Can supplementation of tryptophan in parenteral nutrition increase melatonin and alleviate inflammatory response?

OBJECTIVE: Endogenous melatonin is produced from tryptophan which is an essential amino acid. Besides its role in the regulation of sleep patterns, melatonin has anti-inflammatory effects. In this case-control study, we aimed to compare tryptophan and melatonin levels and their relationship with the inflammatory response, specifically serum interleukin-1, interleukin-6, and c-reactive protein levels following major abdominal surgery in patients with food restriction and who receive parenteral nutritional therapy. METHODS: We enrolled 40 patients between the ages of 18 and 65 years in the study. We collected blood and urine samples 48 h before the operation and on postoperative days 1, 3, and 5. RESULTS AND CONCLUSION: The tryptophan levels in the experimental group were higher than in the control group but failed to reach any statistical difference. Melatonin levels were increased in both groups following the surgery compared with preoperative levels. The increase in the experimental group was statistically different 3 days after the surgery. The difference in the level of interleukin-1 between the control and the experimental groups was greatest on postoperative day 3. On postoperative day 3, the interleukin-6 level in the treatment group was slightly higher than in the control group. We did not find any difference in the levels of c-reactive protein between the groups. As a result, the levels of tryptophan and melatonin were increased in the parenteral nutrition group, irrespective of the postoperative inflammatory response.

Serum interleukin-1 is a new biomarker to predict the risk of rebleeding of ruptured intracranial aneurysm after admission.

Interleukin-1 (IL-1) could induce inflammation of the aneurysm wall, which might be related to intracranial aneurysm rupture. The aim of this study was to investigate whether IL-1 could serve as a biomarker to predict the risk of rebleeding after admission. Data between January 2018 and September 2020 were collected from patients with ruptured intracranial aneurysms (RIAs) and were retrospectively reviewed. The serum IL-1ß and IL-1ra levels were detected using a panel, and IL-1 ratio was calculated as the log10 (IL-1ra/IL-1ß). The predictive accuracy of IL-1 compared with previous clinical morphology (CM) model and other risk factors were evaluated by the c-statistic. Five hundred thirty-eight patients were finally included in the study, with 86 rebleeding RIAs. The multivariate Cox analysis confirmed aspect ratio (AR) > 1.6 (hazard ratio (HR), 4.89 [95%CI, 2.76-8.64], P < 0.001), size ratio (SR) > 3.0 (HR, 2.40 [95%CI, 1.34-4.29], P = 0.003), higher serum IL-1ß (HR, 1.88 [95%CI, 1.27-2.78], P = 0.002), and lower serum IL-1ra (HR, 0.67 [95%CI, 0.56-0.79], P < 0.001) as the independent risk factors for rebleeding after admission. According to the c-statistics, the IL-1 ratio had the highest predictive accuracy (0.82), followed by IL-1ra and IL-1ß (0.80), AR > 1.6 (0.79), IL-1ra (0.78), IL-1ß (0.74), and SR > 3.0 (0.56), respectively. Subgroup analysis based on AR and SR presented similar results. The model combining IL-1 ratio and CM model showed higher predictive accuracy for the rebleeding after admission (c-statistic, 0.90). Serum IL-1, especially IL-1 ratio, could serve as a biomarker to predict the risk of rebleeding after admission.

Plasma IL-36α and IL-36γ as Potential Biomarkers in Interstitial Lung Disease Associated with Rheumatoid Arthritis: a Pilot Study in the Chinese Population.

