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In this paper, a novel electrochemical sensing platform for the sensitive detection of interleukin 6 (IL-6) was designed and fabricated. A label-free aptasensor was fabricated by modifying the glassy carbon electrode (GCE) using a nanocomposite composed of carboxylated multi-walled carbon nanotubes (cMWCNTs), cobalt hexacyanoferrate (CoHCF) and gold nanoparticles (AuNPs). The nanocomposite improved electron transfer rate and increased intercalation of signaling molecules. Moreover, it also offers desirable capabilities for the immobilization of biomolecules. The cMWCNTs/CoHCF/AuNPs modified electrode showed good electrochemical characteristics and biocompatibility, thus achieving excellent sensor performance. The differential pulse voltammetry (DPV) was used to detect the peak current of CoHCF in the redox process. The peak current is proportional to the concentration of IL-6 on the electrode surface. Under optimal conditions, the proposed aptamer sensor exhibits a linear range from 0.5 pg/mL to 1000 pg/mL and has a low detection limit of 0.17 pg/mL. In addition, the IL-6 aptamer sensor has good selectivity, high stability, and satisfactory reproducibility, showing broad potential in clinical research and diagnostic applications.

The present study was carried out in the labs of Technical Institute –Al-Nasiriyah /Community Health Department and Nasiriyah Heart Center in Thi- Qar province, during the period of research was extended from January to July 2022 . The aim of study was to determination polymorphisms of IL-6 gene in patients with Coronary Artery Disease and measuring its levels in serum using a technique enzyme-linked immune sorbent adsorptive (ELISA). The study included a total of 100 Iraqi patients with coronary artery disease(CAD) and healthy control group their age between 3-85 years. DNA has been isolated and PCR was performed by using primers specific for genotypes of IL-6 gene (572 C/G and 174 C/G), the results showed that gel electrophoresis for amplified IL-6 gene of CAD patients, gel electrophoresis of 167bp (IL-6 572C/G) PCR products and 198bp PCR product(IL-6 174C/G). Frequency of genotypes for the IL6 gene showed a high frequency of GG genotype compared to the GC and CC genotypes in all study groups , the frequency of G and C allele in IL6 gene was 95 % and 5 %, respectively with significant differences between genotypes in various groups, in the patient group (90 %) had GC genotype, (10%) were heterozygote and had (0%) had CC genotype compare with control group, (100%) had GC genotype, (0%) were heterozygote and had (0%) had CC genotype. The immunological study showed that there was a significant increase of concentrations of (IL-6) in patients compared to the healthy control group. Thus it seems There is no correlation between IL-6 gene polymorphisms and the risk of coronary artery disease in Thi- Qar province and the Serological Assay (ELISA) showed a significant increase in the concentration of IL-6 in patients with coronary artery disease compared with the healthy control group.

BACKGROUND AND AIM: The identification of reliable biomarkers for severe Coronavirus Disease 2019 (COVID-19) is still needed. Therefore, we analyzed mannose-binding lectin (MBL) in conjunction with interleukin-6 (IL-6) to elucidate their association with disease severity in COVID-19. METHODS: In this prospective, observational cohort study, 88 patients with COVID-19 [severe (n=28), non-severe (n=60)] were analyzed. Correlations of serum MBL and IL-6 levels with laboratory parameters were analyzed. Receiver operating characteristic (ROC) curves were used to analyze the impact of MBL and IL-6 levels on disease severity. Logistic regression analysis (LRA) was performed to assess the association between severity and risk factors. RESULTS: MBL level was similar in both groups (0.81 vs. 0.80 ng/mL, p=0.76) and showed no correlation between laboratory parameters nor hospitalization duration. The ROC curve showed that the area under the curve (AUC) of MBL was 0.520 (95% Cl: 0.390-0.650, p=0.76). IL-6 levels were higher in the severe group (36.6 vs. 14.5 pg/mL, p=0.03) and correlated with hospitalization duration. At 32.75 pg/mL, IL-6 could differentiate the severe group with an AUC of 0.642 (95% Cl: 0.512-0.771, p=0.03). In multivariate LRA, interleukin-6 level >32.75 pg/mL (Odds Ratio (OR): 3.991, 95% Cl: 1.475–10.799, p=0.006) remained a significant risk factor for severe disease. CONCLUSIONS: IL-6 has predictive value for both disease severity and hospitalization duration in COVID-19, while MBL is not a reliable biomarker for disease severity. [ABSTRACT FROM AUTHOR]

Colorectal cancer is one of the most prevalent and lethal malignancies, affecting approximately 900,000 individuals each year worldwide. Patients with colorectal cancer are found with elevated serum interleukin-6 (IL-6), which is associated with advanced tumor grades and is related to their poor survival outcomes. Although IL-6 is recognized as a potent inducer of colorectal cancer progression, the detail mechanisms underlying IL-6-induced colorectal cancer epithelial–mesenchymal transition (EMT), one of the major process of tumor metastasis, remain unclear. In the present study, we investigated the regulatory role of IL-6 signaling in colorectal cancer EMT using HCT116 human colorectal cancer cells. We noted that the expression of epithelial marker E-cadherin was reduced in HCT116 cells exposed to IL-6, along with the increase in a set of mesenchymal cell markers including vimentin and α-smooth muscle actin (α-SMA), as well as EMT transcription regulators—twist, snail and slug. The changes of EMT phenotype were related to the activation of Src, FAK, ERK1/2, p38 mitogen-activated protein kinase (p38MAPK), as well as transcription factors STAT3, κB and C/EBPβ. IL-6 treatment has promoted the recruitment of STAT3, κB and C/EBPβ toward the Twist promoter region. Furthermore, the Src-FAK signaling blockade resulted in the decline of IL-6 induced activation of ERK1/2, p38MAPK, κB, C/EBPβ and STAT3, as well as the decreasing mesenchymal state of HCT116 cells. These results suggested that IL-6 activates the Src-FAK-ERK/p38MAPK signaling cascade to cause the EMT of colorectal cancer cells. Pharmacological approaches targeting Src-FAK signaling may provide potential therapeutic strategies for rescuing colorectal cancer progression. [ABSTRACT FROM AUTHOR]

Butea monosperma (Fabaceae) has been used in traditional Indian medicine to treat a variety of ailments, including abdominal tumors. We aimed to investigate the anti-IL-6 activity of butein in ovarian cancer and elucidate the underlying molecular mechanisms. Butein was isolated and identified from B. monosperma flowers, and the inhibition of IL-6 signaling was investigated using the HEK-Blue™ IL-6 cell line. The surface plasmon resonance assay was used to estimate the binding of butein to IL-6, IL-6Rα, and gp130. After treatment with butein, ovarian cancer cell migration, apoptosis, and tumor growth inhibition were evaluated in vitro and in vivo. Furthermore, we used STAT3 siRNA to identify the mechanistic effects of butein on the IL-6/STAT3/FoxO3a pathway. Butein suppressed downstream signal transduction through higher binding affinity to IL-6. In ovarian cancer, butein inhibited cell proliferation, migration, and invasion, and induced cell cycle arrest and apoptosis. In addition, it decreased the growth of ovarian cancer cells in xenograft tumor models. Butein inhibited STAT3 phosphorylation and induced FoxO3a accumulation in the nucleus by inhibiting IL-6 signaling. The anticancer activity of butein was mediated by blocking the IL-6/IL-6Rα interaction and suppressing IL-6 bioactivity via interfering with the IL-6/STAT3/FoxO3a pathway. [ABSTRACT FROM AUTHOR]

Introduction: C-type lectin receptor (CLR) agonists emerged as superior inducers of primary B cell responses in early life compared with Toll-like receptor (TLR) agonists, while both types of adjuvants are potent in adults. Methods: Here, we explored the mechanisms accounting for the differences in neonatal adjuvanticity between a CLR-based (CAF®01) and a TLR4-based (GLASE) adjuvant administered with influenza hemagglutinin (HA) in neonatal mice, by using transcriptomics and systems biology analyses. Results: On day 7 after immunization, HA/CAF01 increased IL6 and IL21 levels in the draining lymph nodes, while HA/GLA-SE increased IL10. CAF01 induced mixed Th1/Th17 neonatal responses while T cell responses induced by GLA-SE had a more pronounced Th2-profile. Only CAF01 induced T follicular helper (Tfh) cells expressing high levels of IL21 similar to levels induced in adult mice, which is essential for germinal center (GC) formation. Accordingly, only CAF01-induced neonatal Tfh cells activated adoptively transferred hen egg lysozyme (HEL)- specific B cells to form HEL+ GC B cells in neonatal mice upon vaccination with HEL-OVA. Discussion: Collectively, the data show that CLR-based adjuvants are promising neonatal and infant adjuvants due to their ability to harness Tfh responses in early life. [ABSTRACT FROM AUTHOR]

Study Design.: We performed histologic, immunohistochemical, immunoblot examination and suspension array analyses of cytokine expression in cultured cells derived from human cervical ossification of the posterior longitudinal ligament (OPLL). Objective.: To determine the roles of interleukin-6 (IL-6) during the maturation of osteoblasts and chondrocytes associated with the development of OPLL. Summary of Background Data.: Ectopic OPLL affects ~3% of the general population, with a higher incidence in Asian ethnic groups. Alterations in cytokine profiles may influence osteoblast differentiation, but the mechanisms and signaling pathways associated with the ossification process remain unclear. Methods.: Samples were collected from 14 patients with OPLL who had undergone spinal surgery and seven with cervical spondylotic myelopathy without OPLL. Tissue sections were used for histologic and immunohistochemical studies, and primary cells from ligamentum samples were used for cytokine array and immunoblotting. A suspension array was used to measure the concentrations of 27 inflammatory cytokines or growth factors. Results.: Suspension array and immunoblot analyses revealed significantly elevated levels of IL-6 in OPLL patients. Alterations in IL-6 concentrations were found to alter the expression of the genes Sox9 , Runx2 , and SIRT1. In addition, immunohistochemical analysis revealed that these factors are present in mesenchymal cells within the degenerative portion of the ligament matrix that is adjacent to the ossification front. Conclusions.: IL-6 plays a profound role in the osteoblast differentiation process along with the induction of chondrocyte hypertrophy and cell apoptosis in the early stages of ossification in OPLL. These changes in cytokine profiles are essential factors for regulation of the ectopic ossified plaque in OPLL. [ABSTRACT FROM AUTHOR]

