Synthesis Of Proinflammatory Cytokines Research Articles

Harnessing cGAS-STING axis for therapeutic benefits in systemic lupus erythematosus.

The cyclic GMP-AMP synthase (cGAS), a prominent intracellular DNA sensor in mammalian cells, controls the innate immune response and the stimulator of interferon genes (STING)-mediated synthesis of pro-inflammatory cytokines, such as type-I interferon (IFN-I). For decades, IFN-I has been hypothesized to be essential in the development of systemic lupus erythematosus (SLE), a chronic multisystem autoimmunity characterized by immune complex (IC) deposition in small vessels. Recent findings revealed that the activation of the cGAS-STING pathway by self-DNA would propagate the autoimmune responses via upregulating IFN-I production in SLE. In this review, we aimed to provide a comprehensive outlook of the role of the cGAS-STING pathway in SLE pathobiology, as well as, a better understanding of current therapeutic opportunities targeting this axis.

Harnessing cGAS-STING axis for therapeutic benefits in systemic lupus erythematosus.

The cyclic GMP-AMP synthase (cGAS), a prominent intracellular DNA sensor in mammalian cells, controls the innate immune response and the stimulator of interferon genes (STING)-mediated synthesis of pro-inflammatory cytokines, such as type-I interferon (IFN-I). For decades, IFN-I has been hypothesized to be essential in the development of systemic lupus erythematosus (SLE), a chronic multisystem autoimmunity characterized by immune complex (IC) deposition in small vessels. Recent findings revealed that the activation of the cGAS-STING pathway by self-DNA would propagate the autoimmune responses via upregulating IFN-I production in SLE. In this review, we aimed to provide a comprehensive outlook of the role of the cGAS-STING pathway in SLE pathobiology, as well as, a better understanding of current therapeutic opportunities targeting this axis.

Joint damage among the patients with COVID-19 in nurse practice

Rheumatoid pathology of the articular apparatus is a significant social problem due to the high incidence of disability. Cases of the development of arthropathy after SARS-CoV-2 infection have been described.The basis of the pathogenesis of this condition may be the excessive synthesis of pro-inflammatory cytokines (cytokine storm), which is characteristic of the acute course of COVID-19. In patients with a severe form of coronavirus infection, a high concentration of a number of cytokines was observed: IFN-γ, IL-1, IL-6, IL-12, TGFβ. Due to the activation of osteoclasts, resorptive processes in bone tissue were significantly enhanced.Autoimmunization due to cross-reactivity of the virus can also lead to joint damage. Reactive arthritis tends to be acute, occurs in the form of monoarthritis or oligoarthritis. The pathological process develops mainly in the joints of the wrist, ankles and small joints of the distal parts of the arms and legs.

Effect of photobiomodulation in the balance between effector and regulatory T cells in an experimental model of COPD.

Currently, Chronic Obstructive Pulmonary Disease (COPD) has a high impact on morbidity and mortality worldwide. The increase of CD4+, CD8+ cells expressing NF-κB, STAT4, IFN-γ and perforin are related to smoking habit, smoking history, airflow rate, obstruction and pulmonary emphysema. Furthermore, a deficiency in CD4+CD25+Foxp3+ regulatory T cells (Tregs) may impair the normal function of the immune system and lead to respiratory immune disease. On the other hand, the anti-inflammatory cytokine IL-10, produced by Treg cells and macrophages, inhibits the synthesis of several pro-inflammatory cytokines that are expressed in COPD. Therefore, immunotherapeutic strategies, such as Photobiomodulation (PBM), aim to regulate the levels of cytokines, chemokines and transcription factors in COPD. Consequently, the objective of this study was to evaluate CD4+STAT4 and CD4+CD25+Foxp3+ cells as well as the production of CD4+IFN- γ and CD4+CD25+IL-10 in the lung after PBM therapy in a COPD mice model. We induced COPD in C57BL/6 mice through an orotracheal application of cigarette smoke extract. PMB treatment was applied for the entire 7 weeks and Bronchoalveolar lavage (BAL) and lungs were collected to study production of IFN- γ and IL-10 in the lung. After the last administration with cigarette smoke extract (end of 7 weeks), 24 h later, the animals were euthanized. One-way ANOVA followed by NewmanKeuls test were used for statistical analysis with significance levels adjusted to 5% (p < 0.05). This result showed that PBM improves COPD symptomatology, reducing the number of inflammatory cells (macrophages, neutrophils and lymphocytes), the levels of IFN-γ among others, and increased IL-10. We also observed a decrease of collagen, mucus, bronchoconstriction index, alveolar enlargement, CD4+, CD8+, CD4+STAT4+, and CD4+IFN-γ+ cells. In addition, in the treated group, we found an increase in CD4+CD25+Foxp3+ and CD4+IL-10+ T cells. This study suggests that PBM treatment could be applied as an immunotherapeutic strategy for COPD.

