Higher Cytokine Concentrations Research Articles

Concomitant parasite infections influence tuberculosis immunopathology and favor rapid sputum conversion of pulmonary tuberculosis patients

Immunopathology of human tuberculosis (TB) in a subgroup of patients is characterized by aberrantly high concentrations of inflammatory cytokines, for example Interleukin (IL)-6. Concomitant (co-)infections by parasites can affect host immunity, but the impact on immunopathology in TB patients is poorly defined. Here we characterized a group of patients with TB ( n = 76) from Ghana with different protozoan and helminth co-infections. Plasma cytokines were measured at the onset of disease and anti-mycobacterial treatment efficacy was monitored during disease course. A subgroup of TB patients had co-infections with protozoan (n = 19) or helminth (n = 16) parasites. Plasma analyses for candidate cytokines identified lower levels of IL-6 in parasite co-infected patients with TB. Moreover, it took less time for co-infected patients to become sputum-negative for Mycobacterium tuberculosis during treatment. These results indicated an influence of parasite co-infections on immunopathology in TB and suggested positive effects on treatment efficacy.

β2-integrins control HIF1α activation in human neutrophils.

During inflammation, human neutrophils engage β2-integrins to migrate from the blood circulation to inflammatory sites with high cytokine but low oxygen concentrations. We tested the hypothesis that the inhibition of prolyl hydroxylase domain-containing enzymes (PHDs), cytokines, and β2-integrins cooperates in HIF pathway activation in neutrophils. Using either the PHD inhibitor roxadustat (ROX) (pseudohypoxia) or normobaric hypoxia to stabilize HIF, we observed HIF1α protein accumulation in adherent neutrophils. Several inflammatory mediators did not induce HIF1α protein but provided additive or even synergistic signals (e.g., GM-CSF) under pseudohypoxic and hypoxic conditions. Importantly, and in contrast to adherent neutrophils, HIF1α protein expression was not detected in strictly suspended neutrophils despite PHD enzyme inhibition and the presence of inflammatory mediators. Blocking β2-integrins in adherent and activating β2-integrins in suspension neutrophils established the indispensability of β2-integrins for increasing HIF1α protein. Using GM-CSF as an example, increased HIF1α mRNA transcription via JAK2-STAT3 was necessary but not sufficient for HIF1α protein upregulation. Importantly, we found that β2-integrins led to HIF1α mRNA translation through the phosphorylation of the essential translation initiation factors eIF4E and 4EBP1. Finally, pseudohypoxic and hypoxic conditions inducing HIF1α consistently delayed apoptosis in adherent neutrophils on fibronectin under low serum concentrations. Pharmacological HIF1α inhibition reversed delayed apoptosis, supporting the importance of this pathway for neutrophil survival under conditions mimicking extravascular sites. We describe a novel β2-integrin-controlled mechanism of HIF1α stabilization in human neutrophils. Conceivably, this mechanism restricts HIF1α activation in response to hypoxia and pharmacological PHD enzyme inhibitors to neutrophils migrating toward inflammatory sites.

Impaired tolerance of monocyte-macrophages to lipopolysaccharide in patients with coronary atherosclerosis

Atherosclerosis is a chronic disease in which lipids, cells and various proteins accumulate in the walls of the arteries, forming atherosclerotic plaques. The growth of plaques leads narrowing of the lumen of the blood vessels. Atherosclerosis is accompanied by local inflammation, while the number of hematogenous macrophages are derived from monocytes increases in the vascular wall. The reasons why the inflammatory reaction cannot be completed and becomes chronic are not clear. To resolve inflammation and protect tissues from high concentrations of cytokines that can cause apoptosis, there is a mechanism of immune tolerance of innate immunity. Lipopolysaccharide (LPS) tolerance of monocyte-macrophages is a phenomenon in which cells reduce their sensitivity to repeated exposure to LPS. This condition is characterized by a decrease in the ability of macrophages to produce proinflammatory cytokines and promotes resolution of inflammation. We hypothesized that in atherosclerosis, tolerance violations in monocyte-macrophages are possible. The study included patients who were admitted to the department of cardiac surgery, Moscow Regional Research and Clinical Institute (MONIKI). Patients were divided into patients with coronary atherosclerosis (CAD) with detected stenosis in 2 or more arteries and healthy controls without stenosis in the arteries according to the results of coronary angiography. In the present study, we examined the ability of macrophages from 13 patients with CAD and 11 patients without CAD to develop tolerance to LPS. To do this, we isolated CD14+ monocytes from the blood by positive selection using immunomagnetic separation and subjected them to two sequential LPS stimulations, immediately after cell isolation and after 6 days of culture. The secretion of cytokines TNFα, IL-1b, IL-6, IL-10, IL-8, and CCL2 was measured in cell culture supernatants using by ELISA. Our results showed impaired macrophage tolerance for CCL2 secretion and improved tolerance for IL-8 secretion in macrophages from patients with CAD compared with patients without. Since IL-8 and CCL2 are chemoattractants for other immune cells, it can be assumed that the observed impairment of macrophage tolerance to LPS in atherosclerosis increases the infiltration of other monocytes into the inflammatory site, contributing to the chronicity of inflammation.

