High Levels Of Pro-inflammatory Cytokines Research Articles

Gardnerella subgroup dominant microbiomes are associated with divergent cervicovaginal immune responses in a longitudinal cohort of Kenyan women.

Most cervicovaginal microbiome-immunology studies to date have relied on 16S rDNA microbial profiling which does not resolve the molecular subgroups of Gardnerella, believed to be central to the pathogenesis of bacterial vaginosis (BV) and subsequent risk of HIV acquisition. Here we used the cpn60 universal target which in addition to other microbial taxa, resolves four Gardnerella subgroups, for cervicovaginal microbial profiling in a longitudinal cohort of Kenyan women to examine associations with cellular and soluble markers of inflammation and HIV susceptibility. Participants (N = 41) were sampled, contributing 362 samples for microbiome analysis. All non-Lactobacillus dominant microbial communities were associated with high pro-inflammatory cytokine levels. Divergent associations were observed among different Gardnerella subgroup dominated communities with respect to the chemokine IP-10. Specifically, Gardnerella subgroup A dominant and polymicrobial communities were associated with reduced concentrations of IP-10 in adjusted linear mixed models (p<0.0001), compared to microbial communities dominated by Lactobacillus (non-iners) species. However, these associations did not translate to significant differences in the proportion or absolute number of CCR5, HLA-DR and CD38 expressed on cervical CD4+ T- cells. These findings suggest that some associations between Gardnerella subgroup dominant microbiomes and mucosal immunity differ and are relevant for the study of BV-pathogenesis and understanding the mechanisms of BV-associated HIV risk.

How wound environments trigger the release from Rifampicin-loaded liposomes

BackgroundChronic wounds often contain high levels of proinflammatory cytokines that prolong the wound-healing process. Patients suffering from these conditions are likely to benefit from topical rifampicin therapy. Although recent research indicates considerable anti-inflammatory properties of the antibiotic, currently, there are no commercial topical wound healing products available. To address this medical need, a liposomal drug delivery system was developed. A mechanistic investigation outlined major influences of wound environments that affect the release kinetics and, as a consequence, local bioavailability. MethodsLiposomes were prepared using the thin-film hydration method and subsequently freeze-dried at the pilot scale to improve their stability. We investigated the influence of oxidation, plasma proteins, and lipolysis on the in vitro release of rifampicin and its two main degradation products using the Dispersion Releaser technology. A novel simulated wound fluid provided a standardized environment to study critical influences on the release. It reflects the pathophysiological environment regarding pH, buffer capacity, and protein content. ResultsDuring storage, the liposomes efficiently protect rifampicin from degradation. After the dispersion of the vesicles in simulated wound fluid, despite the significant albumin binding (>70%), proteins have no considerable effect on the release. Also, the presence of lipase at pathophysiologically elevated concentrations did not trigger the liberation of rifampicin. Surprisingly, the oxidative environment of the wound bed represents the strongest accelerating influence and triggers the release. ConclusionA stable topical delivery system of rifampicin has been developed. Once the formulation comes in contact with simulated wound fluid, drug oxidation accelerates the release. The influence of lipases that are assumed to trigger the liberation from liposomes depends on the drug-to-lipid ratio. Considering that inflamed tissues exhibit elevated levels of oxidative stress, the trigger mechanism identified for rifampicin contributes to targeted drug delivery.

The Many Faces of Immune Activation in HIV-1 Infection: A Multifactorial Interconnection.

Chronic immune activation has a significant role in HIV-1 disease pathogenesis and CD4+ T-cell depletion. The causes of chronic inflammation and immune activation are incompletely understood, but they are likely multifactorial in nature, involving both direct and indirect stimuli. Possible explanations include microbial translocation, coinfection, and continued presence of competent replicating virus. In fact, long-term viral suppression treatments are unable to normalize elevated markers of systemic immune activation. Furthermore, high levels of pro-inflammatory cytokines increase susceptibility to premature aging of the immune system. The phenomenon of "inflammaging" has begun to be evident in the last decades, as a consequence of increased life expectancy due to the introduction of cART. Quality of life and survival have improved substantially; however, PLWH are predisposed to chronic inflammatory conditions leading to age-associated diseases, such as inflammatory bowel disease, neurocognitive disorders, cardiovascular diseases, metabolic syndrome, bone abnormalities, and non-HIV-associated cancers. Several approaches have been studied in numerous uncontrolled and/or randomized clinical trials with the aim of reducing immune activation/inflammatory status in PLWH, none of which have achieved consistent results.