Disparity of gene expression in coronary artery disease: insights from MEIS1, HIRA, and Myocardin.

Coronary artery disease (CAD) in young adults can have devastating consequences. The cardiac developmental gene MEIS1 plays important roles in vascular networks and heart development. This gene effects on the regeneration capacity of the heart. Considering role of MEIS1 in cardiac tissue development and the progression of myocardial infarction this study investigated the expression levels of the MEIS1, HIRA, and Myocardin genes in premature CAD patients compared to healthy subjects and evaluated the relationships between these genes and possible inflammatory factors. The study conducted a case-control design involving 35 CAD patients and 35 healthy individuals. Peripheral blood mononuclear cells (PBMCs) were collected, and gene expression analysis was performed using real-time PCR. Compared with control group, the number of PBMCs in the CAD group exhibited greater MEIS1 and HIRA gene expression, with fold changes of 2.45 and 3.6. The expression of MEIS1 exhibited a negative correlation with IL-10 (r= -0.312) expression and positive correlation with Interleukin (IL)-6 (r = 0.415) and tumor necrosis factor (TNF)-α (r = 0.534) gene expression. Moreover, there was an inverse correlation between the gene expression of HIRA and that of IL-10 (r= -0.326), and a positive correlation was revealed between the expression of this gene and that of the IL-6 (r = 0.453) and TNF-α (r = 0.572) genes. This research demonstrated a disparity in expression levels of MEIS1, HIRA, and Myocardin, between CAD and healthy subjects. The results showed that, MEIS1 and HIRA play significant roles in regulating the synthesis of proinflammatory cytokines, namely, TNF-α and IL-6.

Guideline-Optimised Treatment in Heart Failure-Do Higher Doses Reduce Systemic Inflammation More Significantly?

Background: Chronic inflammation is a constant phenomenon which accompanies the heart failure pathophysiology. In all phenotypes of heart failure, irrespective of the ejection fraction, there is a permanent low-grade activation and synthesis of proinflammatory cytokines. Many classes of anti-remodelling medication used in the treatment of chronic heart failure have been postulated to have an anti-inflammatory effect. Methods: This retrospective study enrolled 220 patients and focused on evaluating the effect of the most used active substances from these classes in reducing the level of inflammatory biomarkers (C reactive protein, erythrocyte sedimentation rate and fibrinogen) after initiation or up-titration. Our research is evaluating if this anti-inflammatory effect intensifies while raising the dose. The evaluation was performed at two visits with an interval between them of 6 months. Results: From the beta-blockers class, carvedilol showed a reduction in erythrocyte sedimentation rate (ESR), in low (6.25 mg, bi daily) and medium (12.5 mg, bi daily) doses. At the same time, sacubitril/valsartan showed a reduction in CRP levels. This effect was obtained only in the medium (49/51 mg, bi daily) and high (97/103 mg, bi daily) doses, with the maximum reduction being observed in the high dose. Conclusions: From the classes of medication evaluated, the study showed a significant reduction in ESR levels in the low and medium doses of carvedilol and a reduction in CRP values in the cases of medium and high doses of ARNI.

