Action Of Cytokines Research Articles

Cross-sectional analysis of blood leukocyte responsiveness to interleukin-10 and interleukin-6 across age and physical activity level

Abstract Objectives To determine how the anti-inflammatory actions of interleukin-10 (IL-10) and IL-6 differ across age and physical activity levels. Methods Using a cross-sectional design, fasted blood samples were obtained from younger physically inactive (YI: n=10, age: 22.7 ± 3.7 years, BMI: 24.8 ± 4.8 kg/m2, <150 min of weekly moderate-to-vigorous physical activity [MVPA]), younger highly active (YA: n=11 varsity cross country running athletes, 20.7 ± 2.7 years, 21.1 ± 1.8 kg/m2, >300 min of weekly MVPA), and older highly active (OA: 12, 56.0 ± 10.3 years, 22.8 ± 3.2 kg/m2, >300 min of weekly MVPA) individuals and analyzed for leukocyte counts, IL-10 and IL-6-related signaling, and cytokine secretion ex vivo. Results Total white blood cells and monocytes were similar between groups (p=0.8) but YA and OA had lower lymphocyte counts than YI (p<0.01). The ability of IL-10 (1 ng/mL) to phosphorylate signal transducer and activator of transcription 3 (STAT3) in CD14 monocytes was greater in YA vs. YI (p<0.03) despite YA having lower IL-10 receptor expression (p<0.01). IL-6 (10 ng/mL) mediated STAT3 phosphorylation in CD4 lymphocytes was higher in OA compared YI (p<0.01), with a similar tendency observed for YA vs. YI (p=0.08). Despite enhanced responsiveness of STAT3 to IL-10/6 in active individuals, the ability of IL-10/6 to inhibit tumor necrosis factor-alpha (TNF-⍺) secretion from lipopolysaccharide-stimulated whole-blood was similar between groups. Conclusions Highly active younger and older individuals demonstrate enhanced IL-10- and IL-6-mediated activation of immune cell STAT3. Although the ability of IL-10/6 to inhibit TNF-⍺ secretion appeared unimpacted by activity level, anti-inflammatory cytokine actions were preserved in older active individuals.

Regulatory T cells engineered with polyphenol-functionalized immunosuppressant nanocomplexes for rebuilding periodontal hard tissue under inflammation-challenged microenvironment

Global aging heightens the risk of oral disorders, among which periodontitis is the major cause of tooth loss in the aging population. The regeneration of damaged periodontal hard tissue is highly challenging due to the existence of the refractory local inflammation. Owing to the potent anti-inflammatory capabilities, regulatory T cells hold great promise in immunotherapies for tissue regeneration. However, the transferred regulatory T cells can alter their phenotypes and functions in local inflammatory milieu, significantly impairing their therapeutic efficacy. Herein, we introduce a novel regulatory T cell-based nanobiohybrid system bearing polyphenol-functionalized rapamycin nanocomplexes. The sustained in situ release of immunosuppressant rapamycin from the cell-attached nanocomplexes maintains the anti-inflammatory phenotype of regulatory T cells in the inflammatory milieu. The synergistic actions of the anti-inflammatory cytokines secreted and the immunosuppressant released guide a pro-resolving polarization of macrophages and enhance osteogenic differentiation of bone marrow-derived stromal cells. The stabilized phenotype of the regulatory T cells dramatically promoted the resolution of periodontal inflammation and the repair of the hard tissue (alveolar bone) in vivo. Overall, these studies highlight a potent regulatory T cell-based nanobiohybrid therapy to treat periodontitis by modulating periodontal immune microenvironment.

Correlation between portal hypertension and somatic constitution: rationale behind the concept

