Activation Of Proinflammatory Cytokines Research Articles

Unraveling the Pathways: A Meta-Analysis Exploring the Biopsychosocial Mechanisms Linking Psychosomatic Symptoms and Systemic Lupus Erythematosus

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a complex interplay of biological, psychological, and social factors. Psychosomatic symptoms, such as depression, anxiety, and stress, are common in individuals with SLE and can significantly impact disease activity and overall well-being. This meta-analysis aims to explore the biopsychosocial mechanisms linking psychosomatic symptoms and SLE. Methods: A systematic search of PubMed, Embase, PsycINFO, and Web of Science databases was conducted from January 2013 to December 2024. Studies examining the relationship between psychosomatic symptoms and SLE were included. Data were extracted and analyzed using random-effects models to calculate pooled effect sizes. Results: Six studies met the inclusion criteria. The meta-analysis revealed a significant association between psychosomatic symptoms (depression, anxiety, and stress) and SLE disease activity (pooled effect size: r = 0.42, 95% CI: 0.31-0.53, p < 0.001). Furthermore, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, pro-inflammatory cytokine activity, and impaired coping mechanisms emerged as key biopsychosocial pathways linking these factors. Conclusion: This meta-analysis highlights the significant impact of psychosomatic symptoms on SLE and identifies potential underlying mechanisms. These findings underscore the need for integrated biopsychosocial interventions in SLE management, targeting both physical and psychological well-being to improve patient outcomes.

Health Implications of Proinflammatory Cytokine Activity at Different Levels of Fluoride Exposure: A Systematic Review.

The chronic intake of excessive fluoride (F-) (> 1.5 mg/L) affects several tissues, organs, and systems. This represents a worldwide issue due to the presence of the compound in nature, with drinking water being the main source of exposure. The underlying mechanisms by which F- is toxic are not completely understood, but proinflammatory cytokine activity is implicated in these events. The aim of this study was to perform a systematic review of the health implications of proinflammatory cytokine activity at different levels of F- exposure. The search for original studies in which the activity of proinflammatory cytokines was assessed under exposure to F- was performed using the PubMed, Scopus, Springer, EBSCO, and Google Scholar databases by applying the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The study protocol was registered with PROSPERO (CRD42024546726). Sixteen studies were analyzed in the present review. Tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1 beta (β), IL-6, IL-2, IL-12, IL-17, IL-18, C-reactive protein, and transforming growth factor-β (TGF-β) were the proinflammatory cytokines identified in the included reports. Alterations in cytokine activity were observed in response to varying levels of F- exposure, implicating an increased risk of toxicity and damage to the evaluated structures by highlighting the role of inflammation in the progression of these processes. Hence, the activity of proinflammatory cytokines at different levels of F- exposure has important implications for health, where inflammation plays a relevant role in the underlying mechanisms related to the resulting toxicity.

Physical inactivity exacerbates pathologic inflammatory signalling at the single cell level in patients with systemic lupus