Cytokine Profile in Patients with Postacute Sequelae of COVID-19.

The enduring impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its disease manifestation, COVID-19, on public health remains significant. Postacute sequelae of SARS-CoV-2 infection (PASC) affect a considerable number of patients, impairing their quality of life. While the role of the cytokine storm in acute COVID-19 is well established, its contribution to the pathophysiology of PASC is not fully understood. This study aimed to analyze the cytokine profile of patients with PASC following in vitro stimulation of Toll-like receptor (TLR) pathways, comparing them with a healthy control group. From October 2020 till March 2021, Brugmann University Hospital's clinical research unit included patients with PASC in the study. Whole blood samples were collected from 50 patients and 25 healthy volunteers. After in vitro stimulation under five different conditions, cytokine levels were measured using a multiplex method. Significantly decreased cytokine levels were observed in patients with PASC compared with healthy volunteers, particularly after TLR4 (interleukin [IL]-1α, IL-1β, IL-2, IL-10, interferon (IFN)α, IFNγ, IFNω, and tumor necrosis factor (TNF)α) and TLR7/8 (IL-1α, IL-1β, IFNα, IFNω, IFNγ, and TNFα) pathway stimulation. Principal component analysis identified two distinct clusters, suggesting a likely dysregulation of immunity involving TLR4 and TLR7/8 pathways in patients with PASC. Our study suggests that TLR4 and TLR7/8 pathways play a role in the pathophysiology of PASC. Continuous basal activation of immunity could explain the high basal concentrations of cytokines described in these patients and the decreased amplitude of response of these signaling pathways following specific stimulation.

THP1-based cybrid cells with various mtDNA mutations differ by the ability to form inflammatory response

Most age-related human diseases are accompanied by chronic inflammation. Modern research is aimed at studying the principles of the formation of the immune response. The reasons why the local inflammatory reaction cannot be resolved and becomes a sluggish chronic form are still unknown. Immune cells secrete cytokines in response to pathogens. To avoid cell death as a result of high concentrations of cytokines and resulting tissue damage, there is a mechanism of innate immune tolerance. Innate immune tolerance involves a decrease in the secretion of proinflammatory cytokines in response to repeated exposure to a pathogen. It is known that mitochondria play an important role in the formation of the immune response. Consequently, impaired mitochondrial function can lead to impaired immune response. To control the quality of mitochondria in the cell, there is a mechanism – mitophagy. Previously, we have created cybrid lines based on the monocytic cell line THP-1. Cybrids were obtained by fusion of THP-1 cells (mitochondria were removed) with platelets from patients. Each of the cybrid lines had the THP-1 nuclear genome and an individual patient’s mitochondrial genome. In our study, we decided to study the ability of cells carrying different mitochondrial genomes to generate a proinflammatory response, as well as to form tolerance in the future. For this purpose, we chose a model of ecdotoxin tolerance. Thus, we stimulated the cybrid lines twice with lipopolysaccharide and then assessed the secretion of the cytokines TNFα, IL-1β, IL-6, IL-8, and CCL2 using ELISA. The cybrids demonstrated two levels of proinflammatory response: high and low. Moreover, cybrids with a high proinflammatory response either did or did not develop tolerance upon repeated stimulation. In our study, cells that differed from each other only in mitochondrial genome demonstrated three types of reactions upon the induction of immune tolerance to LPS. Future studies will improve our understanding of the mechanisms of mitochondrial involvement in pathological processes. It is likely that studies of deficient mitophagy and the role of certain mtDNA mutations in its development will yield promising results.