Opioid use disorder (OUD) and HIV are comorbid epidemics that can increase depression. HIV and the viral protein Tat can directly induce neuronal injury within reward and emotionality brain circuitry, including the prefrontal cortex (PFC). Such damage involves both excitotoxic mechanisms and more indirect pathways through neuroinflammation, both of which can be worsened by opioid co-exposure. To assess whether excitotoxicity and/or neuroinflammation might drive depressive behaviors in persons infected with HIV (PWH) and those who use opioids, male mice were exposed to HIV-1 Tat for eight weeks, given escalating doses of morphine during the last two weeks, and assessed for depressive-like behavior. Tat expression decreased sucrose consumption and adaptability, whereas morphine administration increased chow consumption and exacerbated Tat-induced decreases in nesting and burrowing—activities associated with well-being. Across all treatment groups, depressive-like behavior correlated with increased proinflammatory cytokines in the PFC. Nevertheless, supporting the theory that innate immune responses adapt to chronic Tat exposure, most proinflammatory cytokines were unaffected by Tat or morphine. Further, Tat increased PFC levels of the anti-inflammatory cytokine IL-10, which were exacerbated by morphine administration. Tat, but not morphine, decreased dendritic spine density on layer V pyramidal neurons in the anterior cingulate. Together, our findings suggest that HIV-1 Tat and morphine differentially induce depressive-like behaviors associated with increased neuroinflammation, synaptic losses, and immune fatigue within the PFC. [ABSTRACT FROM AUTHOR]

[Display omitted] • Interleukin-6 (IL-6), serum ferritin, and d -dimer were the markers of severe SARS-CoV-2 infection. • IL-6, serum ferritin, and d -dimer were not associated with the use of a ventilator and the severity of SARS-CoV-2 infection. • ROC curves showed poor area under the curve for IL-6, serum ferritin, and d -dimer for mortality in COVID-19 patients. • IL-6, serum ferritin, and d -dimer were not associated with in-hospital mortality in COVID-19 patients. Various studies have observed an association between interleukin-6 (IL-6), serum ferritin, d -dimer, and in-hospital mortality in COVID-19 patients. However, multivariate regression analysis was not done in the majority of the studies, Also, the role of interleukin-6 (IL-6), serum ferritin, and d -dimer in hospitalized COVID-19 patients was not adequately studied and reported from our region. It was a retrospective cohort study in which the serum IL-6, serum ferritin, and d -dimer of 305 hospitalized COVID-19 patients were analyzed, and their association with mortality was determined. In COVID-19 patients, the levels of IL-6 (P = 0.007), serum ferritin (P = 0.011), and d -dimer (P = 0.004) were significantly elevated in patients with severe SARS-CoV-2 illness (SpO2 < 90 % at admission). IL-6 levels were significantly elevated (186 pg/ml vs. 215 pg/ml, P = 0.003) in non-survivors compared to survivors. However, d -dimer (mg/ml) (P = 0.129) and serum ferritin (mg/ml) (P = 0.051) levels were similar between the two groups. The ROC curve (receiver operating characteristic curve) analysis showed a significant but poor area under the curve (AUC) between elevated IL-6 (>208 pg/ml) and in-hospital mortality (P < 0.008, AUC = 0.61). Kaplan-Meir survival analysis showed poor survival in patients with elevated IL-6 (>208 pg/ml) (P by log-rank: 0.010) and elevated d -dimer (>1780 mg/ml) (P by log-rank: 0.036). The multivariate cox-regression analysis did not show any association between IL-6, serum ferritin, d -dimer, and in-hospital mortality (P > 0.05). Also, no association was found between serum levels of IL-6, serum ferritin, d -dimer, and the use of a ventilator (P > 0.05) and the severity of SARS-CoV-2 illness (P > 0.05) on multivariate binary logistic regression analysis. In this study, the serum levels of IL-6, serum ferritin, and d -dimer were not associated with in-hospital mortality in hospitalized COVID-19 patients on multivariate cox-regression analysis, and were the markers of severe SARS-CoV-2 illness. [ABSTRACT FROM AUTHOR]

To investigate the influence of preservation methods and processes on the plasma interleukin-6 (IL-6) stability.

IntroductionC-type lectin receptor (CLR) agonists emerged as superior inducers of primary B cell responses in early life compared with Toll-like receptor (TLR) agonists, while both types of adjuvants are potent in adults.MethodsHere, we explored the mechanisms accounting for the differences in neonatal adjuvanticity between a CLR-based (CAF®01) and a TLR4-based (GLA-SE) adjuvant administered with influenza hemagglutinin (HA) in neonatal mice, by using transcriptomics and systems biology analyses.ResultsOn day 7 after immunization, HA/CAF01 increased IL6 and IL21 levels in the draining lymph nodes, while HA/GLA-SE increased IL10. CAF01 induced mixed Th1/Th17 neonatal responses while T cell responses induced by GLA-SE had a more pronounced Th2-profile. Only CAF01 induced T follicular helper (Tfh) cells expressing high levels of IL21 similar to levels induced in adult mice, which is essential for germinal center (GC) formation. Accordingly, only CAF01- induced neonatal Tfh cells activated adoptively transferred hen egg lysozyme (HEL)-specific B cells to form HEL+ GC B cells in neonatal mice upon vaccination with HEL-OVA.DiscussionCollectively, the data show that CLR-based adjuvants are promising neonatal and infant adjuvants due to their ability to harness Tfh responses in early life.

Background: Chronic active antibody‐mediated rejection (CAAMR) constitutes a dominant form of late allograft failure. Several treatment strategies directed at CAAMR have been attempted but proven ineffective at delaying kidney function decline or reducing donor‐specific antibodies (DSA). We describe our single‐center experience using tocilizumab in patients with CAAMR. Methods: This is a retrospective analysis using electronic medical records. 38 kidney transplant recipients at Columbia University Irving Medical Center who had been prescribed tocilizumab and followed for at least 3 months between August 2013 through December 2019 were included. Results: Tocilizumab use was associated with a decrease in the rate of estimated glomerular filtration rate (eGFR) decline in the 6 months following treatment initiation as compared to the 3 months before tocilizumab was initiated (difference between slopes before and after initiation of treatment = 2.6 mL/min/1.73 m2 (SE =.8, p =.002) per month for up to 6 months following Tocilizumab initiation). Allograft biopsies showed significant improvement in interstitial inflammation scores (score 1(0,1) to 0 (0,1), p =.03) while other histologic scores remained stable. There was no significant change in proteinuria or DSA titers post‐treatment with tocilizumab. Conclusions: Treatment of CAAMR with tocilizumab was associated with a decrease in the rate of eGFR decline and a reduction in interstitial inflammation scores in patients with CAAMR. [ABSTRACT FROM AUTHOR]

Background: Cervical insufficiency is a recurrent, passive, and painless dilation of the cervix in the second trimester. The etiology is unclear, but there may be an association with subclinical intraamniotic infection. Interleukin-6 (IL-6) production in the amniotic cavity is induced by bacterial invasion, it is the major proinflammatory cytokine released in response to infection. Although the gold standard method to measure it is through an amniocentesis, the procedure constitutes an invasive technique with several associated risks. The objective of this study is to determine if there is a correlation between intraamniotic and vaginal IL-6 in patients with cervical insufficiency and bulging membranes during the second trimester of pregnancy, in order to avoid an amniocentesis before the rescue cerclage. Methods: A cohort study was performed in which all patients with cervical insufficiency and bulging membranes admitted into our tertiary hospital between 2019 and 2020 were included, and a control group of asymptomatic women in the second trimester of gestation where studied at the same time. Patients with bulging membranes underwent an amniocentesis to quantify amniotic IL-6, and a sample of vaginal fluid for vaginal IL-6 determination was obtained from both the study and the control group. Results: A total of 20 women were included in each group. Median gestational age at diagnosis was 22 weeks in patients with bulging membranes, and 21 weeks in the control group. Vaginal IL-6 in control group (10.875 pg/mL) is much lower than the study group one (1308.77 pg/ml). In patients with bulging membranes, vaginal IL-6 expression was lower in the vagina than in the amniotic cavity [average IL-6 in the amniotic cavity 26890.07 pg/mL, vs 1308.77 pg/mL in the vagina (p <.01)]. Through a Spearman coefficient correlation rank [rho = 0.709 (p <.001)], there is a positive correlation between amniotic and vaginal IL-6 values. The best value of this correlation was calculated with the ROC curve, being the area under the curve 0.929 (CI 95% 0.721–0.995), and the cutoff of point less than 61.4 pg/ml (sensitivity 83.33%; specificity 92.86%). Patients with vaginal IL-6 < 61.4 pg/ml associated a longer latency time between diagnosis and delivery, a higher neonatal weight and a lower perinatal mortality. Rescue cerclage in vaginal IL-6 < 61.4 pg/ml was the best predictor of good pregnancy outcome. Conclusion: There is a correlation between intraamniotic and vaginal IL-6 in patients with cervical insufficiency and bulging membranes during the second trimester of pregnancy. However, further studies are needed in order to considerate the avoidance of an amniocentesis before an emergency cerclage. [ABSTRACT FROM AUTHOR]