Microglia Mitigate Neuronal Activation in a Zebrafish Model of Dravet Syndrome.

It has been known for a long time that epileptic seizures provoke brain neuroinflammation involving the activation of microglial cells. However, the role of these cells in this disease context and the consequences of their inflammatory activation on subsequent neuron network activity remain poorly understood so far. To fill this gap of knowledge and gain a better understanding of the role of microglia in the pathophysiology of epilepsy, we used an established zebrafish Dravet syndrome epilepsy model based on Scn1Lab sodium channel loss-of-function, combined with live microglia and neuronal Ca2+ imaging, local field potential (LFP) recording, and genetic microglia ablation. Data showed that microglial cells in scn1Lab-deficient larvae experiencing epileptiform seizures displayed morphological and biochemical changes characteristic of M1-like pro-inflammatory activation; i.e., reduced branching, amoeboid-like morphology, and marked increase in the number of microglia expressing pro-inflammatory cytokine Il1β. More importantly, LFP recording, Ca2+ imaging, and swimming behavior analysis showed that microglia-depleted scn1Lab-KD larvae displayed an increase in epileptiform seizure-like neuron activation when compared to that seen in scn1Lab-KD individuals with microglia. These findings strongly suggest that despite microglia activation and the synthesis of pro-inflammatory cytokines, these cells provide neuroprotective activities to epileptic neuronal networks, making these cells a promising therapeutic target in epilepsy.

Compatibility with Fructus Ligustri Lucidi Effectively Mitigates Idiosyncratic Liver Injury of Epimedii Folium by Modulating NOD-like Receptor Family Pyrin Domain Containing 3 Inflammasome Activation

Abstract Background: Idiosyncratic drug-induced liver injury (IDILI) is a serious side effect of drugs, Epimedii Folium (EF) is unequivocally implicated in idiosyncratic liver injury onset, potentially due to its ability to perturb the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. Fructus Ligustri Lucidi (FLL), a frequently used medicinal combination with EF, has not yet been investigated for its ability to ameliorate EF-associated hepatotoxicity. Aims and Objectives: Study on the mechanism of compatibility of FLL to alleviate liver injury caused by EF. Materials and Methods: Western blot was used to determine the expression of related proteins, ELISA was used to detect the secretion of related inflammatory factors IL-1β, IL-18, IL-6 and TNF-α, liver injury indexes were detected and liver pathological tissue staining was used to evaluate the liver injury. Results: Our results demonstrated that EF exerted a particular augmenting effect on the stimulation of the NLRP3 inflammasome mediated by nigericin or ATP, whereas FLL suppressed the NLRP3 inflammasome stimulation. Furthermore, an equal EF to FLL ratio significantly reduced the stimulatory effects of EF. Moreover, EF has the potential to induce hepatic injury and augment pro-inflammatory cytokine synthesis in rats subjected to LPS. However, when combined with FLL, the detrimental effects of EF were mitigated. Conclusions: FLL possesses the capacity to attenuate EF-associated hepatotoxicity by suppressing EF-triggered NLRP3 inflammasome activation. Thus, FLL holds promise for improving the clinical safety profile of EF, shedding light on the potential of compatibility and detoxification theories in traditional Chinese medicine.

Nebulized pH-Responsive Nanospray Combined with Pentoxifylline and Edaravone to Lungs for Efficient Treatments of Acute Respiratory Distress Syndrome.

The COVID-19 pandemic has become an unprecedented global medical emergency, resulting in more than 5 million deaths. Acute respiratory distress syndrome (ARDS) caused by COVID-19, characterized by the release of a large number of pro-inflammatory cytokines and the production of excessive toxic ROS, is the most common serious complication leading to death. To develop new strategies for treating ARDS caused by COVID-19, a mouse model of ARDS was established by using lipopolysaccharide (LPS). Subsequently, we have constructed a novel nanospray with anti-inflammatory and antioxidant capacity by loading pentoxifylline (PTX) and edaravone (Eda) on zeolite imidazolate frameworks-8 (ZIF-8). This nanospray was endowed with synergetic therapy, which could kill two birds with one stone: (1) the loaded PTX played a powerful anti-inflammatory role by inhibiting the activation of inflammatory cells and the synthesis of pro-inflammatory cytokines; (2) Eda served as a free radical scavenger in ARDS. Furthermore, compared with the traditional intravenous administration, nanosprays can be administered directly and inhaled efficiently and reduce the risk of systemic adverse reactions greatly. This nanospray could not only coload two drugs efficiently but also realize acid-responsive release on local lung tissue. Importantly, ZIF8-EP nanospray showed an excellent therapeutic effect on ARDS in vitro and in vivo, which provided a new direction for the treatment of ARDS.

