Release Of Tumor Necrosis Factor Research Articles

Concomitant Assessment of Monocyte HLA-DR Expression and Ex Vivo TNF-α Release as Markers of Adverse Outcome after Various Injuries-Insights from the REALISM Study.

Intensive care unit (ICU) patients develop an altered host immune response after severe injuries. This response may evolve towards a state of persistent immunosuppression that is associated with adverse clinical outcomes. The expression of human leukocyte antigen DR on circulating monocytes (mHLA-DR) and ex vivo release of tumor necrosis factor α (TNF-α) by lipopolysaccharide-stimulated whole blood are two related biomarkers offered to characterize this phenomenon. The purpose of this study was to concomitantly evaluate the association between mHLA-DR and TNF-α release and adverse clinical outcome (i.e., death or secondary infection) after severe trauma, sepsis or surgery in a cohort of 353 ICU patients. mHLA-DR and TNF-α release was similarly and significantly reduced in patients whatever the type of injury. Persistent decreases in both markers at days 5–7 (post-admission) were significantly associated with adverse outcomes. Overall, mHLA-DR (measured by flow cytometry) appears to be a more robust and standardized parameter. Each marker can be used individually as a surrogate of immunosuppression, depending on center facilities. Combining these two parameters could be of interest to identify the most immunosuppressed patients presenting with a high risk of worsening. This last aspect deserves further exploration.

Susbstance P Levels in Children with Atopic Dermatitis

Background: Atopic dermatitis (AD) is the most common skin disease in infants and children. AD is influenced by hereditary and environmental factors, and it is characterized by an inflammatory reaction in the skin. In developing countries, children suffering from AD are estimated around 10–20%, of which 60% of the cases persist into adulthood. Substance P is a cutaneous neuropeptide that contributes to the pathogenesis of AD. Substance P promotes the production of nerve growth factors from keratinocytes, and the release of histamine, leukotriene, or tumor necrosis factor from mast cells, which cause the growth of sensory nerve fibers, augmentation of skin inflammation, and are considered pruritogenic factors. Purpose: This study aims to determine the description of substance P in children with atopic dermatitis using a descriptive observational study with a cross-sectional approach. Methods: This is a destructive observational study with a crossectional approach samples were selected from AD patients at the Universitas Sumatera Utara Hospital. Result: The largest group of subjects were childhood (2–12 years old), there was 60%, followed by the adolescent group (12–18 years old) and the infant group (<2 years old). In the childhood group, the highest level of substance P was found in girls with a mean of 349.03 ± 146.7. On the other hand, the highest levels of substance P in the adolescent were found in males with a mean of 243.73 ± 64.57 ng/L. Conclusion: In this study, we found that the level of substance p was higher in the childhood group.

Emodin alleviates sepsis-mediated lung injury via inhibition and reduction of NF-kB and HMGB1 pathways mediated by SIRT1.

Inflammation plays an important role during sepsis, and excessive inflammation can result in organ damage, chronic inflammation, fibrosis, and scarring. The study aimed to investigate the specific mechanism of emodin by constructing in vivo and in vitro septic lung injury models via inhibition and reduction of NF-kB and high mobility group box 1 (HMGB1) pathways. A cecal ligation and puncture (CLP) model was built for adult male Sprague-Dawley rats. Concentrations of TNF-α, IL-1β, and IL-6 in bronchoalveolar lavage fluid were determined using commercially available ELISA kits. Hematoxylin and eosin staining was used for the right lung inferior lobes. Myeloperoxidase (MPO) activity of the lung tissue was detected by using the MPO kit. Murine alveolar epithelial cell line (MLE-12) cells were used for flow cytometry and Western blot to analyze the apoptosis rate and protein expression. Emodin significantly decreased CLP-induced cell apoptosis, upregulated expression of sirtuin 1 (SIRT1), and inhibited p-p65/p65 and HMGB1. In lipopolysaccharide (LPS) treated cell model, emodin treatment markedly decreased LPS-induced release of IL-1, IL-6, and tumor necrosis factor (TNF)-α, inhibited LPS-induced cell apoptosis and suppressed protein levels of P-P65/P65 and HMGB1. However, science of SIRT1 reversed the above effects by treatment of emodin. In summarize, this study found that emodin can alleviate sepsis-induced lung injury in vivo and in vitro through regulation of SIRT1.

Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation.

Misdirected immunity gives rise to the autoimmune tissue inflammation of rheumatoid arthritis, in which excess production of the cytokine tumor necrosis factor (TNF) is a central pathogenic event. Mechanisms underlying the breakdown of self-tolerance are unclear, but T cells in the arthritic joint have a distinctive metabolic signature of ATPlo acetyl-CoAhi proinflammatory effector cells. Here we show that a deficiency in the production of mitochondrial aspartate is an important abnormality in these autoimmune T cells. Shortage of mitochondrial aspartate disrupted the regeneration of the metabolic cofactor nicotinamide adenine dinucleotide, causing ADP deribosylation of the endoplasmic reticulum (ER) sensor GRP78/BiP. As a result, ribosome-rich ER membranes expanded, promoting co-translational translocation and enhanced biogenesis of transmembrane TNF. ERrich T cells were the predominant TNF producers in the arthritic joint. Transfer of intact mitochondria into T cells, as well as supplementation of exogenous aspartate, rescued the mitochondria-instructed expansion of ER membranes and suppressed TNF release and rheumatoid tissue inflammation.

Bisdemethoxycurcumin Reduces Methicillin-Resistant Staphylococcus aureus Expression of Virulence-Related Exoproteins and Inhibits the Biofilm Formation.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen of nosocomial infection, which is resistant to most antibiotics. Presently, anti-virulence therapy and anti-biofilm therapy are considered to be promising alternatives. In the current work, we investigated the influence of bisdemethoxycurcumin (BDMC) on the virulence-related exoproteins and the biofilm formation using a reference strain and clinic isolated strains. Western blotting, quantitative RT-PCR, and tumor necrosis factor (TNF) release assay were performed to assess the efficacy of BDMC in reducing the expression of Staphylococcus enterotoxin-related exoproteins (enterotoxin A, enterotoxin B) and α-toxin in MRSA. The anti-biofilm activity of BDMC was evaluated through a biofilm inhibition assay. The study suggests that sub-inhibitory concentrations of BDMC significantly inhibited the expression of sea, seb, and hla at the mRNA level in MRSA. Moreover, the expression of virulence-related exoproteins was significantly decreased by down-regulating accessory gene regulator agr, and the inhibition of biofilms formation was demonstrated by BDMC at sub-inhibitory concentrations. Consequently, the study suggests that BDMC may be a potential natural antibacterial agent to release the pressure brought by antibiotic resistance.

Gasdermin D Mediates Inflammation-Driven Pathogenesis of the Myelodysplastic Syndromes

The myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell diseases characterize by cytopenia(s), dysplasia in one or more of the major myeloid cell lines, ineffective hematopoiesis, and increased risk of development of acute myeloid leukemia (AML). Growing evidence revealed the significance of pyroptotic cell death in the inflammatory bone marrow in MDS. However, the detailed mechanisms of pyroptosis in the pathogenesis and progression of MDS remain unknown.Gasdermin D is a pore-forming protein that is cleaved upon inflammasome assembly by inflammatory caspases at the linker between the N-terminus pore-forming domain and the C-terminus autoinhibitory domain. The activation of gasdermin D results in increased cell permeability, cell pyroptosis, and the release of cytokines including Interleukin 1 (IL-1) family. Binding of these cytokines to the IL-1 receptor triggers the activation and release of other pro-inflammatory cytokines, including IL-6 and tumor necrosis factor (TNF).Our group recently established a Diap1 (encoding mDia1) and miR-146a double knockout (DKO) mouse model phenocopying MDS. These two genes are involved in the innate immune signaling and inflammation. DKO mice develop aging-related anemia and thrombocytopenia with over-secretion of pro-inflammatory cytokines. Many DKO mice progress to acute myeloid leukemia (AML) with monocytic differentiation and bone marrow fibrosis at 12 months of age. We found that gasdermin D is upregulated and activated (cleaved) in the bone marrow and spleens of the DKO mice. To study the role of gasdermin D in MDS, we crossed DKO mice with gasdermin D knock out mice to generate gasdermin D, mDia1, miR-146a triple knock out (TKO) mice. Gasdermin D knock out in the background of DKO significantly antagonized the increase of leukocyte count, especially the monocyte count, in the aging mice, and partially rescued the anemia. We transplanted bone marrow from 5-month-old TKO, DKO, and wildtype mice to 5-month-old lethally irradiated mice, respectively, to investigate whether the rescue effect of gasdermin D knock out was hematopoietic cell intrinsic. As expected, TKO bone marrow transplanted (BMT) mice had significantly less leukocyte count compared with DKO BMT mice, the anemia was also ameliorated in TKO BMT mice. More importantly, gasdermin D depletion in hematopoietic cells significantly extended the survival of DKO mice and reverted the progression to AML, suggesting a critical role of GSDMD in the pathogenesis of MDS.These findings indicate that gasdermin D plays a pivotal role in inflammation related MDS development and progression. This is further supported by the evidence that gasdermin D is highly upregulated in patients with MDS in our preliminary immunohistochemical studies in the bone marrow from patients with different types of MDS. Therefore, targeting gasdermin D could be a novel therapeutic approach in the management of MDS. DisclosuresNo relevant conflicts of interest to declare.