Physical activity is an adjunctive therapy that improves symptoms in people living with systemic lupus erythematosus (SLE), yet the mechanisms underlying this benefit remain unclear. We carried out a cohort study of 123 patients with SLE enrolled in the California Lupus Epidemiology Study (CLUES). The primary predictor variable was self-reported physical activity, which was measured using a previously validated instrument. We analyzed peripheral blood mononuclear cell (PBMC) single-cell RNA sequencing (scRNA-seq) data available from the cohort. From the scRNA-seq data, we compared immune cell frequencies, cell-specific gene expression, biological signalling pathways, and upstream cytokine activation states between physically active and inactive patients, adjusting for age, sex and race. We found that physical activity influenced immune cell frequencies, with sedentary patients most notably demonstrating greater CD4+ T cell lymphopenia (Padj=0.028). Differential gene expression analysis identified a transcriptional signature of physical inactivity across five cell types. In CD4+ and CD8+ T cells, this signature was characterized by 686 and 445 differentially expressed genes (Padj<0.1). Gene set enrichment analysis demonstrated enrichment of proinflammatory genes in the TNF-α signalling through NF-kB, interferon-γ (IFN-γ), IL2/STAT5, and IL6/JAK/STAT3 signalling pathways. Computational prediction of upstream cytokine activation states suggested CD4+ T cells from physically inactive patients exhibited increased activation of TNF-α, IFN-γ, IL1Β, and other proinflammatory cytokines. Network analysis demonstrated interconnectivity of genes driving the proinflammatory state of sedentary patients. Findings were consistent in sensitivity analyses adjusting for corticosteroid treatment and physical function. Taken together, our findings suggest a mechanistic explanation for the observed benefits of physical activity in patients with SLE. Specifically, we find that physical inactivity is associated with altered frequencies and transcriptional profiles of immune cell populations and may exacerbate pathologic inflammatory signalling via CD4+ and CD8+ T cells. This work was supported by the US National Institutes of Health (NIH) (R01 AR069616, K23HL138461-01A1, K23AT011768) the US CDC (U01DP0670), and the CZ Biohub.

Cell therapy for a rare disease- hairy cell leukemia variant

ABSTRACT Hairy cell leukemia variant (HCL-v) is a rare malignancy of clonal mature B-cells that follows a chronic disease course. HCL-v patients are often resistant to purine nucleoside analogs, which are the first-line therapy. To address the shortcomings of current therapy for HCL-v, we investigated the activity of a BAFF ligand-based CAR-T cell which binds to all three BAFF receptors, BAFF-receptor, TACI, and BCMA. Here, we demonstrate that HCLv patient-derived cells highly express all three BAFF receptors and that BAFF CAR-T cells induce significant cytotoxicity in vitro against both cell lines and HCL-v patient cells. This cytotoxicity corresponds with significant CAR-T cell activation, degranulation, and release of pro-inflammatory cytokines after co-incubation with HCLv cells. Furthermore, we successfully generated BAFF CAR-T cells directly from an HCLv patient and observed direct autologous killing against patient tumor cells in vitro. These HCLv patient-derived CAR-T cells were also effective in killing the Hair-M cell line and tumor cells derived from a different HCLv patient. Lastly, we also developed two mouse xenograft models for HCL, a subcutaneous Bonna-12 model and intravenous Hair-M xenograft model. We observed decreases in tumor burden and prolonged overall survival without significant toxicity. In conclusion, here we show that BAFF CAR-T cells exert anti-tumor effects in vitro and in vivo against multiple cell lines and patient-derived HCL-v samples and may be a successful therapeutic strategy for HCLv patients.

Abstract B042: The impact of opioids on the pancreatic tumor immune microenvironment

Abstract Pancreatic cancer is a highly lethal malignancy with a 5-year survival rate of 12.8%. Due to the high prevalence of cancer-related pain, 75% of pancreatic cancer patients are prescribed opioids. Opioids, which signal through the G protein-coupled receptor (GPCR) mu-opioid receptor (MOR), have peripheral effects outside of their analgesic function. Importantly, several studies have correlated opioids with worsened survival of patients receiving immunotherapy. However, the mechanism behind this is unknown. Immunotherapy is largely ineffective in pancreatic cancer, due in part to the tumor microenvironment (TME) characterized by dense, desmoplastic stroma, with cancer-associated fibroblasts (CAFs) comprising up to 90% of the tumor volume. CAFs play a large role in immunosuppression and therapy resistance, such as through promoting infiltration of immunosuppressive cells, resulting in reduced presence of antitumor immune cells and impaired immunotherapy efficacy. While the role of CAFs in promoting immunosuppression in the tumor microenvironment is well characterized, the effect of opioids on this phenomenon is unknown. We now provide evidence that MOR directly regulates CAF function. Specifically, knockdown of MOR in CAFs reduces gene expression of alpha-smooth muscle actin (aSMA) and leukemia inhibitory factor. MOR knockdown in CAFs also decreases protein expression of aSMA and type 1a collagen. We hypothesize that opioids promote MOR-dependent CAF activation and secretion of pro-inflammatory cytokines, resulting in a more immunosuppressive TME, and thus impaired immunotherapy response. The long-term goal of this work is to determine the role of opioids on CAFs in the pancreatic TME, as well as the role of MOR in promoting immunosuppression and the resulting value of MOR as a target to improve immunotherapy efficacy. This research is clinically significant because it could uncover a novel mechanism driving immunosuppression caused by a medication commonly prescribed to almost all pancreatic cancer patients. Citation Format: Kathryn Maraszek, Michael Feigin. The impact of opioids on the pancreatic tumor immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B042.