Introduction: The Indonesian INOVASIA study is an ongoing multicentre randomized, open controlled trial of pravastatin for the prevention of preeclampsia in patients deemed to be high risk. Here we evaluate the effects of pravastatin on circulating inflammatory and endothelial markers, i.e. Vascular Endothelial Growth Factor (VEGF), Interleukin-6 (IL-6), Endothelin-1 (ET-1), and Nitric Oxide (NO). Methods: Pregnant women deemed to be at a high risk of developing preeclampsia women were recruited based on the Fetal Medicine Foundation preeclampsia screening test or a history of preterm preeclampsia, or clinical risk factors in combination with an abnormal uterine artery Doppler flow pattern at 11–20 week's gestation. This is a nested cohort study within the larger trial (INOVASIA); 38 patients were consecutively recruited and assigned to the pravastatin group and the control group. Participants in the pravastatin group received pravastatin (2 × 20 mg p.o) in addition to a standard regimen of aspirin (80 mg p.o) and calcium (1 g p.o), from 14 to 20 weeks until delivery. Blood samples to measure the various biomarkers were obtained in consecutive patients before starting the research medication and just before delivery (pre and post-test examination). Result: The number of samples on the 2 time points for the various biomarkers was: VEGF: 38, IL-6: 30, ET-1: 38, and NO: 35. IL-6 levels decreased significantly in the pravastatin group (mean ± SD): (191.87 ± 82.99 vs. 151.85 + 48.46, p =.013), while levels in the control group did not change significantly (median (interquartile range)) (144.17 (53.91) vs. 140.82 (16.18), p =.177). ET-1 levels decreased significantly in the pravastatin group (3.64 ± 0.85 vs. 3.01 ± 0.74, p =.006) while the control group had more or less stable levels (3.57 ± 1.12 vs. 3.78 ± 0.73 p =.594). NO was the only serum marker that showed significant changes in both groups. NO levels increased in pravastatin group (11.30 (17.43) vs. 41.90 (53.18), p =.044) and decreased in control group (38.70 (34.80) vs. 10.03 (26.96), p =.002). VEGF levels appeared to follow opposite trends in the 2 groups (NS) (Pravastatin: 3.22 (0.62) vs. 3.28 (0.75), p =.402. Control: 3.38 (0.83) vs. 3.06 (0.74), p =.287). Conclusion: Administration of 40 mg pravastatin resulted in an improvement in NO levels, and a decrease in IL-6 and endothelin (ET-1) levels. The direction of the effect of pravastatin on these biomarkers appears to underpin the potential for a beneficial effect of pravastatin in the prevention of preeclampsia. [ABSTRACT FROM AUTHOR]

A 35-year-old woman with no prior history of epilepsy developed status epilepticus (SE), which was highly resistant to multiple antiseizure medications and sedatives. The etiology of SE was not identified despite extensive investigation, and the patient was diagnosed with cryptogenic new-onset refractory status epilepticus (C-NORSE). Although first-line immunotherapies such as high-dose corticosteroids and plasma exchange were ineffective, the patient manifested a resolution of SE after the administration of tocilizumab, which inhibits interleukin-6. Non-antibody-mediated inflammation has been hypothesized to be a probable pathophysiology of C-NORSE in recent studies, and tocilizumab may be a plausible second-line treatment.

Abstract Background Cellular dedifferentiation is a regenerative prerequisite that warrants cell cycle reentry and appropriate mitotic division during de novo formation of cardiomyocytes. In the light of our previous finding that expression of injury-responsive element, Wilms Tumor factor 1 (WT1), in pericardial adipose stromal cells (ADSC) conferred a compelling reparative activity with concomitant IL-6 upregulation, we then aim to unravel the mechanistic network that governs the process of regenerative dedifferentiation after ADSC-based therapy. Methods and results WT1-expressing ADSC (eGFP:WT1) were irreversibly labeled in transgenic mice (WT1-iCre/Gt(ROSA)26Sor-eGFP) primed with myocardial infarction. EGFP:WT1 cells were enzymatically isolated from the pericardial adipose tissue and cytometrically purified (ADSCgfp+). Bulk RNA-seq revealed upregulation of cardiac-related genes and trophic factors in ADSCgfp+ subset, of which IL-6 was most abundant as compared to non-WT1 ADSC (ADSCgfp−). Injection of ADSCgfp+ subset into the infarcted hearts yielded striking structural repair and functional improvement in comparison to ADSCgfp− subset. Notably, ADSCgfp+ injection triggered significant quantity of dedifferentiated cardiomyocytes recognized as round-sharp, marginalization of sarcomeric proteins, expression of molecular signature of non-myogenic genes (Vimentin, RunX1), and proliferative markers (Ki-67, Aurora B and pH3). In the cultured neonatal cardiomyocytes, spontaneous dedifferentiation was accelerated by adding tissue extracts from the ADSC-treated hearts, which was neutralized by IL-6 antibody. Genetical lack of IL-6 in ADSC dampened cardiac dedifferentiation and reparative activity. Conclusions Taken collectively, our results revealed a previous unappreciated effect of IL-6 on cardiac dedifferentiation and regeneration. The finding, therefore, fulfills the promise of stem cell therapy and may represent an innovative strategy in the treatment of ischemic heart disease.

Objectives: The decision to surgically intervene in a hydronephrotic kidney in children is based on many debatable guidelines, some requiring repeated ultrasounds or renal scans. Urinary proteins have the potential to reflect renal disorders and hence can be the alternatives to such scans. Here, we aim to assess the role of urinary Neutrophil Gelatinase-Associated Lipocalin, Monocyte Chemoattractant Protein-1, and Interleukin-6 (IL-6) in such patients.Methods: Seventeen children had obstructive hydronephrosis requiring pyeloplasty (UPJO), while seven were kept on conservative management in view of non-obstructive dilation (NOD). Urine samples were measured for the three urinary proteins at the time of presentation and following pyeloplasty using commercially available ELISA kits.Results: The levels of all three urinary proteins were significantly higher in patients with UPJO children compared to the NOD group. Cut-off values to differentiate obstructive from non-obstructive hydronephrosis were obtained. A significant fall in the post-operative value of urinary IL-6 was also observed.Conclusion: This study highlights the potentiality of urinary proteins as biomarkers in identifying children with hydronephrosis and picking out the ones with obstructive hydronephrosis who will require pyeloplasty. The drop in levels after pyeloplasty can be employed to evaluate the effectiveness of pyeloplasty when sent serially. [ABSTRACT FROM AUTHOR]

Sustained production of elevated levels of the cytokines interleukin (IL)-6 or interferon (IFN)-α in the central nervous system (CNS) is detrimental and directly contributes to the pathogenesis of neurological diseases such as neuromyelitis optica spectrum disorders or cerebral interferonopathies, respectively. Using transgenic mice with CNS-targeted production of IL-6 (GFAP-IL6) or IFN-α (GFAP-IFN), we have recently demonstrated that microglia are prominent target and effector cells and mount stimulus-specific responses to these cytokines. In order to further clarify the phenotype and function of these cells, we treated GFAP-IL6 and GFAP-IFN mice with the CSF1R inhibitor PLX5622 to deplete microglia. We examined their ability to recover from acute microglia depletion, as well as the impact of chronic microglia depletion on the progression of disease. Following acute depletion in the brains of GFAP-IL6 mice, microglia repopulation was enhanced, while in GFAP-IFN mice, microglia did not repopulate the brain. Furthermore, chronic CSF1R inhibition was detrimental to the brain of GFAP-IL6 and GFAP-IFN mice and gave rise to severe CNS calcification which strongly correlated with the absence of microglia. In addition, PLX5622-treated GFAP-IFN mice had markedly reduced survival. Our findings provide evidence for novel microglia functions to protect against IFN-α-mediated neurotoxicity and neuronal dysregulation, as well as restrain calcification as a result of both IL-6- and IFN-α-induced neuroinflammation. Taken together, we demonstrate that CSF1R inhibition may be an undesirable target for therapeutic treatment of neuroinflammatory diseases that are driven by elevated IL-6 and IFN-α production. [ABSTRACT FROM AUTHOR]

Abstract Background Accumulating evidence shows that physical exercise has a positive effect on the release of neurotrophic factors and myokines. However, evidence regarding the optimal type of physical exercise for these release is still lacking. The aim of this study was to assess the acute and chronic effects of open-skill exercise (OSE) compared to closed-skill exercise (CSE) on serum and plasma levels of brain derived neurotrophic factor (BDNFS, BDNFP), and serum levels of insulin like growth factor 1 (IGF-1), and interleukin 6 (IL-6) in healthy older adults. Methods To investigate acute effects, thirty-eight participants were randomly assigned to either an intervention (badminton (aOSE) and bicycling (aCSE), n = 24, 65.83 ± 5.98 years) or control group (reading (CG), n = 14, 67.07 ± 2.37 years). Blood samples were taken immediately before and 5 min after each condition. During each condition, heart rate was monitored. The mean heart rate of aOSE and aCSE were equivalent (65 ± 5% of heart rate reserve). In a subsequent 12-week training-intervention, twenty-two participants were randomly assigned to either a sport-games (cOSE, n = 6, 64.50 ± 6.32) or a strength-endurance training (cCSE, n = 9, 64.89 ± 3.51) group to assess for chronic effects. Training intensity for both groups was adjusted to a subjective perceived exertion using the CR-10 scale (value 7). Blood samples were taken within one day after the training-intervention. Results BDNFS, BDNFP, IGF-1, and IL-6 levels increased after a single exercise session of 30 min. After 12 weeks of training BDNFS and IL-6 levels were elevated, whereas IGF-1 levels were reduced in both groups. However, only in the cOSE group these changes were significant. We could not find any significant differences between the exercise types. Conclusion Our results indicate that both exercise types are efficient to acutely increase BDNFS, BDNFP, IGF-1 and IL-6 serum levels in healthy older adults. Additionally, our results tend to support that OSE is more effective for improving basal BDNFS levels after 12 weeks of training.

