[Old and New Biologics and Small Molecules in Inflammatory Bowel Disease: Anti-interleukins].

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disease of the gastrointestinal tract. The introduction of biologics, particularly anti-interleukin (IL) agents, has revolutionized IBD treatment. This review summarizes the role of ILs in IBD pathophysiology and describes the efficacy and positioning of anti-IL therapies. We discuss the functions of key ILs in IBD and their potential as therapeutic targets. The review then discusses anti-IL therapies, focusing primarily on ustekinumab (anti-IL-12/23), risankizumab (anti-IL-23), and mirikizumab (anti-IL-23). Clinical trial data demonstrate their efficacy in inducing and maintaining remission in Crohn's disease and ulcerative colitis. The safety profiles of these agents are generally favorable. However, long-term safety data for newer agents are still limited. The review also briefly discusses emerging therapies such as guselkumab and brazikumab. Network meta-analyses suggest that anti-IL therapies perform well compared to other biological agents. These agents may be considered first- or second-line therapies for many patients, especially those with comorbidities or safety concerns. Anti-IL therapies represent a significant advancement in IBD treatment, offering effective and relatively safe options for patients with moderate to severe disease.

Interleukin-mediated therapies in liver diseases and comorbidity effects.

Cytokines like interleukins (ILs) play important roles in inflammation and innate immune. Yang and Zhang carried out an interesting study related to ILs and hepatic diseases. They described the role of ILs in the pathogenesis and resolution of hepatic disorders. The authors summarized alcohol-related liver disease and virus-induced hepatitis, as far as clinical studies a fortiori carried out on IL-mediated treatments pertaining to these dysfunctions. This editorial contributes to the review by Yang and Zhang titled, "Interleukins in liver disease treatment", and focuses on therapies mediated by ILs in comorbid liver diseases. The documentary search was conducted on recent pertinent literature, primarily using the Google Scholar and PubMed databases.

Balancing the Scales: The Dual Role of Interleukins in Bone Metastatic Microenvironments.

Bone metastases, a common and debilitating consequence of advanced cancers, involve a complex interplay between malignant cells and the bone microenvironment. Central to this interaction are interleukins (ILs), a group of cytokines with critical roles in immune modulation and inflammation. This review explores the dualistic nature of pro-inflammatory and anti-inflammatory interleukins in bone metastases, emphasizing their molecular mechanisms, pathological impacts, and therapeutic potential. Pro-inflammatory interleukins, such as IL-1, IL-6, and IL-8, have been identified as key drivers in promoting osteoclastogenesis, tumor proliferation, and angiogenesis. These cytokines create a favorable environment for cancer cell survival and bone degradation, contributing to the progression of metastatic lesions. Conversely, anti-inflammatory interleukins, including IL-4, IL-10, and IL-13, exhibit protective roles by modulating immune responses and inhibiting osteoclast activity. Understanding these opposing effects is crucial for developing targeted therapies aimed at disrupting the pathological processes in bone metastases. Key signaling pathways, including NF-κB, JAK/STAT, and MAPK, mediate the actions of these interleukins, influencing tumor cell survival, immune cell recruitment, and bone remodeling. Targeting these pathways presents promising therapeutic avenues. Current treatment strategies, such as the use of denosumab, tocilizumab, and emerging agents like bimekizumab and ANV419, highlight the potential of interleukin-targeted therapies in mitigating bone metastases. However, challenges such as therapeutic resistance, side effects, and long-term efficacy remain significant hurdles. This review also addresses the potential of interleukins as diagnostic and prognostic biomarkers, offering insights into patient stratification and personalized treatment approaches. Interleukins have multifaceted roles that depend on the context, including the environment, cell types, and cellular interactions. Despite substantial progress, gaps in research persist, particularly regarding the precise mechanisms by which interleukins influence the bone metastatic niche and their broader clinical implications. While not exhaustive, this overview underscores the critical roles of interleukins in bone metastases and highlights the need for continued research to fully elucidate their complex interactions and therapeutic potential. Addressing these gaps will be essential for advancing our understanding and treatment of bone metastases in cancer patients.

