TNF-alpha Ratio Research Articles

Abstract 13023: Exercise Training Potentiates Diuretic Benefits on Mechanism of Arterial Pressure Control in Hypertensive Postmenopausal Rats: Role of Inflammatory and Redox Balance

Introduction: Thiazide diuretic is a classic drug used to treat elevated arterial pressure (AP). However, their neuroinflammatory effects are limited when compared with other therapies. Objective: To compare the effect of hydrochlorothiazide (HCTZ) alone or combined with concurrent exercise training (aerobic+resistance, CET) on mechanisms of AP control and on inflammatory and redox balance in hypertensive postmenopausal rats. Methods: Female spontaneously hypertensive rats were distributed into sedentary (S) and ovariectomized groups: sedentary (OS), sedentary treated with HCTZ (OSH), trained (OT) and trained treated with HCTZ (OTH). HCTZ treatment (30 mg/kg) and CET (40-60% maximal capacity, 3 days/wk) were conducted for 8wks. AP was directly recorded at rest and after vasopressor system blockade (vasopressin antagonist, losartan and hexamethonium). Inflammation and oxidative stress were evaluated in cardiac tissue. Results: Trained groups presented higher exercise tests performance. Systolic (OT:178±18 and OTH:178±17 vs. OS:205±15) and mean AP (mmHg) (OTH:153±17 vs. OS:176±16) were reduced in trained groups. CET promoted an increase in both bradycardic and tachycardic responses of baroreflex sensitivity and a reduction in AP variability indexes in relation to OS group. After sympathetic blockade, AP (mmHg) reduction was higher in OS group (-75.7±19.2 vs. S:-53.2±12.6 and OTH:-49.8±12.4). In addition, IL-10 (OTH vs. OS and OSH) and IL-10/TNF-alpha ratio (OTH vs. S, OS, OSH and OT) were higher in OTH group. OS group showed increased NAPDHoxidase and reduced catalase (vs. S); however, these changes were not observed in OTH group. Negative correlation was observed between sympathetic vascular modulation and IL/TNF-alpha ratio (p<0.001, r:-0.6). Conclusions: We concluded that CET alone or combined with HCTZ are more efficient approaches than HCTZ to reduce AP and improve AP control of circulation. Specifically, the combination HCTZ plus CET induces additional positive adaptations on physical, autonomic, inflammatory and redox balance. These results highlight the key role of exercise in the management of HTN, probably impacting on the quality of life and reducing the residual risk in post menopause. Grants: FAPESP (2019/06277-0).

Selected adipocytokine concentrations in patients hospitalized for exacerbated chronic heart failure

Introduction: The role of adipose tissue as energy storage and endocrine organ is an area of interest in the treatment of several diseases. This study aimed to to evaluate blood adiponectin (ADP), leptin, tumor necrosis factor type alpha (TNF-alpha) concentrations, and their prognostic value in patients with exacerbated chronic heart failure (CHF). Methods and results: The following were assessed in 64 consecutive patients hospitalized for exacerbated CHF and a control group of 32 age and sex-matched individuals admitted due to life-limiting symptoms of peripheral artery disease: serum leptin, ADP, TNF-alpha concentrations, and body composition determined by bioelectrical impedance analysis. Compared to the control group, CHF patients had significantly higher blood ADP concentrations, a higher ratio of ADP to fat mass expressed as a percentage of body mass, and lower blood TNF-alpha concentrations and ratios of TNF-alpha to the visceral fat level (VFL). Compared to patients who survived, patients with CHF who died during the one-year follow-up had significantly higher values of ADP and higher ratios of ADP to body surface area. In the Cox regression model, blood ADP concentration was the only independent risk factor in respect of all-cause mortality during the one-year follow-up (HR; 95% CI: 1.16; 1.03-1.31). Conclusions: Patients with CHF present dysregulation in the secretion of ADP and TNF-alpha. Increased blood ADP concentration was associated with an increase in one-year all-cause mortality by 16%.