Interstitial lung disease (ILD) is a frequent extra-articular manifestation of rheumatoid arthritis (RA) and increases mortality in patients with RA. Early identification of ILD, especially the usual interstitial pneumonia (UIP) pattern with a poor prognosis, is important for guiding treatment of RA-ILD and preventing damage resulting from a delay in diagnosis. Interleukin-36 (IL-36) cytokines are involved in connective tissue diseases. However, IL-36 expression in RA-ILD is unknown. In this study, the clinical relevance of plasma IL-36 cytokines was evaluated in 39 patients with RA-ILD and three other groups (30 healthy controls [HCs], 35 RA patients without ILD, and 27 patients with idiopathic pulmonary fibrosis [IPF]) in the Chinese population. Plasma IL-36α and IL-36γ concentrations were elevated in patients with RA-ILD compared with those in HCs and patients with RA. RA-ILD patients with UIP pattern had higher plasma IL-36γ concentrations than those with RA-ILD without UIP, but these were lower than those in patients with IPF. Receiver operating curve analysis suggested that IL-36α and IL-36γ were potential biomarkers for identifying ILD in patients with RA. Additionally, the optimal cutoff value of IL-36γ for distinguishing RA-ILD with the UIP pattern from RA-ILD without UIP was 555.40 pg/mL and that for distinguishing RA-ILD from IPF was 655.10 pg/mL. No significant difference in plasma IL-36ß or IL-36Ra concentrations was found between patients with RA-ILD and the three other groups. We also found that the lungs originating from different types of patients with PF, including RA-ILD and IPF, and those from mice following bleomycin-induced PF were characterized by increased IL-36γ expression. Our findings suggest that using IL-36 cytokines to identify patients with RA for further ILD workups may provide additional diagnostic value to the current clinically available assays. Moreover, IL-36γ may help to identify the presence of the UIP pattern in patients with RA-ILD and to discriminate RA-ILD from IPF.

Interleukin-37 suppresses the cytotoxicity of hepatitis B virus peptides-induced CD8+ T cells in patients with acute hepatitis B.

Interleukin-37 (IL-37) is a newly identified anti-inflammatory cytokine, owning immunosuppressive activity in infectious diseases. The aim of this study was to investigate the regulatory function of IL-37 on CD8+ T cells during hepatitis B virus (HBV) infection. Eighteen acute hepatitis B (AHB) patients, thirty-nine chronic hepatitis B (CHB) patients, and twenty controls were enrolled. IL-37 concentration was measured by ELISA. IL-37 receptor subunits expressions on CD8+ T cells were assessed by flow cytometry. Purified CD8+ T cells were stimulated with HBV peptides and recombinant IL-37. Perforin and granzyme B secretion was investigated by ELISPOT. Programmed death-1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4) mRNA expressions were semi-quantified by real-time PCR. CD8+ T cell cytotoxicity was assessed in direct contact and indirect contact coculture with HepG2.2.15 cells. Plasma IL-37 level was down-regulated and negatively correlated with aminotransferase levels in AHB patients. There were no significant differences of IL-37 receptor subunits among AHB patients, CHB patients, and controls. Exogenous IL-37 stimulation suppressed HBV peptides-induced perforin and granzyme B secretion by CD8+ T cells in AHB patients, but not in CHB patients. Exogenous IL-37 stimulation did not affect proinflammatory cytokines secretion as well as PD-1/CTLA-4 mRNA expressions in CD8+ T cells in AHB and CHB patients. Exogenous IL-37 stimulation dampened HBV peptide-induced CD8+ T cell cytotoxicity in a cell-to-cell contact manner. The current data indicated that acute HBV infection might induce down-regulation of IL-37, which might be associated with enhanced CD8+ T cell cytotoxicity and liver damage.

Interleukin-36α is elevated in diffuse systemic sclerosis and may potentiate fibrosis.

Systemic sclerosis (SSc) is an autoimmune prototypical connective tissues disease that results in alterations in vasculature, inflammation and fibrosis of the skin. Interleukin-1 family cytokines has been implicated in the disease including IL-1. IL-36α is an IL-1 family member that is clearly implicated in psoriatic skin disease but its role in systemic sclerosis disease is not clear. The aim of this work is to evaluate the levels and role of IL-36α in systemic sclerosis. Early diffuse SSc patients sera was isolated along with healthy controls and IL-36 levels quantified by ELISA. In vitro analysis was also undertaken with primary dermal fibroblasts with recombinant IL-36α and keratinocyte cells were also incubated with IL-36α. Cytokines were measured by ELISA. Serum IL-36 was significantly elevated compared to healthy controls. Elevated neutrophil elastase was also elevated in the matched sera. IL-36 was not directly pro-fibrotic in dermal fibroblasts but did induce pro-inflammatory cytokines that were dependant on the MAPK pathway for their release. IL-36α also led to release of CCL20 and CCL2 in keratinocytes which may potentiate fibrosis. IL-36α is elevated in SSc serum and whilst not directly pro-fibrotic it may through keratinocytes, potentiate fibrosis through keratinocyte-immune fibroblast cross-talk.