Biochemical implication of acetylcholine, histamine, IL-18, and interferon-alpha as diagnostic biomarkers in hepatitis C virus, coronavirus disease 2019, and dual hepatitis C virus-coronavirus disease 2019 patients.

Globally, hepatitis C virus (HCV) and coronavirus disease 2019 (COVID-19) are the most common causes of death due to the lack of early predictive and diagnostic tools. Therefore, research for a new biomarker is crucial. Inflammatory biomarkers are critical central players in the pathogenesis of viral infections. IL-18, produced by macrophages in early viral infections, triggers inflammatory biomarkers and interferon production, crucial for viral host defense. Finding out IL-18 function can help understand COVID-19 pathophysiology and predict disease prognosis. Histamine and its receptors regulate allergic lung responses, with H1 receptor inhibition potentially reducing inflammation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. angiotensin-converting enzyme 2 (ACE-2) receptors on cholangiocytes suggest liver involvement in SARS-CoV-2 infection. The current study presents the potential impact of circulating acetylcholine, histamine, IL-18, and interferon-Alpha as diagnostic tools in HCV, COVID-19, and dual HCV-COVID-19 pathogenesis. The current study was a prospective cross-section conducted on 188 participants classified into the following four groups: Group 1 COVID-19 (n = 47), Group 2 HCV (n = 47), and Group 3 HCV-COVID-19 patients (n = 47), besides the healthy control Group 4 (n = 47). The levels of acetylcholine, histamine, IL-18, and interferon-alpha were assayed using the ELISA method. Liver and kidney functions within all groups showed a marked alteration compared to the healthy control group. Our statistical analysis found that individuals with dual infection with HCV-COVID-19 had high ferritin levels compared to other biomarkers while those with COVID-19 infection had high levels of D-Dimer. The histamine, acetylcholine, and IL-18 biomarkers in both COVID-19 and dual HCV-COVID-19 groups have shown discriminatory power, making them potential diagnostic tests for infection. These three biomarkers showed satisfactory performance in identifying HCV infection. The IFN-Alpha test performed well in the HCV-COVID-19 group and was fair in the COVID-19 group, but it had little discriminative value in the HCV group. Moreover, our findings highlighted the pivotal role of acetylcholine, histamine, IL-18, and interferon-Alpha in HCV, COVID-19, and dual HCV-COVID-19 infection. Circulating levels of acetylcholine, histamine, IL-18, and interferon-Alpha can be potential early indicators for HCV, COVID-19, and dual HCV-COVID-19 infection. We acknowledge that further large multicenter experimental studies are needed to further investigate the role biomarkers play in influencing the likelihood of infection to confirm and extend our observations and to better understand and ultimately prevent or treat these diseases.

Causality between various cytokines and asthma: a bidirectional two-sample Mendelian randomization analysis.

Background: Many studies have shown that cytokines play an important role in the pathogenesis of asthma, but their biological effects on asthma remain unclear. The Mendelian randomization (MR) method was used to evaluate the causal relationship between various cytokines [such as interleukins (ILs), interferons (IFNs), tumor necrosis factors (TNFs), colony-stimulating factors (CSFs), transforming growth factor (TGF), etc.,] and asthma. Methods: In this study, inverse variance weighting was used to evaluate the causal relationship between asthma and cytokines. In addition, the reliability of the results is ensured by multiple methods such as MR-Egger, weighted median, MR-Raps, MR-Presso, and RadialMR, as well as sensitivity analysis. Results: The results showed that none of the 11 cytokines was associated with the risk of asthma. In contrast, asthma can increase levels of IL-5 [odds ratio (OR) = 1.112, 95% confidence interval (CI): 1.009-1.224, P = 0.032] and IL-9 (OR = 1.111, 95% CI: 1.013-1.219, P = 0.025). Conclusion: Genetically predicted asthma was positively associated with elevated levels of IL-5 and IL-9, indicating the downstream effects of IL-5 and IL-9 on asthma. Medical treatments can thus be designed to target IL-5 and IL-9 to prevent asthma exacerbations.

Immunology of Cytokine Storm Syndromes: Natural Killer Cells.