Preclinical characterization of MTX-101: a novel bispecific CD8 Treg modulator that restores CD8 Treg functions to suppress pathogenic T cells in autoimmune diseases.

Regulatory CD8 T cells (CD8 Treg) are responsible for the selective killing of self-reactive and pathogenic CD4 T cells. In autoimmune disease, CD8 Treg may accumulate in the peripheral blood but fail to control the expansion of pathogenic CD4 T cells that subsequently cause tissue destruction. This CD8 Treg dysfunction is due in part to the expression of inhibitory killer immunoglobulin-like receptors (KIR; KIR2DL isoforms [KIR2DL1, KIR2DL2, and KIR2DL3]); these molecules serve as autoimmune checkpoints and limit CD8 Treg activation. Here we describe the pre-clinical characterization of MTX-101, a bispecific antibody targeting inhibitory KIR and CD8. Using human peripheral blood mononuculear cells (PBMC) derived from healthy donors and autoimmune patients, humanized mouse models, and human derived tissue organoids, we evaluated the molecular mechanisms and functional effects of MTX-101. By binding to KIR, MTX-101 inhibited KIR signaling that can restore CD8 Treg ability to eliminate pathogenic CD4 T cells. MTX-101 bound and activated CD8 Treg in human peripheral blood mononuclear cells (PBMC), resulting in increased CD8 Treg cytolytic capacity, activation, and prevalence. Enhancing CD8 Treg function with MTX-101 reduced pathogenic CD4 T cell expansion and inflammation, without increasing pro-inflammatory cytokines or activating immune cells that express either target alone. MTX-101 reduced antigen induced epithelial cell death in disease affected tissues, including in tissue biopsies from individuals with autoimmune disease (i.e., celiac disease, Crohn's disease). The effects of MTX-101 were specific to autoreactive CD4 T cells and did not suppress responses to viral and bacterial antigens. In a human PBMC engrafted Graft versus Host Disease (GvHD) mouse model of acute inflammation, MTX-101 bound CD8 Treg and delayed onset of disease. MTX-101 induced dose dependent binding, increased prevalence and cytolytic capacity of CD8 Treg, as well as increased CD4 T cell death. MTX-101 selectively bound CD8 Treg without unwanted immune cell activation or increase of pro-inflammatory serum cytokines and exhibited an antibody-like half-life in pharmacokinetic and exploratory tolerability studies performed using IL-15 transgenic humanized mice with engrafted human lymphocytes, including CD8 Treg at physiologic ratios. Collectively, these data support the development of MTX-101 for the treatment of autoimmune diseases.

Delayed macrophage targeting by clodronate liposomes worsens the progression of cytokine storm syndrome.