Later sleep timing and social jetlag are related to increased inflammation in a population with a high proportion of OSA: findings from the Cleveland Family Study.

STUDY OBJECTIVES: To examine the association between sleep midpoint and inflammation in a population with a large proportion of individuals diagnosed with obstructive sleep apnea syndrome (OSAS), a group that is already prone to increased inflammation. METHODS: Subjects from the Cleveland Family Study underwent overnight polysomnography and completed surveys on sleep habits. Morning and evening blood samples were collected and assayed for proinflammatory biomarkers interleukin (IL)-1, IL-6, and tumor necrosis factor α (TNF-α). Linear regression models were used, adjusting for potential confounders and sleep duration. RESULTS: The study population included 587 adults (52.3% with OSAS). Mean ± standard deviation weekday sleep midpoint was 3.52 ± 2.09 (3:31 am) and weekend sleep midpoint was 4.46 ± 1.69 (4:28 am). The Mean difference between weekday and weekend sleep midpoint (social jetlag) was 0.94 ± 2.08 hours. After adjusting for OSA severity, greater social jetlag was associated with higher levels of the inflammatory cytokine IL-1 (beta: 0.435 pg/mL, 95% confidence interval [CI]: 0.091 to 0.779). Additionally, later timing of sleep during both the weekdays and the weekends was associated with increased levels of IL-6 (weekday beta: 0.182 pg/mL; 95% CI: 0.013 to 0.350; and weekend beta: 0.188 pg/mL; 95% CI: 0.004 to 0.373). No trends were observed with TNF-α and any sleep exposure. CONCLUSIONS: Later sleep timing was associated with elevated levels of IL-6 while increased social jetlag was associated with elevated levels of IL-1. Our results indicate that later sleep schedules and increased social jetlag may lead to higher inflammation, even after controlling for OSA severity. CITATION: Girtman KL, Baylin A, O'Brien LM, Jansen EC. Later sleep timing and social jetlag are related to increased inflammation in a population with a high proportion of OSA: findings from the Cleveland Family Study. J Clin Sleep Med. 2022;18(9):2179-2187.

Analysis of serum cytokine and protective vitamin D levels in severe cases of COVID-19.

In this study, we investigated the role and relationship between the cytokine profile and protective vitamin D by measuring their serum levels in COVID-19 intensive care unit patients with severe illnesses. A total of 74 patients were included in our study. Patients were divided into two groups. Patients in the COVID-19 group (n = 31) and individuals without a history of serious illness or infection were used as the control group (n = 43). The serum concentrations of interleukin-1 (IL-1), IL-6, IL-10, IL-21, and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assays. Levels of serum vitamin D were detected with Liquid chromatography-mass spectrometry methodologies. TNF-α, IL-1, IL-6, IL-10, IL-21, and vitamin D levels were measured in all patients. The serum cytokine levels in the COVID-19 patient group were significantly higher (151.59 ± 56.50, 140.37 ± 64.32, 249.02 ± 62.84, 129.04 ± 31.64, and 123.58 ± 24.49, respectively) than control groups. Serum vitamin D was also significantly low (6.82 ± 3.29) in patients in the COVID-19 group than the controls (21.96 ± 5.39). Regarding the correlation of vitamin D with cytokine levels, it was significantly variable. Our study shows that COVID-19 patients are associated with lower serum vitamin D and higher pro-inflammatory cytokines associated with increased virus presence. Our data provide more evidence of the anti-inflammatory effect of vitamin D on COVID-19 patients and the protective effects of vitamin D on risk were demonstrated.

IL-35 and IL-37 are negatively correlated with high IgE production among children with asthma in Saudi Arabia.