Natural killer (NK) cells are innate immune lymphocytes that rapidly produce cytokines upon activation and kill target cells. NK cells have been of particular interest in primary hemophagocytic lymphohistiocytosis (pHLH) since all of the genetic defects associated with this disorder cause diminished cytotoxic capacity of NK cells and T lymphocytes, and assays of NK cell killing are used clinically for the diagnosis of HLH. Herein, we review human NK cell biology and the significance of alterations in NK cell function in the diagnosis and pathogenesis of HLH.

[Features of inflammatory endotypes and phenotypes in chronic rhinosinusitis]. / Osobennosti endotipov i fenotipov vospaleniya pri khronicheskom rinosinusite.

Recently, significant progress has been made in identifying the cellular and molecular mechanisms responsible for the pathogenesis of chronic rhinosinusitis (CRS). Cohort studies of CRS have led to advances in the clinical understanding of this disease. New therapeutic agents have been approved or are undergoing clinical trials to expand treatment options for this disease. One of the promising areas in medicine is the provision of personalized clinical care. From this perspective, CRS can be divided into three different endotypes depending on the type of underlying inflammatory response. In the United States, CRS with and without nasal polyps is predominantly characterized as the second inflammatory endotype. CRS with nasal polyps (about 17%) and without nasal polyps (up to 20%) belongs to the 1st and 3rd inflammatory endotypes, respectively. And if for the second inflammatory endotype the effectiveness of targeted biological therapy is beyond doubt, then for the first and third inflammatory endotypes the principles of such conservative therapy are under active development. Moreover, large validated studies to confirm associations between CRS phenotypes and endotypes, as well as to find effective biological markers of inflammatory endotypes, remain to be performed.

STAT4 and STAT6, their role in cellular and humoral immunity and in diverse human diseases.

Signal transducer and activator of transcription (STAT) 4 and STAT6 play a crucial role in immune cells by transducing signals from specific cytokine receptors, and inducing transcription of genes involved in cell-mediated and humoral immunity. These two different defense mechanisms against pathogens are regulated by two specific CD4+ T helper (Th) cells known as Th1 and Th2 cells. Many studies have shown that several diseases including cancer, inflammatory, autoimmune and allergic diseases are associated with a Th1/Th2 imbalance caused by increased or decreased expression/activity of STAT4 or STAT6 often due to genetic and epigenetic aberrances. An altered expression of STAT4 has been observed in different tumors and autoimmune diseases, while a dysregulation of STAT6 signaling pathway is frequently observed in allergic conditions, such as atopic dermatitis, allergic asthma, food allergy, and tumors such as Hodgkin and non-Hodgkin lymphomas. Recently, dysregulations of STAT4 and STAT6 expression have been observed in SARS-CoV2 and monkeypox infections, which are still public health emergencies in many countries. SARS-CoV-2 can induce an imbalance in Th1 and Th2 responses with a predominant activation of STAT6 in the cytosol and nuclei of pneumocytes that drives Th2 polarization and cytokine storm. In monkeypox infection the virus can promote an immune evasion by inducing a Th2 response that in turn inhibits the Th1 response essential for virus elimination. Furthermore, genetic variations of STAT4 that are associated with an increased risk of developing systemic lupus erythematosus seem to play a role in defense against SARS-CoV-2 infection.

Signal transducer and activator of transcription (STAT) proteins are important and complex regulators of transcription that mediate many aspects of cellular immunity, proliferation, apoptosis and differentiation. STAT proteins are phosphorylated/activated in the cytoplasm by Janus Kinases (JAKs) a family of nonreceptor tyrosine kinases associated to type I and type II cytokine receptors. There are seven STAT family members that have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. STAT4 is activated by IL-12 after binding with its specific receptor and induces the production in Th1 cells of IFN-γ, which allows these cells to be particularly effective in protecting against viruses and intracellular bacteria. STAT6 is activated by IL-4 and IL-13 and is required for the development of Th2 immune response and for the production of Th2 cytokines IL-4, IL-5, and IL-13 that contribute to humoral response with the synthesis of antigen specific antibodies in B cells. Although STAT4 plays an important role in many physiological functions, an altered expression of this transcription factor, often due to genetic and epigenetic aberrances, has been observed in different tumors and autoimmune diseases. Dysregulation of STAT6 signaling pathway, often caused by genetic mutations in the STAT6 gene, has been observed in several allergic conditions and tumors such as Hodgkin and non-Hodgkin lymphomas.