Prone positioning is an established treatment for severe acute lung injury conditions. Neuronal dysfunction frequently occurs with mechanical ventilation-induced acute lung injury (VILI) and clinically manifests as delirium. We previously reported a pathological role for systemic interleukin 6 (IL-6) in mediating neuronal injury. However, currently no studies have investigated the relationship between prone or supine positioning and IL-6 mediated neuronal dysfunction. Here, we hypothesize that prone positioning mitigates neuronal injury, via decreased IL-6, in a model of VILI. VILI was induced by subjecting C57BL/6J mice to high tidal volume (35 cc/kg) mechanical ventilation. Neuronal injury markers [cleaved caspase-3 (CC3), c-fos, heat shock protein 90 (Hsp90)] and inflammatory cytokines (IL-6, IL-1β, TNF-α) were measured in the frontal cortex and hippocampus. We found statistically significantly less neuronal injury (CC3, c-Fos, Hsp90) and inflammatory cytokines (IL-6, IL-1β, TNF-α) in the frontal cortex and hippocampus with prone compared to supine positioning (p < 0.001) despite no significant group differences in oxygen saturation or inflammatory infiltrates in the bronchoalveolar fluid (p > 0.05). Although there were no group differences in plasma IL-6 concentrations, there was significantly less cortical and hippocampal IL-6 in the prone position (p < 0.0001), indicating supine positioning may enhance brain susceptibility to systemic IL-6 during VILI via the IL-6 trans-signaling pathway. These findings call for future clinical studies to assess the relationship between prone positioning and delirium and for investigations into novel diagnostic or therapeutic paradigms to mitigate delirium by reducing expression of systemic and cerebral IL-6.

Retinal and choroidal inflammatory lesions increase the levels of the pro-inflammatory cytokine interleukin-6 (IL-6). Pigment epithelium-derived factor (PEDF) has anti-inflammatory properties, but it is not known if it can prevent the production of IL-6 by the retinal pigment epithelium. To investigate the anti-inflammatory effects of PEDF in the RPE, we used human ARPE-19 cells stimulated with human recombinant tumor necrosis factor-alpha (TNF-α) to induce overexpression of the IL6 gene. We found that the viability of ARPE-19 cells decreased by 22% with TNF-α at 10 ng/ml, being drastically decreased at ≥50 ng/ml. TNF-α at 5–100 ng/ml elevated the production and secretion of IL-6 protein, as measured by ELISA. To challenge the TNF-α-mediated stimulation of IL-6, we used recombinant human PEDF protein. PEDF at 100 nM recovered the TNF-α-mediated loss of cell viability and repressed IL-6 gene expression as determined by RT-PCR. PEDF at 10–100 nM attenuated the IL-6 protein secretion in a dose dependent fashion (IC50 = 65 nM), being abolished with 100 nM PEDF. To map the region that confers the IL-6 blocking effect to the PEDF polypeptide, we used chemically synthesized peptides designed from its biologically active domains, pro-death 34-mer, and pro-survival 44-mer and 17-mer (H105A), to challenge the IL-6 overproduction. The pro-survival peptides recovered the TNF-α-mediated cell viability loss, and inhibited IL-6 secretion, while the 34-mer did not have an effect, suggesting a role for the pro-survival domain in blocking TNF-α-mediated cell death and IL-6 stimulation. Our findings position PEDF as a novel antagonistic agent of IL-6 production in RPE cells, underscoring its use for the management of retinal disease-related inflammation.

Sustained production of elevated levels of the cytokines interleukin (IL)-6 or interferon (IFN)-α in the central nervous system (CNS) is detrimental and directly contributes to the pathogenesis of neurological diseases such as neuromyelitis optica spectrum disorders or cerebral interferonopathies, respectively. Using transgenic mice with CNS-targeted production of IL-6 (GFAP-IL6) or IFN-α (GFAP-IFN), we have recently demonstrated that microglia are prominent target and effector cells and mount stimulus-specific responses to these cytokines. In order to further clarify the phenotype and function of these cells, we treated GFAP-IL6 and GFAP-IFN mice with the CSF1R inhibitor PLX5622 to deplete microglia. We examined their ability to recover from acute microglia depletion, as well as the impact of chronic microglia depletion on the progression of disease. Following acute depletion in the brains of GFAP-IL6 mice, microglia repopulation was enhanced, while in GFAP-IFN mice, microglia did not repopulate the brain. Furthermore, chronic CSF1R inhibition was detrimental to the brain of GFAP-IL6 and GFAP-IFN mice and gave rise to severe CNS calcification which strongly correlated with the absence of microglia. In addition, PLX5622-treated GFAP-IFN mice had markedly reduced survival. Our findings provide evidence for novel microglia functions to protect against IFN-α-mediated neurotoxicity and neuronal dysregulation, as well as restrain calcification as a result of both IL-6- and IFN-α-induced neuroinflammation. Taken together, we demonstrate that CSF1R inhibition may be an undesirable target for therapeutic treatment of neuroinflammatory diseases that are driven by elevated IL-6 and IFN-α production.

Abstract Background Accumulating evidence indicates that schizophrenia is accompanied by significant activation of the immune system; however, there is limited data from low and middle-income countries (LMIC). Inflammatory markers may be more relevant in LMIC settings where infectious conditions are more prevalent and may thus play some role in the causation and maintenance of schizophrenia. The aim of this study was to assess the level of inflammatory markers high sensitive C-reactive protein (hsCRP) and interleukin-6 (IL-6) in patients with schizophrenia. Materials and methods The study population consisted of a total of 132 study participants; 82 participants with schizophrenia and 50 controls. hsCRP and IL-6 were measured using Cobas Integra 400 Plus and Cobas e 411 analysers respectively. Results The levels of hsCRP and IL-6 were significantly increased among participants with schizophrenia compared to controls: hsCRP mean value 2.87 ± 5.6 vs 0.67 ± 0.6 mg/L; IL-6 mean value 6.63 ± 5.6 vs 3.37 ± 4.0 pg/ml. Controlling for potential confounders (age, sex and body mass index), having a diagnosis of schizophrenia remained significantly associated with increased hsCRP and IL-6. Conclusion The results confirm that inflammatory processes may have a role in the pathophysiology of schizophrenia regardless of setting. Despite failure of some interventions with anti-inflammatory properties, interventions to reduce inflammation are still worth pursuing.

Exogenous assaults interfere with homeostatic processes in the body by inducing stress responses. Corticosteroid-binding globulin (CBG) binds to stress hormone glucocorticoids to transport and dynamically control their availability to target tissues. In our previous study, we confirmed that CBG is locally produced by Leydig cells in the testes. Here, we explored the potential regulators of CBG using a murine Leydig tumor cell line (mLTC-1). Results indicated that luteinizing hormone (LH) and interleukin-6 (IL-6) were important factors stimulating the release of CBG from mLTC-1 cells. In addition, IL-6 stimulated mLTC-1 cells to release alpha-1 antitrypsin (AAT), a serine proteinase inhibitor (serpin) that affects CBG conformation. The results implied that any challenge that altered LH or IL-6 levels also changed the release and binding status of CBG with steroid hormones in the testicular microenvironment and modulated cellular responses to these stress hormones. In addition, secretory proteomic analysis indicated that the extracellular matrix (ECM), cytoskeleton, and proteasomes were essentially produced by the mLTC-1 cells, and LH evoked the secretion of proteins involved in binding and metabolism. These results emphasize that Leydig cells may undertake more functions than just steroidogenesis, and the regulation of Leydig cells by LH is versatile. [Display omitted] • LH and IL-6 stimulates the release of CBG from mLTC-1 cells. • LH stimulates plenty secretory proteins release in mLTC-1 cells. • Leydig cells undertakes more functions than just steroidogenesis [ABSTRACT FROM AUTHOR]

Objective: Previous research conducted with samples of children suggest that individuals with attention-deficit/hyperactivity disorder (ADHD) have altered fatty acid concentrations and may have increased systemic inflammation. Whether these differences are also apparent in other populations of individuals with heightened ADHD symptoms (e.g., pregnant adults) is unknown. The goal of the current study was to examine whether there are ADHD-associated differences in polyunsaturated fatty acid concentrations or pro-inflammatory cytokine concentrations during pregnancy, a developmental period when fatty acid concentrations and systemic inflammation have implications for the health of both the pregnant person and the developing child. We hypothesized that plasma levels of the ratio of omega-6s to omega-3s (n-6:n-3) and plasma inflammatory cytokine levels would be higher in individuals with heightened ADHD symptoms, consistent with previous findings in children with ADHD. Methods: Data (N = 68) came from a prospective study of pregnant community volunteers who were oversampled for ADHD symptoms. During the 3rd trimester, plasma concentrations of fatty acids and the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were assessed. Dietary intake was examined in the 3rd trimester using three 24-h recalls conducted by trained dietitians and by examining plasma levels of conjugated linoleic acid (n-6) and α-linolenic acid (n-3), essential fatty acids that must come from dietary intake. Results: The group with heightened ADHD symptoms had higher n-6:n-3s (β = 0.30, p < 0.01) and higher TNF-α concentrations (β = 0.35, p < 0.001) relative to controls. There were no group differences in dietary variables, as assessed by self-report and via plasma concentrations of essential fatty acids. IL-6 was not reliably associated with ADHD status in this sample. Conclusion: Pregnant individuals with ADHD, on average, had higher plasma n-6:n-3s and higher TNF-α concentrations relative to controls. A difference was not detected in their dietary intake of fatty acids or other relevant nutrients. Though these null findings are inconclusive, they are consistent with the hypothesis that ADHD-associated differences in plasma fatty acid concentrations are the result of ADHD-associated differences in fatty acid metabolism, rather than simply differences in dietary intake. [ABSTRACT FROM AUTHOR]