BACKGROUND: Asthma is one of the most prevalent inflammatory disorders among children in Saudi Arabia. OBJECTIVE: This study aimed to determine the correlation between the serum levels of vitamin D, immunoglobulin E (IgE), and cytokine (interferon-gamma (IFN-γ), interleukin (IL)-1ß, IL-4, IL-6, IL-10, IL-13, IL-35, and IL-37) in relation to the severity of disease in patients with asthma. METHODS: This case-control study was carried out at King Abdullah Specialist Children's Hospital, Saudi Arabia, and included 48 patients with asthma and 47 matched controls, aged 6-14 years. A validated questionnaire was administered to the participants, after which each patient with asthma underwent pulmonary function tests. The serum levels of vitamin D, IgE, IFN-γ, IL-1ß, IL-4, IL-6, IL-10, IL-13, IL-35, and IL-37 of each participant were also measured. RESULTS: Patients with asthma demonstrated significantly higher IgE and cytokine (IL-1ß, IL-4, IL-6, IL-10, IL-13, IL-35, and IL-37) levels compared to the control group (p value < .001). The levels of IL-1ß, IL-4, IL-10, and IL-13 were consistently positively correlated with the serum levels of IgE among patients with asthma. However, the IgE levels in patients with asthma were consistently negatively correlated with IL-35 and IL-37. CONCLUSIONS: We found significantly higher levels of eosinophils, IgE, IL-1ß, IL-4, IL-6, IL-10, IL-13, IL-35, and IL-37 in patients with asthma compared to the controls, but no relationship between vitamin D and asthma.

Elevated IL-37 Serum Levels in Patients with Transitional Cell Carcinoma of Bladder.

BACKGROUND: Interleukin-37 (IL-37) is a recently described cytokine that emerges as a natural inhibitor of inflammatory and immune responses. However, IL-37 has not yet been investigated in bladder cancer, and its biological role is unknown. OBJECTIVE: The purpose of this study was to investigate IL-37 serum levels in patients with bladder cancer and determine whether they were linked to the patients' pathological characteristics. METHODS: IL-37 serum levels were measured using a commercial ELISA kit in 60 patients with transitional cell carcinoma (TCC) of the bladder (mean age: 64.55±12.93) and 50 healthy controls (mean age: 62.94±12.69). Non-parametric tests were used for statistical comparisons, and the Cohen's d effect size was calculated to evaluate the practical and clinical significance of the results. RESULTS: Our findings indicated an increasing trend in IL-37 serum levels in patients with TCC (42.77±3.36 pg/ml) in comparison with controls (40.51±7.32 pg/ml, p=0.09). However, IL-37 serum levels were found to be significantly higher in male patients (44.72±3.81 pg/ml) and patients aged ≥70 (46.92±6.77 pg/ml) in comparison with male controls (29.96±3.30 pg/ml, p=0.026) and controls aged ≥70 (23.62±4.43 pg/ml, p=0.009). In comparison to similar controls, Cohen's d effect size for patients aged ≥70 years was found to be 0.90. CONCLUSION: The findings reveal a higher serum level of IL-37 in patients with TCC, which might be clinically associated with immunosuppression and tumor growth. However, this is a preliminary study, and more research on the biological role of IL-37 and its potential therapeutic effects in bladder cancer is required.

Evaluation of Serum Interleukin-38 Levels in Different Radiographic Grades of Idiopathic Knee Osteoarthritis.

The aim of this study was to assess interleukin-1ß (IL-1ß), IL-1Ra, IL-36, and IL-38 levels together with hs-CRP levels in patients with different radiographic grades of knee osteoarthritis (OA) in comparison to healthy individuals. Consecutive patients aged over 50 years who were admitted to our Orthopaedics and Traumatology department between November 2018 and March 2019 and diagnosed as knee OA according to the American College of Rheumatology criteria were included in this prospective case-control study. Patients with knee OA were staged according to radiographic Kellgren-Lawrence (K-L) classification and 20 patients were assigned to each group. An age and gender matched control group consisted healthy volunteers with no clinical and radiographic sign of arthritis were conducted as the control group. Venous blood samples were collected and assessed for hs-CRP, IL-1ß, IL-1Ra, IL-36, and IL-38 levels using the double-antibody sandwich ELISA method. The hs-CRP, IL-1ß, IL-36 and IL-38 levels did not significantly differ among controls and independent radiographic stage groups except IL-1Ra levels which was significantly higher in K-L grade 4 knee OA groups compared to healthy controls (P = 0.045). When we compared all patients with knee OA and healthy controls, we detected that IL-1 and IL-1Ra were significantly lower and IL-38 levels were significantly higher in healthy control group compared to patients with knee OA (P = <0.001, <0.001, and 0.019, respectively). According to results obtained from our study, IL-1ß, IL-1Ra, and IL-38 levels significantly differed between healthy individuals and patients with knee OA. However, we did not observe a significant difference and correlation between radiographic grade of knee OA and interleukin levels.