Full Skin Equivalent Models for Simulation of Burn Wound Healing, Exploring Skin Regeneration and Cytokine Response.

Healing of burn injury is a complex process that often leads to the development of functional and aesthetic complications. To study skin regeneration in more detail, organotypic skin models, such as full skin equivalents (FSEs) generated from dermal matrices, can be used. Here, FSEs were generated using de-epidermalized dermis (DED) and collagen matrices MatriDerm® and Mucomaix®. Our aim was to validate the MatriDerm- and Mucomaix-based FSEs for the use as in vitro models of wound healing. Therefore, we first characterized the FSEs in terms of skin development and cell proliferation. Proper dermal and epidermal morphogenesis was established in all FSEs and was comparable to ex vivo human skin models. Extension of culture time improved the organization of the epidermal layers and the basement membrane in MatriDerm-based FSE but resulted in rapid degradation of the Mucomaix-based FSE. After applying a standardized burn injury to the models, re-epithelization occurred in the DED- and MatriDerm-based FSEs at 2 weeks after injury, similar to ex vivo human skin. High levels of pro-inflammatory cytokines were present in the culture media of all models, but no significant differences were observed between models. We anticipate that these animal-free in vitro models can facilitate research on skin regeneration and can be used to test therapeutic interventions in a preclinical setting to improve wound healing.

Цитомегаловирусная инфекция как фактор риска неблагоприятных сердечно-сосудистых событий у больных с хронической сердечной недостаточностью

The purpose — to study the effect of cytomegalovirus (CMV) infection on the production of pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and its relationship with functional status in patients with chronic heart failure (CHF) of ischemic genesis. Material and methods. We examined 187 patients with CHF of ischemic etiology, hospitalized in the cardiology department for decompensated heart failure (functional class (FC) CHF II-IV). Subsequently, patients were prospectively monitored for 24 months. The end point was a combined one and was defined as an increase by 1 or more in the FC of CHF (according to NYHA), hospitalization for decompensation of CHF, progressive deterioration of the structural and functional parameters of the left ventricle during the study period, the occurrence of adverse clinical events (cardiovascular death, non-fatal myocardial infarction or acute cerebrovascular accident, pulmonary embolism) during 24 months of prospective observation. After stabilization of patients upon inclusion in the study, plasma concentrations of TNF-α and IL-1β were determined by enzyme-linked immunosorbent assay. Qualitative determination of cytomegalovirus DNA in blood was carried out using the polymerase chain reaction method. Results. Based on the results of quantitative determination of CMV DNA, patients were divided into two groups: group 1 — seropositive (CMV+) (n = 128) and group 2 — seronegative (CMV-) (n = 59). In seropositive patients, functional class IV of CHF was significantly more often recorded (p &lt; 0.035), as well as higher levels of TNF-α (p &lt; 0.001) and IL-1β (p &lt; 0.001) regardless of the FC of CHF. In the group of patients with positive CMV serostatus, adverse cardiovascular events were recorded significantly more often during 24 months of observation compared to seronegative patients: there was a significantly higher number of hospitalizations due to decompensation of CHF (p = 0.023), development of acute coronary syndrome (p = 0.031) and pulmonary embolism (p = 0.042), and lethal cases (p = 0.018). Conclusion. High levels of proinflammatory cytokines in patients with CHF correlate with carriage of CMV infection. Seropositive patients have an increased risk of adverse cardiovascular events compared to seronegative patients with CHF.