Circulating IL-6, IL-10, and TNF-alpha and IL-10/IL-6 and IL-10/TNF-alpha ratio profiles of polyparasitized individuals in rural and urban areas of gabon

Malaria, blood-borne filarial worms and intestinal parasites are all endemic in Gabon. This geographical co-distribution leads to polyparasitism and, consequently, the possibility of immune-mediated interactions among different parasite species. Intestinal protozoa and helminths could modulate antimalarial immunity, for example, thereby potentially increasing or reducing susceptibility to malaria. The aim of the study was to compare the cytokine levels and cytokine ratios according to parasitic profiles of the population to determine the potential role of co-endemic parasites in the malaria susceptibility of populations. Blood and stool samples were collected during cross-sectional surveys in five provinces of Gabon. Parasitological diagnosis was performed to detect plasmodial parasites, Loa loa, Mansonella perstans, intestinal helminths (STHs) and protozoan parasites. Nested PCR was used to detect submicroscopic plasmodial infection in individuals with negative blood smears. A cytometric bead array was used to quantify interleukin (IL)-6, IL-10 and tumour necrosis factor (TNF)-α in the plasma of subjects with different parasitological profiles. Median IL-6 and IL-10 levels and the median IL-10/TNF-α ratio were all significantly higher among individuals with Plasmodium (P.) falciparum infection than among other participants (p<0.0001). The median TNF-α level and IL-10/IL-6 ratio were higher in subjects with STHs (p = 0.09) and P. falciparum-intestinal protozoa co-infection (p = 0.04), respectively. IL-6 (r = -0.37; P<0.01) and IL-10 (r = -0.37; P<0.01) levels and the IL-10/TNF-α ratio (r = -0.36; P<0.01) correlated negatively with age. Among children under five years old, the IL-10/TNF-α and IL-10/IL-6 ratios were higher in those with intestinal protozoan infections than in uninfected children. The IL-10/TNF-α ratio was also higher in children aged 5-15 years and in adults harbouring blood-borne filariae than in their control counterparts, whereas the IL-10/IL-6 ratio was lower in those aged 5-15 years with filariae and intestinal parasites but higher in adults with intestinal parasitic infections. Asymptomatic malaria is associated with a strong polarization towards a regulatory immune response, presenting high circulating levels of IL-10. P. falciparum/intestinal protozoa co-infections were associated with an enhanced IL-10 response. Immunity against malaria could differ according to age and carriage of other parasites. Helminths and intestinal protozoa can play a role in the high susceptibility to malaria currently observed in some areas of Gabon, but further investigations are necessary.

Excessive Ingestion Of Parental Fructose Causes Autonomic Dysfunction Since Birth In Offspring: Impact on Adulthood

The aim this study was to evaluate the effects on hemodynamic, autonomic and inflammatory profile in offspring (from birth to adulthood) of parents submitted to chronic fructose overload.The Fructose genitor group was formed by adult Wistar rats (males and females) that underwent a fructose overload (10%) in drinking water for 60 days. The Control genitor group was formed by adult Wistar rats who were only followed for the same period receiving a standard diet. Mating was carried out and the females continued to receive the same diet (fructose or standard) during all gestation and lactation. On the day of birth, the fructose (F) and control (C) offspring were submitted to an electrocardiogram to analyze heart rate variability (n = 10/group). On the day of weaning two groups were evaluated, the CW group (descendants of the control parents, n = 10) and the FW group (descendants of the fructose parents, n = 10). Another two groups were evaluated 30 days after weaning, group C30 (from control parents, n = 10) and the F30 group (from fructose parents, n = 10). During lifespan, all offspring received a standard diet without fructose. Arterial pressure (AP) were recorded directly. Baroreflex sensitivity was evaluated by increasing dosing of phenylephrine and sodium nitroprusside. Cardiovascular autonomic modulation was evaluated by spectral analysis. Inflammatory profile was measured by ELISA in cardiac tissue.Regarding the autonomic evaluations, the fructose groups presented an impairment from birth to adulthood evidenced by a sympathovagal imbalance (LF/HF) when compared to control groups (F: 0.71 ± 0.08; FW: 0.91 ± 0.08 and F30: 0.72 ± 0.09 vs. C: 0.37 ± 0.04; CW: 0.48 ± 0.07 and C30: 0.38 ± 0.04). Additionally, only the F30 group showed higher vascular sympathetic modulation among groups (4.7 ± 0.6 vs. C30: 2.8 ± 0.4; CW: 1.8 ± 0.4 and FW: 2.9 ± 0.4 mmHg2). Moreover, the fructose groups had a worse tachycardic response when compared to control groups at the same time (FW: −2.8 ± 0.3 and F30: −3.1 ± 0.2 vs. CW: −3.9 ± 0.4 and C30: −4.0 ± 0.1 bpm/mmHg). Finally, group F30 presented worse inflammatory profile compared to group C30, evidenced by the increase of IL‐6 (167.2 ± 9.5 vs C30: 104.9 ± 11.9 pg/ml) and decrease of the IL‐10/TNF alpha ratio (P&lt;0.01). The mean, systolic and diastolic AP was increased only in group F30 when compared to the C30 group (mean AP, F30: 109 ± 1.9 vs. C30: 103 ± 1.3 mmHg).In conclusion, the offspring of parents submitted to fructose overload presented autonomic, hemodynamic and inflammatory cardiovascular dysfunctions. Moreover, the results suggest early autonomic dysfunctions, and these seem to precede hemodynamic and inflammatory changes. These findings suggest cardiovascular autonomic variability as a possible early marker of risk of developing disease in offspring of parents exposed to high fructose consumption.Support or Funding InformationFAPESP (2018/17183‐4); CAPES.