Excessive macrophage activation and production of pro-inflammatory cytokines are hallmarks of the Cytokine Storm Syndrome (CSS), a lethal condition triggered by sepsis, autoimmune disorders, and cancer immunotherapies. While depletion of macrophages at disease onset protects from lethality in an infection-induced CSS murine model, patients are rarely diagnosed early, hence the need to characterize macrophage populations during CSS progression and assess the therapeutic implications of macrophage targeting after disease onset. In this study, we identified MHCII+F4/80+Tim4- macrophages as the primary contributors to the pro-inflammatory environment in CSS, while CD206+F4/80+Tim4+ macrophages, with an anti-inflammatory profile, become outnumbered. Additionally, we observed an expansion of Tim4- macrophages coinciding with increased hematopoietic stem progenitor cells and reduction of committed myeloid progenitors in bone marrow and spleen. Critically, macrophage targeting with clodronate liposomes at disease onset prolonged survival, while their targeting in mice with established CSS exacerbated disease severity, leading to a more dramatic loss of Tim4+ macrophages and an imbalance in pro- versus anti-inflammatory Tim4- macrophage ratio. Our findings highlight the significance of timing in macrophage-targeted interventions for effective management of CSS and suggest potential therapeutic strategies for diseases characterized by uncontrolled inflammation, such as sepsis.

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.

Inhibition of NLRP3 inflammasome contributes to paclitaxel efficacy in triple negative breast cancer treatment.

Chronic inflammation and NLRP3 inflammasome activation are among the determining factors of breast malignancies. Paclitaxel (PTX) is a drug used in breast cancer treatment which sustains prolonged inflammation, reducing the effectiveness of chemotherapy. Considering the impact of inflammatory processes in cancer progression, there is a strong concern to develop therapeutic strategy targeting NLRP3 inflammasome for triple-negative breast cancer (TNBC) treatment. Therefore, the aim of this study was to evaluate the potential of PTX and NLRP3 inflammasome modulation to counterbalance TNBC by inducing programmed cell death and inhibiting the activity of pro-inflammatory cytokines. The obtained results suggested the strong interaction between NLRP3 inflammasome and TNBC and revealed that pharmacological inhibition, using NLRP3-specific inhibitor MCC950, and genetic silencing of NLRP3 inflammasome using specific small interfering RNA, reduced inflammatory responses and facilitated PTX-determined tumor cell death. Thus, NLRP3 inflammasome manipulation in combination with anti-tumor drugs opens up new therapeutic perspectives for TNBC therapy.

Enhanced Effect of β-Lactoglobulin Immunization in Mice with Mild Intestinal Deterioration Caused by Low-Dose Dextran Sulphate Sodium: A New Experimental Approach to Allergy Studies.

Cow's milk allergy is one of the most common food allergies in children, and its pathomechanism is still under investigation. Recently, an increasing number of studies have linked food allergy to intestinal barrier dysfunction. The present study aimed to investigate changes in the intestinal microenvironment during the development of β-lactoglobulin (β-lg) allergy under conditions of early intestinal dysfunction. BALB/c mice received intraperitoneal β-lg with Freund's adjuvant, followed by oral β-lg while receiving dextran sulphate sodium salt (DSS) in their drinking water (0.2% w/v). The immunized group without DSS and the groups receiving saline, oral β-lg, or DSS served as controls. The study showed that the immunization effect was greater in mice with mild intestinal barrier dysfunction. Although DSS did not affect the mice's humoral response to β-lg, in combination with β-lg, it significantly altered their cellular response, affecting the induction and distribution of T cells in the inductive and peripheral tissues and the activation of immune mediators. Administration of β-lg to sensitized mice receiving DSS increased disease activity index (DAI) scores and pro-inflammatory cytokine activity, altered the distribution of claudins and zonulin 1 (ZO-1) in the colonic tissue, and negatively affected the balance and activity of the gut microbiota. The research model used appears attractive for studying food allergen sensitization, particularly in relation to the initial events leading to mucosal inflammation and the development of food hypersensitivity.

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.

