConclusionsIDWE could effectively alleviate the course of liver cirrhosis in rat model, which may be a potent hepatoprotective agent in clinical therapy in the future.

Anti-inflammatory Effect of Woodfordia fructicosa Leaves Ethanolic Extract on Adjuvant and Carragenan Treated Rats.

Background: Woodfordia fructicosa is used traditionally for the treatment of inflammation associated with arthritis.Methods: In the present study, the anti-inflammatory activity of W. fructicosa (WFE) leaves ethanolic extract was assessed in Sprague Dawley rats by giving 200 mg/kg dose orally. Inflammation was studied by using carrageenan induced paw edema, Freund’s adjuvant (FA) and monosodium iodo acetate (MIA) induced arthritis as animal models. Serum tumor necrosis factor-alpha (TNF-α) was estimated in blood sample of animals treated with FA. The one way ANOVA followed by Bonferroni’s test was used for statistical analysis.Results: WFE significantly decreased (P<0.05, P<0.001) paw thickness in carrageenan induced paw edema and FA induced arthritis. The significant decrease in knee diameter (P<0.001) in MIA induced arthritis as well as inhibitory effect (P<0.001) on elevated TNF-α was observed.Conclusion: These results showed that the WFEexerted an inhibitory effect on TNF-α and carrageenan paw edema which may justify its traditional use in inflammatory conditions. Thus, the study shows that leaves of W. fruticose afford anti-inflammatory activity by preventing the inflammation in different animal models.

P1008THERAPY WITH SODIUM-GLUCOSE COTRANSPORTER TYPE 2 INHIBITORS INCREASES KLOTHO IN TYPE 2 DIABETIC PATIENTS

Abstract Background and Aims Klotho (KL) is a transmembrane protein that is expressed the highest in the tubular cells of the kidneys. In addition to membrane KL, a secreted form of this protein that is present in blood and urine is generated by ectodomain shedding of membrane KL from the cell surface or from the KL gene through alternative splicing. Preserved KL expression has been related to physiological protection in the human kidneys. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a new class of antidiabetic drugs with important renal benefits. The aim of the present proof-of-concept study was to analyze if treatment with SGLT2i is associated with changes in soluble KL concentrations as well as with modifications in mRNA expression levels of the KL gene in renal tubular cells. Method Thirty-four patients (18 males and 16 males; mean age 61±5 years) with type 2 diabetes (mean diabetes time higher than 10 years) and CKD G2-A2, all treated with metformin and blockers of the renin-angiotensin system during more than one year, were included in the study. Twenty-four of them received SGLT2i during 6 months (8 empagliflozin, 8 canagliflozin, 8 dapagliflozin), and their data and evolution were compared with a group of 10 patients matched by age, sex and stage of CKD who received sulfonylureas or DPP4 inhibitors. Serum and urine levels of soluble KL and tumor necrosis factor-alpha (TNFa) were determined by ELISA. In addition, the effect of SGLT2i on mRNA expression levels of KL was assessed in vitro in renal tubular cells cultures. Results Baseline median values of serum and urinary KL and TNFa were similar in both groups. Urinary KL was inversely correlated with albuminuria and TNFa excretion (r = -0.39 and r = -0.37, respectively, P&amp;lt;0.05). There were no relationship between the serum and urinary levels of these molecules, suggesting their renal origin. At the end of the study, there was a similar improvement in metabolic control, with a reduction in blood pressure significantly higher in patients treated with SGLT2i. Estimated glomerular filtration rate and albuminuria decreased by 5.8% and 17%, respectively, in subjects receiving SGLT2i (P&amp;lt;0.0001), without changes in the control group. In patients under SGLT2i therapy there was a 21% significant reduction in urinary TNFa with a concomitant 41% increase in urinary KL (P&amp;lt;0.001); there was also a small but significant rise in serum KL (P&amp;lt;0.01 vs baseline). Partial correlation analysis showed that the changes in the urinary excretion of albumin and TNFa were associated with the variation in urinary KL after controlling for other variables (r = -0.50, P&amp;lt;0.01, and r = -0.41, P&amp;lt;0.05, respectively). Finally, renal tubular cells cultured with dapagliflozin showed a significant and dose-dependent increase of mRNA expression levels of KL. Conclusion Treatment with SGLT2i induces a reduction in albuminuria and modulates inflammation (as reflected by a decrease in the urinary excretion of TNFa), which is associated with a significant increase in soluble KL concentrations as well as mRNA expression levels of the KL gene. The preservation of KL by SGLT2i may be an important mechanism of renal protection in type 2 diabetes.