A Phase-I Clinical Trial of Donor-Derived MIC Cell Infusion for the Induction of Donor-Specific Hyporesponsiveness after Living Donor Kidney Transplantation (TOL-1 study)

MIC cells are donor-derived monocytes that gain immunosuppressive properties after incubation with the proliferation inhibitor mitomycin C. PBMCs were harvested from living donors by leukapheresis and MIC cells were manufactured under GMP conditions. Kidney transplant recipients received either 1.5x10E6 MIC cells per kg body weight on day −2 (N=3, group A), or 1.5x10E8 MIC cells per kg body weight on day −2 (N=3, group B) or day −7 (N=4, group C) before living donor kidney transplantation. Patients received immunosuppressive therapy with CyA, EC-MPS and CS. Primary outcome measure was the frequency of adverse events (AE) on day 30. A total of 70 AEs including 4 severe AEs occurred in treated patients that were unrelated to MIC cell infusion. No positive cross match results, de novo donor specific antibodies, or rejection episodes but 2 infectious complications were recorded. Median serum creatinine on day 30 was 1.4 mg/dL with no significant proteinuria. In vitro, MIC cells were capable of inducing tolerogenic dendritic cells with low expression of costimulatory molecules CD80, CD86 and a 30% increase of immunosuppressive molecule CD103. During the observation phase beyond day 30 after surgery, serum creatinine remained stable (median 1.48 mg/dL on day 180) with no significant proteinuria (median 10 g/mol creatinine on day 180) and no rejection episodes. The patients from group C who received low-dose CyA and low-dose EC-MPS during the observation phase had no or only minimal reactivity against irradiated donor lymphocytes in mixed lymphocyte culture while reactivity against 3rd party lymphocytes was preserved. CD19+ B cells increased to a median of 300/μL until day 30 but decreased to a median of 35/μL on day 180. CD19+CD24highCD38high transitional Bregs increased from a median of 2% on day 30 to a median of 20% of the total CD19+ B cell pool on day 180. There was a strong increase in the plasma IL-10/TNFalpha ratio from a median of 0.05 before cell therapy to a median of 0.11 on day 180. In summary, MIC cell therapy represents a promising option for individualized immunosuppression after living donor kidney transplantation.

Silicosis and its progress influenced by genetic variation on TNF-alpha locus- 308, TNF-alpha and IL-10 cytokine on cement factory workers in Indonesia.

This study aimed to assess the association of Tumor Necrosis Factor (TNF-alpha) Locus-308 variant, TNF-alpha and Interleukin (IL-10) Cytokine with the risk of silicosis and its progress in Indonesian cement factory workers, There is an urgent need to explore the determining factors other than exposure since silicosis is chronic progressive and life threatening but remains found, though much industrial hygiene effort has been made. This study population was 6,069 workers registered during 31 December 1990 to 31 December 2003. First, prospective study with Nested Case Control design was conducted on 336 workers in 2003, ten years later the progression of silicosis was assessed in 2013. The result showed proportion of the genetic variation on TNF-alpha on Locus -308 in Indonesia was significantly (p = 0.02) higher on silicosis (13.45%) than nonsilicosis (5.45%) but lower than silicosis in Africa and US miners, since susceptibility loci might vary in different ethnic groups. The sign and symptoms remained as simple silicosis after ten years; The TNF-alpha:IL-10 ratio > 1 was a risk factor in silicosis; the ratio of TNF-alpha:IL-10 > 1 caused a rapid decline of lung function compare to ratio < 1, the decline was chronic progressive during ten years yet not causing significant dyspnea among the cases. Further studies with enlarged sample size are needed. The study concluded, the genetic variation on TNF-alpha gene locus -308 was a risk factor of silicosis in Indonesia cement factory. Its role is indirect, but through mechanism of controlling the blood Cytokine level ratio of TNF-alpha toward IL-10.