Decreased serum profile of the interleukin-36α in polycystic ovary syndrome.

OBJECTIVE: The aim of this study was to determine the serum adiponectin and interleukin-36 alpha (IL-36α) levels in polycystic ovary syndrome (PCOS), and their relationship with obesity. MATERIALS AND METHODS: This observatory study included 80 PCOS patients and 58 controls. The clinical, biochemical, and hormonal parameters, and serum adiponectin and IL-36α levels of the patients were evaluated. RESULTS: The serum IL-36α levels of the PCOS patients were significantly lower when compared to the control group, despite a similar mean body mass index (BMI) (P = 0.000). The adiponectin levels were significantly lower in the obese PCOS group when compared to the obese control group (P = 0.03). The plasma IL-36α level was positively correlated with adiponectin level, but negatively correlated with the serum LH level (P = 0.000 and P = 0.004, respectively). Using receiver operating characteristic analysis, the cut-off value of IL-36α was calculated as 0.815 for PCOS. In the multiple binary logistic regression analysis, IL-36α (OR [95% CI] 0.432 [0.303, 0.616], P < 0.001) and adiponectin (OR [95% CI] 1.044 [1.005, 1.084], P = 0.028) were determined to be significantly associated with PCOS. CONCLUSION: A reduced IL-36α level may play a role in the pathogenesis of ovulatory disfunction and insulin resistance in PCOS patients. Further studies are needed to understand the pathogenic and clinical significance of the IL-36 system in PCOS.

Improvement of clinical outcome, laboratory findings and inflammatory cytokines levels using plasmapheresis therapy in severe COVID-19 cases.

INTRODUCTION: Cytokine storm is one of the consequences of the severe forms of COVID-19 due to excessive immune response. In this study, we investigated the therapeutic effect of plasmapheresis and its role on the inflammatory cytokines levels in patients suffering from severe COVID-19. METHODS: In plasmapheresis group, 22 severe cases of COVID-19 receiving three cycles of plasmapheresis with time interval of 24-36 h and 22 COVID-19 patients as the control group were enrolled. Clinical history and laboratory parameters as well as IL-1, IL-6, IFN-γ and IL-17 cytokines serum levels in the time points of before and after plasmapheresis were studied. RESULTS: In severe COVID-19 patients, plasmapheresis significantly improved clinical and laboratory parameters such as cough, weakness, fever, blood oxygen saturation and CRP levels. Serum levels of IL-1, IL-6, IFN-γ and IL-17 in the group of patients receiving plasmapheresis, had a significant decrease following plasmapheresis courses. Although only IL-6 level in the control group had a significant decrease between the days 1-14 of disease. Also, at both time points of before and after plasmapheresis, serum levels of IL-1, IL-6, IFN-γ and IL-17 were inversely correlated to blood oxygen saturation. CONCLUSION: Based on the obtained results, plasmapheresis therapy in severe forms of COVID-19 can effectively improve the clinical symptoms of the disease and reduce inflammatory markers. Therefore, it is suggested that plasmapheresis can be evaluated in standard treatment protocols for severe forms of COVID-19.

Analysis of Serum Interleukin-37 Level and Prognosis in Patients with ACS.

OBJECTIVE: To explore the level of serum interleukin-37 in patients with acute coronary syndrome (ACS) and its prognostic value. METHODS: Altogether, 121 continuous ACS cases from September 2017 to June 2020 were selected as the research group (RG), and 107 healthy individuals during the same period were obtained as the control group (CG). ELISA was applied to test IL-37 in the serum of the CG and the RG. Chemiluminescence immunoassay was applied to test NT-pro BNP and hs-cTnI in each group and immune scattering turbidimetry to test hs-CRP. The correlation of IL-37 with serum NT-pro BNP, hs-cTnI, and CRP was analyzed, and the value of IL-37 in diagnosis and prognosis prediction of patients with ACS was tested. Logistic regression was applied to test the independent risk factors affecting poor prognosis of patients with ACS. RESULTS: IL-37 was poorly expressed in patients with ACS, which had a high diagnostic value for ACS (sensitivity: 94.39%, specificity: 74.38%, and area under curve: 0.945). There was a negative correlation of IL-37 with serum NT-pro BNP, hs-cTnI, and CRP. IL-37 in patients with poor prognosis was markedly declined compared with that of patients with good prognosis, and the predicted AUC was 0.965. Logistic regression revealed that low IL-37, diabetes, high CRP, NT-pro BNP, and hs-cTnI in the blood were independent risk factors for poor prognosis in patients with ACS. CONCLUSION: IL-37 is low expressed in patients with ACS, which has a good diagnostic and prognostic value for ACS, and may be applied as an important marker for the prediction of patients with ACS.

