Serum Levels of Interleukins in Endometriosis Patients: A Systematic Review and Meta-analysis.

OBJECTIVE: The aims of this systematic review and meta-analysis were to produce a comprehensive survey of the serum levels of interleukins (ILs) in untreated people with endometriosis compared with people without endometriosis. DATA SOURCES: A systematic literature search of English language studies within Cinahl, Medline Complete, PubMed, and Scopus from inception to May 2023 was performed. METHODS OF STUDY SELECTION: We included studies that compared IL serum levels in people with endometriosis to those without endometriosis. Meta-analysis was performed on IL-1RA, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17A, IL-18, IL-23, and IL-37. TABULATION, INTEGRATION, AND RESULTS: The systematic search retrieved 651 studies, of which 77 underwent a full-text review. A total of 30 studies met inclusion criteria for the meta-analysis. IL-1Ra, IL-6, and IL-37 serum levels were 2.56 (95% CI 2.20-2.92, p <.001), 1.38 (95% CI 0.58-2.17, p <.001), and 1.77 (95% CI 1.33-2.20, p <.001) standard deviations higher in the patients with endometriosis compared with patients without endometriosis while IL-23 serum levels 0.40 (95% CI -0.73 to -0.07, p = .02) standard deviations lower, respectively. CONCLUSION: There is mounting evidence that ILs, especially IL-6, may be good candidates for unique noninvasive diagnostic tools and/or treatment pathways for endometriosis.

[Effect of acupuncture preconditioning combined with PI3K blocker LY294002 on airway inflammation in asthmatic rats].

OBJECTIVE: To observe the effect of acupuncture preconditioning combined with PI3K blocker LY294002 on the expression of PI3K and Akt proteins and genes in the lung tissue and the contents of serum IL-12 and IL-13 in asthmatic rats, so as to explore its preprotective mechanism underlying improving asthma. METHODS: Sixty male Wistar rats were randomly divided into blank control, model, acupuncture pretreatment + blank, acupuncture pretreatment, acupuncture pretreatment + LY294002 and LY294002 groups (n=10 in each group). The asthma model was established by intraperitoneal injection of mixture solution of OVA and Al(OH)3 and followed inhalation of 1%OVA for 30 min, once daily for 7 days. Rats of the blocker groups received inhalation of atomized LY294002 solution for 30 min before inhalation of 1% OVA, and acupuncture was applied to "Feishu"(BL13), "Dazhui"(GV14) and "Fengmen"(BL12) for 20 min, once daily for 7 days before modeling. H.E. staining was used to assess histopathological changes of the lung tissue, and ELISA was used to detect the contents of serum IL-12 and IL-13. The immunoactivity of PI3K and Akt and expression of Akt mRNA of the lung tissue were detected by using immunohistochemistry and fluorescence quantitative real-time PCR, separately. RESULTS: Compared with the blank control group, the content of serum IL-12 was significantly decreased (P<0.01), and the content of serum IL-13, the expression levels of PI3K, Akt protein and Akt mRNA were remarkably increased (P<0.01) in the model group. In comparison with the model group, the content of serum IL-12 in the pretreatment, pretreatment + LY294002 and LY294002 groups was significantly increased (P<0.01, P<0.05), while the content of IL-13 and the expression levels of PI3K, Akt protein and Akt mRNA were considerably decreased (P<0.01, P<0.05) in the acupuncture pretreatment, acupuncture pretreatment+LY294002 and LY294002 groups. The therapeutic effect of acupuncture pretreatment+LY294002 was obviously superior to that of simple acupuncture pretreatment and LY294002 (except PI3K and Akt in the LY294002 group) in up-regulating serum IL-12 level, and in down-regulating serum IL-13, and PI3K and Akt protein levels in the lung tissue (P<0.01). H.E. staining showed severe inflammatory factor infiltration in the bronchus and pulmonary interstitium, and obvious bronchial lumen narrowing with increased exudate in rats of the model group, which was relatively milder in rats of the acupuncture pretreatment, acupuncture pretreatment+LY294002 and LY294002 groups. There were no significant diffe-rences between blank control and pretreatment+blank groups in all of the above indicators （P>0.05）. CONCLUSION: Acupuncture preconditioning can inhibit airway inflammation in asthmatic rats, which may be associated with its functions in down-regulating the levels of pulmonary PI3K and Akt and serum IL-13 and up-regulating the content of serum IL-12. Acupuncture preconditioning combined with LY294002 has the best effect.