Лікувально-профілактичні підходи до хворих на псоріаз після перенесеної коронавірусної інфекції

The results of preliminary observations indicate that the SARS-COV-2 virus can also affect the skin and affect the course of chronic diseases, including dermatoses. The cause and pathogenesis of skin manifestations have not yet been established and are under study, but they are most likely caused by infectious and allergic damage to blood vessels, as well as a high level of pro-inflammatory cytokines. The subject is to increase the effectiveness of the therapy of patients with psoriasis after suffering from the coronavirus disease by using drugs that affect the state of the endothelium of blood vessels and the blood coagulation system. Materials and methods. 69 patients with psoriasis associated with COVID-19 infection were under observation. The patients were divided into two clinical and therapeutic groups, which were representative in terms of age, sex, and severity of the disease: The first experimental group (36 patients) in complex treatment received drugs that had an effect on the normalization of endothelial dysfunction and the blood coagulation system. Patients of the II group (33 persons) received treatment according to the protocols. The control group consisted of 20 practically healthy persons, representative in terms of age and sex. Control of the treatment was carried out on the basis of clinical and laboratory data. Subjective and objective signs of the disease were evaluated, clinical and biochemical indicators were determined, including a general blood test, the state of the coagulation system using modern standardized laboratory tests. The degree of inflammatory reaction was assessed by the level of C-reactive protein and IL-6. Statistical processing of data was carried out using methods of variational statistics. Significance of differences was assessed using Student’s test for independent samples. The results. When using drugs that had an effect on the normalization of endothelial dysfunction and the blood coagulation system, in the complex treatment of patients of the 1st group, a significant improvement in the general condition was noted, a decrease in the subjective symptoms of the disease: itching, dryness, soreness in the foci of inflammation, which decreased 3–4 days earlier, than in patients from the comparison group who received traditional therapy. Clinical remission in patients of the I group occurred in (22.3 ± 2.7) days, while in patients in the II group – in (29.2 ± 3.5) days, that is, 6.9 days earlier (p &lt; 0, 05). The use of the proposed treatment-prophylactic approach improved the parameters of the blood coagulation system in patients with psoriasis who suffered a coronavirus infection, which was manifested by the normalization of AChT, PTI, fibrinogen content and a significant decrease in D-dimer, which indicates a probable reduction in the risk of thrombotic complications. At the same time, there was a significant decrease in inflammation indicators – PSA and IL-6. Conclusions. The use of the proposed treatment-prophylactic approach contributed to an earlier onset of clinical remission: the subjective and objective signs of the disease stopped almost 7 days earlier than in patients treated only by traditional methods, normalization of indicators of the state of the coagulation system, endothelial dysfunction, which prevented development of complications from the cardiovascular system.

Lexical markers of cognitive reappraisal, bereavement, and proinflammatory cytokine production.

The loss of a spouse is considered one of the most significant life change-related stressors. Bereaved spouses have significantly increased risk of chronic inflammation, and ultimately greater morbidity and mortality. High levels of proinflammatory cytokines are related to negative health outcomes. In bereavement, the ability to successfully regulate emotion is a vital skill for healthy coping and may represent a key psychological mechanism accounting for varying degrees of resilience. Psychological distancing is a frequently adaptive emotion regulation strategy in which an individual appraises a negative situation by taking a step back and distancing oneself, and coolly evaluates what is happening. The objective of the present work was to investigate whether psychological distancing, implemented implicitly via natural language use (i.e., linguistic distancing [LD]), is related to inflammation and bereavement-related health indicators. Participants (N = 144) underwent a blood draw for the inflammation assay, completed questionnaire measures evaluating grief symptoms and health, and completed an oral task describing their relationship with their deceased spouse, which was used for the lexical analyses. We found that LD was significantly associated with a panel of a priori proinflammatory stimulated cytokines (TNF-α, IL-6, IFN-γ, IL-17A, and IL-2), bereavement-related health indices, and the relationship between grief symptoms and inflammation varied depending on the participants' implementation of LD. LD may have a buffering effect for this vulnerable population. This work elucidates novel dependencies among language, emotion, and health. This work identifies resilience factors and probes the translational value of LD. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Sirolimus- and cyclosporine-loaded nanostructured lipid carriers: Development, characterization, and in vitro evaluation in T-cell profiles of patients with a history of recurrent pregnancy loss.