Study on chromatography-efficacy relationship of anti-inflammatory activity of Qizhi Weitong particle compound herbs with neural network and gray correlation method

To establish the chromatography-efficacy relation method for analyzing the anti-inflammatory activity of Qizhi Weitong particles, in order to lay a foundation for quality control and pharmacodynamic evaluation of traditional Chinese medicine compounds. On the basis of a full-time multi-wavelength fusion fingerprint of Qizhi Weitong particles, the latin hypercube sampling was used to divide six herbs in Qizhi Weitong particles into groups of different proportions to determine their inhibition ratios of TNF-alpha, IL-6 and NO released by LPS-induced RAW264. 7 cells. Pharmaeodynamic data and chemical information of HPLC fingerprints of each group were analyzed with the gray correlation method to get the anti-inflammatory effect of each chromatographic peak, and then fitted with BP neural network to establish the chromatography-efficacy relation. There were 25 peaks closely related to the anti-inflammatory activity. With the 25 peaks as input items, the 3-BP network was adopted to establish the neural network model for anti-inflammatory effect of Qizhi Weitong particles. With an error of less than 7%, the model could better fit with the complicated non-linear relation of the compound, and applied in studying the chromatography-efficacy relation. In this study on the chromatography-efficacy relation, a new method is established to evaluate the anti-inflammatory activity of Qizhi Weitong particles. It is of practical significance as an effective approach for controlling quality and exploring the material basis for efficacy of traditional Chinese medicine compounds.

Gender specificity of altered human immune cytokine profiles in aging

Cytokine generation by T cells and monocytes was determined for 50 subjects aged 65 yr or older and concurrently studied young subjects individually matched to each old subject for sex, race, and national origin. Highly significant differences between cytokine levels of old and young subjects all were gender specific. For T cells stimulated with anti-CD3 plus anti-CD28 antibodies, mean ratios of IFN-gamma generation for healthy old to young subjects were 0.22 for men (P<0.001; n=15) and 3.35 for women (P<0.001; n=13), and those of IL-17 were 0.30 for men (P<0.001) and no difference for women. CD8 T cells were the source of high IFN-gamma in healthy old women. For old men with an inflammatory or immune disease (n=10), mean old to young ratios of T-cell-generated IFN-gamma and IL-17 increased with disease severity up to 5.78 and 2.97 (both P<0.01), respectively, without changes for old women with similar diseases (n=12). For differentiated LPS-stimulated monocytes, old to young ratios of TNF-alpha and IL-6 generation were high only in women with immune or inflammatory disease (2.38, P<0.05 and 1.62, P<0.01, respectively), whereas ratios of IFN-gamma-evoked IP-10 chemokine were low in all groups. Alterations in immune cytokine profiles with aging show significant gender specificity.

Immature Osteoblast Lineage Cells Increase Osteoclastogenesis in Osteogenesis Imperfecta Murine

This study addressed the role of impairment of osteoblastic differentiation as a mechanism underlying pathophysiology of the osteogenesis imperfecta (OI). We hypothesized that combination of impaired osteogenic differentiation with increased bone resorption leads to diminished bone mass. By introducing visual markers of distinct stages of osteoblast differentiation, pOBCol3.6GFP (3.6GFP; preosteoblast) and pOBCol2.3GFP (2.3GFP; osteoblast/osteocytes), into the OIM model, we assessed osteoblast maturation and the mechanism of increased osteoclastogenesis. Cultures from oim/oim;2.3GFP mice showed a marked reduction of cells expressing GFP relative to +/+;2.3GFP littermates. No significant difference in expression of 3.6GFP between the +/+ and oim/oim mice was observed. Histological analysis of the oim/oim;3.6GFP mice showed an increased area of GFP-positive cells lining the endocortical surface compared with +/+;3.6GFP mice. In contrast GFP expression was similar between oim/oim;2.3GFP and +/+;2.3GFP mice. These data indicate that the osteoblastic lineage is under continuous stimulation; however, only a proportion of cells attain the mature osteoblast stage. Indeed, immature osteoblasts exhibit a stronger potential to support osteoclast formation and differentiation. We detected a higher Rankl/Opg ratio and higher expression of TNF-alpha in sorted immature osteoblasts. In addition, increased osteoclast formation was observed when osteoclast progenitors were cocultured with oim/oim-derived osteoblasts compared with osteoblasts derived from +/+ mice. Taken together, our data indicate that osteoblast lineage maturation is a critical aspect underlying the pathophysiology of OI.