This review summarizes recent data on the correlation of somatic constitution and portal hypertension.Somatotype reflects the constitutional composition of the human body. Excess endomorphic component (i.e. obesity) increases the risk of portal hypertension (PH - elevated pressure in the portal system above 12 mmHg) development. Among the prehepatic and posthepatic PH causes only congestive hepatopathy, a consequence of heart failure, is connected with obesity. A number of pathways connect the hepatic PH causes with obesity. Firstly, the action of proinflammatory cytokines produced by adipose tissue in greater amount in obesity promotes fatty acid uptake and storage by hepatocytes, leading to elevated oxidative stress and metabolic dysfunctions, activation of stellate cells, that differentiate into myofibroblasts and produce components of the intercellular matrix such as collagen into the perisinusoidal space resulting in fibrosis. Secondly, insulin resistance associated with obesity promotes dysfunction of the hepatic microcirculatory blood vessels, hyperlipidemia and liver steatosis. Thirdly, AMISS (Absence of Meal-induced Insulin Sensitization Syndrome), caused by regular high-carbohydrate and low-protein food consumption, manifested in decreased postprandial secretion of hepatic hormone hepatalin, which increases glucose uptake by skeletal and cardiac muscle, results in prolonged postprandial hyperglycemia, compensatory hyperinsulinemia and hyperlipidemia, leading to increased insulin resistance and a prediabetic state, associated with steatohepatosis. Thus, excess endomorphic component is to be regarded as a prognostic factor for portal hypertension.

Screening of hub genes for sepsis-induced myopathy by weighted gene co-expression network analysis and protein-protein interaction network construction

Sepsis-induced myopathy is one of the serious complications of sepsis, which severely affects the respiratory and peripheral motor systems of patients, reduces their quality of life, and jeopardizes their lives, as evidenced by muscle atrophy, loss of strength, and impaired regeneration after injury. The pathogenesis of sepsis-induced myopathy is complex, mainly including cytokine action, enhances free radical production in muscle, increases muscle protein hydrolysis, and decreases skeletal muscle protein synthesis, etc. The above mechanisms have been demonstrated in existing studies. However, it is still unclear how the overall pattern of gene co-expression affects the pathological process of sepsis-induced myopathy. Therefore, we intend to identify hub genes and signaling pathways. Weighted gene co-expression network analysis was our main approach to study gene expression profiles: skeletal muscle transcriptome in ICU patients with sepsis-induced multi-organ failure (GSE13205). After data pre-processing, about 15,181 genes were used to identify 13 co-expression modules. Then, 16 genes (FEM1B, KLHDC3, GPX3, NIFK, GNL2, EBNA1BP2, PES1, FBP2, PFKP, BYSL, HEATR1, WDR75, TBL3, and WDR43) were selected as the hub genes including 3 up-regulated genes and 13 down-regulated genes. Then, Gene Set Enrichment Analysis was performed to show that the hub genes were closely associated with skeletal muscle dysfunction, necrotic and apoptotic skeletal myoblasts, and apoptosis in sepsis-induced myopathy. Overall, 16 candidate biomarkers were certified as reliable features for more in-depth exploration of sepsis-induced myopathy in basic and clinical studies.

Exploring diagnostic biomarkers of type 2 cardio-renal syndrome based on secreted proteins and bioinformatics analysis

Chronic heart failure (CHF) can induce chronic kidney disease (CKD), called type 2 cardio-renal syndrome (CRS2). The mechanism is not completely clear, and there is a lack of early warning biomarkers of CKD in the context of CHF. Two CKD, one CHF-PBMC and four CHF-cardiac tissue expression profile datasets were obtained from GEO database. Differential expression analysis and WGCNA were used to detect CKD key genes and CHF-related secreted proteins. Protein–protein interaction (PPI), functional enrichment, and cMAP analysis reveal potential mechanisms and drugs of CHF-related CKD. Five machine learning algorithms were used to screen candidate biomarkers, construct a diagnostic nomogram for CKD and validate it in two external cohorts. Clinical serum samples were collected in our hospital to evaluate the correlation and diagnostic value of biomarkers and CKD. 225 CKD key genes and 316 CHF-related secreted proteins were identified. Four key subgroups, including 204 genes, were identified as CRS2-related pathogenic genes by PPI analysis. Enrichment analysis revealed that the identified subgroups exhibited significant enrichment in cytokine action, immune responses, and inflammatory processes. The cMAP analysis highlighted metiradone as a drug with greater potential for therapeutic intervention for CRS2. Utilizing five machine learning algorithms, three hub genes (CD48, COL3A1, LOXL1) were pinpointed as potential biomarkers for CKD, and a nomogram model was constructed. Receiver operating characteristic analysis demonstrated that the nomogram’s area under the curve (AUC) exceeded 0.80 in both the CKD combined dataset and two external cohorts. In addition, the three biomarkers were significantly correlated with the glomerular filtration rate, and the AUC of the model predicting disease progression was 0.944. Furthermore, analysis of immune cell infiltration indicated a correlation between the three biomarkers and the infiltration fraction of macrophages, neutrophils, and other immune cells in CKD. Our clinical cohort validated the expression patterns of three biomarkers in serum, and the diagnostic model achieved an AUC of 0.876. CHF has the potential to facilitate the progression of CKD via the release of cardiac and PBMC secreted proteins. Furthermore, CD48, COL3A1, and LOXL1 have been identified as potential biomarkers for the detection of CKD.