The authors developed nanostructured lipid carriers (NLCs) loaded with sirolimus (SRL) and cyclosporine (CsA) to improve their therapeutic efficacy in recurrent pregnancy loss (RPL) patients. Mono-delivery and co-delivery of SRL and CsA by NLCs (S-NLCs, C-NLCs, and S-C-NLCs) were developed. The MTT assay was used to study the optimum dose of formulations. PCR, Western blotting, and ELISA were also conducted. Well-designed nanodrugs with a suitable size, zeta potential, desirable encapsulation efficiency drug loading, and cellular uptake confirmed optimum formulations. Based on cell viability, the amounts of SRL and CsA could be reduced greatly due to the co-delivery by NLCs. Following S-NLCs and C-NLCs interventions in T cells of patients with RPL and immune abnormality, a significant difference was observed in transcription factors and cytokine levels of Th1, Th17, and Tregs compared with healthy samples. Thus, a higher level of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-17, and IL-21) and their regulators (T-bet and RORγt), as well as a lower level of an anti-inflammatory cytokine (IL-10) and its regulatory (Foxp3), were observed. However, no significant difference was found following the S-C-NLCs intervention. S-C-NLCs effectively balance the immune responses in peripheral T cells in RPL patients to induce maternal immune tolerance.

A Cross-Sectional Study to Evaluate the Alteration of Cytokine Expression and Activation of Inflammatory Pathway in Response to NOD1 and NOD2 Signal in Leprosy.

Leprae bacilli are identified as foreign by pattern recognition receptors (PRRs) present in the microbes but absent in the host. The Nucleotide oligomerization domain (NOD)-like receptor (NLR) family comprises the nucleotide-binding oligomerisation domain (NOD1 and NOD2) proteins, which are two well-known PRRs. The objectives of this study were to study the expression of cytoplasmic NOD1 and NOD2 in the pathogenesis of leprosy and the serum level of expressed cytokines and to measure the messenger Ribonucleic Acid (mRNA) expression. Clinically suspected Hansen's patients were analysed for 4 years. Newly diagnosed leprosy patients were considered leprosy disease control (LDC). The cases with active or new lesions and an increase in Bacteriological index (BI) by at least 2 + after 12 months of completion of Multidrug therapy (MDT) were considered leprosy disease relapse (LDR) cases. Age- and sex-matched healthy individuals served as our control group (healthy control (HC)). enzyme-linked immunosorbent assay (ELISA) was performed to measure the concentration of five human cytokines in serum, including three pro-inflammatory cytokines (Tumor necrosis factor (TNF)-α, Interferon gamma (IFN-γ) and IL-6), one anti-inflammatory cytokine (IL-10) and one chemokine (IL-8). Quantitative expression of receptor genes (NOD1 and NOD2) and cytokine genes (TNF-α, IFN-γ, IL-6, IL-10 and IL-8) was evaluated by quantitative real-time polymerase chain reaction (PCR) (qRT-PCR). We studied NOD1 and NOD2 expression in the tissues through fluorescence immunohistochemistry. Differential NLR intracellular expression on peripheral blood monocytes (PBMs) and their response to stimulation with specific ligands (lipopolysaccharide (LPS) and muramyl dipeptide (MDP)) were studied. A significant difference in the expression of the NOD1 gene was observed in unstimulated monocytes of the LDC and LDR cases when compared to HC. The NOD2 transcript level was significantly higher in stimulated monocytes from LDC and LDR patients than in similarly stimulated cells from HC. The LDC patients had a significantly higher level of pro-inflammatory cytokines as compared to the HC. In conclusion, this study has demonstrated the expression of both cytokines and chemokines in response to NLR activation in the skin of leprosy patients.

Olfactomedin-4 deletion exacerbates DSS-induced colitis through a matrix metalloproteinase-9-dependent mechanism.