Role of toll-like receptor signaling pathway in a rat model of spinal cord injury: a transcriptomic analysis

Spinal cord injury (SCI) is a debilitating condition characterized by primary and secondary damage to the spinal cord tissue encompassing the site of injury. In this study, we analyzed transcriptomic data from Rattus norvegicus with SCI induced by aneurysm clip impact-compression at seventh thoracic vertebra to explore the main alterations in pathways expression. RNA was extracted from the specific SCI region after 2 weeks and hybridized on Affymetrix GeneChip arrays. Differential gene expression analysis identified 5213 DEGs among which 25 showing a fold change &lt; -2 or &gt; 2. Over-representation analysis was performed using the 25 DEGs above mentioned and revealed the toll-like receptor (TLR) signaling pathway signaling pathway (rno04620) as the only significantly enriched pathway (q-value &lt; 0.05). Further examination of the regulation of this pathway unveiled upregulation of MyD88, Tlr2, and Tlr4, activating NF-κB and MAPK pathways, leading to proinflammatory cytokine synthesis and cellular apoptosis. Upregulation of Cd80 and Cd86 indicated T-cell activation, while IFN-β downstream regulation showed increased expression of JAK-STAT signaling pathway genes. This transcriptomic perspective highlights the dysregulation of the TLR signaling pathway in SCI at 2 weeks and emphasizes its potential role in the pathology.

Investigation of the «Structure – analgesic activity» Relationship Using Molecular Docking for Cyclooxygenases 1 and 2 in the Series 5-&lt;i&gt;N&lt;/i&gt;-arylaminocarbonyl-6-(get)aryl-4-methyl-1,2,3,6-tetrahydropyrimidine-2-thiones

Introduction. Molecular modeling methods are very popular in the scientific community at the present time. The value of the pharmacological action depends on the affinity of the substance to the biological target. Molecular docking makes it possible to assess the degree of affinity of the studied compound with the active center of the molecular target. The enzyme cyclooxygenase (COX) plays a key role in the cascade of synthesis of proinflammatory cytokines and, as a consequence, in pain.Aim. To identify the dependence "structure – analgesic activity" using the method of molecular docking for cyclooxygenase type 1 and type 2 in the series of 5-N-arylaminocarbonyl-6-(get)aryl-4-methyl-1,2,3,6-tetrahydropyrimidine-2-thions.Materials and methods. 19 compounds 5-N-arylaminocarbonyl-6-(get)aryl-4-methyl-1,2,3,6-tetrahydropyrimidine-2-thions are objects of research The study of the interaction of tetrahydropyridine derivatives with COX 1 and 2 was carried out by the method of molecular docking by the AutoDock 4 program using scoring functions.Results and discussion. Molecular docking of 5-N-arylaminocarbonyl-6-(get)aryl-4-methyl-1,2,3,6-tetrahydropyrimidine-2-thions (I–XIX) with COX 1 and 2 is described. Quantitative studies of the "structure – analgesic activity" in the studied series of compounds of the dependence of experimental values of analgesic activity (ААex.) on scoring functions (BeCOX1, KiCOX1, BeCOX2, KiCOX2) and physico-chemical descriptors (log Ppred., рКаpred., рКvpred.) were performed. By checking on an independent sample of 5 compounds, equation No. 3 (ААpred. 3 = 32,6215 – 4,4894 × Becox1 + 0,0066 × Kicox1 + 3,6032 × log Ppred. (R = 0,854, F = 9,01, S = 7,73, Q2LOO = 0,53) was found, with a high value of the correlation coefficient of the predicted values ААex. with experimental values (Rpred. = 0,878) and a minimum forecast error (Spred. = 6,74).Conclusion. The "structure-activity" models for predicting analgesic activity in a series of 5-N-arylaminocarbonyl-6-(get)aryl-4-methyl-1,2,3,6-tetrahydropyrimidine-2-thions are obtained. The result of the prediction of biological activity is confirmed by the values of the correlation coefficient (R) obtained when testing models on independent samples.