Regression of Triple-Negative Breast Cancer in a Patient-Derived Xenograft Mouse Model by Monoclonal Antibodies against IL-12 p40 Monomer.

Although some therapies are available for regular breast cancers, there are very few options for triple-negative breast cancer (TNBC). Here, we demonstrated that serum level of IL-12p40 monomer (p40) was much higher in breast cancer patients than healthy controls. On the other hand, levels of IL-12, IL-23 and p40 homodimer (p402) were lower in serum of breast cancer patients as compared to healthy controls. Similarly, human TNBC cells produced greater level of p40 than p402. The level of p40 was also larger than p402 in serum of a patient-derived xenograft (PDX) mouse model. Accordingly, neutralization of p40 by p40 mAb induced death of human TNBC cells and tumor shrinkage in PDX mice. While investigating the mechanism, we found that neutralization of p40 led to upregulation of human CD4+IFNγ+ and CD8+IFNγ+ T cell populations, thereby increasing the level of human IFNγ and decreasing the level of human IL-10 in PDX mice. Finally, we demonstrated the infiltration of human cytotoxic T cells, switching of tumor-associated macrophage M2 (TAM2) to TAM1 and suppression of transforming growth factor ß (TGFß) in tumor tissues of p40 mAb-treated PDX mice. Our studies identify a possible new immunotherapy for TNBC in which p40 mAb inhibits tumor growth in PDX mice.

Safety levels of systemic IL-12 induced by cDNA expression as a cancer therapeutic.

Aim: The aim of this work is to utilize a gene expression procedure to safely express systemic IL-12 and evaluate its effects in mouse tumor models. Materials & methods: Secondary lymphoid organs and tumors from EL4 and B16 tumor-bearing mice were analyzed by supervised and unsupervised methods. Results: IL-12 cDNA induced systemic IL-12 protein levels lower than the tolerated dose in patients. Control of tumor growth was observed in subcutaneous B16 and EL4 tumors. Systemic IL-12 expression induced a higher frequency of both total tumor-infiltrated CD45+ cells and proliferative IFN-γ+CD8+ T cells along with a lower frequency of CD4+FOXP3+ and CD11b+Gr-1+ cells. Conclusion: This approach characterizes the systemic effects of IL-12, helping to improve treatment of metastases or solid tumors.

Lay abstract IL-12 has emerged as a potent cytokine in mediating antitumor activity in preclinical models of cancer. However, this antitumor response has not yet been translated into the clinic because of toxic side effects. The aim of our work is to analyze the effects of IL-12 in mouse tumor models. We demonstrate that one injection of IL-12 cDNA can induce systemic IL-12 levels in serum even lower than the tolerated dose in patients. At this dose, an efficient control of tumor growth can be observed. We found a higher frequency of both total tumor-infiltrated leukocytes and IFN-γ-producing CD8⁺ T cells along with a lower frequency of regulatory CD4⁺FOXP3⁺ and CD11b⁺Gr1⁺ cells. Our work demonstrates that IL-12 cDNA can safely be used to treat cancer.

The Role of Serum Th1, Th2, and Th17 Cytokines in Patients with Alopecia Areata: Clinical Implications.

Alopecia areata is a type of non-scarring hair loss. The dysregulation of numerous systemic Th1 (IL-2, IFN-γ, TNF, IL-12, and IL-18), Th2 (IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17E, IL-31 and IL-33) and Th17 (IL-17, IL-17F, IL-21, IL-22, IL-23 and TGF-ß) cytokines was observed in patients with alopecia areata. Positive correlations between the severity of alopecia areata and an increased serum level of various cytokines including IL-2, TNF, IL-12, IL-17, and IL-17E were reported in the literature. An increased serum level of numerous cytokines, such as IL-2, IL-6, TNF, IL-12, IL-17E, and IL-22, was described as positively correlated with the duration of the disease. Moreover, it was shown that increased pre-treatment serum level of IL-12 was a positive, while increased serum levels of IL-4 and IL-13 were negative prognostic markers for the efficacy of diphenylcyclopropenone. In conclusion, alopecia areata is associated with the dysregulation of systemic Th1, Th2 and Th17 cytokines with their role in the pathogenesis, clinical manifestations and prognosis of the disease. Available data indicate the most significant role of serum IL-2, TNF, IL-12, IL-17, and IL-17E as markers of disease activity. The serum levels IL-4, IL-12 and IL-13 may be useful as potential predictors of diphenylcyclopropenone efficacy.