Characterization by Quantitative Serum Proteomics of Immune-Related Prognostic Biomarkers for COVID-19 Symptomatology.

The COVID-19 pandemic caused by SARS-CoV-2 challenges the understanding of factors affecting disease progression and severity. The identification of prognostic biomarkers and physiological processes associated with disease symptoms is relevant for the development of new diagnostic and therapeutic interventions to contribute to the control of this pandemic. To address this challenge, in this study, we used a quantitative proteomics together with multiple data analysis algorithms to characterize serum protein profiles in five cohorts from healthy to SARS-CoV-2-infected recovered (hospital discharge), nonsevere (hospitalized), and severe [at the intensive care unit (ICU)] cases with increasing systemic inflammation in comparison with healthy individuals sampled prior to the COVID-19 pandemic. The results showed significantly dysregulated proteins and associated biological processes and disorders associated to COVID-19. These results corroborated previous findings in COVID-19 studies and highlighted how the representation of dysregulated serum proteins and associated BPs increases with COVID-19 disease symptomatology from asymptomatic to severe cases. The analysis was then focused on novel disease processes and biomarkers that were correlated with disease symptomatology. To contribute to translational medicine, results corroborated the predictive value of selected immune-related biomarkers for disease recovery [Selenoprotein P (SELENOP) and Serum paraoxonase/arylesterase 1 (PON1)], severity [Carboxypeptidase B2 (CBP2)], and symptomatology [Pregnancy zone protein (PZP)] using protein-specific ELISA tests. Our results contributed to the characterization of SARS-CoV-2-host molecular interactions with potential contributions to the monitoring and control of this pandemic by using immune-related biomarkers associated with disease symptomatology.

Interleukin-37 is down-regulated in serum of patients with severe coronavirus disease 2019 (COVID-19).

Pro-inflammatory and anti-inflammatory cytokines are indicated to play a prominent role in mediating the immunopathogenesis of coronavirus disease 19 (COVID-19). Interleukin (IL-37) is one of the anti-inflammatory cytokines that has been proposed to be involved in disease progression but the data are not overwhelming. Therefore, a case-control study was performed to analyze IL-37 levels in serum of 100 patients with severe COVID-19 and 100 blood donors (control group). Median age was significantly higher in COVID-19 cases than in controls. Stratification by gender, body mass index and ABO and Rh blood group systems showed no significant differences between patients and controls. Chronic diseases (cardiovascular and diabetes) were observed in 57.0% of patients. Serum levels of IL-37 and vitamin D were significantly decreased in patients compared to controls. The low level of IL-37 was more pronounced in males, overweight/obese cases, blood group B or AB cases, Rh-positive cases, and cases with no chronic disease. Low producers of IL-37 were more likely to develop COVID-19 (odds ratio = 2.66; 95% confidence interval = 1.51-4.70; corrected probability = 0.015). Receiver operating characteristic curve analysis demonstrated that a low serum level of IL-37 was a good predictor of COVID-19. Spearman's rank correlation analysis showed that IL-37 and vitamin D were significantly correlated. In conclusion, IL-37 was down-regulated in serum of patients with severe COVID-19 compared to controls. This down-regulation may be associated with an increased risk of disease. Gender, body mass index, blood groups and chronic disease status may also affect IL-37 levels.

Circulating Interleukin-37 Levels in Healthy Adult Humans - Establishing a Reference Range.