Monoclonal antibodies targeting interleukins for systemic lupus erythematosus: updates in early clinical drug development.

INTRODUCTION: The advent of biological therapies has already revolutionized treatment strategies and disease course of several rheumatologic conditions, and monoclonal antibodies (mAbs) targeting cytokines and interleukins represent a considerable portion of this family of drugs. In systemic lupus erythematosus (SLE) dysregulation of different cytokine and interleukin-related pathways have been linked to disease development and perpetration, offering palatable therapeutic targets addressable via such mAbs. AREAS COVERED: In this review, we provide an overview of the different biological therapies under development targeting cytokines and interleukins, with a focus on mAbs, while providing the rationale behind their choice as therapeutic targets and analyzing the scientific evidence linking them to SLE pathogenesis. EXPERT OPINION: An unprecedented number of clinical trials on biological drugs targeting different immunological pathways are ongoing in SLE. Their success might allow us to tackle present challenges of SLE management, including the overuse of glucocorticoids in daily clinical practice, as well as SLE heterogenicity in treatment response among different individuals, hopefully paving the way toward precision medicine.

Recent Advances in Targeted Management of Inflammation In Atherosclerosis: A Narrative Review.

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality despite effective low-density lipoprotein cholesterol-targeted therapies. This review explores the crucial role of inflammation in the residual risk of ASCVD, emphasizing its impact on atherosclerosis progression and plaque stability. Evidence suggests that high-sensitivity C-reactive protein (hsCRP), and potentially other inflammatory biomarkers, can be used to identify the inflammatory residual ASCVD risk phenotype and may serve as future targets for the development of more efficacious therapeutic approaches. We review the biological basis for the association of inflammation with ASCVD, propose new therapeutic strategies for the use of inflammation-targeted treatments, and discuss current challenges in the implementation of this new treatment paradigm for ASCVD.

Stasis and Inflammation in Varicose Vein Development: An Interleukin-Mediated Process from Intima to Media.

INTRODUCTION: This study investigated the combination of venous stasis and inflammation in varicose vein development. METHODS: The study included patients with primary varicose veins operated using high ligation and stripping of greater saphenous vein. All of them showed reflux at sapheno-femoral junction on preoperative Doppler ultrasound. Mesenteric veins from early or advanced gastric cancer specimens were used as control group. Inflammatory mediators expressed in the venous wall were measured via immunohistochemistry and compared between the two groups. RESULTS: Thirty-five (59.3%) men and 24 women with a mean age of 52.8 years (range, 23-77 years) were included and 29 (49.2%) patients had edema or skin changes according to Clinical-Etiology-Anatomy-Pathophysiology (CEAP) classification and reporting standards for chronic venous disorders. The expression of interleukin 6 (IL-6) and transforming growth factor ß1 (TGF-ß1) in intima and those of IL-6 in media of greater saphenous veins increased, with statistically significant differences between the two groups (p < 0.001). IL-6 in media and TGF-ß1 levels in intima were independent predictors of varicose veins (adjusted odds ratios 74.62 and 66.69, respectively). CONCLUSION: Elevated venous pressure represented by reflux on Doppler ultrasound and increased expression of inflammatory cytokines including IL-6 in media and TGF-ß1 in intima are associated with the development of varicose veins.

Expression of IL-1ß, IL-6, TNF-α, and a-MMP-8 in sites with healthy conditions and with periodontal and peri-implant diseases: A case-control study.