Chronic low frequency/low volume resistance training reduces pro-inflammatory cytokine protein levels and TLR4 mRNA in rat skeletal muscle

Skeletal muscle is the source of pro- and anti-inflammatory cytokines, and recently, it has been recognized as an important source of interleukin 6 (IL-6), a cytokine that exerts inhibitory effects on several pro-inflammatory cytokines. Although dynamic chronic resistance training has been shown to produce the known "repeated bout effect", which abolishes the acute muscle damage, performing of high-intensity resistance training has been regarded highly advisable, at least from the hypertrophy perspective. On the other hand, a more therapeutic, "non-damaging" resistance training program, mainly composed of concentric forces, low frequency/low volume of training, and the same exercise, could theoretically benefit the muscle when the main issue is to avoid muscle inflammation (as in the treatment of several "low-grade" inflammatory diseases) because the acute effect of each resistance exercise session could be diminished/avoided, at the same time that the muscle is still being overloaded in a concentric manner. However, the benefits of such "less demanding" resistance training schedule on the muscle inflammatory profile have never been investigated. Therefore, we assessed the protein expression of IL-6, TNF-alpha, IL-10, IL-10/TNF-alpha ratio, and HSP70 levels and mRNA expression of SCF(beta-TrCP), IL-15, and TLR-4 in the skeletal muscle of rats submitted to resistance training. Briefly, animals were randomly assigned to either a control group (S, n = 8) or a resistance-trained group (T, n = 7). Trained rats were exercised over a duration of 12 weeks (two times per day, two times per week). Detection of IL-6, TNF-alpha, IL-10, and HSP70 protein expression was carried out by western blotting and SCF(beta-TrCP) (SKP Cullin F-Box Protein Ligases), a class of enzymes involved in the ubiquitination of protein substrates to proteasomal degradation, IL-15, and TLR-4 by RT-PCR. Our results show a decreased expression of TNF-alpha and TLR4 mRNA (40 and 60%, respectively; p < 0.05) in the plantar muscle from trained, when compared with control rats. In conclusion, exercise training induced decreased TNF-alpha and TLR-4 expressions, resulting in a modified IL-10/TNF-alpha ratio in the skeletal muscle. These data show that, in healthy rats, 12-week resistance training, predominantly composed of concentric stimuli and low frequency/low volume schedule, down regulates skeletal muscle production of cytokines involved in the onset, maintenance, and regulation of inflammation.

Alterações na produção de IL-10 e TNF-α no músculo esquelético em ratos com insuficiência cardíaca secundária ao infarto do miocárdio

Recent studies show that the expression of inflammatory mediators, such as cytokines, is an important factor for the development and progression of heart failure (HF), especially in the presence of left ventricular dysfunction. These changes have been demonstrated both in the plasma and heart muscle and, more recently, in skeletal muscle of rats and in patients with HF. To investigate the production and expression of tumor necrosis factor-alpha (TNF) and interleukin-10 (IL-10) in the soleus and the extensor digitorum longus (EDL) muscles of animals with left ventricular dysfunction after myocardial infarction (MI). We used male Wistar rats that underwent ligation of the left coronary artery without reperfusion. Four weeks after this procedure, the animals underwent echocardiography and were divided into the following experimental groups: sham operated (sham) and IM. They remained under observation for a further period of 8 weeks. The level of the cytokine TNF-alpha increased by 26.5% (p <0.05), and its gene expression increased 3 times (p <0.01). The level of IL-10 decreased by 38.2% (p <0.05). Both changes occurred only in the soleus muscle, with no change in the EDL. The decrease (36.5%, p <0.05) in the IL-10/TNF-alpha ratio was due to both increased tissue levels of TNF-alpha and decreased tissue levels of IL-10. Our results showed significant changes in the IL-10/TNF-alpha ratio, which may have an additive role in the assessment of deterioration and progression of left ventricular dysfunction post-MI. Furthermore, our study suggests that these changes seem to be related to the muscle fiber type.