Intratumoral expression of IL-12 from lentiviral or RNA vectors acts synergistically with TLR4 agonist (GLA) to generate anti-tumor immunological memory.

Systemic interleukin-12 (IL12) anti-tumor therapy is highly potent but has had limited utility in the clinic due to severe toxicity. Here, we present two IL12-expressing vector platforms, both of which can overcome the deficiencies of previous systemic IL12 therapies: 1) an integrating lentiviral vector, and 2) a self-replicating messenger RNA formulated with polyethyleneimine. Intratumoral administration of either IL12 vector platform resulted in recruitment of immune cells, including effector T cells and dendritic cells, and the complete remission of established tumors in multiple murine models. Furthermore, concurrent intratumoral administration of the synthetic TLR4 agonist glucopyranosyl lipid A formulated in a stable emulsion (GLA-SE) induced systemic memory T cell responses that mediated complete protection against tumor rechallenge in all survivor mice (8/8 rechallenged mice), whereas only 2/6 total rechallenged mice treated with intratrumoral IL12 monotherapy rejected the rechallenge. Taken together, expression of vectorized IL12 in combination with a TLR4 agonist represents a varied approach to broaden the applicability of intratumoral immune therapies of solid tumors.

Supplementation with a Natural Source of Amino Acids, Sil-Q1 (Silk Peptide), Enhances Natural Killer Cell Activity: A Redesigned Clinical Trial with a Reduced Supplementation Dose and Minimized Seasonal Effects in a Larger Population.

The aim of this study was to re-validate the changes in natural killer (NK) cell cytotoxicity and cytokines related to T cells after Sil-Q1 (SQ; silk peptide) supplementation in a larger pool of Korean adults with minimized daily dose of SQ and controlling seasonal influence compared to the previous study. A total of 130 subjects were randomly assigned (1:1) to consume either 7.5 g of SQ or placebo for 8 weeks. NK cell cytotoxicity and cytokines were measured at T0 (baseline) and T8 (follow-up). Comparing the NK cell cytotoxicity values at T0 and T8 within each group, the cytotoxicity at all effector cell (E) to target cell (T) ratios of 10:1, 5:1, 2.5:1, and 1.25:1 was significantly increased in the SQ group at T8. Additionally, significant differences in the changed value (Δ, subtract baseline values from follow-up values) comparison between the groups at E:T = 10:1, 5:1, and 2.5:1 were found. As a secondary endpoint, the interleukin (IL)-12 level in the SQ group was significantly increased for 8 weeks, and Δ IL-12 in the SQ group was greater than in the placebo group. In conclusion, the present study showed considerable practical implications of SQ supplementation. Thus, SQ is an effective and safe functional food supplement for enhancing immune function.

Immune response profiling in patients with traumatic injuries associated with alcohol ingestion.

Traumatic injuries afflict more than 5 million people globally every year. Current and past animal research has demonstrated association among alcohol, trauma, and impaired immune function, whereas human registries have shown association between alcohol and morbidity as well as mortality. The purpose of this study is to elucidate the immune interactions with alcohol in traumatically injured patients. We prospectively enrolled 379 patients after trauma at three medical centers in the Surgical Critical Care Initiative. Plasma was analyzed using Luminex for up to 35 different cytokines. Collected samples were grouped by patients with detectable plasma alcohol levels versus those without. Univariate testing determined differences in analytes between groups. We built Bayesian belief networks with multiple minimum descriptive lengths to compare the two groups. All 379 patient samples were analyzed. Two hundred eighty-two (74.4%) patients were men, and 143 (37.7%) were White. Patients had a median intensive care unit length of stay (LOS) of 5.8 days and hospital LOS of 12 days. Using single variate analyses, eight different cytokines were differentially associated with alcohol. Cytokines IL-12 and IL-6 were important nodes in both models and IL-10 was a prominent node in the nonalcohol model. This study found select immune function differed between traumatically injured patients with measurable serum alcohol levels as compared with those without. Traumatically injured patients with positive blood alcohol content appear less able to inhibit inflammatory stress. Alcohol appears to suppress pro-inflammatory IL-12 and IL-6, whereas patients without alcohol have greater levels of anti-inflammatory IL-10 expressed at injury and may better regulate anti-inflammatory pathways. Future studies should determine the relationship with these markers with clinically oriented outcomes.