Elevated levels of pro-thrombotic eNOS-negative platelets in COVID-19 patients

BackgroundPlatelet-rich microvascular thrombi are common in severe COVID-19. Endogenous nitric oxide (NO)-signaling limits thrombus formation and previously we identified platelet subpopulations with a differential ability to produce NO based on the presence or absence of endothelial nitric oxide synthase (eNOS). eNOS expression is counter-regulated by cytokines, and COVID-19-associated immune/inflammatory responses may affect the transcriptome profile of megakaryocytes and their platelet progeny. ObjectivesWe investigated whether the percentage of eNOS-negative to eNOS-positive platelets increases in COVID-19 patients and whether this change may be due to the actions of pro-inflammatory cytokines on megakaryocytes. MethodsPlatelets were isolated from hospitalized COVID-19 patients and COVID-19-negative controls. Platelet eNOS was measured by flow cytometry and plasma inflammatory cytokines by ELISA. Megakaryocytes from eNOS-GFP transgenic mice and the Meg-01 cell line were characterized to identify an appropriate model to study eNOS-based platelet subpopulation formation in response to inflammatory cytokines. ResultsCOVID-19 patients demonstrated a significant increase in eNOS-negative and a concomitant decrease in eNOS-positive platelets compared to controls, and this change was associated with disease severity as assessed by ICU admission. A higher eNOS-negative to –positive platelet percentage was associated with enhanced platelet activation as measured by surface CD62P. Accordingly, COVID-19 patients demonstrated higher TNF-α, IL-6, and IL-1β plasma concentrations than controls. Inflammatory cytokines associated with COVID-19 promoted eNOS-negative Meg-01 formation and enhanced subsequent eNOS-negative platelet-like particle formation. ConclusionsCOVID-19 patients have a higher percentage of eNOS-negative to –positive platelets, likely as a result of inflammatory response reducing megakaryocyte eNOS expression, which predisposes to thrombosis.

Cytokine Storm in Pathogenesis of COVID-19 Complications

The aim. To explore the current literature and key findings concerning the cytokine storm contribution to pathogenesis of COVID-19 complications and mortality, and summarize clinical and pathologic features of cytokine storm in COVID-19 patients. A cytokine storm is a hyperinflammatory state secondary to excessive production of cytokines by deregulated immune system. It manifests clinically as an influenza-like syndrome, which can be complicated by multi-organ failure and coagulopathy, leading in most severe cases even to death. Cytokine storm has recently emerged as key aspect in COVID-19 disease, as affected patients show high levels of several key pro-inflammatory cytokines, some of which also correlate with disease severity. The current review describes the role of critical cytokines in COVID-19-mediated cytokine storm. Key findings of the studies are provided further. A cytokine storm is associated with COVID-19 severity and is also a crucial cause of death from COVID-19. Impaired acquired immune responses and uncontrolled inflammatory innate responses may be associated with the mechanism of cytokine storm in COVID-19. Cytokine storm is defined as acute overproduction and uncontrolled release of pro-inflammatory markers, both locally and systemically. In COVID-19 patients, pyroptosis triggers the release of proinflammatory cytokines and affects macrophage and lymphocyte functions, causing peripheral lymphopenia. Cytokine storm is characterized by a clinical presentation of overwhelming systemic inflammation, hyperferritinemia, hemodynamic instability, and multi-organ failure. The cytokine storm clinical findings are attributed to the action of pro-inflammatory cytokines like interleukin-1, interleukin-6, tumor necrosis factor alpha, vascular endothelial growth factor.