Cardioprotective effect of CB1 receptor antagonist AM251 against β receptor-stimulated myocardial infarction via modulation of NF-kB signaling pathway in diabetic mice

We substantiated the effect of AM251, a cannabinoid receptor-1 (CB1R) antagonist, against β-receptor stimulated myocardial infarction (MI) in streptozotocin (STZ)-induced diabetic mice via modulation- of the NF-kB signaling pathway. The different parameters were assessed such as ECG, hemodynamic, cardiac injury markers, oxidative stress parameters, pro-inflammatory cytokines, and histopathological abnormalities. Mice were fed a high-fat diet for 30 days. On day 7, to trigger diabetes, 150 mg/kg of STZ was injected intraperitoneally. On day 10, to determine whether diabetes developed, the blood level of glucose was monitored. From days 11–30, diabetic mice were injected with either CB1R agonist oleamide or antagonist AM251 or both, with concurrent administrations of β-agonist isoproterenol on days 28 and 29 to induce MI. In comparison to normal, the myocardial infarcted diabetic animals demonstrated alterations in ECG, hemodynamic profiles, and diminished enzymatic activities (CK-MB, LDH, SOD, GSH, catalase), with concurrently increased MDA levels, which indicated increased oxidative stress in the myocardium. Additionally, higher concentrations of cytokines that signal myocardial inflammation, such as IL-1β, IL-6, and TNF-α, were also noted. Furthermore, elevated myonecrosis, edema, and cell infiltration which is confirmed by histopathology of heart tissue. Treatment with AM251 significantly ameliorated myocardial redox status, reduced cytokines, and repaired enzymatic activities leading to subsequent recovery in cardiac function. AM251 effectively suppressed myonecrosis and edema. This study also showed that AM251 protects against myocardial inflammation and oxidative stress triggered by isoproterenol by blocking NF-kB signalling pathway. However, upregulation of the CB1R through oleamide showed significant cardiac toxicity. Conversely, the concurrent administration of oleamide and AM251 failed to induce cardiotoxic effects in isoproterenol-induced MI in diabetic mice which indicates downregulation of the CB1R might be associated with the cardioprotective effect.

A common secretomic signature across epithelial cancers metastatic to the pleura supports IL-6 axis therapeutic targeting.

Many cancers metastasize to the pleura, resulting in effusions that cause dyspnea and discomfort. Regardless of the tissue of origin, pleural malignancies are aggressive and uniformly fatal, with no treatment shown to prolong life. The pleural mesothelial monolayer is joined by tight junctions forming a contained bioreactor-like space, concentrating cytokines and chemokines secreted by the mesothelium, tumor, and infiltrating immune cells. This space represents a unique environment that profoundly influences tumor and immune cell behavior. Defining the pleural secretome is an important step in the rational development localized intrapleural immunotherapy. We measured cytokine/chemokine content of 252 malignant pleural effusion (MPE) samples across multiple cancers using a 40-analyte panel and Luminex multiplexing technology. Eleven analytes were consistently present in concentrations ≥ 10.0 pM: CXCL10/IP10 (geometric mean = 672.3 pM), CCL2/MCP1 (562.9 pM), sIL-6Rα (403.1 pM), IL-6 (137.6 pM), CXCL1/GRO (80.3 pM), TGFβ1 (76.8 pM), CCL22/MDC (54.8 pM), CXCL8/IL-8 (29.2 pM), CCL11/Eotaxin (12.6 pM), IL-10 (11.3 pM), and G-CSF (11.0 pM). All are capable of mediating chemotaxis, promotion of epithelial to mesenchymal transition, or immunosuppression, and many of are reportedly downstream of a pro-inflammatory cytokine cascade mediated by cytokine IL-6 and its soluble receptor. The data indicate high concentrations of several cytokines and chemokines across epithelial cancers metastatic to the pleura and support the contention that the pleural environment is the major factor responsible for the clinical course of MPE across cancer types. A sIL-6Rα to IL-6 molar ratio of 2.7 ensures that virtually all epithelial, immune and vascular endothelial cells in the pleural environment are affected by IL-6 signaling. The central role likely played by IL-6 in the pathogenesis of MPE argues in favor of a therapeutic approach targeting the IL-6/IL-6R axis.