Elevated levels and enhanced sensing of the pro-inflammatory cytokine interleukin-6 (IL-6) are key features of many autoimmune and inflammatory diseases. To better understand how IL-6 signaling may influence human T cell fate, we investigated the relationships between levels of components of the IL-6R complex, pSTAT responses, and transcriptomic and translational changes in CD4+ and CD8+ T cell subsets from healthy individuals after exposure to IL-6. Our findings highlight the striking heterogeneity in mbIL-6R and gp130 expression and IL-6-driven pSTAT1/3 responses across T cell subsets. Increased mbIL-6R expression correlated with enhanced signaling via pSTAT1 with less impact on pSTAT3, most strikingly in CD4+ naïve T cells. Additionally, IL-6 rapidly induced expression of transcription factors and surface receptors expressed by T follicular helper cells and altered expression of markers of apoptosis. Importantly, many of the features associated with the level of mbIL-6R expression on T cells were recapitulated both in the setting of tocilizumab therapy and when comparing donor CD4+ T cells harboring the genetic variant, IL6R Asp358Ala (rs2228145), known to alter mbIL-6R expression on T cells. Collectively, these findings should be taken into account as we consider the role of IL-6 in disease pathogenesis and translating IL-6 biology into effective therapies for T cell-mediated autoimmune disease. [ABSTRACT FROM AUTHOR]

Introduction: Sleepiness has been associated with cognitive decline and dementia in the elderly. Older adults with excessive daytime sleepiness appear to be more vulnerable to longitudinal amyloid PET accumulation before the onset of the dementia. However, it remains unclear whether sleepiness is similarly associated with other biomarkers of Alzheimer's disease (AD), axonal integrity, and inflammation, which may also contribute to neurodegeneration and cognitive decline. Methods: In this cross-sectional analysis, we identified 260 cognitively unimpaired adults (>60 years) from the Mayo Clinic Study of Aging, a population-based cohort from Olmsted County (MN), who underwent CSF quantification of AD biomarkers (Ab42, p-tau, p-tau/Ab42) in addition to at least one of the following biomarkers [neurofilament light chain (NfL) interleukin-6 (IL-6), IL-10, and tumor necrosis factor-a (TNF-a)]. We fit linear regression models to assess associations between sleepiness, as measured by the Epworth Sleepiness Scale (ESS), and CSF biomarkers, controlling for age, sex, APO+4 status, body mass index, hypertension, dyslipidemia, and prior diagnosis of obstructive sleep apnea. Results: Higher ESS scores were associated with higher CSF IL-6 and NfL, but not with the other CSF biomarkers. For every ESS score point increase, there was a 0.009 ([95% CI 0.001-0.016], p = 0.033) increase in the log of IL-6 and 0.01 ([95% CI 0.002-0.018], p = 0.016) increase in the log of NfL. A sensitivity analysis showed an association between ESS scores and log of p-tau/Ab42 only in participants with an abnormal ratio (>0.023), highly predictive of amyloid positivity. For every ESS score point increase, there was a 0.006 ([95% CI 0.001-0.012], p = 0.021) increase in the log of CSF p-tau/Ab42. Conclusion: Sleepiness was associated with greater CSF IL-6 and NfL levels, which could contribute to neurodegeneration or alternatively cause sleepiness. Higher NfL levels may result from sleep disruption and/or contribute to sleepiness via disturbed connectivity or damage to wake-promoting centers. Associations between sleepiness and p-tau/Ab42 in participants with abnormal ratio suggest that amyloid positivity contributes to vulnerability to sleep disturbance, which may further amyloid accumulation in a feed-forward loop process. Prospective studies of these markers are needed to determine cause-effect relationships between these associations. [ABSTRACT FROM AUTHOR]

Background: Cognitive impairment is among the core dimensions in schizophrenia and is a significant predictor of everyday functioning in people with schizophrenia. Given the enormous burden of schizophrenia, the search for its clinically relevant biomarkers is essential. Researchers have been trying to elucidate factors of cognitive impairment as well as personal performance, but the search is still ongoing. The aim of the study was to search for associations between BDNF, CRP, IL-6 and clinical symptoms, cognitive and personal performance in patients with paranoid schizophrenia. Methods: A total of 86 patients (53.5% women, mean age 31.1 ± 6.5) with paranoid schizophrenia (F20.0; ICD-10) in remission were examined. Clinical and neuropsychological examination included the Positive and Negative Syndrome Scale, Personal and Social Performance Scale, Calgary Depression Scale for Schizophrenia and the Brief Assessment of Cognitive Function in Schizophrenia. IL-6, BDNF, CRP levels were determined in the patients' blood serum. Results: Cognitive impairment was revealed in 79.1% of patients and was more profound in patients with higher number of hospitalizations (p = 0.006). The average BDNF levels were 13.38 ± 15.84 ng/ml, CRP concentration was 2.09 ± 2.54 mg/l, and IL-6 levels were 12.14 ± 5.88 pg/ml. There were no differences in biomarker levels or BACS results in patients that had different antipsychotic therapy or differed in the presence of anticholinergic therapy. CRP levels were higher in patients with longer disease duration, lower age of onset, more impaired personal social performance and processing speed. IL-6 was higher in individuals with lower working memory scores. PANSS negative subscale score negatively correlated and PSP score positively correlated with most cognitive domains. A linear regression established that the first episode vs. multiple episodes of schizophrenia could statistically significantly predict personal and social performance and cognition, including speech fluency and planning, as well as CRP levels. Conclusions: This study continues the search for biomarkers of schizophrenia and cognitive impairment in schizophrenia to improve the reliability of diagnosing the disorder and find new treatment approaches. The role of the number of psychoses experienced (first episode vs. multiple episodes of schizophrenia) in cognition, personal and social performance and inflammation is shown. [ABSTRACT FROM AUTHOR]

Charcot-Marie-Tooth disease type 1 (CMT1A) is a hereditary peripheral neuropathy for which there is no available therapy. Alpha-1 antitrypsin (AAT) is an abundant serine protease inhibitor with anti-inflammatory and immunomodulating properties. Here, we tested whether treatment with human AAT (hAAT) would have a therapeutic effect on CMT1A in a PMP22 transgenic mouse model. Our results show that hAAT significantly improved compound muscle action potential and histopathological features and decreased circulating IL-6 in CMT1A mice. We also investigated some of the possible underlying mechanisms in vitro. We confirmed that hAAT inhibits ADAM-17, a protease that has been implicated in blocking myelination. Furthermore, both hAAT and recombinant human AAT (rhAAT) were able to attenuate the activation of a macrophage/microglia cell line, markedly decreasing the activation of the MHC class II promoter and the expression of pro-inflammatory genes such as IL-1β and the endoplasmic reticulum (ER) stress marker ATF3. Taken together, our results demonstrate for the first time that hAAT is able to reduce the progression of CMT1A, possibly by dampening inflammation and by regulating ADAM-17. Given the already well-established safety profile of hAAT, specifically in AAT deficiency disease (AATD), we suggest that the findings of our study should be promptly investigated in CMT1A patients. [ABSTRACT FROM AUTHOR]

Objectives: Localized scleroderma (LSc) is a disease characterized by the excessive deposition of collagen and thereby thickening of the dermis. In recent years, studies reported that LSc demonstrated compromised skin barrier related to the progression of the disease. However, human studies examining epidermis in scleroderma are still sparse and lack systematic research. This study aims to investigate the structural and functional changes in the LSc epidermis and further explore the underlying mechanisms, providing a new angle to treat LSc in the clinic. Methods: A total of 136 skin sites, including lesion and non-lesion control, from 27 LSc patients were analyzed. Ultrasonic testing, trans-epidermal water loss (TEWL), and epidermal hydration were assessed to investigate the structural and functional alternations; correlations between these parameters were analyzed. To explore the underlying mechanism, skin-fibrosis mouse model and cellular model by bleomycin (BLM) were deployed. Results: The epidermal thickness was markedly increased, with a significant decline of hydration (dryness) in the LSc lesion skin. Epidermal hydration presented a negative correlation with the thickness. TEWL was not altered. The mouse model validated these morphological changes in the epidermis and indicated that interleukin-6 (IL-6) was significantly elevated. Furthermore, cellular study demonstrated that increased phosphorylation of p38 in keratinocyte promoted the secretion of IL-6, stimulating cell proliferation. Conclusion: This study characterized the epidermal alterations in LSc patients, suggesting that keratinocyte-derived abnormal IL-6 secretion can lead to the thickening of the epidermis, promoting dryness. The topical application of moisturizer may largely relieve dryness and related pruritus, thus improve the quality of life in LSc patients. Key Points • Epidermal thickness was increased in LSc lesion skin with declined hydration level. • Skin fibrosis mouse model validated the epidermal alteration in LSc patient. • p38-dependent IL-6 overexpression in keratinocyte result in epidermal thickening. [ABSTRACT FROM AUTHOR]