Peculiarities of the influence of recombinant cytokines on the functional activity of hematopoietic progenitor cells in myelodysplastic syndrome in vitro

Populations of hematopoietic progenitor cells are the closest descendants of stem cells. It is at their level that the processes of proliferation and differentiation occur, since they are sensitive, unlike stem cells, to the action of cytokines, which are released in the event of a shortage of blood cells in the periphery. However, for a long time the role of hematopoietic progenitor cells in the implementation of the pathological process in disorders of hematopoiesis was underestimated, while now it has turned out to be more significant than previously thought. This is especially true of myelodysplastic syndrome, which, despite its name, is a clonal disease that precedes acute leukemia. The purpose of the study was to determine the peculiarities of the functioning of hematopoietic progenitor cells in normal and impaired hematopoiesis at the initial stages of the malignant process of MDS (MDS-IB) under the conditions of exposure to different concentrations of cytokines to assess the hematopoietic potential of these cells. Their colony-forming activity (CFU) was studied in two groups of patients — control (10 people) and experimental (20 people) in culture in vitro. It was found that CFU increases with increasing concentration of cytokines and requires twice as much stimulus when culturing hematopoietic cells from patients with MDS-IB. The optimal concentration in the control for G-CSF, GM-CSF, IL-3 was 20 ng/ml, and for cells from patients with MDS-IB — 40 ng/ml. It has been proven that in the case of using a complex of cytokines (GM-CSF, G-CSF, IL-3), the colonyforming ability of progenitor cells from patients with MDS-IB increases significantly, compared to such indicators for cytokines acting alone (28.7±3.2 to 18.3±1.8, 12.1±1.5 and 24.5±2.1, respectively). The paper reveals the latent potential for cell proliferation from patients with MDS-IB, which can be used both in experimental studies and in the creation of protocols for the treatment of patients with MDS in the initial stage of the disease.

Pharmacologic inhibition of Il6st/gp130 improves dermatological inflammation and pruritus

Chronic dermatitis is a disease with large unmet need for pharmacological improvement. Dermatitis conditions are maintained and exacerbated by various cytokine actions in the context of inflammation. Interleukin 6 signal transducer (Il6st), also known as glycoprotein 130 (Gp130), is a key component for surface reception of a multitude of cytokines and transduction and amplification of their pro-inflammatory signals. We hypothesized accordingly that pharmacological inhibition of Il6st can alter dermatitis pathology. Treatment with SC-144 and bazedoxifene, two representative small molecule Il6st inhibitors with different binding modes led to moderate but significant improvement of skin conditions in a 1-chloro-2,4-dinitrobenzene animal model. Part of cytokine expressions indicating the dermatological index were normalized particularly when treated with SC-144. Pruritic behaviors were blunted, also possibly giving limited contribution to disease improvement. In psoriatic skin and itch of an imiquimod animal model, those two treatments appeared to be relatively moderate. Collectively, pharmacological inhibition of Il6st seems to lessen pathological irritation. Inversely, this experimental attempt newly implies that Il6st participates in pathological mechanisms. In conclusion, we suggest Il6st as a novel target for improving dermatitis, and that agents with suitable efficacy and safety for its modulation are translatable.

OxInflammatory Responses in the Wound Healing Process: A Systematic Review.

Significant sums are spent every year to find effective treatments to control inflammation and speed up the repair of damaged skin. This study investigated the main mechanisms involved in the skin wound cure. Consequently, it offered guidance to develop new therapies to control OxInflammation and infection and decrease functional loss and cost issues. This systematic review was conducted using the PRISMA guidelines, with a structured search in the MEDLINE (PubMed), Scopus, and Web of Science databases, analyzing 23 original studies. Bias analysis and study quality were assessed using the SYRCLE tool (Prospero number is CRD262 936). Our results highlight the activation of membrane receptors (IFN-δ, TNF-α, toll-like) in phagocytes, especially macrophages, during early wound healing. The STAT1, IP3, and NF-kβ pathways are positively regulated, while Ca2+ mobilization correlates with ROS production and NLRP3 inflammasome activation. This pathway activation leads to the proteolytic cleavage of caspase-1, releasing IL-1β and IL-18, which are responsible for immune modulation and vasodilation. Mediators such as IL-1, iNOS, TNF-α, and TGF-β are released, influencing pro- and anti-inflammatory cascades, increasing ROS levels, and inducing the oxidation of lipids, proteins, and DNA. During healing, the respiratory burst depletes antioxidant defenses (SOD, CAT, GST), creating a pro-oxidative environment. The IFN-δ pathway, ROS production, and inflammatory markers establish a positive feedback loop, recruiting more polymorphonuclear cells and reinforcing the positive interaction between oxidative stress and inflammation. This process is crucial because, in the immune system, the vicious positive cycle between ROS, the oxidative environment, and, above all, the activation of the NLRP3 inflammasome inappropriately triggers hypoxia, increases ROS levels, activates pro-inflammatory cytokines and inhibits the antioxidant action and resolution of anti-inflammatory cytokines, contributing to the evolution of chronic inflammation and tissue damage.