An Approach to Improve Endometrial Receptivity: Is It Beneficial to Flush The Uterine Cavity with Follicular Fluid and Granulosa Cells? A Phase III Randomised Clinical Trial.

The follicular fluid (FF) of mature oocytes contains a high concentration of growth factors and cytokines that have the potential to influence implantation in either a paracrine or autocrine manner. During the physiological processes of ovulation, FF enters the fallopian tubes in conjunction with the oocyte. The purpose of this study is to evaluate implantation and clinical pregnancy rates following uterine flushing with FF and granulosa cells in infertile women with moderate male factor infertility after ovum retrieval for intracytoplasmic sperm injection (ICSI). This phase III randomised clinical trial enrolled 140 women with moderate male factor infertility who intended to undergo ICSI at Royan Infertility Clinic (Tehran, Iran). A computer-generated program and opaque sealed envelopes were used to randomly allocate patients to either an intervention group (n=70) or a control group (n=70). Participants in the intervention group received 2 ml of clear FF (without blood contamination) from 2 to 3 dominant follicles after oocyte retrieval. The control group only underwent uterine cavity catheterisation. The intervention group had a clinical pregnancy rate of 38.5% (25/65) compared to the control group [42.9% (27/63); P=0.719] and an implantation rate of 24.1% compared to the control group (27%; P=0.408). These rates did not differ between the groups. There were no statistically significant differences between the intervention and control groups in terms of pregnancy-related complications-ectopic pregnancy, blighted ovum or anembryonic pregnancy, and abortion. Uterine cavity flushing with FF from mature follicles following oocyte retrieval had no effect, either positively or negatively, on clinical pregnancy or implantation rates in women with moderate male factor infertility (registration number: NCT04077970).

Use of the CytoSorb adsorber in patients with acute-on-chronic liver failure.

CytoSorb is a hemoadsorptive column used to remove high concentrations of proinflammatory cytokines in septic shock. Data on CytoSorb application in acute-on-chronic liver failure (ACLF) is lacking. This retrospective observational study analyzed 21 ACLF patients admitted to ICUs at the Vienna General Hospital who received CytoSorb adsorber therapy between 2017 and 2023. Median ICU length of stay was 8days (IQR: 3-13), the ICU survival rate was 23.8% (n = 5). Significant decreases in bilirubin (median peak: 20.7mg/dL to median post-treatment: 10.8mg/dL; - 47.8%; p < 0.001), procalcitonin (1.34 to 0.74pg/mL; - 44.6%; p < 0.001), interleukin-6 (385 to 131ng/mL; - 66.0%; p = 0.0182)-but also of platelets (72 to 31 G/L; - 56.9%; p = 0.0014) and fibrinogen (230 to 154mg/dL; - 33.0%; p = 0.0297) were detected. ICU survivors had a trend towards a stronger relative decrease in bilirubin (- 76.1% vs. - 48.2%), procalcitonin (- 90.6% vs. - 23.5%), and IL-6 (- 54.6% vs. - 17.8%) upon CytoSorb treatment. Moreover, no serious CytoSorb-attributed complications were detected. In conclusion, use of CytoSorb adsorber in ACLF patients results in a significant decrease in bilirubin and proinflammatory cytokines, while platelets and fibrinogen were also lowered. Prospective trials are warranted to investigate the impact of CytoSorb on clinical outcomes of ACLF patients with high proinflammatory cytokine levels.

The role of inflammation and antithrombin supplementation on thromboelastographic parameters during veno-venous ECMO for respiratory failure.