Long-Term Suppression of Circulating Proinflammatory Cytokines in Multiple Sclerosis Patients Following Autologous Haematopoietic Stem Cell Transplantation.

Autologous haematopoietic stem cell transplantation (AHSCT) is a therapeutic option for haematological malignancies, such as non-Hodgkin's lymphoma (NHL), and more recently, for autoimmune diseases, such as treatment-refractory multiple sclerosis (MS). The immunological mechanisms underlying remission in MS patients following AHSCT likely involve an anti-inflammatory shift in the milieu of circulating cytokines. We hypothesised that immunological tolerance in MS patients post-AHSCT is reflected by an increase in anti-inflammatory cytokines and a suppression of proinflammatory cytokines in the patient blood. We investigated this hypothesis using a multiplex-ELISA assay to compare the concentrations of secreted cytokine in the peripheral blood of MS patients and NHL patients undergoing AHSCT. In MS patients, we detected significant reductions in proinflammatory T helper (Th)17 cytokines interleukin (IL)-17, IL-23, IL-1ß, and IL-21, and Th1 cytokines interferon (IFN)γ and IL-12p70 in MS patients from day 8 to 24 months post-AHSCT. These changes were not observed in the NHL patients despite similar pre-conditioning treatment for AHSCT. Some proinflammatory cytokines show similar trends in both cohorts, such as IL-8 and tumour necrosis factor (TNF)-α, indicating a probable treatment-related AHSCT response. Anti-inflammatory cytokines (IL-10, IL-4, and IL-2) were only transiently reduced post-AHSCT, with only IL-10 exhibiting a significant surge at day 14 post-AHSCT. MS patients that relapsed post-AHSCT exhibited significantly elevated levels of IL-17 at 12 months post-AHSCT, unlike non-relapse patients which displayed sustained suppression of Th17 cytokines at all post-AHSCT timepoints up to 24 months. These findings suggest that suppression of Th17 cytokines is essential for the induction of long-term remission in MS patients following AHSCT.

Acute pancreatic injuries: A complication of Stevens-Johnson syndrome/toxic epidermal necrolysis associated with cytotoxic immunocell activation.

BACKGROUND: Complications involving internal organs are usually present in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, pancreatic complications are rarely reported and studied. OBJECTIVE: To summarize clinical characteristics of SJS/TEN-associated acute pancreatic injuries and to investigate underlying inflammatory mechanisms. METHODS: Clinical records of 124 inpatients with SJS/TEN were reviewed. Serum levels of tumor necrosis factor α, interleukin (IL) 6, IL-18, IL-15, IL-12p70, and soluble CD56 were determined in 18 healthy donors and 17 patients with SJS/TEN, including 3 with acute pancreatic injuries. RESULTS: Acute pancreatic injury was diagnosed in 7.3% of patients (9/124) in the SJS/TEN cohort. Elevation of serum transaminase level and hypoalbuminemia occurred more frequently in patients with acute pancreatic injuries compared with those without pancreatic symptoms (P = .004 and <.001, respectively). Although acute pancreatic injury did not alter mortality rate of SJS/TEN, it was associated with longer hospitalization stays (P = .008). Within the serum cytokines whose levels were elevated in SJS/TEN, only IL-18 was found to be selectively increased in patients with acute pancreatic injuries compared with those without them (P = .03). LIMITATIONS: Cohort was small. CONCLUSION: Acute pancreatic injury is a gastrointestinal complication of SJS/TEN in which hepatotoxicity is more likely to occur. Overexpression of IL-18 might be involved in this unique entity.

Association between serum interleukin (IL)-12 level and severity of non-alcoholic fatty liver disease (NAFLD).