Nanomaterial strategies in wound healing: A comprehensive review of nanoparticles, nanofibres and nanosheets

AbstractWound healing is a complex process that orchestrates the coordinated action of various cells, cytokines and growth factors. Nanotechnology offers exciting new possibilities for enhancing the healing process by providing novel materials and approaches to deliver bioactive molecules to the wound site. This article elucidates recent advancements in utilizing nanoparticles, nanofibres and nanosheets for wound healing. It comprehensively discusses the advantages and limitations of each of these materials, as well as their potential applications in various types of wounds. Each of these materials, despite sharing common properties, can exhibit distinct practical characteristics that render them particularly valuable for healing various types of wounds. In this review, our primary focus is to provide a comprehensive overview of the current state‐of‐the‐art in applying nanoparticles, nanofibres, nanosheets and their combinations to wound healing, serving as a valuable resource to guide researchers in their appropriate utilization of these nanomaterials in wound‐healing research. Further studies are necessary to gain insight into the application of this type of nanomaterials in clinical settings.

Is there a role for essential fatty acids in osteoporosis?

Inflammatory markers are inversely associated with bone density, geometry, and strength in postmenopausal women, and elderly subjects suggesting that osteoporosis is a low-grade systemic inflammatory condition. But glucocorticoids that are potent anti-inflammatory compounds instead of arresting/preventing osteoporosis induce osteoporosis. These results indicate that IL-6 and TNF-α, post-menopausal state, and steroids produce osteoporosis by an unidentified mechanism. Pro-inflammatory cytokines, estrogen, and steroids bring about their actions by influencing the metabolism of essential fatty acids (EFAs). I propose that EFAs and their metabolites act as second messengers of actions of corticosteroids, cytokines, and estrogen. This implies that EFAs are of benefit in the prevention and management of osteoporosis. This argument is supported by the observation that plasma phospholipid content of unsaturated fatty acids is decreased in those with osteoporosis. The reports that long-chain metabolites of EFAs including arachidonic acid, docosahexaenoic acid and eicosapentaenoic acid, and lipoxin A4 are of benefit in the prevention and management of osteoporosis lends further support to this proposal.

Evaluation of interleukin-18 levels in patients affected by multiple myeloma and monoclonal gammopathy of undetermined significance: analysis and review of the literature.

Monoclonal gammopathy of undetermined significance (MGUS) is a preneoplastic disease that often precedes multiple myeloma. The multistep evolutionary pattern of multiple myeloma is driven by genetic instability, a pro-inflammatory and immunosuppressive microenvironment, and tumor growth. Inflammation has long been recognized as a factor in both the onset and progression of cancer. In this study, interleukin-18 plasma levels were compared in patients with multiple myeloma and monoclonal gammopathy of undetermined significance, as well as in a group of healthy controls. Our study shows that monoclonal gammopathy of undetermined significance patients have lower levels of interleukin-18 than healthy controls (521.657 ± 168.493 pg/ml vs. 1,266.481 ± 658.091 pg/ml for controls, p < 0.001). Thus, we discovered a significant difference in interleukin-18 levels between multiple myeloma patients and controls (418.177 ± 197.837 pg/ml; p = 0.001). In our work, we identified a reduction of interleukin-18 in monoclonal gammopathies. Furthermore, in this paper, we aimed to evaluate the existing literature on the potential mechanisms of action of this pro-inflammatory cytokine in the development of these diseases.

Direct assessment of leukocyte signalling and cytokine secretion reveals exercise intensity-dependent reductions in anti-inflammatory cytokine action.