Rab6b localizes to the Golgi complex in murine macrophages and promotes tumor necrosis factor release in response to mycobacterial infection.

The proinflammatory cytokine tumor necrosis factor (TNF) plays a central role in the host control of mycobacterial infections. Expression and release of TNF are tightly regulated, yet the molecular mechanisms that control the release of TNF by mycobacteria-infected host cells, in particular macrophages, are incompletely understood. Rab GTPases direct the transport of intracellular membrane-enclosed vesicles and are important regulators of macrophage cytokine secretion. Rab6b is known to be predominantly expressed in the brain where it functions in retrograde transport and anterograde vesicle transport for exocytosis. Whether it executes similar functions in the context of immune responses is unknown. Here we show that Rab6b is expressed by primary mouse macrophages, where it localized to the Golgi complex. Infection with Mycobacterium bovis bacille Calmette-Guérin (BCG) resulted in dynamic changes in Rab6b expression in primary mouse macrophages in vitro as well as in organs from infected mice in vivo. We further show that Rab6b facilitated TNF release by M. bovis BCG-infected macrophages, in the absence of discernible impact on Tnf messenger RNA and intracellular TNF protein expression. Our observations identify Rab6b as a positive regulator of M. bovis BCG-induced TNF trafficking and secretion by macrophages and positions Rab6b among the molecular machinery that orchestrates inflammatory cytokine responses by macrophages.

Carbon-Based Nanomaterials Increase Reactivity of Primary Monocytes towards Various Bacteria and Modulate Their Differentiation into Macrophages.

The evaluation of carbon-based nanomaterials’ (C-BNMs’) interactions with the immune system, notably their ability to cause inflammation, is a critical step in C-BNM health risk assessment. Particular attention should be given to those C-BNMs that do not cause direct cytotoxicity or inflammation on their own. However, the intracellular presence of these non-biodegradable nanomaterials could dysregulate additional cell functions. This is even more crucial in the case of phagocytes, which are the main mediators of defensive inflammation towards pathogens. Hence, our study was focused on multi-walled carbon nanotubes (MWCNTs) and two different types of graphene platelets (GPs) and whether their intracellular presence modulates a proinflammatory response from human primary monocytes towards common pathogens. Firstly, we confirmed that all tested C-BNMs caused neither direct cytotoxicity nor the release of tumour necrosis factor α (TNF-α), interleukin (IL)-6 or IL-10. However, such pre-exposed monocytes showed increased responsiveness to additional bacterial stimuli. In response to several types of bacteria, monocytes pre-treated with GP1 produced a significantly higher quantity of TNF-α, IL-6 and IL-10. Monocytes pre-treated with MWCNTs produced increased levels of IL-10. All the tested C-BNMs enhanced monocyte phagocytosis and accelerated their differentiation towards macrophages. This study confirms the immunomodulatory potential of C-BNMs.

A-Lipoic Acid Alleviates Folic Acid-Induced Renal Damage Through Inhibition of Ferroptosis.