Impact of a short-term synbiotic supplementation on metabolic syndrome and systemic inflammation in elderly patients: a randomized placebo-controlled clinical trial.

The connection between gut microbiota imbalance, inflammation and its role in the pathogenesis of metabolic syndrome (MetS) clustering factors has been increasingly recognized. However, data on the efficacy of probiotics supplementation on MetS components are few and almost lacking in the elderly. To address this issue, we conducted a randomized, double-blind, placebo-controlled, parallel-group, clinical study on a large sample of MetS elderly patients. After 14days of diet and physical activity standardization, 60 elderly patients were randomized to treatment with a synbiotic formula of Lactobacillus plantarum PBS067, Lactobacillus acidophilus PBS066 and Lactobacillus reuteri PBS072 with active prebiotics or placebo. Patients were evaluated anamnestically and by the execution of a physical examination and laboratory and haemodynamic analyses at the baseline and after 60days of treatment. At enrollment and at the end of the trial, all enrolled patients complete the EuroQol-5 Dimension (EQ-5D) questionnaire. Through the 2-month period of treatment, patients who received active treatment experienced a statistically significant improvement in waist circumference and in fasting plasma insulin, total cholesterol, high-density lipoprotein cholesterol, non-HDL-C, triglycerides (TG), low-density lipoprotein cholesterol, high-sensitivity C-reactive protein and tumor necrosis factor alpha serum levels, compared both to the baseline and the control group. Visceral adiposity index improvement in the synbiotic treatment group was significantly greater than in placebo group. Compared to baseline, treatment with synbiotics also significantly reduced mean arterial pressure and fasting plasma glucose. All treatment groups demonstrated a significant decrease in TG. TG reduction in the synbiotic group was significantly greater than in the control group. The EQ-5D VAS questionnaire significantly improved only in probiotics-treated subjects. Treatment with a synbiotic formula of L. plantarum PBS067, L. acidophilus PBS066 and L. reuteri PBS072 with active prebiotics decreased MetS syndrome prevalence, several cardiovascular risk factors and markers of insulin resistance in elderly patients.

Laetiporus sulphureus–fermented wheat bran enhanced the broiler growth performance by improving the intestinal microflora and inflammation status

This study investigates the effects of Laetiporus sulphureus–fermented wheat bran (LS) as a feed supplementation on the immunomodulative properties in broiler chickens. Crude phenolic compounds, crude polysaccharides, crude triterpenoids, and ergosterol were determined in LS water extracts. In animal experiments, 400 male broilers (Ross 308) were randomly assigned into 5 groups fed with a corn–soybean–based diet (control) and a control diet replaced with 5% wheat bran (WB), 10% WB, 5% LS, and 10% LS, respectively. Each group had 4 replicates and 20 birds per pen (total of 80 birds/treatment). The results showed that the 5% LS–supplemented group had significantly higher BW in the finisher phase (22–35 D). Better feed conversion ratio (P < 0.05) of LS-supplemented groups was observed in both the finisher phase and the overall experimental period. The LS-supplemented groups had significantly lower coliform counts in the ileum than the other treatment and control groups (P < 0.05). The results of serum immunoglobulin showed that LS supplementation significantly increased serum IgA concentration compared with the control and WB-supplemented groups (P < 0.05). Simultaneously, ileal IgA contents of the LS groups were significantly higher than in the WB and control groups (P < 0.05). Regarding proinflammatory cytokines, serum tumor necrosis factor alpha and IL-6 in the LS-supplemented groups were significantly lower than those in the 10% WB group (P < 0.05), whereas serum tumor necrosis factor alpha and IL-1β in the 5% LS group were significantly lower than in both the control and WB-supplemented groups (P < 0.05). An investigation on the effects of LS on immune-related genes in broiler showed that chickens supplemented with 5% LS had lower levels of liver and jejunum IL-1β and NF-κB mRNA compared with the control group and WB groups (P < 0.05). In conclusion, LS supplementation can potentially enhance growth performance of broilers by improving intestinal microflora and inflammation status.