Circulating interleukin (IL)-6 and IL-10 concentrations are widely used to evaluate the anti-inflammatory effects of exercise but do not capture cytokine action at the cellular level. Whether and how acute exercise impacts anti-inflammatory cytokine action in humans is unknown. To determine how exercise intensity and pattern impact IL-6 and IL-10 action in blood leukocytes, 16 active adults (eight males/eight females; age: 30±3years; body mass index: 22.8±2.3kg/m2; : 51±6mL/kg/min) completed a no-exercise control condition (CTL) or isocaloric bouts of cycling performed below (moderate continuous exercise; MCE) or above (heavy continuous or heavy intermittent exercise; HCE or HIE, respectively) lactate threshold. Venous blood (before, after, 30min after and 90min after exercise) was analysed for immune cell subpopulations, plasma cytokine concentrations, anti-inflammatory cytokine action and monocyte phenotype. Exercise induced rapid leukocytosis (P<0.001) and increased plasma IL-6 (P<0.001), IL-10 (P=0.0145) and tumour necrosis factor-⍺ (TNF-⍺) (P=0.0338) concentrations in an intensity-dependent manner (HCE and/or HIE vs. CTL). These systemic changes coincided with a diminished ability of IL-10/6 to phosphorylate STAT3 (P<0.001) and inhibit TNF-⍺ secretion (P=0.0238) in blood leukocytes following HCE and HIE. Monocyte polarization experiments revealed lower CD80 [MCE (P=0.0933) and HIE (P=0.0187) vs. CTL] and a tendency for higher CD163 expression (HCE vs. CTL, P=0.0985), suggesting that hyporesponsiveness to anti-inflammatory cytokine action does not impede the ability of exercise to promote an anti-inflammatory monocyte phenotype. These findings provide novel insights into the immunomodulatory effects of exercise in humans and highlight the importance of directly measuring cellular cytokine action when evaluating the anti-inflammatory effects of exercise. KEY POINTS: Circulating cytokine concentrations are frequently used to evaluate the anti-inflammatory effects of exercise but may not capture changes in cytokine action occurring at the cellular level. We directly assessed anti-inflammatory cytokine action - measured using a combination of intracellular signalling and cytokine secretion ex vivo - in distinct immune cell subpopulations after acute calorie-matched exercise bouts differing in intensity and pattern. Anti-inflammatory cytokine action was blunted following higher intensity exercise despite corresponding increases in circulating cytokine concentrations and immune cell counts. Changes in cytokine action were not explained by changes in cytokine receptor expression on circulating immune cells. Our findings provide new insights into the immunomodulatory effects of exercise in humans and highlight the importance of directly measuring cellular cytokine action when evaluating the anti-inflammatory effects of exercise.

β-Cell-selective regulation of gene expression by nitric oxide.

Nitric oxide is produced at low micromolar levels following the induction of inducible nitric oxide synthase (iNOS) and is responsible for mediating the inhibitory actions of cytokines on glucose-stimulated insulin secretion by islets of Langerhans. It is through the inhibition of mitochondrial oxidative metabolism, specifically aconitase and complex 4 of the electron transport chain, that nitric oxide inhibits insulin secretion. Nitric oxide also attenuates protein synthesis, induces DNA damage, activates DNA repair pathways, and stimulates stress responses (unfolded protein and heat shock) in β-cells. In this report, the time- and concentration-dependent effects of nitric oxide on the expression of six genes known to participate in the response of β-cells to this free radical were examined. The genes included Gadd45α (DNA repair), Puma (apoptosis), Hmox1 (antioxidant defense), Hsp70 (heat shock), Chop (UPR), and Ppargc1α (mitochondrial biogenesis). We show that nitric oxide stimulates β-cell gene expression in a narrow concentration range of ∼0.5-1 µM or levels corresponding to iNOS-derived nitric oxide. At concentrations greater than 1 µM, nitric oxide fails to stimulate gene expression in β-cells, and this is associated with the inhibition of mitochondrial oxidative metabolism. This narrow concentration range of responses is β-cell selective, as the actions of nitric oxide in non-β-cells (α-cells, mouse embryonic fibroblasts, and macrophages) are concentration dependent. Our findings suggest that β-cells respond to a narrow concentration range of nitric oxide that is consistent with the levels produced following iNOS induction, and that these concentration-dependent actions are selective for insulin-containing cells.

TNFR1 Absence Is Not Crucial for Different Types of Cell Reaction to TNF: A Study of the TNFR1-Knockout Cell Model.