PAN–DR‐Binding Hsp60 self epitopes induce an interleukin‐10–mediated immune response in rheumatoid arthritis

Human Hsp60 is expressed in the joints of patients with rheumatoid arthritis (RA) and can elicit a regulatory T cell response in the peripheral blood and synovial fluid. However, Hsp60 can also trigger strong proinflammatory pathways. Thus, to understand the nature of these Hsp60-directed responses in RA, it is necessary to study such responses at the molecular, epitope-specific level. This study was undertaken to characterize the disease specificity and function of pan-DR-binding Hsp60-derived epitopes as possible modulators of autoimmune inflammation in RA. Lymphocyte proliferation assays (using (3)H-thymidine incorporation and carboxyfluorescein diacetate succinimidyl ester [CFSE] staining) and measurement of cytokine production (using multiplex immunoassay and intracellular staining) were performed after in vitro activation of peripheral blood mononuclear cells from patients with RA, compared with healthy controls. A disease (RA)-specific immune recognition, characterized by T cell proliferation as well as increased production of tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), and IL-10, was found for 3 of the 8 selected peptides in patients with RA as compared with healthy controls (P < 0.05). Intracellular cytokine staining and CFSE labeling showed that CD4+ T cells were the subset primarily responsible for both the T cell proliferation and the cytokine production in RA. Interestingly, the human peptides had a remarkably different phenotype, with a 5-10-fold higher IL-10:TNFalpha ratio, compared with that of the microbial peptides. These results suggest a disease-specific immune-modulatory role of epitope-specific T cells in the inflammatory processes of RA. Therefore, these pan-DR-binding epitopes could be used as a tool to study the autoreactive T cell response in RA and might be suitable candidates for use in immunotherapy.

Exhaustive exercise causes an anti-inflammatory effect in skeletal muscle and a pro-inflammatory effect in adipose tissue in rats

It is well known that exhaustive exercise increases serum and skeletal muscle IL-6 concentrations. However, the effect of exhaustive exercise on the concentrations of other cytokines in the muscle and in the adipose tissue is controversial. The purpose of this study was to evaluate the effect of exhaustive exercise on mRNA and protein expression of IL-10, TNF-alpha and IL-6 in different types of skeletal muscle (EDL, soleus) and in two different depots of white adipose tissue (mesenteric-MEAT and retroperitoneal-RPAT). Rats were killed by decapitation immediately (E0 group, n = 6), 2 (E2 group, n = 6) and 6 (E6 group, n = 6) hours after the exhaustion protocol, which consisted of running on a treadmill (approximately 70% VO(2max) for 50 min and then subsequently at an elevated rate that increased at 1 m/min every minute, until exhaustion). The control group (C group, n = 6) was not subjected to exercise. Cytokine protein expression increased in EDL, soleus, MEAT and RPAT from all exercised groups, as detected by ELISA. EDL IL-10 and TNF-alpha expression was higher than that of the soleus. The IL-10/TNF-alpha ratio was increased in the skeletal muscle, especially in EDL, but it was found to be decreased in the adipose tissue. These results show that exhaustive exercise presents a different effect depending on the tissue which is analysed: in the muscle, it induces an anti-inflammatory effect, especially in type 2 fibres, while the pro-inflammatory effect prevails in adipose tissue, possibly contributing to increased lipolysis to provide energy for the exercising muscle.

Interleukin-10 to tumor necrosis factor-alpha ratio is a predictive biomarker in nonalcoholic fatty liver disease: interleukin-10 to tumor necrosis factor-alpha ratio in steatohepatitis

Fatty liver disease is commonly associated with diabetes mellitus (DM). Insulin resistance (IR) as an investigative biomarker is only concerned with fatty liver that results from DM type 2 associated with metabolic syndrome. Irrespective of IR, DM is generally characterized by overproduction of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), whereas action of the latter is modulated by the anti-inflammatory cytokine interleukin-10 (IL-10). The aim of this study was to investigate the efficacy of using TNF-alpha alone or IL-10/TNF-alpha ratio compared to IR, as a promising biomarker for fatty liver assessment in DM. Furthermore, we hypothesized that using garlic as an immunomodulator may decrease TNF-alpha and increase IL-10 production to improve steatohepatitis. DM was induced metabolically by a high-fat diet to bring about IR, or chemically by alloxan, producing insulin deficiency, in male albino rats. Garlic powder was supplemented (15 mg/kg per day) for 3 weeks. Fatty liver was depicted histologically and biochemically (aspartic aminotransferase, alanine aminotransferase, HOMA-IR, TNF-alpha, IL-10, IL-10/TNF-alpha ratio). We found that, in contrast to obese rats, garlic decreased IL-10/TNF-alpha ratio, despite decreasing TNF-alpha in alloxan diabetic rats in agreement with the histology, which revealed more prominent improvement in the obese group. Moreover, the effect of garlic was not linked to improvement of IR in obese rats. We conclude that IL-10/TNF-alpha ratio may be considered as a convenient biomarker for investigation of fatty liver of different grades, apart from being associated with IR, and immunomodulation of this ratio in favor of increasing it may exert significant improvement.