Cytokine regulation disbalance: the basis for COVID-19 immunopathogenesis

Coronavirus infection activates two main signaling pathways for type I and III IFN and the gene expression and synthesis of proinflammatory cytokines. These cytokines are required for antiviral defense and inflammatory reaction formation. SARS-CoV-2 coronavirus could inhibit the IFN system by depressing signaling pathways for IFN gene expression, synthesis, and secretion. IFN inhibition should be considered the primary reason for coronavirus escape from the immune system and a key factor for COVID-19 immunopathogenesis. Cytokine regulation disbalance in patients with severe COVID-19 is closely associated with low and delayed IFN synthesis, while proinflammatory cytokine production by macrophages and T-lymphocytes continues simultaneously with intensive virus replication. Thus, the reason for COVID-19 immunopathogenesis is the cytokine regulation disbalance where IFN inhibition and intensive proinflammatory cytokine synthesis lead to cytokine storm, inadequate inflammation, respiratory distress syndrome development, respiratory failure, systemic inflammatory complications, and polyorganic failure.

Peculiarities of cytokine and chemokine content in blood serum of children with psoriasis vulgaris

Psoriasis is a chronic auto-inflammatory skin disease with a hereditary predisposition due to the activation of T-lymphocytes and the synthesis of pro-inflammatory cytokines. The pathogenesis involves populations of Th1 and Th17 lymphocytes that produce TNFa, IFNy, IL-17, IL-21 and IL-23. The aim of the study was to identify the features of the content of cytokines and chemokines in the blood serum of children with psoriasis. 88 children with psoriasis of varying severity were examined. The level of circulating cytokines was determined by the multiplex method on the Bio-plex 200 device using the MILLIPLEX MAP Human Th17 kit. In children with psoriasis, increased levels of IL-23, IL-22, IL-12p70, IL-27, IL-17E, IL-17F and TNFa were detected. The consistency of the functioning of the cytokine network in children with psoriasis was shown, which was expressed in the high strength of the connection between cytokines of the IL-17 family and cytokines of the IL-12 family, between IL-31 and IL-33, as well as in significant correlations between GM-CSF and cytokines IL-2, IL-5, IL-9, IL-10, IL-15 and TNFa. In children with psoriasis, the dependence of the level of IL-17A, TNFa, IL-2, IL-6, IL-9, CCL20/MIP3a with the severity of the disease according to PASI was revealed. The study confirmed the pathogenetic role of the cytokine network in the development and maintenance of an inflammatory response in children with psoriasis. The data obtained substantiate the need for targeted anti-cytokine therapy. The level of proinflammatory cytokines in children with psoriasis can be used as an additional laboratory criterion for the severity of the condition and monitoring the effectiveness of therapy.

Immunoregulatory properties of the dry extract of the herb &lt;i&gt;Cichorium intybus L.&lt;/i&gt; in &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt; systems