One of the mechanisms regulating the biological activity of tumor necrosis factor (TNF) in cells is the co-expression of TNFR1/TNFR2 receptors. A model with a differential level of receptor expression is required to evaluate the contribution of these mechanisms. The development of a cellular model to compare the effects of TNF on cells depending on the presence of both receptors and TNFR2 alone. TNFR1 absence modifications of ZR-75/1 and K-562 cell lines were obtained by TNFR1 knockout. The presence of deletions was confirmed by Sanger sequencing, and the absence of cell membrane receptor expression was confirmed by flow cytometry. The dose-dependent effect of TNF on intact and knockout cells was comparatively evaluated by the effect on the cell cycle, the type of cell death, and the profile of expressed genes. Knockout of TNFR1 resulted in a redistribution of TNFR2 receptors with an increased proportion of TNFR2+ cells in both lines and a multidirectional change in the density of expression in the lines (increased in K562 and decreased in ZR75/1). The presence of a large number of cells with high TNFR2 density in the absence of TNFR1 in the K562 cells was associated with greater sensitivity to TNF-stimulating doses and increased proliferation but did not result in a significant change in cell death parameters. A twofold increase in TNFR2+ cell distribution in this cell line at a reduced expression density in ZR75/1 cells was associated with a change in sensitivity to low cytokine concentrations in terms of proliferation; an overall increase in cell death, most pronounced at standard stimulating concentrations; and increased expression of the lymphocyte-activation gene groups, host-pathogen interaction, and innate immunity. The absence of TNFR1 leads to different variants of compensatory redistribution of TNFR2 in cellular models, which affects the type of cell response and the threshold level of sensitivity. The directionality of cytokine action modulation and sensitivity to TNF levels depends not only on the fraction of cells expressing TNFR2 but also on the density of expression.

Mechanisms and therapeutic research progress in intestinal fibrosis.

Intestinal fibrosis is a common complication of chronic intestinal diseases with the characteristics of fibroblast proliferation and extracellular matrix deposition after chronic inflammation, leading to lumen narrowing, structural and functional damage to the intestines, and life inconvenience for the patients. However, anti-inflammatory drugs are currently generally not effective in overcoming intestinal fibrosis making surgery the main treatment method. The development of intestinal fibrosis is a slow process and its onset may be the result of the combined action of inflammatory cells, local cytokines, and intestinal stromal cells. The aim of this study is to elucidate the pathogenesis [e.g., extracellular matrix (ECM), cytokines and chemokines, epithelial-mesenchymal transition (EMT), differentiation of fibroblast to myofibroblast and intestinal microbiota] underlying the development of intestinal fibrosis and to explore therapeutic advances (such as regulating ECM, cytokines, chemokines, EMT, differentiation of fibroblast to myofibroblast and targeting TGF-β) based on the pathogenesis in order to gain new insights into the prevention and treatment of intestinal fibrosis.

Therapeutic Applications of Ginseng Natural Compounds for Health Management.

Ginseng is usually consumed as a daily food supplement to improve health and has been shown to benefit skeletal muscle, improve glucose metabolism, and ameliorate muscle-wasting conditions, cardiovascular diseases, stroke, and the effects of aging and cancers. Ginseng has also been reported to help maintain bone strength and liver (digestion, metabolism, detoxification, and protein synthesis) and kidney functions. In addition, ginseng is often used to treat age-associated neurodegenerative disorders, and ginseng and ginseng-derived natural products are popular natural remedies for diseases such as diabetes, obesity, oxidative stress, and inflammation, as well as fungal, bacterial, and viral infections. Ginseng is a well-known herbal medication, known to alleviate the actions of several cytokines. The article concludes with future directions and significant application of ginseng compounds for researchers in understanding the promising role of ginseng in the treatment of several diseases. Overall, this study was undertaken to highlight the broad-spectrum therapeutic applications of ginseng compounds for health management.