Interleukin (IL)-37 has an important function in limiting excessive inflammation. Its expression is increased in numerous inflammatory and autoimmune conditions and correlates with disease activity, suggesting it could have potential as a disease biomarker. Nevertheless, a reference range has yet to be determined. Our aim was to establish the first reference range of circulating IL-37 levels in healthy adult humans. PubMed was searched for studies reporting blood IL-37 concentrations in healthy adult subjects as measured by enzyme-linked immunosorbent assay. Nineteen studies were included in the analysis. Mean IL-37 levels were weighted by sample sizes, and weighted mean lower and upper levels ( ± 2SD of means) were calculated to provide a weighted mean and reference range. IL-37 levels were quantified in either serum or plasma from a total of 1035 (647 serum; 388 plasma) healthy subjects. The serum, plasma and combined matrix weighted means (reference ranges) were 72.9 (41.5 - 104.4) pg/mL, 83.9 (41.1 - 126.8) pg/mL, and 77.1 (41.4 - 112.8) pg/mL, respectively. There were no significant differences between serum and plasma means and upper and lower limits. Study means and upper IL-37 levels were significantly higher in Chinese population studies. From our analysis, a preliminary reference range for circulating IL-37 levels in healthy human adults has been established. In order to determine a reliable reference range for clinical application, large, prospective, multi-ethnic, healthy population studies are necessary. In addition, demographics, sample matrix, collection, processing and storage methods potentially affecting IL-37 detection levels should be thoroughly investigated.

Hsa_circ_0054633 association of C peptide is related to IL-17 and TNF-α in patients with diabetes mellitus receiving insulin treatment.

BACKGROUND: Chronic inflammation damaged the islet and resulted in dysfunction of T2D. Circular RNA is stable and better for biomarker in many diseases. Here, we aimed to identify potential circular RNA hsa_circ_0054633 that can be a biomarkers for the effects of insulin therapy in T2D. METHODS: In this retrospective case-control study, patients were from Li Huili Hospital, Ningbo, China, from February 10, 2019, to August 15, 2019. We included 47 healthy adults, 46 new-onset T2D with insulin resistance, and 51 patients with insulin therapy. Serum inflammation factors were tested by ELISA assays. We selected hsa_circ_0054633 as a candidate biomarker and measured its concentration in serum by qRT-PCR. The Pearson correlation test was used to evaluate the correlation between this circRNA and clinical variables. RESULTS: Clinical data indicated that serum C peptide was increased in T2D treatment with insulin. Serum hsa_circ_0054633 was decreased in insulin treatment group. Hsa_circ_0054633 was negative correlated with C peptide (r = -0.2841, p = 0.0433,). IL-1 and IL-6, IL-17, and TNF-α were higher in T2D patients and decreased after insulin treatment, only IL-17 and TNF-α showed a positive correlation to hsa_circ_0054633 (r = 0.4825, p < 0.0001, and r = 0.6190, p < 0.0001). The area under ROC curve was 0.7432, 0.5839, and 0.7573 for Hsa_circ_0054633, C peptide, and their combination. CONCLUSION: Hsa_circ_0054633 level was lower in T2D with insulin treatment than untreated and was a negative correlation with C peptide, and positively correlated with IL-17 and TNF-α, suggesting that hsa_circ_0054633 may be a potential early indicator of insulin treatment effect to improve inflammation condition.

The effect of Apis dorsata honey as complementary therapy on IL-37 levels and fatigue in breast cancer patients undergoing chemotherapy.

OBJECTIVE: The purpose of this study is to determine the effect of Apis dorsata Honey as a complementary therapy on IL-37 levels and fatigue in breast cancer patients undergoing chemotherapy. METHOD: The study used a quasi-experimental pretest-posttest design with a control group. A total of 30 subjects were recruited using a concurrent sampling technique. The intervention group consisted of 15 subjects who received oral honey at a dose of 13 ml (1 tablespoon × 3) for 15 days, and the control group consisted of 15 subjects. The groups' samples were chosen at random. The Fatigue Symptom Inventory (FSI) was used to assess the side effects of chemotherapy. RESULTS: Although the effect of Apis dorsata Honey on IL-37 levels was not statistically significant (p > 0.05), the group given honey experienced a clinically significant increase in IL-37 levels, with a mean before (632.37514.93) and post (632.37514.93). (1,003.021,248.88). Fatigue decreased statistically significantly in the group given mean honey values prior to 13.205.59 and after 11.805.07 (p = 0.004). CONCLUSION: Honey administration increases IL-37 levels clinically, though the increase is not statistically significant. Giving honey to patients with breast cancer can help alleviate fatigue caused by chemotherapy.