Adipose tissue inflammation is observed in multiple metabolically-altered states including cancer-associated cachexia and obesity. Although cachexia is a syndrome of adipose loss and obesity is a disease of adipose excess, both pathologies demonstrate increases in circulating levels of IL-6 family cytokines, β-adrenergic signaling, and adipocyte lipolysis. While β-adrenergic-stimulated adipocyte lipolysis is well described, there is limited mechanistic insight into how cancer cachexia-associated inflammatory cytokines contribute to adipocyte lipolysis under pathologic conditions. Here, we set out to compare adipocyte lipolysis signaling by cancer cachexia-associated IL-6 family cytokines (IL-6 and LIF) to that of the β-adrenergic agonist isoproterenol. Unlike isoproterenol, the IL-6 family of cytokines required JAK/STAT3-dependent transcriptional changes to induce adipocyte lipolysis. Furthermore, cachexia-associated cytokines that used STAT3 to induce lipolysis were primarily dependent on the lipase ATGL and its cofactor CGI-58 rather than lipases HSL and MAGL. Finally, administration of JAK but not β-adrenergic inhibitors suppressed adipose STAT3 phosphorylation and associated adipose wasting in a murine model of cancer cachexia characterized by increased systemic IL-6 family cytokine levels. Combined, our results demonstrate how the IL-6 family of cytokines diverge from β-adrenergic signals by employing JAK/STAT3-driven transcriptional changes to promote adipocyte ATGL/CGI-58-dependent lipolysis contributing to adipose wasting in cancer cachexia. [ABSTRACT FROM AUTHOR]

To date SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), a member of the Coronaviridae family, has infected more than 40 million people worldwide. A second wave of SARS-CoV-2 infection is aggressively surging. The clinical worsening of SARSCoV-2 infection appears to be strictly associated with comorbidities, which can be used to establish an intrinsic patient network whose molecular profile is pivotal for identifying and successfully treating populations at risk. Herein, we focus on the direct interaction between SARS-CoV-2 and virus-associated cancers, exploring the critical role of interleukin-6 (IL-6) as a mediator of this complex cross talk. IL-6 production is enhanced in diverse viral infections ranging from human papilloma virus (HPV) to hepatitis B virus (HBV), human immunodeficiency virus (HIV), and SARS-CoV-2 infection. High systemic levels of IL-6 are associated with viral persistence and poor clinical outcomes in SARS-CoV-2–infected patients. Blockade of IL-6/IL-6R, using specific molecules, is under investigation in active clinical trials for the treatment of patients with SARS-CoV-2. Although the data are as yet inconclusive, they pave the way for selective targeting of crucial cytokine-activated aberrant signaling in SARS-CoV-2 infection.

BackgroundCognitive impairment is among the core dimensions in schizophrenia and is a significant predictor of everyday functioning in people with schizophrenia. Given the enormous burden of schizophrenia, the search for its clinically relevant biomarkers is essential. Researchers have been trying to elucidate factors of cognitive impairment as well as personal performance, but the search is still ongoing. The aim of the study was to search for associations between BDNF, CRP, IL-6 and clinical symptoms, cognitive and personal performance in patients with paranoid schizophrenia.MethodsA total of 86 patients (53.5% women, mean age 31.1 ± 6.5) with paranoid schizophrenia (F20.0; ICD-10) in remission were examined. Clinical and neuropsychological examination included the Positive and Negative Syndrome Scale, Personal and Social Performance Scale, Calgary Depression Scale for Schizophrenia and the Brief Assessment of Cognitive Function in Schizophrenia. IL-6, BDNF, CRP levels were determined in the patients' blood serum.ResultsCognitive impairment was revealed in 79.1% of patients and was more profound in patients with higher number of hospitalizations (p = 0.006). The average BDNF levels were 13.38 ± 15.84 ng/ml, CRP concentration was 2.09 ± 2.54 mg/l, and IL-6 levels were 12.14 ± 5.88 pg/ml. There were no differences in biomarker levels or BACS results in patients that had different antipsychotic therapy or differed in the presence of anticholinergic therapy. CRP levels were higher in patients with longer disease duration, lower age of onset, more impaired personal social performance and processing speed. IL-6 was higher in individuals with lower working memory scores. PANSS negative subscale score negatively correlated and PSP score positively correlated with most cognitive domains. A linear regression established that the first episode vs. multiple episodes of schizophrenia could statistically significantly predict personal and social performance and cognition, including speech fluency and planning, as well as CRP levels.ConclusionsThis study continues the search for biomarkers of schizophrenia and cognitive impairment in schizophrenia to improve the reliability of diagnosing the disorder and find new treatment approaches. The role of the number of psychoses experienced (first episode vs. multiple episodes of schizophrenia) in cognition, personal and social performance and inflammation is shown.

Elevated levels and enhanced sensing of the pro-inflammatory cytokine interleukin-6 (IL-6) are key features of many autoimmune and inflammatory diseases. To better understand how IL-6 signaling may influence human T cell fate, we investigated the relationships between levels of components of the IL-6R complex, pSTAT responses, and transcriptomic and translational changes in CD4+ and CD8+ T cell subsets from healthy individuals after exposure to IL-6. Our findings highlight the striking heterogeneity in mbIL-6R and gp130 expression and IL-6-driven pSTAT1/3 responses across T cell subsets. Increased mbIL-6R expression correlated with enhanced signaling via pSTAT1 with less impact on pSTAT3, most strikingly in CD4+ naïve T cells. Additionally, IL-6 rapidly induced expression of transcription factors and surface receptors expressed by T follicular helper cells and altered expression of markers of apoptosis. Importantly, many of the features associated with the level of mbIL-6R expression on T cells were recapitulated both in the setting of tocilizumab therapy and when comparing donor CD4+ T cells harboring the genetic variant, IL6R Asp358Ala (rs2228145), known to alter mbIL-6R expression on T cells. Collectively, these findings should be taken into account as we consider the role of IL-6 in disease pathogenesis and translating IL-6 biology into effective therapies for T cell-mediated autoimmune disease.

ObjectivePrevious research conducted with samples of children suggest that individuals with attention-deficit/hyperactivity disorder (ADHD) have altered fatty acid concentrations and may have increased systemic inflammation. Whether these differences are also apparent in other populations of individuals with heightened ADHD symptoms (e.g., pregnant adults) is unknown. The goal of the current study was to examine whether there are ADHD-associated differences in polyunsaturated fatty acid concentrations or pro-inflammatory cytokine concentrations during pregnancy, a developmental period when fatty acid concentrations and systemic inflammation have implications for the health of both the pregnant person and the developing child. We hypothesized that plasma levels of the ratio of omega-6s to omega-3s (n-6:n-3) and plasma inflammatory cytokine levels would be higher in individuals with heightened ADHD symptoms, consistent with previous findings in children with ADHD.MethodsData (N = 68) came from a prospective study of pregnant community volunteers who were oversampled for ADHD symptoms. During the 3rd trimester, plasma concentrations of fatty acids and the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were assessed. Dietary intake was examined in the 3rd trimester using three 24-h recalls conducted by trained dietitians and by examining plasma levels of conjugated linoleic acid (n-6) and α-linolenic acid (n-3), essential fatty acids that must come from dietary intake.ResultsThe group with heightened ADHD symptoms had higher n-6:n-3s (β = 0.30, p < 0.01) and higher TNF-α concentrations (β = 0.35, p < 0.001) relative to controls. There were no group differences in dietary variables, as assessed by self-report and via plasma concentrations of essential fatty acids. IL-6 was not reliably associated with ADHD status in this sample.ConclusionPregnant individuals with ADHD, on average, had higher plasma n-6:n-3s and higher TNF-α concentrations relative to controls. A difference was not detected in their dietary intake of fatty acids or other relevant nutrients. Though these null findings are inconclusive, they are consistent with the hypothesis that ADHD-associated differences in plasma fatty acid concentrations are the result of ADHD-associated differences in fatty acid metabolism, rather than simply differences in dietary intake.

IntroductionSleepiness has been associated with cognitive decline and dementia in the elderly. Older adults with excessive daytime sleepiness appear to be more vulnerable to longitudinal amyloid PET accumulation before the onset of the dementia. However, it remains unclear whether sleepiness is similarly associated with other biomarkers of Alzheimer’s disease (AD), axonal integrity, and inflammation, which may also contribute to neurodegeneration and cognitive decline.MethodsIn this cross-sectional analysis, we identified 260 cognitively unimpaired adults (>60 years) from the Mayo Clinic Study of Aging, a population-based cohort from Olmsted County (MN), who underwent CSF quantification of AD biomarkers (Aβ42, p-tau, p-tau/Aβ42) in addition to at least one of the following biomarkers [neurofilament light chain (NfL) interleukin-6 (IL-6), IL-10, and tumor necrosis factor-α (TNF-α)]. We fit linear regression models to assess associations between sleepiness, as measured by the Epworth Sleepiness Scale (ESS), and CSF biomarkers, controlling for age, sex, APOε4 status, body mass index, hypertension, dyslipidemia, and prior diagnosis of obstructive sleep apnea.ResultsHigher ESS scores were associated with higher CSF IL-6 and NfL, but not with the other CSF biomarkers. For every ESS score point increase, there was a 0.009 ([95% CI 0.001–0.016], p = 0.033) increase in the log of IL-6 and 0.01 ([95% CI 0.002–0.018], p = 0.016) increase in the log of NfL. A sensitivity analysis showed an association between ESS scores and log of p-tau/Aβ42 only in participants with an abnormal ratio (>0.023), highly predictive of amyloid positivity. For every ESS score point increase, there was a 0.006 ([95% CI 0.001–0.012], p = 0.021) increase in the log of CSF p-tau/Aβ42.ConclusionSleepiness was associated with greater CSF IL-6 and NfL levels, which could contribute to neurodegeneration or alternatively cause sleepiness. Higher NfL levels may result from sleep disruption and/or contribute to sleepiness via disturbed connectivity or damage to wake-promoting centers. Associations between sleepiness and p-tau/Aβ42 in participants with abnormal ratio suggest that amyloid positivity contributes to vulnerability to sleep disturbance, which may further amyloid accumulation in a feed-forward loop process. Prospective studies of these markers are needed to determine cause-effect relationships between these associations.