ROS-Driven Structural and Functional Fibrinogen Modifications Are Reverted By JAK Inhibition in Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPNs) are bone marrow diseases characterized by excess clonal hematopoiesis resulting in elevated peripheral blood counts. Subtypes include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). They share clinical features (e.g., splenomegaly, thrombotic complications, risk of leukemic transformation), and a common molecular basis: the dysregulation of the JAK-STAT pathway, which confers a hypersensitivity of hematopoietic stem cells (HSC) to the action of growth factors and cytokines, and, as a result, an overproduction of blood cells. Genetic analysis of patients with MPNs revealed that &amp;gt;95% of patients with PV and about 50% of patients with ET or PMF carry an activating point mutation in the JAK2 gene (JAK2-V617F). Despite clinical evidence indicating a higher susceptibility of MPN patients to develop thrombotic disease, the underlying pathogenetic mechanisms are not fully understood. It appears that thrombosis is the result of a severe inflammatory response associated to remarkable oxidative stress in the presence of endothelial dysfunction and a procoagulant environment. Hypercoagulability is a consequence of disrupted hemostasis and fibrinolysis due to damage of the endothelium and defective fibrinolysis. Evidence suggests that overproduction of ROS and a deprived antioxidant system play a major role in the pathogenesis of MPN, as well as in the resistance to tyrosine-kinase inhibitor therapy. Moreover, systemic inflammation is thought to be the main trigger of thrombosis and seems to be mainly mediated by pro-inflammatory cytokines along with endothelial cell dysfunction. Recent studies have provided evidence that fibrinogen plays a multifaceted role in inflammatory responses and autoimmunity. The ability of fibrinogen to participate in the inflammatory response depends on its specific interaction with integrins, the leukocyte cell surface adhesion receptors expressed on neutrophils, monocytes, macrophages, and several subsets of lymphocytes. In MPN patients, endothelial cell dysfunction, increased reactive oxygen species (ROS) production, and proinflammatory cytokines have been reported, together with impaired fibrinolysis. We also investigated the potential role of oxidative stress and inflammation in the promotion of thrombosis. In order to study the mechanisms of inflammation-induced thrombosis in MPN patients, the aim of the present study was to investigate the role of oxidation-induced structural and functional fibrinogen modifications in MPN patients. The eventual counteracting effects of ruxolitinib, a first-in-class JAK inhibitor, were also assessed. 40 MPN patients and 40 age- and sex-matched healthy control subjects were included in the study. We measured specific oxidative stress markers andtheir modifications in plasma, and functional and structural parameters in purified fibrinogen fractions. Marked signs of oxidative stress in plasma (P&amp;lt;0.01 versus controls) and, correspondingly, an increased extent of fibrinogen oxidation (P&amp;lt;0.01 versus controls) were observed in patients. Furthermore, fibrinogen fractions purified from MPN patients exhibited significantly reduced clotting ability and decreased susceptibility to plasmin-induced lysis (P&amp;lt;0.01 versus controls). Alterations in fibrinogen secondary structure, as suggested by circular dichroism spectroscopy, and in fibrin clot architecture were also identified. Importantly, clot structure obtained by stimulated emission depletion (STED) super-resolution microscopy indicated modifications in fiber diameter and clot porosity in MPN patients (P&amp;lt;0.01 versus controls). In patient samples, fibrinogen clot analysis and oxidative-dependent changes reveal novel structural and functional fibrinogen modifications which may favor thrombotic complications in MPNs. In patients receiving ruxolitinib, a significant improvement in redox status was observed, accompanied by a significant improvement in fibrinogen structural and functional features, suggesting a potential impactof ruxolitinib on cardiovascular prevention in MPNs.

Protective effects and mechanisms of Momordica charantia polysaccharide on early-stage diabetic retinopathy in type 1 diabetes

Momordica charantia polysaccharide (MCP) is a potential drug for the prevention and alleviation of diabetes mellitus (DM) and diabetic retinopathy (DR). This study aimed to investigate the potential protective effects of MCP on early-stage DR and explore the underlying mechanisms. The model group (DM group) and treatment group (D+H group) were established by inducing type 1 DM using a single dose of streptozotocin (STZ) at 60 mg/kg. After modeling, the D+H group was orally administered a 500 mg/kg dose of MCP solution once daily for 12 weeks. Monitoring of systemic indicators (FBG, body weight, general condition) and retinal tissue inflammation and apoptosis (HE staining, IL-6, MCP-1, TNF-α, VEGF, NF-κB, Caspase-3) in this study demonstrated that MCP intervention alleviated both DM and DR. MCP improved the body weight and general condition of DM rats by reducing FBG levels. It also enhanced the anti-inflammatory and anti-apoptotic capabilities of retinal neurons and microvessels by modulating the actions of cytokines, thereby further regulating the inflammation and apoptosis of retinal neurons and microvessels. The underlying mechanisms may be associated with the downregulation of NF-κB and Caspase-3 pathway protein expression, as well as the downregulation of mRNA expression of NF-κB and Caspase-3 pathway genes. Further research is needed to elucidate the potential mechanisms underlying the protective effects of MCP on DR. MCP may emerge as a selective medication for the prevention and alleviation of DM and a novel natural medicine for the prevention and alleviation of DR.