Background and Aims: Olfactomedin-4 is a glycoprotein that is upregulated in inflamed gastrointestinal tissues. This study aimed to investigate the role and underlying mechanisms of olfactomedin-4 in ulcerative colitis. Methods: C57BL/6 mice and olfactomedin-4 knockout mice were fed dextran sulfate sodium in drinking water to establish a colitis model. An in vitro inflammation model was constructed in HCT116 and NCM460 cells stimulated with lipopolysaccharide. The expression of olfactomedin-4 was detected by Western blotting, immunohistochemistry staining, and qRT‒PCR. The differences in the severity of colitis between olfactomedin-4 knockout mice and wild-type mice were compared, and the underlying mechanisms were explored. Results: Olfactomedin-4 expression was significantly upregulated in colonic tissues of active ulcerative colitis patients and in cellular and mouse models of colitis. Compared with wild-type littermates, olfactomedin-4 knockout mice were more susceptible to dextran sulfate sodium-induced colitis and produced higher levels of proinflammatory cytokines and chemokines. In addition, olfactomedin-4 deficiency significantly promoted intestinal epithelial cell apoptosis and increased intestinal permeability, which was mediated by the p53 pathway. Moreover, olfactomedin-4 directly interacted with and negatively regulated matrix metalloproteinase-9. Inhibiting matrix metalloproteinase-9 significantly decreased colonic p53 expression and ameliorated experimental colitis in olfactomedin-4 knockout mice, while overexpression of matrix metalloproteinase-9 aggravated colitis. Further experiments showed that matrix metalloproteinase-9 regulated p53 through the Notch1 signaling pathway to promote ulcerative colitis progression. Conclusions: Olfactomedin-4 is significantly upregulated in ulcerative colitis and may protect against colitis by directly inhibiting matrix metalloproteinase-9 and further decreasing p53-mediated apoptosis via Notch1 signaling.

Highlights on molecular targets in the management of COVID-19: Possible role of pharmacogenomics

By the end of 2022, there had been a reduction in new cases and deaths caused by coronavirus disease 2019 (COVID-19). At the same time, new variants of the severe acute respiratory syndrome coronavirus 2 virus were being discovered. Critically ill patients with COVID-19 have been found to have high serum levels of proinflammatory cytokines, especially interleukin (IL)-6. COVID-19-related mortality has been attributed in most cases to the cytokine storm caused by increased levels of inflammatory cytokines. Dexamethasone in low doses and immunomodulators such as IL-6 inhibitors are recommended to overcome the cytokine storm. This current narrative review highlights the place of other therapeutic choices such as proteasome inhibitors, protease inhibitors and nuclear factor kappa B inhibitors in the treatment of patients with COVID-19.

Mapping the T cell epitopes of the M-type transmembrane phospholipase A2 receptor in primary membranous nephropathy

The M-type phospholipase A2 receptor (PLA2R) is the major autoantigen of primary membranous nephropathy (MN). Despite many studies on B-cell epitopes recognized by antibodies, little is known about T-cell epitopes. Herein, we synthesized 123 linear peptides, each consisting of 15-22 amino acids with 8-12 amino acid overlaps, across ten domains of PLA2R. Their binding capacity to risk (DRB1∗1501, DRB1∗0301) and protective (DRB1∗0901, DRB1∗0701) HLA molecules was then assessed by flow cytometry. Proliferation of CD4+ T cells from patients with anti-PLA2R positive MN was analyzed after peptide stimulation. Cytokines produced by activated peripheral blood mononuclear cells were measured by cytometric bead arrays. We identified 17 PLA2R peptides that bound to both DRB1∗1501 and DRB1∗0301 molecules with high capacity. Some of these peptides showed decreased binding to heterozygous DRB1∗1501/0901 and DRB1∗0301/0701. Ten of the 17 peptides (CysR1, CysR10, CysR12, FnII-3, CTLD3-9, CTLD3-10, CTLD3-11, CTLD5-2-1, CTLD7-1 and CTLD7-2) induced significant proliferation of CD4+ T cells from patients with MN than cells from healthy individuals. Upon activation by these peptides, peripheral blood mononuclear cells from patients with MN produced higher levels of pro-inflammatory cytokines, predominantly IL-6, TNF-α, IL-10, IL-9 and IL-17. Thus, we mapped and identified ten peptides in the CysR, FnII, CTLD3, CTLD5, and CTLD7 domains of PLA2R as potential T-cell epitopes of MN. These findings are a first step towards developing peptide-specific immunotherapies.