Aim: to evaluate the effect of a dry extract of the herb of Cichorium intybus L. on the production of cytokines by human peripheral mononuclear cells in the systems in vitro and on the mass (thymus, spleen) and number of cells (thymus, spleen, bone marrow) of immune organs of mice in a model experiment of immunodeficiency in the systems in vivo.&#x0D; Materials and methods. The study of the immunoregulatory properties of the dry extract of chicory herb was evaluated by the ability to change the production of cytokines on the model of mononuclear cells during co-cultivation under in vitro conditions and by the ability to restore the mass (thymus, spleen) and the number of cells (thymus, spleen, bone marrow) of the organs of the immune system of outbred mice under conditions of immunosuppression induced by methotrexate to the level of intact mice in vivo.&#x0D; Results. An analysis of the immunoregulatory properties of dry extract of chicory herb in the systems in vitro showed that a solution of chicory extract increased the concentration of the anti-inflammatory cytokine IL-10 and reduced the production of pro-inflammatory cytokines TNFα, IL-6, IFNγ and anti-inflammatory cytokine IL-1Ra. Evaluation of the effect of the dry extract of chicory herb in the systems in vivo found that the dry extract of the herb of Cichorium intybus L. had no effect on the mass (thymus, spleen) and number of cells (thymus, spleen, bone marrow) of the immune system organs in intact mice and restored these parameters of the immune system in animals treated with cytostatic MTX to the level of intact animals, and the effect of the extract was comparable to the effect of the reference drug “Immunal”.&#x0D; Conclusion. The dry extract of the herb of Cichorium intybus L. can be considered as a promising agent that normalizes the parameters of the immune system under conditions of MTX-induced immunosuppression, suppresses the synthesis of pro-inflammatory cytokines and stimulates the secretion of anti-inflammatory IL-10, and the activity of this extract is associated with high content of phenolic compounds. Given the above, further study of chicory herb and dry extract from it is expedient and aimed at creating new effective herbal preparations that regulate the functions of the body’s immune system.

Остеоартрит и коморбидные заболевания: патогенетические связи

Secondary inflammatory processes, primarily synovitis, accompany the course of osteoarthritis, play a significant role in the formation of both clinical manifestations of the disease and further destruction of articular structures. In a patient with osteoarthritis over the age of 50, more than 5 diseases coexist simultaneously and there are practically no persons who do not have concomitant somatic diseases. Atherosclerosis refers to inflammatory diseases in which inflammation is associated with dyslipidemia and chronic immune dysregulation. It has been established that one of the main elements of atherothrombosis is an increase in the synthesis of proinflammatory cytokines. Common risk factors for primary osteoarthritis and cardiovascular diseases: age, overweight, heredity, metabolic disorders (high cholesterol, glucose tolerance, diabetes mellitus).

In silico molecular docking studies of 2, 4 and 2, 6-di-tert-butylphenol against NAGK and SPP1 proteins to recuperate rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that primarily affects the synovial joints. It is connected to progressive disability, early death and socioeconomic burdens. So, there is an urgent need to develop novel drugs that effectively treat patients at each stage of disease progression. N-acetylglucosamine kinase (NAGK) and secreted phosphoprotein 1(SPP1) are two attractive drug targets for RA. NAGK protein converts endogenous N-acetyl-D-glucosamine (GlcNAc) into GlcNAc 6-phosphate. GlcNAc has suppressive effects on experimental RA in mouse models. SPP1 stimulates the synthesis of a key proinflammatory cytokine implicated in the pathogenesis of RA. In order to design new drug candidates, crystal structure of human NAGK (PDB Id: 2CH5) was retrieved from the protein data bank. Amino acid sequence of SPP1 (Uniprot Id: P10451) was retrieved from uniprot database and modeled by the Phyre2 server. Computed SPP1 model energy was minimized using the YASARA energy minimization server and validated by the Ramachandran plot and the ProSA-web error-detection tool. 2, 4-Di-tert-butylphenol and 2, 6-Di-Tert-butylphenol are known compound isolates from bark extract of Schleichera oleosa having anti-arthritic and anti-inflammatory activities as accessed by PASS online server. These compounds were docked against active site of NAGK and SPP1 proteins using MTiAutoDock server. The binding affinity of these compounds against NAGK and SPP1 proteins ranges from -6.12 to -7.17 kcal/mol. The findings of this study will open the way for the development of herbal remedies for rheumatoid arthritis based on the Schleichera oleosa plant, potentially leading to the development of novel drugs.