Interleukin‐10 improves left ventricular function in rats with heart failure subsequent to myocardial infarction

Evidence has shown that pro-inflammatory cytokines, especially TNF-alpha, are involved in the inflammatory response in the remodelling process after myocardial infarction (MI). Although IL-10, an anti-inflammatory cytokine, has been shown to antagonize some of the deleterious effects of TNF-alpha, little is known about its role in post-MI left ventricular (LV) dysfunction. The aim of the present study was to investigate whether a therapy with rhIL-10 could be beneficial in an animal model of post-MI heart failure (HF). Rats with experimental MI were treated with rhIL-10 (75 microg/kg/d sc) starting directly after MI induction, and continuing for 4 weeks. Controls were untreated MI and sham-operated rats. Cardiac function was assessed by echocardiography and cardiac catheterization 4 weeks after MI induction. Membrane-bound and soluble fractions of TNF-alpha, IL-6 and IL-10, the ratio of TNF-alpha to IL-10, serum levels of MCP-1 as well as myocardial macrophage infiltration, were analyzed. Treatment with rhIL-10 significantly improved post-MI LV function (FS +127%;, dP/dt(max) +131%; LVEDP -36%). This effect was associated with a significant decrease in pro-inflammatory cytokine and chemokine levels (TNF-alpha, IL-6, MCP-1) and furthermore resulted in a reduced myocardial infiltration of macrophages.

Nutritional Supplements with Oral Amino Acid Mixtures Increases Whole-Body Lean Mass and Insulin Sensitivity in Elderly Subjects with Sarcopenia

Decreases in whole-body lean mass can cause sarcopenia, a disease frequently found in the elderly. This condition is frequently associated with frailty and disability in aging as well as the onset and progression of several geriatric syndromes. Sarcopenia therefore must be managed with multidimensional approaches that include physical training, nutritional support, and metabolic and anabolic treatment. The purpose of our study was to assess the effect of an orally administered special mixture of amino acids (AAs) in elderly subjects with reduced lean body mass and sarcopenia. A randomized, open-label, crossover study was conducted in 41 elderly subjects (age range: 66-84 years) with sarcopenia, assigned to 2 distinct treatments (AAs and placebo). All subjects had normal body weight (body mass index within 19-23). The AA treatment consisted of 70.6 kcal/day (1 kcal = 4.2 kJ) of 8 g of essential AA snacks, given at 10:00 am and 5:00 pm. Lean mass was measured with dual-energy x-ray absorptiometry in leg, arm, and trunk tissues. Significant increases in whole-body lean mass in all areas were seen after 6 months and more consistently after 18 months of oral nutritional supplementation with AAs. Fasting blood glucose, serum insulin, and homeostatic model assessment of insulin resistance (an index of insulin resistance) significantly decreased during AA treatment. Furthermore, a significant reduction in serum tumor necrosis factor-alpha (TNF-alpha) and a significant increase in both insulin-like growth factor-1 (IGF-1) serum concentrations and in the IGF-1/TNF-alpha ratio were also found. No significant adverse effects were observed during AA treatment. These preliminary data indicate that nutritional supplements with the oral AA mixture significantly increased whole-body lean mass in elderly subjects with sarcopenia. The improvement in the amount of whole-body lean mass could be linked to increased insulin sensitivity and anabolic conditions related to IGF-1 availability.

Cytokine production and hospital mortality in patients with sepsis-induced stress hyperglycemia

To investigate whether stress hyperglycemia affects the production of the main pro- and anti-inflammatory cytokines and the 28-day hospital mortality in patients with severe sepsis. The study included 62 patients with severe sepsis, divided in three groups according to their glycemic profile within 24h after admission: patients with stress hyperglycemia (group SH, n=16), diabetes mellitus type II (group DM, n=27), and normal glucose levels (group NG, n=19). The serum levels of the cytokines TNF-alpha, IL-6, IL-10 and TGFbeta-1 were measured within 24h after admission. A higher percentage of septic patients with stress hyperglycemia died compared to diabetic patients (43.7 vs. 14.8%) and group NG (43.7 vs. 5.2%). Group SH had higher SOFA score and levels of IL-6 and IL-10 than group DM and group NG. It also had higher levels of TNF-alpha than group DM but not group NG. There was no difference in the levels of TGFbeta-1 among the three groups. Non-survivors had higher levels of IL-10, no difference was detected for IL-6, TNF-alpha, IL-10/TNF-alpha ratio and TGFbeta-1. Interleukin-10 values, mean fasting glucose values and age were found as prognostic factors associated with outcome. Stress hyperglycemia is associated with increased cytokine production and an adverse clinical outcome in patients with severe sepsis.