Background: This study evaluated the gingival crevicular fluid (GCF) and Peri- implant crevicular fluid (PICF) concentrations of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and active metalloproteinase-8 (a-MMP-8) in sites with healthy conditions vs. sites affected by periodontitis (PER) and peri-implantitis (PIM). Methods: Periodontally healthy (PH) sites with PER, sites with peri-implant health (PIH), and sites with PIM were investigated intra-individually, according to the inclusion criteria of each group. Probing pocket depth (PPD), plaque index, gingival index, and the presence or absence of bleeding on probing (BoP) were evaluated. In GCF and PICF samples, IL-1ß, IL-6, and TNF-α were quantified by ELISA Duoset® kit in combination with Ultramark® micro-ELISA digital reader; a-MMP8 concentration was analyzed by a chairside test (Perio/ImplantSafe®) in combination with a digital reader (ORALyzer®). Results: The concentrations of IL-6 and IL-1ß, TNF-α, and a-MMP-8 were significantly higher in the PIM and PER sites compared to healthy sites (P<0.05). Significantly higher concentrations of IL-1ß and a-MMP-8 were found in PIM vs. PER sites (P<0.05), while the concentrations of IL-6 and TNF-α did not differ between the PIM and PER groups (P>0.05). Conclusion: aMMP-8, IL-6, IL-1ß, and TNF-α presented higher GCF/PICF concentrations in diseased periodontal and peri-implant sites. However, only the concentrations of IL-1ß and a-MMP-8 were significantly higher in PIM than in PER sites.

Innate neuroimmunity across aging and neurodegeneration: a perspective from amyloidogenic evolvability.

In Alzheimer's Disease (AD), amyloidogenic proteins (APs), such as ß-amyloid (Aß) and tau, may act as alarmins/damage-associated molecular patterns (DAMPs) to stimulate neuroinflammation and cell death. Indeed, recent evidence suggests that brain-specific type 2 immune networks may be important in modulating amyloidogenicity and brain homeostasis. Central to this, components of innate neuroimmune signaling, particularly type 2 components, assume distinctly specialized roles in regulating immune homeostasis and brain function. Whereas balanced immune surveillance stems from normal type 2 brain immune function, appropriate microglial clearance of aggregated misfolded proteins and neurotrophic and synaptotrophic signaling, aberrant pro-inflammatory activity triggered by alarmins might disrupt this normal immune homeostasis with reduced microglial amyloid clearance, synaptic loss, and ultimately neurodegeneration. Furthermore, since increased inflammation may in turn cause neurodegeneration, it is predicted that AP aggregation and neuroinflammation could synergistically promote even more damage. The reasons for maintaining such adverse biological conditions which have not been weeded out during evolution remain unclear. Here, we discuss these issues from a viewpoint of amyloidogenic evolvability, namely, aEVO, a hypothetic view of an adaptation to environmental stress by AP aggregates. Speculatively, the interaction of AP aggregation and neuroinflammation for aEVO in reproduction, which is evolutionally beneficial, might become a co-activating relationship which promotes AD pathogenesis through antagonistic pleiotropy. If validated, simultaneously suppressing both AP aggregation and specific innate neuroinflammation could greatly increase therapeutic efficacy in AD. Overall, combining a better understanding of innate neuroimmunity in aging and disease with the aEVO hypothesis may help uncover novel mechanism of pathogenesis of AD, leading to improved diagnostics and treatments.

Prospective therapeutic targets and recent advancements in the treatment of inflammatory bowel disease.

OBJECTIVE: Inflammatory Bowel Disease (IBD) poses a persistent challenge in the realm of gastroenterology, necessitating continual exploration of innovative treatment strategies. The limited efficacy and potential side effects associated with existing therapeutic modalities underscore the urgent need for novel approaches in IBD management. This study aims to examine potential therapeutic targets and recent advancements in understanding the disease's intricate pathogenesis, with a spotlight on the gut microbiome, immune dysregulation, and genetic predispositions. METHODS: A comprehensive review was conducted to delve into the pressing demand for new avenues in IBD treatment. The study examined potential therapeutic targets such as phosphodiesterase 4 (PDE4) inhibitors, immune system modulators, Tyrosine kinase receptors (TYK), Toll-like receptors (TLRs), modulation of the gut microbiota, stem cell therapy, fibrosis management, interleukins (ILs) regulation, and oxidative stress mitigation. Additionally, advances in precision medicine, biologics, small molecule inhibitors, and microbiome modulation techniques were explored. RESULTS: The investigation unveiled promising therapeutic targets and provided insights into recent breakthroughs that herald a transformative era in the therapeutic landscape for IBD. Advances in precision medicine, biologics, small molecule inhibitors, and the exploration of microbiome modulation techniques stood out as pivotal milestones in the field of gastroenterology. CONCLUSIONS: The findings offer renewed hope for enhanced efficacy, reduced side effects, and improved patient outcomes in the treatment of IBD. These innovative approaches necessitate continual exploration and underscore the urgent need for novel strategies in IBD management, potentially revolutionizing the realm of gastroenterology.