Extracorporeal membrane oxygenation (ECMO) may act as a driver or propagator of systemic inflammation. In turn, cytokine release can modify thromboelastographic (TEG) tests which are commonly used for anticoagulation monitoring. In this context, antithrombin (AT) supplementation might further modify TEG. This is a pre-specified sub-study of the "Randomized Controlled Trial of Antithrombin Supplementation During Extracorporeal Membrane Oxygenation" study (investigator-initiated, randomized, single-blind, two-arm trial) conducted in two Italian ECMO referral ICUs. Adult patients requiring vv-ECMO for respiratory failure and undergoing unfractioned heparin (UFH) administration were enrolled and randomized whether to receive AT supplementation. Plasma samples for cytokine assay (IL-8, IL-10, IL-6, IL-1β, TNF-α and Pro-ADM) and heparinase TEG were collected from every patient before ECMO start, 24h and 72h after ECMO start, before ECMO removal, and 7days after ECMO removal or upon ICU discharge whichever happened first. AT concentration, coagulation and clinical data were collected before ECMO start and at pre-fixed time points. Thirty-nine patients were enrolled (21 treatments, 18 controls). TEG-R had a weak-to-moderate positive correlation with IL-8, IL-6, IL-10 and TNF-α and a moderate positive correlation with Pro-ADM. TEG-ANG showed a weak negative correlation with IL-8, IL-6 and TNF-α, while TEG-MA negatively correlated with IL-8, TNF-α and Pro-ADM. AT supplementation seemed to modify the association between TEG-MA and IL-8, IL-10 and Pro-ADM; conversely, AT did not affect the relationship among TEG-R or TEG-ANG and the studied cytokines. High concentrations of systemic cytokines correlated with longer reaction times and decreased angle and amplitude at TEG, suggesting that an increase in inflammation is related with hypocoagulability as revealed by thromboelastography.

Імунопатологічні аспекти етіопатогенезу міокардиту

Myocarditis is a group of inflammatory diseases of the heart muscle against the background of the absence of acute or chronic ischemic heart disease, which are diagnosed according to established histological, immunological and immunohistochemical criteria.Objective. Summarize current information on the immunopathogenesis of myocarditis based on data from open sources of information.Methods. Publications were selected based on PubMed, Clinical Key Elsevier, Cochrane Library, eBook Business Collection and Google Scholar databases, which covered information on the immunopathogenesis of myocarditis.Results. Viral infections are the most common cause of myocarditis, along with some bacteria and protozoa. Chronic immune stimulation or autoimmunity in chronic viral myocarditis results from incomplete resolution of the viral infection or response to a previous virus or immune-mediated chronic tissue injury. An active autoimmune response in human myocarditis, both at the cellular and humoral levels, is the immunological basis for the development of this pathology. Myocarditis caused by COVID-19 is a new entity. At the moment, four main manifestations of myocarditis in the context of SARS-CoV-2 have been identified: myocarditis associated with an acute infection of COVID-19, post-acute syndrome of COVID-19 (or prolonged syndrome of COVID-19), multisystem inflammatory syndrome, and myocarditis due to related to vaccination. Autoimmune reactions probably contribute to molecular mimicry – they activate virus-specific T-cells that attack the myocardium. During this phase, high concentrations of cytokines (eg, tumor necrosis factor, interleukins 1a, 1b, 2, and interferon-γ) are produced. These cytokines, together with antibodies against viral and cardiac proteins, further exacerbate cardiac damage and systolic dysfunction due to contractile dysfunction and matrix proteins.Conclusions. CD4+T-cells are defined as the main driving forces of heart-specific autoimmunity in myocarditis. Dysregulated CD4+ T-cell populations and their associated cytokines are critical for the development and progression of myocarditis and may serve as therapeutic targets and the development of new treatment approaches.

Insight into the Antioxidant Activity of Ascorbic Acid-Containing Gelatin Nanoparticles in Simulated Chronic Wound Conditions.