Folic acid (FA)-induced acute kidney injury (AKI) is characterized by the disturbance of redox homeostasis, resulting in massive tubular necrosis and inflammation. Α-lipoic acid (LA), as an antioxidant, has been reported to play an important role in renal protection, but the underlying mechanism remains poorly explored. The aim of this study is to investigate the protective effect of LA on FA-induced renal damage. Our findings showed that LA could ameliorate renal dysfunction and histopathologic damage induced by FA overdose injection. Moreover, FA injection induced severe inflammation, indicated by increased release of pro-inflammatory cytokines tumor necrosis factor (TNF)-α and IL-1β, as well as infiltration of macrophage, which can be alleviated by LA supplementation. In addition, LA not only reduced the cellular iron overload by upregulating the expressions of Ferritin and ferroportin (FPN), but also mitigated reactive oxygen species (ROS) accumulation and lipid peroxidation by increasing the levels of antioxidant glutathione (GSH) and glutathione peroxidase-4 (GPX4). More importantly, we found that LA supplementation could reduce the number of Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive tubular cells caused by FA, indicating that the tubular cell death mediated by ferroptosis may be inhibited. Further study demonstrated that LA supplementation could reverse the decreased expression of cystine/glutamate antiporter xCT (SLC7A11), which mediated GSH synthesis. What is more, mechanistic study indicated that p53 activation was involved in the inhibitory effect of SLC7A11 induced by FA administration, which could be suppressed by LA supplementation. Taken together, our findings indicated that LA played the protective effect on FA-induced renal damage mainly by inhibiting ferroptosis.

Network Pharmacology Analysis of the Identification of Phytochemicals and Therapeutic Mechanisms of Paeoniae Radix Alba for the Treatment of Asthma.

BackgroundPaeoniae Radix Alba (PRA), the root of the plant Paeonia lactiflora Pall., has been suggested to play an important role for the treatment of asthma. A biochemical understanding of the clinical effects of Paeoniae Radix Alba is needed. Here, we explore the phytochemicals and therapeutic mechanisms via a systematic and comprehensive network pharmacology analysis. Methods Through TCMSP, PubChem, GeneCards database, and SwissTargetPrediction online tools, potential targets of active ingredients from PRA for the treatment of asthma were obtained. Cytoscape 3.7.2 was used to determine the target of active ingredients of PRA. Target protein interaction (PPI) network was constructed through the STRING database. The Gene Ontology (GO) biological process and Kyoto Encyclopedia of Genes and Genes (KEGG) pathway enrichment analysis were analyzed through the biological information annotation database (DAVID). Results Our results indicate that PRA contains 21 candidate active ingredients with the potential to treat asthma. The enrichment analysis of GO and KEGG pathways found that the treatment of asthma by PRA may be related to the process of TNF (tumor necrosis factor) release, which can regulate and inhibit multiple signaling pathways such as ceramide signaling. Conclusions Our work provides a phytochemical basis and therapeutic mechanisms of PRA for the treatment of asthma, which provides new insights on further research on PRA.

Affinity-Guided Isolation and Identification of Procyanidin B2 from Mangosteen (Garcinia mangostana L.) Rinds and its In Vitro LPS Binding and Neutralization Activities.

Garcinia mangostana L. (mangosteen) is a tropical fruit that has been used for medicinal purposes in Southeast Asia for centuries. With an interest in its applications to treat infection, we sought to investigate the bioactive constituents of mangosteen and identified the phenolic compound procyanidin B2 from the mangosteen pericarp by examining lipopolysaccharide (LPS) binding capacity. The LPS binding and neutralization activities of procyanidin B2 were determined by a combination of biophysical and in silico techniques. The affinity of procyanidin B2 to LPS was 1.61 × 10-5M. Procyanidin B2 significantly neutralized LPS and selectively inhibited the LPS-induced release of tumor necrosis factor (TNF)-α from RAW264.7 cells in a dose-dependent manner. Binding thermodynamics revealed favorable hydrogen bonding and hydrophobic interactions between procyanidin B2 and LPS. Molecular simulations suggested that hydrogen bonding and hydrophobic interactions were involved in the binding process. These findings have, for the first time, shed light on the anti-inflammatory properties of procyanidin B2 through LPS binding and neutralization and provided a promising lead for the development of antiendotoxin agents.