Clostridium ramosum alone caused Fournier's gangrene in an older Chinese patient with abnormal interleukin levels: A rare case report.

Clostridium ramosum is an uncommon Clostridium but is one of the essential anaerobic bacteria that makes up the intestinal microbiota. A highly variable body temperature, the white blood cell count, or an elusory prognosis can reflect Clostridium ramosum infection, especially in patients with Fournier's gangrene. Fournier's gangrene is a rare soft-tissue infection with necrosis that occurs mainly in the perianal and genital regions, males being more susceptible. Here, we report a 70-year-old Chinese man with Fournier's gangrene and high levels interleukins who suffered from Clostridium ramosum infection, identified and verified by matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (MALDI-TOF MS) and 16S rRNA sequencing. Fournier's gangrene severity index (FGSI) of the patient was measured once the patient was admitted to hospital. His FGSI was 6, indicating no abnormal condition. He had abnormally high interleukin (IL)-6, IL-8, and IL-10 levels, associated with severe inflammatory conditions. Despite the patient's resuscitation and standardized treatment with antimicrobial drugs, the symptoms did not improve. The patient's condition deteriorated, and he died on hospitalization day 5. Abnormally elevated IL-6, IL-8, and IL-10 levels were a novel finding in a case of Clostridium ramosum infection, leading to Fournier's gangrene. In the present case, a perianal abscess was the predisposing condition for Fournier's gangrene. Close attention should be paid to the isolation and identification of pathogenic Clostridium ramosum during the bacteriological examination of patients with perianal abscesses. IL-6, IL-8, and IL-10 may be critical biomarkers that supplement the FGSI for diagnosing Clostridium ramosum infection leading to Fournier's gangrene in immunosuppressed persons.

Interleukin-2 mediated associations between gut microbiota and acute myeloid leukemia: A population-based mediation Mendelian randomization study.

The relationship between the gut microbiota and acute myeloid leukemia (AML) has been established, but the exact role of interleukin (IL) in mediating this relationship has remained unclear. This study aimed to utilize whether interleukins mediate the relationships between gut microbiota and AML, thereby identifying potential novel targets for future AML treatment. Mendelian randomization (MR) is a method for finding the causality of exposure and outcome. Final instrumental variables were selected based on MR assumptions, and used to judge validity of the results. Our study identified risk and protective factors for AML, and interleukin-related gut microbiota. Finally, mediation MR analyses resulted in Interleukin-2 (IL-2) mediated associations between Clostridiaceae 1, Clostridium sensu stricto 1 and AML, with IL-2 respectively explaining 13.96 % and 12.11 % of the total effect of the aforementioned gut microbiota on AML. Our results successfully identified causal effects between specific gut microbiota, AML, and interleukins, while also elucidating the mediating role of IL-2 in these associations using MR analysis. These findings provide valuable insights into potential therapeutic targets for AML treatment.

Effect of Egyptian spitting cobra Naja nubiae crude venom on immunogenic activity of rats.

Snakes show defensive activities, often counting visual or auditory displays against an aggressor. The study observed what happens to rats administered subcutaneously sub-lethal doses of crude venom Naja nubiae. The pro-inflammatory cytokines, such as tumor necrosis alpha (TNF-α) and interleukin-6 (IL-6), as well as the anti-inflammatory cytokines such as interleukin-10 (IL-10), and inflammatory mediator's prostaglandin E-2 (PG-E2), were evaluated. Vascular permeability (VP) was employed to assess how leaky or permeable blood vessels are in various tissues and organs, including the rat peritoneal cavity and lymphoid organs. Lymphoid organs' histological alterations brought on by Nubiae venom. The study found that the two venom doses-1/4 and 1/2 LD50-induced high levels of inflammatory activity as evidenced by the production of inflammatory cytokines. These findings demonstrated that venom enhanced innate immunity through specifically increased T helper cells, IL-6, TNF-α, IL-10, and PG-E2. The results reveal whether the venom has an immunomodulatory effect and promotes inflammation. The data have a substantial impact on the development of new drugs and treatments for inflammatory conditions.