Chronic wounds differ from acute wounds by remaining in the inflammatory phase for a long time. This chronic inflammation confers a high concentration of inflammatory cytokines, proteases, and ROS. Likewise, the pH environment of chronic wounds has been recorded within the range of 7.2-8.9 due to the alkaline by-products of bacterial proliferation. In this work, differences in pH between healthy skin and chronic cutaneous wounds have been used for the design and development of pH-responsive gelatin-based nanoparticles (NPs). Ascorbic acid (AA), as an antioxidant compound that can neutralize reactive oxygen species (ROS), has been the therapeutic model compound included in these NPs. The goal of the present work has been the preparation and characterization (physicochemical and biological properties) of NPs for the effective release of AA under simulated chronic wound conditions. In vitro experiments demonstrated total AA release at pH corresponding to the chronic wounds. The biocompatible character of these gelatin-based NPs based on their hemolytic and cytotoxicity responses has been highlighted under in vitro conditions. The reversible and protective antioxidant properties of the AA-including NPs in erythrocytes and skin cell lines, respectively, have been confirmed to be modulated by the gelatin A gel strength.

Inflammation-mediated metabolic regulation in adipose tissue.

Chronic inflammation of adipose tissue is a prominent characteristic of many metabolic diseases. Lipid metabolism in adipose tissue is consistentlydysregulated during inflammation, which is characterized by substantial infiltration by proinflammatory cells and high cytokine concentrations. Adipose tissue inflammation is caused by a variety of endogenous factors, such as mitochondrial dysfunction, reactive oxygen species (ROS) production, endoplasmic reticulum (ER) stress, cellular senescence, ceramides biosynthesis and mediators of lipopolysaccharides (LPS) signaling. Additionally, the gut microbiota also plays a crucial role in regulating adipose tissue inflammation. Essentially, adipose tissue inflammation arises from an imbalance in adipocyte metabolism and the regulation of immune cells. Specific inflammatory signals, including nuclear factor-κB (NF-κB) signaling, inflammasome signaling and inflammation-mediated autophagy, have been shown to be involved in the metabolic regulation. The pathogenesis of metabolic diseases characterized by chronic inflammation (obesity, insulin resistance, atherosclerosis and nonalcoholic fatty liver disease [NAFLD]) and recent research regarding potential therapeutic targets for these conditions are also discussed in this review.

Do Intraoperative Platelet-Rich Plasma Injections Influence the Final Appearance of Vertical Scars after Breast Reduction? Spectrophotometric Analysis

Background: Platelet-rich plasma (PRP) has been shown to support wound healing and tissue regeneration due to its high concentration of growth factors and cytokines. This study aims to investigate the effect of intraoperative PRP injections on the final appearance of vertical scars after breast reduction, as well as to identify potential predictors of a scar’s aesthetic assessment using spectrophotometric parameters. Methods: In this prospective, randomized trial, 82 scars from 41 women who underwent bilateral breast reduction with an inverted T pattern were analyzed. PRP or a placebo substance (0.9% sodium chloride solution) was injected intraoperatively into the edges of vertical wounds. Spectrophotometric measurements of scar pigmentation were performed 3 and 6 months after surgery; additionally, two independent observers evaluated the aesthetic appearance of scars based on photographs. Results: The results showed that the use of intraoperative PRP injections did not significantly influence the final appearance of vertical scars after breast reduction. Conclusions: We indicated spectrophotometric variables (b) in the early stages of wound healing (after 3 months) that can be predictors of the final scar’s aesthetic outcome. This can be helpful in detecting scars that may need additional interventions to optimize the healing process.

Association of the key immunological and hemodynamic determinants with cervix ripening in pregnant women.

Aim: To investigate a correlation between cervical ripening, the immunological features and the hemodynamic characteristics of the cervix during the preparation for vaginal labor. Materials and Methods: We examined 75 pregnant women at different gestational age. General clinical and immunological studies were conducted in order to check serum concentration of cytokines IL-6, IL-1β, and TNF-α. Ultrasound and Doppler study were used to determine resistance index and systolic-diastolic ratio of blood flow in the common uterine artery as well as the descending and ascending parts and cervical stromal arteries. Results: Pregnant women with high cervical ripening score had high concentrations of the major proinflammatory cytokines (IL-1β, IL-6, and TNF-α). Analysis of the of the cervical blood flow indicators of the studied groups showed significant differences in the indices of vascular resistance in the vessels that feed the cervix. Our data showed a significant correlation between the cervix ripening and both the serum levels of the studied cytokines and the level of peripheral vascular resistance indices in the common uterine arteries of the cervix, and the blood flow indices in the cervical stromal vessels. Conclusions: Our study shows that the process of preparing the woman's body for labor is associated with immunological adjustment and increased hemodynamics of the cervix. We report that cervical ripening is associated with the immunological components and hemodynamic parameters of the cervix at late-stage pregnancy. Measuring cervix ripening and the accompanied changes in cytokine levels and hemodynamic parameters will form a more accurate assessment of birth preparedness and labor complications.