Adipose tissue inflammation is observed in multiple metabolically-altered states including cancer-associated cachexia and obesity. Although cachexia is a syndrome of adipose loss and obesity is a disease of adipose excess, both pathologies demonstrate increases in circulating levels of IL-6 family cytokines, β-adrenergic signaling, and adipocyte lipolysis. While β-adrenergic-stimulated adipocyte lipolysis is well described, there is limited mechanistic insight into how cancer cachexia-associated inflammatory cytokines contribute to adipocyte lipolysis under pathologic conditions. Here, we set out to compare adipocyte lipolysis signaling by cancer cachexia-associated IL-6 family cytokines (IL-6 and LIF) to that of the β-adrenergic agonist isoproterenol. Unlike isoproterenol, the IL-6 family of cytokines required JAK/STAT3-dependent transcriptional changes to induce adipocyte lipolysis. Furthermore, cachexia-associated cytokines that used STAT3 to induce lipolysis were primarily dependent on the lipase ATGL and its cofactor CGI-58 rather than lipases HSL and MAGL. Finally, administration of JAK but not β-adrenergic inhibitors suppressed adipose STAT3 phosphorylation and associated adipose wasting in a murine model of cancer cachexia characterized by increased systemic IL-6 family cytokine levels. Combined, our results demonstrate how the IL-6 family of cytokines diverge from β-adrenergic signals by employing JAK/STAT3-driven transcriptional changes to promote adipocyte ATGL/CGI-58-dependent lipolysis contributing to adipose wasting in cancer cachexia.

Majeed syndrome, characterized by chronic recurrent multifocal osteomyelitis and congenital dyserythropoeitic anemia, is a rare disease reported in children. We report a case of Majeed Syndrome in a 9-year-old boy, born of consanguineous marriage reporting to us for treatment of anemia, requiring blood transfusion. He underwent below-knee-amputation due to unresolving recurrent osteomyelitis at multiple sites. There was history of pain insensitivity and fever during hot weather as well. His interleukin-6 levels were raised. This is the first case of Majeed Syndrome from Pakistan and first in the world with Hereditary Sensory Autonomic Neuropathy type 4 as an associated feature.

Antioxidant and anti-inflammatory activities of Ficus awkeotsang Makino extract (FAE) on Hs68 fibroblasts and BALB/c nude-mouse models are evaluated in this study. FAE was found to be non-toxic and showed high levels of DPPH, H2O2, and hydroxyl radical scavenging abilities; a ferrous chelating capacity; as well as ferric-reducing antioxidant capability. The antioxidant activity of FAE was strongly associated with polyphenolic content (flavonoids at 10.3 mg QE g−1 and total phenol at 107.6 mg GAE g−1). The anti-inflammatory activity of FAE and the underlying molecular mechanisms were also investigated. The a* value of the mouse dorsal skin after treatment with FAE at 1.5 mg/mL in addition to chronic UVB exposure was found to decrease by 19.2% during a ten-week period. The anti-inflammatory effect of FAE was evidenced by the decreased accumulation of inflammatory cells and skin thickness. Expression levels of UVB-induced inflammatory proteins, including ROS, NF-κB, iNOS, COX-2, and IL-6, were significantly reduced upon FAE treatment in vitro and in vivo. Collectively, our results suggest that the inhibition of ROS and UVB-induced activation of the NF-κB downstream signaling pathway by FAE, indicating considerable potential as a versatile adjuvant against free radical damage in pharmaceutical applications. [ABSTRACT FROM AUTHOR]

(1) Background: To explore the effect of exercise on the formation and recovery of alcoholic liver disease (ALD) and whether the IL-6–p47phox oxidative–stress axis is involved in that process. (2) Methods: Firstly, 23 six-week-old male C57BL/6J mice were randomly divided into the Con group, ALD group, ALD + NOXI group, ALD + Ex group, and ALD + Ex + NOXI group. The Liber–DeCarli alcoholic liquid diet was used for 6 weeks to establish the ALD mice model, and the Con group was given the TP4030C control diet. The remaining groups were fed with the TP4030B alcoholic diet, and exercise intervention was started after the ALD model establishment and lasted for another 6 weeks, with or without administration of the NOX inhibitor apocynin by intraperitoneal injection on every exercise training day. Secondly, 28 mice were randomly divided into the Sed group, Eth group, Eth + Ex group and Eth + Ex + NOXI group. The Sed group was given the TP4030C control diet. The remaining groups were fed with the TP4030B alcoholic diet and exercise intervention was started synchronously combined with or without administration of intraperitoneal apocynin injections on every exercise training day for 5 weeks. After each individual experiment was accomplished, physiological assessment and biochemical analysis of blood and tissue samples were examined. (3) Results: The levels of TG in serum and IL-6 protein content in liver tissue in the ALD group were significantly increased compared to the Con group (p < 0.05); compared with ALD, p47phox expression in muscle was increased significantly in the ALD + NOXI group (p < 0.05), and TG in serum decreased in the ALD + Ex group (p < 0.05). TG in serum, AST/ALT ratio, and IL-6 content in both liver and muscle decreased (p < 0.05) in the ALD + Ex + NOXI group with MDA in muscle significantly increased (p < 0.01). The AST/ALT ratio, TG in serum, SOD in liver, and p47phox in both liver and muscle in the ALD + Ex + NOXI group were significantly decreased compared with the ALD + NOXI group (p < 0.01). Compared with the ALD + Ex group, the liver index and HDL-C levels in serum were decreased (p < 0.05) in the ALD + Ex + NOXI group. The degree of hepatocyte steatosis and inflammatory infiltration were ameliorated after exercise intervention. In the Eth group, the relative epididymal fat content, HDL-C level, and AST/ALT ratio were significantly decreased, and TG and gp91phox in liver were significantly higher than in the Sed group (p < 0.05, p < 0.01). Compared with the Eth group, the AST/ALT ratio, MDA in the liver, and NOX4 and p47phox protein expression in the liver were significantly increased, and body weight decreased significantly in the Eth + Ex group (p < 0.05, p < 0.01), as did TG in the liver and MDA in muscle. In the th + Ex + NOXI group, gp91phox expression in the liver and body weight were significantly decreased (p < 0.05, p < 0.01). In the Eth + Ex + NOXI group, the ratio of AST/ALT and MDA in muscle were increased when compared with the Eth + Ex group, and the protein expression of gp91phox and p47phox were much lower (p < 0.01). (4) Conclusions: 6 weeks of exercise intervention during the recovery phase of ALD ameliorates hepatocyte damage and dyslipidemia through the IL-6–p47phox oxidative–stress axis, and applying a NOX inhibitor in combination could optimize this. However, drinking alcohol during exercise exacerbates dyslipidemia and oxidative stress, with hepatocyte IL-6–p47phox downregulated. [ABSTRACT FROM AUTHOR]

Interleukin-6 (IL-6) is generally used as a biomarker for the evaluation of inflammatory infection in humans and animals. However, there is no approach for the on-site and rapid detection of IL-6 for the monitoring of mastitis in dairy farm scenarios. A rapid and highly sensitive surface enhanced Raman scattering (SERS) immunofiltration assay (IFA) for IL-6 detection was developed in the present study. In this assay, a high sensitivity gold core silver shell SERS nanotag with Raman molecule 4-mercaptobenzoic acid (4-MBA) embedded into the gap was fabricated for labelling. Through the immuno-specific combination of the antigen and antibody, antibody conjugated SERS nanotags were captured on the test zone, which facilitated the SERS measurement. The quantitation of IL-6 was performed by the readout Raman signal in the test region. The results showed that the detection limit (LOD) of IL-6 in milk was 0.35 pg mL−1, which was far below the threshold value of 254.32 pg mL−1. The recovery of the spiking experiment was 87.0–102.7%, with coefficients of variation below 9.0% demonstrating high assay accuracy and precision. We believe the immunosensor developed in the current study could be a promising tool for the rapid assessment of mastitis by detecting milk IL-6 in dairy cows. Moreover, this versatile immunosensor could also be applied for the detection of a wide range of analytes in dairy cow healthy monitoring. [ABSTRACT FROM AUTHOR]

Sepsis or septicemia are severe bloodstream infections that can quickly become life-threatening. Sepsis is most often caused by bacterial infection and it is one of the major causes of mortality and morbidity in newborns (< 1 month). The aim of this study is to investigate the role of interleukin-6 (IL-6) and interleukin-11 (IL-11). The neonates ranged in age from 1 - 30 days, and blood samples were obtained to determine the levels of Interleukins IL-6 and IL-11. The findings of this study showed that (72%) of newborns have early onset sepsis (infected within the first seven days of their lives), while the remaining (28.3 %) have late onset sepsis (infected during 7-30 days of their life). Bacterial isolation was performed on the samples collected. Bacterial culture was positive in (60%) patients versus (40%) patients revealed a negative bacterial culture. The level of Interleukins was quantified using the adsorption test for immune antibodies binds to the enzyme (Sandwich ELISA test). The Interleukin levels showed that a significant increase in the level of interleukin-6 (IL-6) and interleukin-11 (IL-11) for all patients compared with a control group. The results showed that IL-6 and IL-11 can be a reliable marker for predicting neonatal sepsis and can be used as a good guide for early detection of sepsis in neonatal care units. The findings of this study revealed that IL-11 plays a protective role in sepsis patients with thrombocytopenia. [ABSTRACT FROM AUTHOR]