What is new? Serum IL-12 level is associated with NAFLD severity. Elevation in serum IL-12 level is in line with more severe NAFLD based on BARD score and NAFLD fibrosis score. Positive correlation is observed between serum IL-12 level and BARD score.Introduction. Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. Lipid accumulation in the liver triggers inflammation and leads to NAFLD. Prolonged inflammation will worsen the disease progression. Pro-inflammatory cytokines, including interleukin (IL)-12, plays a role in the inflammatory process. This study aimed to determine the association between IL-12 and NAFLD severity.Methods. A cross-sectional study was conducted between January and July 2019 in Haji Adam Malik Hospital Medan, Indonesia. Subjects were patients aged 18 years or older diagnosed with NAFLD based on ultrasound. Exclusion criteria were excessive alcohol consumption, other primary liver diseases, malignancies, and cardio-metabolic disturbances. Serum IL-12 level was determined using an enzyme-linked immunosorbent assay method. The severity of NAFLD was assessed using the BARD score and NAFLD fibrosis score.Results. A total of 100 subjects were enrolled with male predominant. The mean age of subjects was 54.97 ± 8.85 years, and the most frequent comorbidity was obesity. Most subjects had mild to moderate disease progression. Serum IL-12 level was higher in more severe NAFLD based on ultrasound grading (P < 0.001), BARD score (P = 0.003), and NAFLD fibrosis score (P = 0.005). A positive correlation was observed between serum IL-12 level and BARD score (P < 0.001) with sufficient accuracy (AUC = 0.691, P = 0.014).Conclusion. Serum IL-12 level was associated with the severity of NAFLD. Higher serum IL-12 level was observed in more severe NAFLD progression.

Expressions of IL-12 and its receptors in patients with lumbar disc herniation and their relationship with clinical efficacy.

This study aimed to explore the expressions of interleukin-12 (IL-12) and its receptors IL-23R and IL12RB2 in patients with lumbar disc herniation (LDH) before and after treatment and their relationship with clinical efficacy. A total of 172 LDH patients undergoing surgical treatment in Wuhan Third Hospital, Tongren Hospital of Wuhan University were enrolled as the study group, and 170 healthy subjects as the control group. 5 mL of fasting venous blood was taken before surgery (T0), 1 d (T1), 3 d (T2), 5 d (T3) and 7 d (T4) after treatment respectively. The concentrations of IL-12, IL-23R and IL12RB2 in the two groups were detected, and the correlation between them and the treatment duration and clinical efficacy was analyzed. The study group showed significantly higher serum IL-12, IL-23R and IL12RB2 than the control group before treatment (P < 0.001). In the study group, IL-12, IL-23R and IL-12RB2 were the lowest at T4 (P < 0.001), followed by T3 (P < 0.001). There was no significant difference in IL-23R at T1 and T0 (P > 0.050), and in IL12RB2 at T1 and T2 (P > 0.050). Spearman rank correlation showed that IL-12, IL-23R, IL12RB2 were negatively correlated with treatment duration in the study group (P < 0.001), and were positively correlated with clinical efficacy (P < 0.001). In conclusion, the concentrations of serum IL-12, IL-23R and IL12RB2 in LDH patients are significantly higher than those in normal controls. Moreover, the concentrations are closely related to the rehabilitation of patients and are expected to become therapeutic targets for LDH.

The effects of alpha lipoic acid on muscle strength recovery after a single and a short-term chronic supplementation - a study in healthy well-trained individuals after intensive resistance and endurance training.

BACKGROUND: Alpha lipoic acid (ALA) has been demonstrated to have anti-inflammatory activity and was tested as a drug for the treatment of various diseases. ALA is also frequently used as a nutrition supplement, in healthy individuals or in competitive athletes. However, information from intervention studies investigating physiological effects of an ALA in athletes after exercise is limited. Therefore, the aim of this study was to investigate the effects of single and short-term chronic ALA supplementation on the muscle strength recovery and performance of athletes after intensive exercise. METHODS: In a double-blind, randomised, controlled trial in cross-over design, 17 male resistance and endurance-experienced athletes successfully participated. The subjects were divided into two groups (ALA and Placebo) and underwent a standardized single training session and a high intense training week. At certain time points (T0, T1a (+ 3 h), T1b (+ 24 h) and T2 (+7d)) blood samples were taken and markers for muscle damage, inflammation and oxidative stress were investigated. In addition, the maximum performance in the back squat was measured at all time points. RESULTS: In the chronic training experiment, a moderate inhibition of muscle damage and inflammation could be observed in the ALA-group. Performance in the back squat was significantly reduced in the placebo-group, but not in the ALA-group. No anti-oxidative effects could be observed. CONCLUSIONS: Our data indicate possible effects of ALA supplementation, during intensive training periods result in a reduction of muscle damage, inflammation and an increase of recovery. Whether ALA supplementation in general may enhance performance and the exact training / supplementation scenarios needs to be investigated in future studies.