Echinocystic Acid Ameliorates Arthritis in SKG Mice by Suppressing Th17 Cell Differentiation and Human Rheumatoid Arthritis Fibroblast-Like Synoviocytes Inflammation

Echinocystic acid (EA), a pentacyclic triterpene, exhibits anti-inflammatory, antioxidant, and analgesic activities to counteract pathological effects in various diseases. Here, we aimed to determine the immunomodulatory effect of EA on zymosan-induced arthritis in SKG mice and how it would influence Th17 differentiation and human rheumatoid arthritis fibroblast-like synoviocytes inflammation. Our results showed that EA (10 and 25 mg/kg) attenuated arthritis symptoms, including high arthritis scores, infiltrating inflammatory cells, synovial hyperplasia, bone erosion, and the high levels of proinflammatory cytokines, such as TNF-α, interleukin (IL)-6, and IL-1β in paw tissues, and reduced the number of splenic Th17 cells. Mechanistically, we found that in vitro treatment of EA inhibited both IL-6- and transforming growth factor-β (TGF-β)-induced Th17 cell differentiation by suppressing the phosphorylation of signal transducers and transcriptional activators, especially STAT3. In line with the in vivo result, EA significantly reduced the protein and mRNA expression of IL-6 and IL-1β in human RA-FLA cells, MH7A cells. Furthermore, the production of both cytokines was confirmed with the downregulation of mitogen-activated protein kinases (MAPK) and nuclear factor-κB (NF-κB) signaling pathways under the stimulation of TNF-α. In conclusion, these findings revealed that EA was capable of amelioration of arthritic disorders in SKG mice through inhibiting Th17 cell differentiation and synovial fibroblast inflammation, supporting that EA is a promising therapeutic candidate for treating RA patients.

Effects of Ovine Monocyte-Derived Macrophage Infection by Recently Isolated Toxoplasma gondii Strains Showing Different Phenotypic Traits.

Ovine toxoplasmosis is one the most relevant reproductive diseases in sheep. The genetic variability among different Toxoplasma gondii isolates is known to be related to different degrees of virulence in mice and humans, but little is known regarding its potential effects in sheep. The aim of this study was to investigate the effect of genetic variability (types II (ToxoDB #1 and #3) and III (#2)) of six recently isolated strains that showed different phenotypic traits both in a normalized mouse model and in ovine trophoblasts, in ovine monocyte-derived macrophages and the subsequent transcript expression of cytokines and iNOS (inducible nitric oxide synthase). The type III isolate (TgShSp24) showed the highest rate of internalization, followed by the type II clonal isolate (TgShSp2), while the type II PRU isolates (TgShSp1, TgShSp3, TgShSp11 and TgShSp16) showed the lowest rates. The type II PRU strains, isolated from abortions, exhibited higher levels of anti-inflammatory cytokines and iNOS than those obtained from the myocardium of chronically infected sheep (type II PRU strains and type III), which had higher levels of pro-inflammatory cytokines. The present results show the existence of significant intra- and inter-genotypic differences in the parasite-macrophage relationship that need to be confirmed in in vivo experiments.

Brain-body pathways linking racism and health.

Racial disparities in health are a major public health problem in the United States, especially when comparing chronic disease morbidity and mortality for Black versus White Americans. These health disparities are primarily due to insidious anti-Black racism that permeates American history, current culture and institutions, and interpersonal interactions. But how does racism get under the skull and the skin to influence brain and bodily processes that impact the health of Black Americans? In the present article, we present a model describing the possible neural and inflammatory mechanisms linking racism and health. We hypothesize that racism influences neural activity and connectivity in the salience and default mode networks of the brain and disrupts interactions between these networks and the executive control network. This pattern of neural functioning in turn leads to greater sympathetic nervous system signaling, hypothalamic-pituitary-adrenal axis activation, and increased expression of genes involved in inflammation, ultimately leading to higher levels of proinflammatory cytokines in the body and brain. Over time, these neural and physiological responses can lead to chronic physical and mental health conditions, disrupt well-being, and cause premature mortality. Given that research in this area is underdeveloped to date, we emphasize opportunities for future research that are needed to build a comprehensive mechanistic understanding of the brain-body pathways linking anti-Black racism and health. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Adipokines and adipocytokines in men with coronary atherosclerosis and overweight