Elevated levels of interleukin-35 and interleukin-37 in adult patients with obstructive sleep apnea.

BACKGROUND: Systemic inflammation has a critical role in the pathogenesis of obstructive sleep apnea (OSA). Interleukin (IL)-35 and IL-37 have been identified as novel immune-modulating cytokines with anti-inflammatory activities in numerous types of inflammatory disease. The present study aimed to examine the serum levels of IL-35 and IL-37 in patients with OSA, and to investigate their associations with the severity of OSA. METHODS: A total of 97 patients, including 67 cases of OSA and 30 age- and gender-matched healthy control subjects, were enrolled in the present study. All subjects were evaluated by overnight polysomnography. Serum IL-35, IL-37, and pro-inflammatory cytokine IL-1ß levels were examined by ELISA. RESULTS: Compared with those in the control subjects, serum IL-35, IL-37, and IL-1ß levels were significantly elevated in patients with mild, moderate, or severe OSA. Furthermore, a severity-dependent increase in serum IL-35 and IL-37 levels was observed in patients with OSA. IL-35 and IL-37 levels were positively correlated with the apnea-hypopnea index (r = 0.742 and 0.578, respectively; both p < 0.001), while they were negatively correlated with the mean oxygen saturation (r = -0.461 and -0.339, respectively; both p < 0.001) and lowest oxyhaemoglobin saturation (r = -0.616 and -0.463, respectively; both p < 0.001) in patients with OSA. In addition, a positive correlation was observed between IL-35 or IL-37 and IL-1ß levels (all p < 0.001). CONCLUSION: The serum levels of IL-35 and IL-37 were significantly increased in patients with OSA and associated with the severity of OSA, implying that IL-35 and IL-37 may have a protective role in OSA by counteracting inflammatory responses.

Serum Interleukin-37 Increases in Patients after Ischemic Stroke and Is Associated with Stroke Recurrence.

BACKGROUND: This study seeks to assess interleukin-37 (IL-37) serum level in acute ischemic stroke and the value of predicting 3-month stroke recurrence and functional outcome in acute ischemic stroke. METHODS: From January 1, 2018, to June 30, 2019, all consecutive first-ever acute ischemic stroke patients from our hospital, China, were included. Serum samples, clinical information, and stroke severity (defined by the National Institute of Health stroke scale (NIHSS) score) were collected at baseline. Serum IL-37 level was measured by the enzyme-linked immunosorbent assay (ELISA) method. Functional impairment (defined by the modified Rankin scale (mRS)) and recurrent stroke were assessed 3 months after admission. The relation of IL-37 with either clinical severity at baseline, unfavorable functional outcome, or stroke recurrence at follow-up was evaluated by logistic regression analysis, and the results were presented as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Three hundred and ten stroke patients were included. The median IL-37 serum level in those patients was 344.1 pg/ml (interquartile range (IQR), 284.4-405.3 vs. control cases: 122.3 pg/ml (IQR, 104.4-1444.0); P < 0.001). At 3 months, a total of 36 (11.6%) patients had a stroke recurrence. IL-37 serum levels in those patients were higher than in those patients without stroke recurrence (417.0 pg/ml (IQR, 359.3-436.1) vs. 333.3 pg/ml (279.0-391.0)). In a logistic model adjusted for other factors, IL-37 in the highest quartile (>405.3 pg/ml) was still associated with recurrent stroke (OR = 3.32; 95%CI = 2.03-6.13; P < 0.001). IL-37 could promote the NIHSS score (area under the curve (AUC) of the IL-37/NIHSS, 0.75; 95% CI, 0.67-0.83; P < 0.001), corresponding to a difference of 0.085 (0.005). Serum IL-37 increases in patients with poor outcome, and an IL-37 in the highest quartile is related to poor outcome (OR = 4.85; 95%CI = 3.11 - 8.22; P < 0.001). CONCLUSION: Serum IL-37 increased in patients after ischemic stroke and was associated with stroke recurrence events and poor stroke outcomes. Large randomized controlled trials should be carried out to confirm whether IL-37 lowering treatment improves stroke prognosis.