[Dendritic cell tumor vaccine assisted by Tiaohengfang polysaccharides enhances immune function of S180 tumor-bearing mice and inhibits tumor growth].

Objective To investigate the immunotherapeutic effect and mechanism of dendritic cell (DC) vaccine assisted by Tiaohengfang polysaccharides (ThPP) in S180 tumor-bearing mice. Methods Mouse bone marrow-derived cells were cultured in vitro and mature DCs were obtained with the assistance of cytokines and ThPP. The expression of CD80 and CD86 of DCs induced by ThPP was examined, and S180 tumor cells were used as antigens to stimulate dendritic cells to become dendritic cell tumor vaccine. Tumor-bearing models were established in mice by S180 tumor cells inoculated into the armpit of the left forelimb, and the mice were randomly divided into four groups according to body mass, namely tumor-bearing blank group, positive control group (cyclophosphamide), dendritic cell vaccine group adjuvanted by ThPP and TNF-α. The tumor-bearing mice were treated on the 5th and 10th days after inoculation of tumor cells. The tumor-bearing mice were killed on the 12th day and the tumor inhibition was observed by the tumor mass detection. At the same time, peritoneal macrophages were isolated and cultured, and the expression of CD11b and IL-12 were measured by immunohistochemistry. The levels of serum IL-12 and TNF-α in the mice were detected by ELISA. The survival time of the other four groups of tumor-bearing mice was observed after treatment with the same method. Results The expression of CD80 and CD86 in the TNF-α group and ThPP group were higher than those in the blank control group, and the ThPP group was more significant. The tumor inhibition rate and survival extension period of ThPP, TNF-α and positive groups were significantly higher than those of the model blank group. The levels of serum IL-12 and TNF-α in the ThPP group were higher than those in the positive cyclophosphamide group and model black group. There was no significant difference between the ThPP group and TNF-α group. The expression of CD11b in the macrophages of ThPP group was lower than that in the model blank group and positive group, while the expression of IL-12 in the macrophages of ThPP group was higher than that in the model blank group and positive group, without significant difference compared with TNF-α group. Conclusion ThPP-adjuvanted DC tumor vaccine can inhibit tumor growth and prolong survival time of S180 tumor-bearing mice, which is related to promoting the maturation of DCs and increasing the secretion of IL-12 and TNF-α.

Elevated IL-12, TNF-α, and TNF-α/IL-10 Ratios in Stored Plasmodium falciparum-Infected Whole Blood: Implications for Safe Haemotransfusion.

Although Plasmodium falciparum infections in blood donors have been reported, the impact of parasitaemia on cytokine levels in stored whole blood has not been explored. This study evaluated the effect of P. falciparum parasitaemia on circulating cytokines and their relationship with haematological parameters in banked blood. In this case-control study, two groups of donor whole blood were recruited: P. falciparum-infected donors (parasitaemia: 515-1877 parasites/µL) and noninfected blood donors (control). At day 0 (baseline), 7, 14, 21, and 35 of banking circulating cytokine levels of tumor necrosis factor alpha (TNF-α), interleukin- (IL-) 12, IL-10, and IL-6 levels and haematological parameters were determined. Kruskal-Wallis test determined differences in weekly cytokine levels while Dunn's post hoc test determined exact significant points. At baseline, the mean TNF-α (33.81 pg/mL vs. 22.70 pg/mL), IL-12 (28.39 pg/mL vs. 16.15 pg/mL), IL-10 (51.04 pg/mL vs. 18.95 pg/mL), and IL-6 (71.03 pg/mL vs. 30.89 pg/mL) levels were significantly higher in infected donor whole blood. Significant rate of increase was observed in TNF-α, IL-12 levels, and TNF-α/IL-10 ratios in infected blood, while decreased levels were observed in IL-10. IL-6 peaked at day 21 and fell below baseline level at day 35. Significant changes in TNF-α, IL-12, IL-10, IL-6 levels, and TNF-α/IL-10 ratios in infected donor blood were observed 7 days after storage. Unlike in noninfected stored whole blood, TNF-α, IL-6, IL-12, and TNF-α/IL-10 ratio levels in infected stored whole blood related inversely to haematological parameters (white cells, red cells, platelets, and haemoglobin levels) during storage. However, in both groups, significant direct relationship was observed in IL-10 and haematological parameters. In conclusion, banking of P. falciparum-infected donor whole blood may lead to infusion of large quantities of inflammatory cytokines with potential adverse immunological response in recipients.