Role of TGF-β and p38 MAPK in TSG-6 Expression in Adipose Tissue-Derived Stem Cells In Vitro and In Vivo.

Mesenchymal stem cells (MSCs) regulate immune cell activity by expressing tumor necrosis factor-α (TNF-α)-stimulated gene 6 (TSG-6) in inflammatory environments; however, whether anti-inflammatory responses affect TSG-6 expression in MSCs is not well understood. Therefore, we investigated whether transforming growth factor-β (TGF-β) regulates TSG-6 expression in adipose tissue-derived stem cells (ASCs) and whether effective immunosuppression can be achieved using ASCs and TGF-β signaling inhibitor A83-01. TGF-β significantly decreased TSG-6 expression in ASCs, but A83-01 and the p38 inhibitor SB202190 significantly increased it. However, in septic C57BL/6 mice, A83-01 further reduced the survival rate of the lipopolysaccharide (LPS)-treated group and ASC transplantation did not improve the severity induced by LPS. ASC transplantation alleviated the severity of sepsis induced by LPS+A83-01. In co-culture of macrophages and ASCs, A83-01 decreased TSG-6 expression whereas A83-01 and SB202190 reduced Cox-2 and IDO-2 expression in ASCs. These results suggest that TSG-6 expression in ASCs can be regulated by high concentrations of pro-inflammatory cytokines in vitro and in vivo, and that A83-01 and SB202190 can reduce the expression of immunomodulators in ASCs. Therefore, our data suggest that co-treatment of ASCs with TGF-β or p38 inhibitors is not adequate to modulate inflammation.

3D printed strontium-doped calcium phosphate ceramic scaffold enhances early angiogenesis and promotes bone repair through the regulation of macrophage polarization

The vascularization of bone repair materials is one of the key issues that urgently need to be addressed in the process of bone repair. The changes in macrophage phenotype and function play an important role in the process of vascularization, and endowing bone repair materials with immune regulatory characteristics to enhance angiogenesis is undoubtedly a new strategy to improve the effectiveness of bone repair. In order to improve the effect of tricalcium phosphate (TCP) on vascularization and bone repair, we doped strontium ions (Sr) into TCP (SrTCP) and prepared porous 3D printed SrTCP scaffolds using 3D printing technology, and studied the scaffold mediated macrophage polarization and subsequent vascularization and bone regeneration. The results of the interaction between the scaffold and macrophages showed that the SrTCP scaffold can promote the polarization of macrophages from M1 to M2 and secrete high concentrations of VEGF and PDGF-bb cytokines, which shows excellent angiogenic potential. When human umbilical vein endothelial cells (HUVECs) were co-cultured with macrophage-conditioned medium of SrTCP scaffold, HUVECs exhibited excellent early angiogenesis-promoting effects in terms of scratch healing, angiogenic gene expression, and in vitro tube formation performance. The results of in vivo bone repair experiments showed that the SrTCP scaffold formed a vascular network with high density and quantity in the bone defect area, which could increase the rate of new bone formation and advance the period of bone formation, and finally achieved a better bone repair effect. We observed a cascade effect in which Sr-doped SrTCP scaffold regulate macrophage polarization to enhance angiogenesis and promote bone repair, which may provide a new strategy for the repair of clinical bone defects.