Methyltransferase METTL3 regulates neuropathic pain through m6A methylation modification of SOCS1

The mechanisms of neuropathic pain (NP) are considered multifactorial. Alterations in the suppressor of cytokine signaling 1 (SOCS1) play a critical role in neural damage and inflammation. Epigenetic RNA modifications, specifically N6-methyladenosine (m6A) methylation, have increasingly been observed to impact the nervous system. Nevertheless, there is a scarcity of studies investigating the connection between m6A methylation and SOCS1 in the molecular mechanisms of NP. This study investigates the roles and potential mechanisms of the m6A methyltransferase like 3 (METTL3) and SOCS1 in female rats with spinal nerve ligation (SNL)-induced NP. It was found that in NP, both METTL3 and overall m6A levels were downregulated, leading to the activation of pro-inflammatory cytokines, such as interleukin-1β, interleukin 6, and tumor necrosis factor-α. Notably, The SOCS1 mRNA is significantly enriched with m6A methylation modifications, with the most prevalent m6A methyltransferase METTL3 stabilizing the downregulation of SOCS1 by targeting m6A methylation modifications at positions 151, 164, and 966.Exogenous supplementation of METTL3 improved NP-related neuroinflammation and behavioral dysfunctions, but these effects could be reversed by the absence of SOCS1. Additionally, the depletion of endogenous SOCS1 promoted NP progression by inducing the toll-like receptor 4 (TLR4) signaling pathway. The dysregulation of METTL3 and the resulting m6A modification of SOCS1 form a crucial epigenetic regulatory loop that promotes the progression of NP. Targeting the METTL3/SOCS1 axis might offer new insights into potential therapeutic strategies for NP.

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.

A cationic hydrogel with anti-IL-17A-specific nanobodies for rheumatoid arthritis treatment via inhibition of inflammatory activities of neutrophils

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease primarily driven by inappropriate infiltration and activation of immune cells and pro-inflammatory cytokines. Among them, neutrophils with high plasticity play a pathogenic role in RA by abnormal neutrophil immune activities. As anti-IL-17A therapies failed to achieve long-term ideal therapeutic outcomes in clinical trials, we speculated that the underlying cause may be associated with the abnormal activity of neutrophils that have a direct link to IL-17A. Herein, we created a cationic hydrogel loaded with anti-IL-17A nanobodies (Nbs) capable of synergistically weakening the inflammatory activities of neutrophils and relieving inflammation in RA. Based on the host-guest interaction, the hydrogel was comprised of β-cyclodextrin-modified hyperbranched polylysine (HBPL-CD) and adamantane-modified hyaluronic acid (HA-Ad). The physical properties were adjusted to match the mechanical environment of joints and enable injection. The hydrogel with Nbs could adsorb cell-free DNA (cfDNA) persistently and slowly release anti-IL-17A Nbs, which synergistically alleviated the inflammatory activities of neutrophils via inhibiting the IL-17A stimulated neutrophil extracellular traps (NETs) of neutrophils from RA patients and mice with collagen-induced arthritis (CIA), reducing the level of pro-inflammatory cytokines, and suppressing the inflammatory phenotype of neutrophils in vitro. The ankle injection of the hydrogel with Nbs into a mouse model of CIA could alleviate the RA symptoms in vivo. This novel platform is believed to provide a guideline for treating IL-17A-related diseases by combining Nbs with the immunoregulation of neutrophils.

Acute immune system activation exerts time-dependent effects on inhibitory control: Results of both a randomized controlled experiment of influenza vaccination and a systematic review and meta-analysis – ISPNE 2024 Dirk Hellhammer Award

Although coming down with an illness or receiving a vaccine are both common experiences, the influence of such acute immune system activations on cognitive processes, such as inhibitory control, has received relatively little attention. We addressed that issue by assessing the effects of acute immune system activation on inhibitory control in a randomized controlled experiment, and by conducting a meta-analysis of similar studies in humans. In our experiment, we found—somewhat surprisingly—that influenza vaccination improved performance on both of our inhibitory control outcomes (i.e., stop-signal reaction times and flanker interference effects). At the meta-analytic level, we found that at a short delay (1.5–4 hours post-injection) between immune activation and inhibitory control assessment, such activation impaired multiple forms of inhibitory control, whereas after a longer delay (e.g., > 18 hours post-injection), such activation improved inhibitory control—consistent with our experiment. Moreover, proinflammatory cytokine activity predicted poorer interference control but better response inhibition, even with a long delay between injection and testing. Together, these results highlight nuanced, time-dependent, and—perhaps—multiple-mechanism-driven effects of acute immune system activity on inhibitory control.