Changes in cerebrospinal fluid proteome of patients with tick-borne encephalitis.

Tick-borne encephalitis (TBE) is one of the main diseases transmitted by ticks, the incidence of which is increasing. Moreover, its diagnosis and therapy are often long and difficult according to nonspecific symptoms and complex etiology. This study aimed to observe changes in the proteome of cerebrospinal fluid from TBE patients. Cerebrospinal fluid (CSF) of TBE patients (n = 20) and healthy individuals (n = 10) was analyzed using a proteomic approach (QExactiveHF-Orbitrap mass spectrometer) and zymography. Obtained results show that in CSF of TBE patients, the top-upregulated proteins are involved in pro-inflammatory reaction (interleukins), as well as antioxidant/protective response (peroxiredoxins, heat shock proteins). Moreover, changes in the proteome of CSF are not only the result of this disease development, but they can also be an indicator of its course. This mainly applies to proteins involved in proteolysis including serpins and metalloproteinases, whose activity is proportional to the length of patients' convalescence. The obtained proteomic data strongly direct attention to the changes caused by the development of TBE to antioxidant, pro-inflammatory, and proteolytic proteins, knowledge about which can significantly contribute to faster and more accurate diagnosis of various clinical forms of TBE.

Inflammatory Response Genes' Polymorphism Associated with Risk of Rheumatic Heart Disease.

Rheumatic heart disease (RHD) caused by group A streptococcus infection is one of the most important reasons of cardiovascular morbidity and mortality in low- and middle-income countries. Aberrant host immune response modulated by polymorphisms in inflammatory response genes plays an important role in RHD pathogenesis. This study aimed to determine risk-associated polymorphic variants in inflammatory response genes in Caucasian RHD patients. A total of 251 Caucasian RHD patients and 300 healthy donors were recruited for this study, and 27 polymorphic sites in 12 genes (TLR1, TLR2, TLR4, TLR6, IL1B, IL6R, IL6, IL10, IL12RB1, IL12B, TNF and CRP) were analyzed using allele-specific PCR. It was demonstrated that the polymorphic variants rs1800871 and rs1800872 in the IL10 gene, rs 1130864, rs3093077 and rs1205 in the CRP gene, rs375947 in the IL12RB1 gene, rs 5743551 and rs5743611 in the TLR1 gene, and rs3775073 in the TLR6 gene can modify RHD risk in a gender- and age-dependent manner. The obtained results can be used to determine the personalized risk of RHD in healthy donors during medical examination or screening, as well as to develop appropriate early prevention strategies targeting RHD in the risk groups.

Evaluation of effects of bisphenol analogs AF, S, and F on viability, proliferation, production of selected cancer-related factors, and expression of selected transcripts in Caov-3 human ovarian epithelial cell line.

Bisphenol A (BPA) has been a substantial additive in plastics until the reports on its adverse effects have led to its restrictions and replacement. Monitoring studies document the increasing occurrence of bisphenol analogs, however, data on their effects and risks is still insufficient. Based on the indications that BPA might contribute to ovarian cancer pathogenesis, we examined effects of the analogs AF (BPAF), S (BPS) and F (BPF) (10-9-10-4 M) on the Caov-3 epithelial cancer cells, including the impact on cell viability, proliferation, oxidative stress, and production and expression of several factors and genes related to ovarian cancer. At environmentally relevant doses, bisphenols did not exert significant effects. At the highest concentration, BPAF caused varied alterations, including decreased cell viability and proliferation, caspase activation, down-regulation of PCNA and BIRC5, elevation of IL8, VEGFA, MYC, PTGS2 and ABCB1 expressions. Only BPA (10-4 M) increased IL-6, IL-8 and VEGFA output by the Caov-3 cells. Each bisphenol induced generation of reactive oxygen species and decreased superoxide dismutase activity at the highest concentration. Although the effects were observed only in the supraphysiological doses, the results indicate that certain bisphenol analogs might affect several ovarian cancer cell characteristics and merit further investigation.