Biochemical Assessment As Markers For Diagnosis And Evaluation Hepatitis B Virus (HBV)

Abstract 
 This paper summarizes assessment biochemical markers of the development of hepatitis B viruses (HBV), in which any possible connection between certain biochemical parameters and chronic hepatitis was identified. Liver function tests are helpful in diagnosing liver disease and dysfunction, assessing severity, tracking treatment, and determining prognosis. According to the findings of biochemical studies, chronic patients have higher levels of ALP, GPT, GOT, and TSB than carriers. The rise in liver enzymes strongly indicates hepatocellular damage, despite the fact that ALP, GPT, GOT, and TSB levels in the carrier group were all within normal parameters as compared to the reference group. Testing liver function in terms of protein level, albumin, and globulin, the concentration of protein profiles in chronic patients is clearly decreasing as compared to the carrier group. In severe or long-lasting liver disease, the significant decreasing profile of serum proteins is evident in some conditions, the release of tumor necrosis factor hampers the synthesis of albumin, however, induce the synthesis of the acute phase response, hypoalbuminemia is multifactorial, while the hepatic synthesis of albumin is decreased in liver disease.

Circ_USP36 Silencing Attenuates Oxidized Low-Density Lipoprotein-Induced Dysfunction in Endothelial Cells in Atherosclerosis Through Mediating miR-197-3p/ROBO1 Axis.

Circular RNAs (circRNAs) are reported to play pivotal regulatory roles in atherosclerosis progression. In the present study, we explored the biological role of circRNA ubiquitin-specific peptidase 36 (circ_USP36; hsa_circ_0003204) in oxidized low-density lipoprotein (ox-LDL)-induced dysfunction of endothelial cells (ECs). RNA and protein levels were determined by reverse transcription-quantitative polymerase chain reaction and Western blot assay, respectively. Cell proliferation was analyzed by 5-ethynyl-2'-deoxyuridine assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometry was conducted to analyze cell cycle progression and cell apoptosis. The release of tumor necrosis factor α in the supernatant was measured by enzyme linked immunosorbent assay. Cell death was evaluated by lactate dehydrogenase assay. Intermolecular interaction was verified by dual-luciferase reporter assay. Circ_USP36 expression was significantly up-regulated in the serum of atherosclerosis patients and ox-LDL-stimulated HUVECs than that in their corresponding controls. ox-LDL exposure inhibited the proliferation ability and cell cycle progression and triggered the apoptosis and inflammation of HUVECs, and these effects were largely overturned by the knockdown of circ_USP36. microRNA-197-3p (miR-197-3p) was a target of circ_USP36, and circ_USP36 knockdown-mediated protective role in ox-LDL-induced HUVECs was largely counteracted by the silence of miR-197-3p. miR-197-3p interacted with the 3' untranslated region of roundabout guidance receptor 1 (ROBO1). Circ_USP36 knockdown reduced ROBO1 expression partly by up-regulating miR-197-3p in HUVECs. ROBO1 overexpression reversed miR-197-3p accumulation-mediated effects in ox-LDL-induced HUVECs. In conclusion, circ_USP36 interference alleviated ox-LDL-induced dysfunction in HUVECs by targeting miR-197-3p/ROBO1 axis.

Inflammatory Cytokine Profile and Plasticity of Brain and Spinal Microglia in Response to ATP and Glutamate.

Microglia are the primary cells in the central nervous system that identify and respond to injury or damage. Such a perturbation in the nervous system induces the release of molecules including ATP and glutamate that act as damage-associated molecular patterns (DAMPs). DAMPs are detected by microglia, which then regulate the inflammatory response in a manner sensitive to their surrounding environment. The available data indicates that ATP and glutamate can induce the release of pro inflammatory factors TNF (tumor necrosis factor), IL-1β (interleukin 1 beta), and NO (nitric oxide) from microglia. However, non-physiological concentrations of ATP and glutamate were often used to derive these insights. Here, we have compared the response of spinal cord microglia (SM) relative to brain microglia (BM) using physiologically relevant concentrations of glutamate and ATP that mimic injured conditions in the central nervous system. The data show that ATP and glutamate are not significant modulators of the release of cytokines from either BM or SM. Consistent with previous studies, spinal microglia exhibited a general trend toward reduced release of inflammatory cytokines relative to brain-derived microglia. Moreover, we demonstrate that the responses of microglia to these DAMPs can be altered by modifying the biochemical milieu in their surrounding environment. Preconditioning brain derived microglia with media from spinal cord derived mixed glial cultures shifted their release of IL-1ß and IL-6 to a less inflammatory phenotype consistent with spinal microglia.