Prospects for the Use of Thymoquinone (a Component of Nigella sativa) in the Prevention and Therapy of Neuropathologies

Black cumin and its component thymoquinone (TQ) are known as drugs with a wide range of pharmacological activities: immunomodulating, anti-inflammatory, antimicrobial, antiviral, antineoplastic properties. These drugs also have neuroprotective properties in neurodegenerative diseases (Alzheimer's, Parkinson's), ischaemia, epilepsy, encephalomyelitis, traumatic brain injury. The main mechanisms of action are antioxidant activity increased expression of neuroprotective genes and proteins with decreased activity of pro-inflammatory cytokines and the NF-кB pathway, which plays a key role in neuroinflammation. A separate section is devoted to the effects of black cumin and TQ on the course of depression, a common and socially significant illness. Reduced signs of depression and increased levels of a neuroprotective factor belonging to the neutrophin family (BDNF), a characteristic marker of depression, were described in 54 depressed patients. The review discusses the prospects for prevention and therapy with these drugs in central nervous system pathology.

Possible Correlation between Mucin Gene Expression and Symptoms of Dry Eye Syndrome Secondary to Sjogren’s Disease

(1) Background: It is estimated that 10% of dry eye disease (DED) occurs in patients with Sjogren’s syndrome (SS-DED) and represents a challenge when it comes to treatment. Both innate and adaptive immunity participate in the pathogenesis of SS-DED. Previous studies suggest that Th1 and Th17 cell immune responses are the main actors associated with the pathogenesis of this disease. Ocular surface mucins play a fundamental role in ocular surface homeostasis. In particular, the main transmembrane mucins, MUC1, MUC4 and MUC16, are dysregulated in DED and could be involved in the activation of pro-inflammatory cytokines at the ocular interface. Thus, the objective of this work was to analyze mucin and cytokine expression in ocular surface (OS) damage and correlate it with clinical symptoms.; (2) Methods: 18 patients with SS-DED and 15 healthy controls were included in the study. Samples of conjunctival cells were obtained through cytology impression. RNA was extracted from the collected samples and used to determine the expression of MUC1, 4 and 16 by qRT-PCR. Pro-inflammatory cytokines associated with DED pathogenesis (IL17 and IL-22) were also evaluated. The results were contrasted with the clinical findings on examination of the patients. (3) Results: We observed a significant increase in the expression of MUC1 and MUC4 in patients with SS-DED. MUC4 significantly correlated with both lower production and stability of the tear film, as well as greater superficial keratopathy. On the other hand, MUC1 and MUC16 were positively correlated with the presence of more severe DED symptoms. However, we could not reproduce an increase in IL-17 and IL-22 in DED patients as previously reported; (4) Conclusions: This work constitutes an approach to understanding how the gene expression of transmembrane mucins associates with SS-DED symptoms and clinical signs.