Natural Killer, Natural Killer T, Helper and Cytotoxic T Cells in the Decidua from Sporadic Miscarriage

The aim of this cohort study was to assess natural killer (NK) cell and natural killer T (NKT) cell populations and cytokine expressions of helper T (Th) and cytotoxic T (Tc) cells in the decidua of sporadic miscarriage (MS) and induced abortion (IA). The deciduae were obtained from consecutive 40 women whose pregnancies ended in the first trimester MS, and the fetal chromosome karyotypes were analyzed. The cell populations were measured by flow cytometry. No significant differences in NK cell or NKT cell percentages were found among MS with normal chromosome karyotype (MSNK, n = 14), MS with abnormal karyotype (MSAK, n = 26) and IA (n = 14). Interferon (IFN)-gamma(+) cell percentage and interleukin (IL)-4(+)/tumor necrosis factor (TNF)-alpha(+) ratio of Th cells in MS groups were increased, while IL-4(+) cell percentage, IL-4(+)/IFN-gamma(+) and IL-4(+)/TNF-alpha(+) ratios of Tc cells in MS groups were decreased as compared with those in IA. No significant difference in these parameters between MSNK and MSAK was found. These results suggested that Tc1 predominance existed in the decidua of MS. Th1 predominance was not found in MSNK.

Tumor necrosis factor-α and interleukin-10 gene expression in peripheral blood mononuclear cells after cardiac surgery

Cytokine response after cardiac surgery may be genetically influenced. A study was carried out to investigate the relation between cytokine gene expression in peripheral blood mononuclear cells, genotype, and clinical events after cardiac surgery. A case-control study was performed. Cardiac intensive care unit in a university hospital. A total of 82 patients having elective cardiac surgery were divided into those having uncomplicated recovery (n = 48) or recovery complicated by hyperlactatemia or requirement for inotropic support (n = 34). The relative change in peripheral blood mononuclear cell tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) messenger RNA 1 and 6 hrs after cardiopulmonary bypass was compared with a baseline preoperative level using quantitative reverse transcriptase polymerase chain reaction. DNA was analyzed for carriage of TNF-alpha and IL-10 polymorphic alleles. Cardiopulmonary bypass was longer in duration in the complicated group. TNF-alpha gene expression decreased and IL-10 gene expression increased in peripheral blood mononuclear cells after surgery when compared with preoperative levels. One hour after cardiopulmonary bypass, the complicated group had more TNF-alpha and less IL-10 messenger RNA production than the uncomplicated group. The IL-10/TNF-alpha ratio was greater in uncomplicated than in complicated recovery patients. An IL-10 haplotype was identified that was less frequent in the complicated group. There was no difference between groups in TNF-alpha genotype. On multivariate analysis, cardiopulmonary bypass time and the IL-10/TNF-alpha messenger RNA ratio were independent predictors of outcome. There is a predominant anti-inflammatory cytokine response after uneventful cardiac surgery. IL-10 may have a protective role after cardiac surgery.

Stronger host response per parasitized erythrocyte in Plasmodium vivax or ovale than in Plasmodium falciparum malaria

Fever tends to start at a lower level of parasitemia in Plasmodium vivax or ovale than in P. falciparum malaria, but hyperparasitemia and complications are more likely to occur in P. falciparum malaria. Therefore, we compared the relationship between parasitemia and host response parameters before therapy in 97 patients with P. faciparum malaria (18 with complications), and 28 with P. vivax or ovale malaria. In both types of malaria, parasitemia correlated with blood levels of tumour necrosis factor alpha (TNF-alpha), lactate dehydrogenase (LDH), Thrombin-antithrombin III (TAT) and elastase, and these parameters were higher in P. falciparum malaria than in P. vivax or ovale malaria. In contrast, the ratios of TNF-alpha, TAT, elastase, and LDH per parasitized erythrocyte were higher in P. vivax or ovale malaria than in uncomplicated P. falciparum malaria. They were lowest in complicated disease. Multivariate regression analysis confirmed that parasitemia did not affect these differences. The host response may reach full strength at lower parasitemia in Plasmodium vivax or ovale, than in P. falciparum malaria. With hyperparasitemia in P. falciparum malaria, the host response seems to be unable to control parasite multiplication.