Aim To study concentrations of adipokines and their associations with proinflammatory cytokines in overweight men with coronary atherosclerosis.Material and methods This study included 79 men aged 45-60 years with atherosclerosis who had undergone coronary endarterectomy during a coronary bypass surgery, and were overweight (body weight index (BWI), 25.0-29.9 kg /m2). Based on a histological analysis of plaques, the patients were divided into two subgroups: 43 men with stable atherosclerotic plaques and 36 men with unstable plaques in coronary arteries. The control group consisted of 40 age- and BWI-matched men without clinical manifestations of IHD. Blood concentrations of adipokines, including adiponectin, adipsin, lipocalin-2, resistin, and plasminogen 1 activator inhibitor were measured by a multiplex analysis with a MILLIPLEX MAP Human Adipokine Panel 1. Concentrations of proinflammatory cytokines, including tumor necrosis factor α (TNF- α), interleukin (IL)-1β, IL-6, and C-reactive protein (CRP) were measured by enzyme immunoassay.Results The blood concentration of lipocalin -2 was higher in patients with coronary atherosclerosis and stable or unstable atherosclerotic plaques than in the control group (p&lt;0.01). Both subgroups of men with coronary atherosclerosis were characterized by significant differences from the control group in concentrations of TNF-α (p&lt;0.05), CRP, and IL-6 (p&lt;0.01). The most significant direct correlations were found between adipokines and TNF-α, IL-6, and CRP (p&lt;0.01). Results of a logistic regression analysis showed that relative odds for the presence of significant coronary stenoses increased with increasing blood concentrations of lipocalin-2 (OR=1.005, 95 % CI: 1.002-1.008, р=0.011) and IL-6 (OR=1.582 , 95 % CI: 1.241-2.017, р=0.001).Conclusion The changes in blood concentrations of adipokines associated with higher levels of proinflammatory cytokines may represent a factor that increases the probability of clinically significant coronary stenosis in overweight men with coronary atherosclerosis.

Recovery of systemic hyperinflammation in patients with severe SARS-CoV-2 infection

Introduction Patients with cardiovascular disease (CVD) and acute SARS-CoV-2 infection might show an altered immune response during COVID-19. Material and methods Twenty-three patients with CVD and SARS-CoV-2 infection were prospectively enrolled and received a cardiological assessment at study entry and during follow-up visit. Inclusion criteria of our study were age older than 18 years, presence of CVD, and acute SARS-CoV-2 infection. The median age of the patient cohort was 69 (IQR 55–79) years. 12 (52.2%) patients were men. Peripheral monocytes and chemokine/cytokine profiles were analysed. Results Numbers of classical and non-classical monocytes were significantly decreased during acute SARS-CoV-2 infection compared to 3-month recovery. While classical monocytes reached the expected level in peripheral blood after 3 months, the number of non-classical monocytes remained significantly reduced. Discussion All three monocyte subsets exhibited changes of established adhesion and activation markers. Interestingly, they also expressed higher levels of pro-inflammatory cytokines like macrophage migration inhibitory factor (MIF) at the time of recovery, although MIF was only slightly increased during the acute phase. Conclusion Changes of monocyte phenotypes and increased MIF expression after 3-month recovery from acute SARS-CoV-2 infection may indicate persistent, possibly long-lasting, pro-inflammatory monocyte function in CVD patients.