Oropharyngeal Cancer in a Thalassemic Patient: Role of Iron Overload in Carcinogenesis

ABSTRACT The thalassemia syndromes are inherited α and β globin biosynthesis disorders. Patients with β thalassemia major require intensive blood transfusions to survive. Chronic blood transfusions can lead to blood-borne infections, alloimmunization, febrile reactions, and lethal iron overload. With the recent advances in treatment approaches and improvements in chelation therapy, thalassemic patients are living longer. Because of this, new complications are emerging, the majority of which are related to the treatment, and few are related to the primary pathology. One of the rarely reported complications is malignancy. The role of iron in carcinogenesis is still debatable. The role of iron in colorectal, liver, kidney, lung, and stomach cancer either as a cancer initiator or as a promoter is well documented. The most probable causes are iron autooxidation, pro-inflammatory cytokines activation of oxidative responsive transcription factors, and iron-induced hypoxia signaling. However, there is hardly any literature mentioning the role of iron in head-and-neck cancers. We report a case of oropharyngeal cancer in a thalassemia patient and discuss the possibility of association between the two diseases with emphasis on the aggressiveness of the cancer in the background of thalassemia and iron overload.

Neuroprotective Effects of AER-271 in a tMCAO Mouse Model: Modulation of Autophagy, Apoptosis, and Inflammation.

Following ischemic stroke, aquaporin 4 (AQP4) expression modifications have been associated with increased inflammation. However, the underlying mechanisms are not fully understood. This study aims to elucidate the mechanistic basis of post-cerebral ischemia-reperfusion (I/R) inflammation by employing the AQP4-specific inhibitor, AER-271. The middle cerebral artery occlusion (MCAO) model was used to induce ischemic stroke in mice. C57BL/6 mice were randomly allocated into four groups: sham operation, I/R, AER-271, and 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020) treatment, with observations recorded at 1day, 3days, and 7days post-tMCAO. Each group consisted of 15 mice. Procedures included histological examination through HE staining, neurological scoring, Western blot analysis, and immunofluorescence staining. AER-271 treatment yielded significant improvements in post-stroke weight recovery and neurological scores, accompanied by a reduction in cerebral infarction volume. Moreover, AER-271 exhibited a noticeable influence on autophagic and apoptotic pathways, affecting the activation of both pro-inflammatory and anti-inflammatory cytokines. Alterations in the levels of inflammatory biomarkers MCP-1, NLRP3, and caspase 1 were also detected. Finally, a comparative assessment of the effects of AER-271 and TGN-020 in mitigating apoptosis and microglial polarization in ischemic mice revealed neuroprotective effects with no significant difference in efficacy. This study provides essential insights into the neuroprotective mechanisms of AER-271 in cerebral ischemia-reperfusion injury, offering potential clinical applications in the treatment of ischemic cerebrovascular disorders.

Intestinal microbiota in children with chronic viral hepatitis

The article is devoted to a review of the literature on the study of intestinal microbiota in chronic viral hepatitis in children. The results of recent studies of microbial diversity of colon contents using 16S ribosomal RNA sequencing are presented. Scientific research in recent years has proven the influence of changes in the microbiota and its individual representatives on the formation of complications in patients with chronic viral hepatitis, the development of fibrosis/cirrhosis. Changed quantitative and species ratios of microorganisms can lead to the launch of pathological reactions in the intestinal-liver axis system. A significant reduction in the number of bacteria such as Clostridia and Bacteroidia (Faecalibacterium, Roseburia inilinivorans, Roseburia intestinalis, Coprococcus comes) causes low production of short-chain fatty acid butyrate, which can interfere with the functioning of tight junction proteins. Leaks and increased intestinal permeability create conditions for the formation of inflammation due to the activity of pro-inflammatory cytokines. Violation of the intestinal barrier function creates the opportunity for the penetration of bacteria, lipopolysaccharide complexes, bacterial ligands and metabolites, leading to the development of immunopathological reactions. These changes in the pediatric population are less noticeable than in the adult cohort of patients, since the clinical course of chronic viral hepatitis in children has a smoother course. However, periods of exacerbation, which are characterized by clinical and laboratory changes, may maintain the risk of developing fibrogenesis activity in older age groups. Data on intestinal microbial diversity in adult patients with chronic viral hepatitis B and C are presented separately. The possibilities of using pre- and probiotic therapy in the complex treatment of chronic liver diseases in adults and children are considered.