Background: The availability of glucose in tissue has a role in macrophages polarisation into an inflammatory phenotype. The overnutrition condition such as hyperglycaemia induces macrophage infiltration especially the inflammatory macrophages. The aim of this study was to analyse the effect of hyperglycaemia condition on cytokines production by human monocytes-derived macrophages.Materials and Methods: Monocyte cells obtained from peripheral blood mononuclear cells isolation from donors were incubated for 6 days in 37°C, 5% CO2. On day 4, the stimulating factors such as lipopolysaccharide (LPS) and interferon gamma were added to activate monocytes into macrophages. Then, on day 6, two doses of glucose; either normal or high doses along with low or high dose of LPS were given for 24 h, followed by collecting the culture media and cells then stored at -80°C until assayed.Results: There was a significant difference in tumour necrosis factor alpha (TNF-a) levels among groups, with highest level found in group with high-dose glucose plus high-dose LPS. However, the concentration of interleukin-6 (IL-6) among groups was not significantly different.Conclusions: Macrophages treated with high-dose glucose plus high-dose LPS significantly increased production of TNF-a, but not of IL-6. [ABSTRACT FROM AUTHOR]

Coronavirus disease-2019 (COVID-19) associated pneumonia may progress into acute respiratory distress syndrome (ARDS). Some patients develop features of macrophage activation syndrome (MAS). Elevated levels of IL-6 were reported to be associated with severe disease, and anti-IL-6R tocilizumab has been shown to be effective in some patients. This retrospective multicenter case–control study aimed to evaluate the efficacy of tocilizumab in hospitalized COVID-19 patients, who received standard of care with or without tocilizumab. Primary outcome was the progression to intubation or death. PSMATCH (SAS) procedure was used to achieve exact propensity score (PS) matching. Data from 1289 patients were collected, and study population was reduced to 1073 based on inclusion–exclusion criteria. The composite outcome was observed more frequently in tocilizumab-users, but there was a significant imbalance between arms in all critical parameters. Primary analyses were carried out in 348 patients (174 in each arm) after exact PS matching according to gender, ferritin, and procalcitonin. Logistic regression models revealed that tocilizumab significantly reduced the intubation or death (OR 0.40, p = 0.0017). When intubation is considered alone, tocilizumab-users had > 60% reduction in odds of intubation. Multiple imputation approach, which increased the size of the matched patients up to 506, provided no significant difference between arms despite a similar trend for intubation alone group. Analysis of this retrospective cohort showed more frequent intubation or death in tocilizumab-users, but PS-matched analyses revealed significant results for supporting tocilizumab use overall in a subset of patients matched according to gender, ferritin and procalcitonin levels. [ABSTRACT FROM AUTHOR]

Objective * To investigate the values of fecal calprotectin (FC), C-reactive protein (CRP) and interleukin 6 (IL-6) in diagnosing the gastrointestinal mucosal injury in the patients with Crohn's disease (CD). Methods * A total of 52 CD patients admitted to Renji Hospital, Shanghai Jiao Tong University School of Medicine from June 2019 to June 2020 were enrolled in the study. The patients were divided into uninjured mucosa group and injured mucosa group based on the gastrointestinal endoscopic results, and the clinical features of the two groups were compared. The level of IL-6 was detected by cytometric bead array. The content of FC was detected by immunofluorescence chromatography. CRP in the whole blood was detected by nephelometry. IL-6 and CRP were detected within 24 h of admission, while FC was detected within 72 h. The results were compared between the two groups. The independent influence factors of mucosal injury were analyzed by multivariate Logistic regression. The receiver operating characteristic (ROC) curve was used to determine the values of IL-6, CRP, FC and their combination in judging mucosal injury. Results * Among the 52 patients, there were 21 patients in the uninjured mucosa group and 31 in the injured mucosa group. There were no significant differences in the age and gender between the two groups. The significant difference was only identified in the distribution of disease behavior in the Montreal Classification (P<0.05). The levels of IL-6, CRP and FC in the injured mucosa group were 11.1 (3.67, 17.54) pg/mL, 8.02 (2.13, 30.96) mg/L and 448.4 (212.90, 639.50) µg/g, respectively, which were significantly higher than those in the uninjured mucosa group (P< 0.05). Logistic regression analysis suggested that only FC was an independent factor for judging the injured status of gastrointestinal mucosa in the CD patients (OR=1.006, P<0.05). The areas under the ROC curves (AUCs) of IL-6, CRP and FC for judging the state of gastrointestinal mucosal injury were 0.71, 0.88 and 0.85, respectively (all P<0.05). The AUCs of FC+CRP and FC+IL-6 were 0.91 and 0.84, respectively (both P<0.05). The AUC of FC+IL-6+CRP was 0.92 (P<0.05). By comparing the ROC curves of the two-item combined detection and the three-item combined detection, no significant difference could be identified in the AUC between FC+CRP and FC+IL-6+CRP. However, a significant difference was identified between FC+IL-6 and FC+IL-6+CRP (P=0.045). Meanwhile, the sensitivities and specificities of both FC+CRP and FC+IL-6+CRP were 77% and 100%, respectively. Conclusion * The combined detection of FC and CRP, as well as the combined detection of FC, IL-6 and CRP, can effectively judge the gastrointestinal mucosal injury in patients with CD, the diagnostic values of which are similar; based on the simplicity and the cost, the combined detection of FC and CRP is more recommended clinically. [ABSTRACT FROM AUTHOR]

Introduction: The role of proinflammatory cytokines is said to be crucial in the development of colorectal cancer (CRC). IL-6, IL-23, and chemerin have all been proven to take part in tumor growth and progression. Aim of the study: to determine the level of chemerin and the concentrations of interleukin-6 (IL-6) and interleu-kin-23 (IL-23) in the tumor and margin specimens of CRC in relation to histological grade and TNM staging. Material and methods: The study involved 49 samples of tumor and margin tissues obtained from CRC patients. To assess the concentration of chemerin, IL-6, and IL-23, commercially available enzyme-linked immunosorbent assay (ELISA) kits were used. Results: There was no difference in chemerin concentration between the tumor and margin. We found significantly increased levels of IL-6 in tumor tissue compared to margin tissue and higher concentrations of IL-23 in margin tissue than in tumor tissue. Tumor levels of chemerin were significantly correlated with those of IL-23, while its margin concentrations were associated with margin concentrations of IL-6. Additionally, tumor levels of IL-23 were positively correlated with margin levels of IL-6. Conclusions: Chemerin might play an important role in CRC progression through its association with cytokine expression. More studies are needed to investigate the possible role of IL-6, IL-23, and chemerin as potential markers in the development of CRC. [ABSTRACT FROM AUTHOR]

Obesity is a globally common metabolic condition that causes or exacerbates many diseases. High-intensity interval training (HIIT) and orlistat may affect cytokines and adipokines related to obesity. The purpose of this study was to investigate the independent and combined effects of 8 weeks of HIIT and orlistat on body weight, body mass index (BMI), neck circumference, aerobic power, interleukin‑6 (IL-6), tumor necrosis factor α (TNF-α), resistin, and adiponectin in young, obese women. 48 obese individuals were randomly divided into 4 groups: control-placebo (n = 12), HIIT-placebo (n = 12), control-orlistat (n = 12), and HIIT-orlistat (n = 12), and received group-specific interventions. Participant blood samples were taken 48 h before the intervention and 48 h after the last training session. Two-way multivariate analysis of covariance (MANCOVA) was used to investigate the effects of interventions, with significance set at P ≤ 0.05. The results showed that HIIT decreased body weight, BMI, neck circumference, TNF‑α, and resistin concentration, while increasing aerobic power, IL‑6, and adiponectin concentration. Orlistat decreased body weight, BMI, neck circumference, and resistin, and increased plasma IL‑6 levels. In conclusion, although the combined effects of HIIT and orlistat were significant in many factors, no synergistic effect was observed, and there appears to be a limit for changes in each factor that can be reached by either HIIT or medication interventions. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is a global public health emergency with many clinical facets, and new knowledge about its pathogenetic mechanisms is deemed necessary; among these, there are certainly coagulation disorders. In the history of medicine, autopsies and tissue sampling have played a fundamental role in order to understand the pathogenesis of emerging diseases, including infectious ones; compared to the past, histopathology can be now expanded by innovative techniques and modern technologies. For the first time in worldwide literature, we provide a detailed postmortem and biopsy report on the marked increase, up to 1 order of magnitude, of naked megakaryocyte nuclei in the bone marrow and lungs from serious COVID-19 patients. Most likely related to high interleukin-6 serum levels stimulating megakaryocytopoiesis, this phenomenon concurs to explain well the pulmonary abnormal immunothrombosis in these critically ill patients, all without molecular or electron microscopy signs of megakaryocyte infection.

Abstract Background Whether polymorphisms in tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10) or adiponectin (ADIPOQ) influence the risk of gestational diabetes mellitus (GDM) or not remain inconclusive. Therefore, the authors conducted a meta-analysis to robustly assess relationships between polymorphisms in TNF-α, IL-6, IL-10 or ADIPOQ and the risk of GDM by merging the results of eligible publications. Methods A through literature searching in Medline, Embase, Wanfang, VIP and CNKI was conducted by the authors to identify eligible publications, and twenty-two publications were finally found to be eligible for merged quantitative analyses. Results The merged quantitative analyses revealed that ADIPOQ + 45T/G (rs2241766) polymorphism was significantly associated with the risk of GDM in overall population (dominant comparison: OR = 0.70, p