6-Hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline Demonstrates Anti-Inflammatory Properties and Reduces Oxidative Stress in Acetaminophen-Induced Liver Injury in Rats.

We examined the effects of 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline on markers of liver injury, oxidative status, and the extent of inflammatory and apoptotic processes in rats with acetaminophen-induced liver damage. The administration of acetaminophen caused the accumulation of 8-hydroxy-2-deoxyguanosine and 8-isoprostane in the liver and serum, as well as an increase in biochemiluminescence indicators. Oxidative stress resulted in the activation of pro-inflammatory cytokine and NF-κB factor mRNA synthesis and increased levels of immunoglobulin G, along with higher activities of caspase-3, caspase-8, and caspase-9. The administration of acetaminophen also resulted in the development of oxidative stress, leading to a decrease in the level of reduced glutathione and an imbalance in the function of antioxidant enzymes. This study discovered that 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline reduced oxidative stress by its antioxidant activity, hence reducing the level of pro-inflammatory cytokine and NF-κB mRNA, as well as decreasing the concentration of immunoglobulin G. These changes resulted in a reduction in the activity of caspase-8 and caspase-9, which are involved in the activation of ligand-induced and mitochondrial pathways of apoptosis and inhibited the effector caspase-3. In addition, 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline promoted the normalization of antioxidant system function in animals treated with acetaminophen. As a result, the compound being tested alleviated inflammation and apoptosis by decreasing oxidative stress, which led to improved liver marker indices and ameliorated histopathological alterations.

CD137L Inhibition Ameliorates Hippocampal Neuroinflammation and Behavioral Deficits in a Mouse Model of Sepsis-Associated Encephalopathy

Anxiety manifestations and cognitive dysfunction are common sequelae in patients with sepsis-associated encephalopathy (SAE). Microglia-mediated inflammatory signaling is involved in anxiety, depression, and cognitive dysfunction during acute infection with bacterial lipopolysaccharide (LPS). However, the molecular mechanisms underlying microglia activation and behavioral and cognitive deficits in sepsis have not been in fully elucidated. Based on previous research, we speculated that the CD137 receptor/ligand system modulates microglia function during sepsis to mediate classical neurological SAE symptoms. A murine model of SAE was established by injecting male C57BL/6 mice with LPS, and cultured mouse BV2 microglia were used for in vitro assays. RT-qPCR, immunofluorescence staining, flow cytometry, and ELISA were used to assess microglial activation and the expression of CD137L and inflammation-related cytokines in the mouse hippocampus and in cultured BV2 cells. In addition, behavioral tests were conducted in assess cognitive performance and behavioral distress. Immunofluorescence and RT-qPCR analyses showed that hippocampal expression of CD137L was upregulated in activated microglia following LPS treatment. Pre-treatment with the CD137L neutralizing antibody TKS-1 significantly reduced CD137L levels, attenuated the expression of M1 polarization markers in microglia, and inhibited the production of TNF-α, IL-1β, and IL-6 in both LPS-treated mice and BV2 cells. Conversely, stimulation of CD137L signaling by recombinant CD137-Fc fusion protein activated the synthesis and release of pro-inflammatory cytokines in cultures BV2 microglia. Importantly, open field, elevated plus maze, and Y-maze spontaneous alternation test results indicated that TKS-1 administration alleviated anxiety-like behavior and spatial memory decline in mice with LPS-induced SAE. These findings suggest that CD137L upregulation in activated microglia critically contributes to neuroinflammation, anxiety-like behavior, and cognitive dysfunction in the mouse model of LPS-induced sepsis. Therefore, therapeutic modulation of the CD137L/CD137 signaling pathway may represent an effective way to minimize brain damage and prevent cognitive and emotional deficits associated with SAE.