Deficiency of activation-induced cytidine deaminase in a murine model of ulcerative colitis.

Patients with inflammatory bowel disease (IBD) have an increased risk of colorectal cancer, particularly in ulcerative colitis (UC) when the majority of colon epithelial cells may be exposed to inflammation-associated mutagenesis. In addition to mutagenesis generated by oxidative stress, inflammation can induce activation-induced cytidine deaminase (Aicda), a mutator enzyme in the APOBEC family, within colon epithelial cells. This study tested the hypothesis that deletion of the Aicda gene could protect against the development of inflammation-associated colorectal cancers, using a model of UC-like colitis in "T/I" mice deficient in TNF and IL10. Results showed that T/I mice that were additionally Aicda-deficient ("TIA" mice) spontaneously developed moderate to severe UC-like colitis soon after weaning, with histologic features and colon inflammation severity scores similar those in T/I mice. Although the mean survival of TIA mice was decreased compared to T/I mice, multivariable analysis that adjusted for age when neoplasia was ascertained showed a decreased numbers of neoplastic colorectal lesions in TIA mice, with a trend toward decreased incidence of neoplasia. Aicda deficiency increased serum IL1α and slightly decreased IL12p40 and M-CSF, as compared with T/I mice, and led to undetectable levels of IgA, IgG1, IgG2a, IgG2b, and IgG3. Taken together, these studies show that Aicda deficiency can decrease the number of neoplastic lesions but is not sufficient to prevent the risk of inflammation-associated colorectal neoplasia in the setting of severe UC-like inflammation. The TIA model may also be useful for assessing the roles of antibody class-switch recombination deficiency and somatic hypermutation on regulation of microbiota and inflammation in the small intestine and colon, as well as the pathogenesis of colitis associated with hyper-IgM syndrome in humans. Further studies will be required to determine the mechanisms that drive early mortality in TIA mice.

Inflammatory and endothelial dysfunction indices among Egyptian females with obesity classes I-III.

BACKGROUND: Obesity is an alarming threat to health in Egypt. More than one in three Egyptians is obese, the highest rate in the world. We aimed to delineate the variability of inflammation and endothelial dysfunction markers among Egyptian females with different obesity classes. METHODS: Out of 130 females, 70 were categorized into three obesity groups: Class I, body mass index (BMI) 30-34.9 kg/m2; Class II, BMI 35-39.9 kg/m2 and Class III BMI ≥ 40 kg/m2, besides 60 control subjects. Anthropometric measurements were recorded and serum levels of tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukin (IL) 6 (IL-6), IL-12, soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular adhesion molecule 1 (sVCAM-1) were assessed among participants. RESULTS: In all three classes of obesity, significant increase (P <0.05) in BMI, waist-hip ratio, fat mass and body fat mass % were noted. CRP and sVCAM-1 levels were increased among the three obesity groups. TNF-α levels were increased in class II and III obesity groups. IL-6 and IL-12 levels were elevated in class I and class III groups. While, ICAM-1 levels were increased in class III obesity group. CONCLUSION: Based on individuals' BMI, serum levels of TNF-α, CRP, IL-6, IL-12, sVCAM-1 and sICAM-1 are differentially altered with the progression of obesity. We strongly support the hypothesis that, as the obesity rate is still mounting, a subclinical inflammatory reaction has a role in pathogenesis of obesity and emphasize the elevation of endothelial dysfunction in individuals with obesity.