Polydopamine-coated thalidomide nanocrystals promote DSS-induced murine colitis recovery through Macrophage M2 polarization together with the synergistic anti-inflammatory and anti-angiogenic effects

High levels of proinflammatory cytokines, macrophage polarization status and immune-mediated angiogenesis play pivotal roles in the pathogenesis of inflammatory bowel disease (IBD). Thalidomide, an anti-inflammatory, immunomodulatory and antiangiogenic agent, is used off-label for treatment of IBD. The therapeutic potential of thalidomide is limited by its poor solubility and side effects associated with its systemic exposure. To address these issues and promote its therapeutic effects on IBD, thalidomide nanocrystals (Thali NCs) were prepared and coated with polydopamine (PDA), a potential macrophage polarization modulator, to form PDA coated Thali NCs (Thali@PDA). Thali@PDA possessed a high drug loading and displayed average particle size of 764.7 ± 50.30 nm. It showed a better anti-colitis effect than bare thalidomide nanocrystals at the same dose of thalidomide. Synergistic effects of polydopamine on anti-inflammatory and anti-angiogenic activities of thalidomide were observed. Furthermore, PDA coating could direct polarization of macrophages towards M2 phenotype, which boosted therapeutic effects of Thali@PDA on IBD. Upon repeated dosing of Thali@PDA for one week, symptoms of IBD in mice were significantly relieved, and histomorphology of the colitis colons were normalized. Key proinflammatory cytokine levels in the inflamed intestines were significantly decreased. Toxicity study also revealed that Thali@PDA is a safe formulation.

Burn-injured skin is marked by a prolonged local acute inflammatory response of innate immune cells and pro-inflammatory cytokines.

The systemic and local immune response in burn patients is often extreme and derailed. As excessive inflammation can damage healthy tissues and slow down the healing process, modulation of inflammatory responses could limit complications and improve recovery. Due to its complexity, more detailed information on the immune effects of thermal injury is needed to improve patient outcomes. We therefore characterized and quantified subsets of immune cells and mediators present in human burn wound tissue (eschar), sampled at various time points. This study shows that after burn injury, the number of immune cells were persistently increased, unlike the normal wound healing process. There was an immediate, strong increase in neutrophils and a moderate increase in monocytes/macrophages and lymphocytes, especially in the second and third week post burn. The percentage of classical (CD14highCD16-) monocytes/macrophages demonstrated a steady decrease over time, whereas the proportion of intermediate (CD14highCD16+) monocytes/macrophages slowly increased. The absolute numbers of T cells, NK cells and B cells increased up to week 3, while the fraction of γδ T cells was increased only in week 1. Secretome profiling revealed high levels of chemokines and an overall pro-inflammatory cytokine milieu in burn tissue. The local burn immune response shows similarities to the systemic immune reaction, but differs in neutrophil maturity and lymphocyte composition. Altogether, the neutrophil surges, high levels of pro-inflammatory cytokines and limited immunosuppression might be key factors that prolong the inflammation phase and delay the wound healing process in burns.

Cytokines and neurotrophic factors in the severity assessment of children autism.

Due to the steady increase in the number of children with autism and the high heterogeneity of clinical groups, the diagnosis of these disorders and their severity is an urgent problem in modern medicine. In the course of the work, 126 children from 3 to 13 years old with typical neurodevelopment and with severe and mild autism spectrum disorders (ASD) were examined. Disease severity was determined according to the Childhood Autism Rating Scale (CARS). The levels of pro-/anti-inflammatory cytokines and neurotrophic factors (nerve growth factor beta and brain-derived neurotrophic factor) in blood plasma were assessed by enzyme immunoassay. Associations between indicators in each group of patients were assessed using the Spearman test and visualized as a heatmap of correlations. Statistical data processing was carried out in the R software. Significantly high levels of IL-4 in blood plasma and a decrease in the number of significant correlations within/between systems were revealed in children with mild autism compared with children with typical neurodevelopment. Such data can probably reflect the theory that some children with ASD are characterized by slow brain development, as a variant of the evolutionary norm. On the contrary, in children with severe ASD, high systemic levels of IL-6 and IFNg are shown against the background of low values of IL-10, IL-1β, TNFα and NGFβ, supported by the almost complete absence of intra/ and intersystem interactions. This may act as an indicator of maladaptation of the immune and nervous systems in severe autism, which contributes to the pathogenesis of the disease. Thus, a set of indicators: high levels of key pro-inflammatory cytokines - IL-6 and IFNg, low levels of IL-10, NGFβ and disintegration of the cytokine and nervous systems in the periphery can be proposed as an approach to indicate the severity of the condition in children with ASD.