Aflatoksin: Aspek kesehatan, metode reduksi dan deteksinya

Food contaminant aflatoxin is a mycotoxin produced by Aspergillus flavus and A. parasiticus. This article aims to discover the pathophysiological, immunological, pharmacological, toxicity, and reduction and detection methods of aflatoxin. Kinds of literature were obtained from Research Gate, Pubmed, and Science Direct with the primary keyword “aflatoxin”. Pathophysiologically, aflatoxin-contaminated food has been proven to cause necrosis in liver cells, developing into liver cancer. Immunologically, aflatoxin decreases monocyte and dendritic cell phagocytosis, neutrophil cell ATP production, and pro-inflammatory cytokine synthesis. Aflatoxin toxicity is at the LD50 of 12-16 mg/kg b.w, causing death. Pharmacologically, 120-201 µg/kg b.w causes aflatoxicosis, in vivo studies indicated that NovaSil, Sulfarophan, and Monanthotaxis caffra leaf extract may reduce its toxicity. Aflatoxins are highly thermostable; hence, once food has been contaminated, they cannot be destroyed by normal cooking process. The control and reduction should be conducted in post-harvest handling, common physical means practiced are heating, drying, and smoking. Chemically using ozone, 0.5 sodium bisulfate, 1% sodium hydroxide, 5% acetic acid, and prochloraz. Biologically using Flavobacterium aurantiacum B-184, Bacillus velezensis DY3108, and, a consortium of Geobacillus and Tepidimicrobium bacteria. Aflatoxin can be detected using TLC, HPLC, MS, ELISA, and UHPLC-ESI MS/MS. The prevention of aflatoxin occurrence is done through good post-harvest handling, good manufacturing practices, and applying regulations accordingly to ensure food products and feed are at acceptable levels of aflatoxin.

Cytokines in Liver Cirrhosis (Their Importance in Assessing Activity and Decompensation)

Aim: studying the role of pro-inflammatory and anti-inflammatory cytokines in the pathogenesis of liver cirrhosis progression.Materials and methods. The material of the study was the data of clinical-instrumental, biochemical, virological studies of 109 patients with liver cirrhosis of various etiologty, who were hospitalized in the clinic of the Institute of Gastroenterology (Dushanbe, Republic of Tajikistan). The diagnosis of the underlying disease was established according to the clinical recommendations of the Russian Society for the Study of the Liver and the Russian Gastroenterological Association for the diagnosis and treatment of liver fibrosis and cirrhosis and their complications (2021); decompensated liver cirrhosis was established according to the 1996 Child — Pugh classification. The age of the patients ranged from 17 to 79 years (36.9 ± 0.8 years), there were 55 men and 54 women.Results. Among the examined patients, compensated liver cirrhosis (Class A) according to Child — Pugh was detected in 18 persons, subcompensated (Class B) — in 14, decompensated (Class C) — in 77. The study of the content of pro-inflammatory and anti-inflammatory cytokines in the blood serum of patients with Class A liver cirrhosis showed, that levels of tumour necrosis factor alpha (TNF-α), interleukin-2, interleukin-6 were statistically higher compared to healthy individuals, while the concentration of anti-inflammatory interleukin-10 was lower (30.7 ± 4.7 pg/mL) in comparison with the control group. In patients with Class B liver cirrhosis, the level of TNF-α increased to 75.0 ± 4.5 pg/mL (p &lt; 0.001), interleukin-2 — to 328.7 ± 23.9 pg/mL (p &lt; 0.05), and interleukin-6 — to 95.4 ± 7.7 pg/mL (p &lt; 0.001). Serum interleukin-10 decreased compared with the control group (23.1 ± 2.8 pg/mL; p &gt; 0.05). At the decompensated stage of Class C cirrhosis, a huge release of pro-inflammatory cytokines occurs — the content of TNF-α increases by 80 times, of interleukin-2 — by more than 60 times, аs for interleukin-10, its content is progressively reduced.Conclusion. In liver cirrhosis, there is a significant disruption in the synthesis of pro-inflammatory cytokines, which is manifested by a sharp increase in the content of TNF-α, interleukin-2 and interleukin-6. High levels of proinflammatory cytokines in blood serum in liver cirrhosis correlate with the activity and degree of decompensation, which indicates their important role in the pathogenesis and progression of the pathological process.