Neurological manifestations with jugular vein thrombosis linked to an inflammatory profile may be a sequela of long COVID

AbstractMore than 670 million cases of coronavirus disease 2019 (COVID‐19) have been recorded worldwide in the 3 years since the start of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic. About 45% of survivors of COVID‐19 develop a syndrome known as long‐term COVID, in which symptoms persist even months after the acute infection. About 76% of patients with long COVID experience neurological manifestations. Moreover, patients who have survived COVID‐19 have an increased risk of cerebral venous thrombosis. This case report describes a 41‐year‐old woman who developed neurological manifestations associated with jugular vein thrombosis 24 h after administration of the Oxford–AstraZeneca (ChAdOx1 nCoV‐19) vaccine (AstraZeneca‐Serum Institute of India). She had been infected with SARS‐CoV‐2 three months before vaccination. Although initially suspected to be a case of vaccine‐induced immune thrombotic thrombocytopenia (VITT) in view of her recent vaccination, the patient did not have any hallmarks of VITT, such as thrombocytopenia, an increased d‐dimer level, or antibodies against platelet factor‐4. Moreover, the neurological manifestations were associated with a high concentration of inflammatory cytokines, including interleukin (IL)‐6, IL‐17A, and IL‐21, and elevated neutrophil levels in cerebrospinal fluid, suggesting that inflammatory immune components had a role in the development of thrombotic events and pointing to an alternative diagnosis. In this case, the laboratory results indicated that the neurological manifestations associated with jugular vein thrombosis were not associated with VITT. Therefore, we propose that the thrombosis of the left jugular vein was a sequela of SARS‐CoV‐2 infection.

LONG-TERM COVID-19 EFFECT TO ENDOTHELIAL DAMAGE TROUGH EXTRINSIC APOPTOSIS LED TO CARDIOVASCULAR DISEASE PROGRESSION: AN UPDATE REVIEW

COVID-19 can involve persistence, sequelae, and other medical complications that last weeks to months after initial recovery; these prolonged symptoms called as long-term covid-19 effect. Symptoms, signs, or abnormal clinical parameters persisting two or more weeks after COVID-19 onset that do not return to a healthy baseline can potentially be long-term effects of the disease. SARS-CoV-2 affects the cardiovascular system and causes conditions such as myocarditis, arrhythmias, and myocardial injury. Vascular damage from COVID-19 has been affected directly by the SARS-CoV-2 virus infection and indirectly by systemic inflammatory cytokine storm. This damage can be long-lasting and lead to various cardiovascular complications. Fas ligand (FasL)-Fas complex is a death factor that induces cell apoptosis. Fas and FasL have been detected in the endothelial wall, and it has been proposed that Fas-mediated apoptosis has a role in physiological and pathological cell turnover in the endothelial wall. High concentrations of inflammatory cytokines, such as cytokines storm induced by SARS-CoV-2 infection, are thought to increase the expression of FasL, which leads to an increase in the regulation of extrinsic apoptosis in endothelial cells leading to endothelial damage. This article summarises the current understanding of the long-term covid-19 effect on endothelial damage through extrinsic apoptosis Fas-FasL complex.

Determinants of serum cytokines in a population sample of healthy subjects from Iran

IntroductionCytokines are synthesized and released by immune system cells and mediate critical immune responses. Aging is associated with increased serum levels of some pro-inflammatory cytokines . A positive correlation between the concentration of several cytokines and blood pressure has been reported; higher cytokine concentrations may be related to the underlying causes of hypertension through the effects of inflammatory responses or as an independent etiology for hypertension .To assess the relationship between the serum levels of inflammatory cytokines and growth factors, with biochemical and anthropometric characteristics in healthy Iranian subjects.Material and methodsAnthropometric measurements and blood sampling were performed in 103 healthy Iranian participants. Fasting blood glucose (FBG), hs-CRP and lipid profile were measured in these participants. 12 serum cytokines/growth factors (MCP-1, TNF-α, EGF, IFN-γ, VEGF, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8 and IL-10 were measured.ResultsFBG was positively associated with serum IL-2, IL-4 and IL-1α (P = 0.044, &lt; 0.001 and = 0.017, respectively). Serum EGF and IL-4 were positively associated with age (P &lt; 0.001). IL-8 was inversely associated with SBP (P = 0.002) and gender (P = 0.028). There was a positive association between VEGF and HDL (P = 0.007). The serum levels of IFN-γ and TNF-α were positively associated with serum TG (P = 0.018 and 0.006, respectively).ConclusionsThere are associations between various pro-and anti-inflammatory cytokines in serum and several anthropometric measurements.