Irritable bowel syndrome in celiac disease - relationships to celiac disease antibodies and levels of pro-inflammatory cytokines.

BACKGROUND: Evidence indicates that low-grade inflammation can alter gastrointestinal motor and sensory function and might contribute to the genesis of symptoms in IBS. OBJECTIVE: To examine relationships between IBS, disease antibodies and cytokine titers in celiac patients and a control group. MATERIALS AND METHODS: IBS, CD activity and serum levels of IL-6, IL-8 and IL12/23p40 were determined in celiac patients and controls. RESULTS: 123 celiac patients were included, 89% were female. 59% demonstrated disease activity and 32% met IBS criteria. Prevalence of IBS was not different between patients who adhered or did not adhere to GFD as well as between patients with or without positive antibodies. Celiac patients had increased levels of IL-6, IL-8 and IL12/23p40 as compared to controls. Higher levels of cytokines were found in celiac patients with IBS than in those without IBS. No difference in levels of cytokines was found between patients with and without CD positive antibodies. A significant negative correlation between the mental component of QoL and IL-6 and IL12/23p40 levels was found, but not with IL-8. CONCLUSION: Higher levels of inflammatory cytokines were found in CD patients with IBS than in either those without IBS or controls, indicating that IBS symptoms are associated with an increase in the inflammatory response and a decrease in quality of life of CD patients. These differences in cytokine levels were not related to CD antibodies status suggesting that IBS, in CD, is related to a different inflammatory process than that which is relevant to CD.

A natural cell-penetrating nanopeptide combined with pentavalent antimonial as experimental therapy against cutaneous leishmaniasis.

The inadequacy of available treatments for leishmaniasis has presented up to 40% therapeutic failure. This fact suggests an urgency in the discovery of new drugs or alternative approaches for treating this disease. The objective of this study was to evaluate the antileishmanial activity of combined therapy between crotamine (CTA) from Crotalus durissus terrificus and the pentavalent antimonial Glucantime® (GLU). The assays were in vitro performed measuring the inhibition of Leishmania amazonensis amastigotes, followed by the evaluation of cellular production of cytokines and nitrites. After that, analytical methods were performed in order to characterize the molecules involved in the study by Mass Spectrometry, molecular affinity through an in silico assay and Surface Plasmon Resonance. In vivo experiments with BALB/c mice were performed by analyzing parasitemia, lesion size and immunological mediators. In the in vitro experiments, the pharmacological association improved the inhibition of the amastigotes, modulated the production of cytokines and nitric oxide. The therapy improved the effectiveness of the GLU, demonstrating a decreased parasitemia in the infected tissues. Altogether, the results suggest that the combined approach with CTA and GLU may be a promising alternative for the treatment of cutaneous leishmaniasis.

Tumor Suppressors-HTRA Proteases and Interleukin-12-in Pediatric Asthma and Allergic Rhinitis Patients.

Background and objective: Allergy belongs to a group of mast cell-related disorders and is one of the most common diseases of childhood. It was shown that asthma and allergic rhinitis diminish the risk of various cancers, including colon cancer and acute lymphoblastic leukemia. On the other hand, asthma augments the risk of lung cancer and an increased risk of breast cancer in patients with allergy has been observed. Thus, the relation between allergy and cancer is not straightforward and furthermore, its biological mechanism is unknown. The HTRA (high temperature requirement A) proteases promote apoptosis, may function as tumor suppressors and HTRA1 is known to be released by mast cells. Interleukin-12 (Il-12) is an important cytokine that induces antitumor immune responses and is produced mainly by dendritic cells that co-localize with mast cells in superficial organs. Material and methods: In the present study we have assessed with ELISA plasma levels of the HTRA proteins, Il-12, and of the anti-HTRA autoantibodies in children with allergy (40) and in age matched controls (39). Children are a special population, since they usually do not have comorbidities and take not many drugs the processes we want to observe are not influenced by many other factors. Results: We have found a significant increase of HTRA1, 2 and 3, and of the Il-12 levels in the children with atopy (asthma and allergic rhinitis) compared to controls. Conclusion: Our results suggest that the HTRA1-3 and Il-12 levels might be useful in analyzing the pro- and antioncogenic potential in young atopic patients.