Клиническое значение энтезитов при спондилоартритах: от патофизиологии к лечению (обзор литературы)

В статье представлены новейшие взгляды относительно анатомии и патогенеза энтезитов, клинических особенностей, возможностей диагностики и лечения. Поражение энтезисов считается отличительным патолого-клиническим признаком группы спондилоартритов; этот симптом включен в классификационные критерии Международной группы по изучению спондилоартритов (ASAS) для периферических и аксиальных форм. Типичными локализациями энтезитов при спондилоартрите являются: место прикрепления ахиллового сухожилия и подошвенного апоневроза к пяточной кости, латеральный мыщелок плечевой кости, медиальный мыщелок бедренной кости, верхний край надколенника, верхний край подвздошных костей, вертелы бедренных костей, остистые отростки позвонков. Структуры, сосредоточенные в области энтезисов, имеют анатомическую, функциональную и физиологическую взаимосвязь и формируют единый синовиально-энтезиальный комплекс. В отличие от ревматоидного артрита, при котором основной патологический процесс проходит в синовиальной оболочке, при спондилоартритах основой морфологических изменений являются энтезиты, а развивающийся артрит (синовит) является вторичным по отношению к энтезитам. Энтезит выявляется у 30–50 % пациентов со спондилоартритами и ассоциируется с более высокой активностью, высокими показателями боли и худшим качеством жизни. Наличие энтезитов у больных псориатическим артритом ассоциируется с поражением осевых и периферических суставов, высокой вероятностью анкилозирования, высокой активностью заболевания, выраженными болями, ухудшением качества жизни и функционального состояния, нарушением сна. Кроме того, энтезит рассматривается как предвестник негативного прогноза заболевания и может предсказывать меньшую вероятность достижения ремиссии и низкой активности. Энтезиальное воспаление возникает в результате механического и/или инфекционного стресса, приводя к активации простагландина E2 и интерлейкина-23 с последующей вазодилатацией и активацией Т-клеток и врожденных лимфоидных клеток типа 3. Дальнейшее воспаление в результате активации врожденного иммунитета характеризуется высвобождением фактора некроза опухолей и интерлейкина-17, что приводит к притоку иммунных клеток, таких как полиморфноядерные нейтрофилы. Пролиферация мезенхимы под влиянием интерлейкина-17 и -22 характеризуется активацией и пролиферацией резидентных мезенхимальных стволовых клеток надкостницы. Лечебные стратегии остаются неопределенными при энтезитах. Чаще всего используют нестероидные противовоспалительные препараты, локальные инъекции глюкокортикоидов, апремиласт, а также таргетные препараты — ингибиторы фактора некроза опухоли и интерлейкинов-17 и -23.

Therapeutic Potential of Vagus Nerve Stimulation for Inflammatory Bowel Diseases.

The vagus nerve is a mixed nerve, comprising 80% afferent fibers and 20% efferent fibers. It allows a bidirectional communication between the central nervous system and the digestive tract. It has a dual anti-inflammatory properties via activation of the hypothalamic pituitary adrenal axis, by its afferents, but also through a vago-vagal inflammatory reflex involving an afferent (vagal) and an efferent (vagal) arm, called the cholinergic anti-inflammatory pathway. Indeed, the release of acetylcholine at the end of its efferent fibers is able to inhibit the release of tumor necrosis factor (TNF) alpha by macrophages via an interneuron of the enteric nervous system synapsing between the efferent vagal endings and the macrophages and releasing acetylcholine. The vagus nerve also synapses with the splenic sympathetic nerve to inhibit the release of TNF-alpha by splenic macrophages. It can also activate the spinal sympathetic system after central integration of its afferents. This anti-TNF-alpha effect of the vagus nerve can be used in the treatment of chronic inflammatory bowel diseases, represented by Crohn’s disease and ulcerative colitis where this cytokine plays a key role. Bioelectronic medicine, via vagus nerve stimulation, may have an interest in this non-drug therapeutic approach as an alternative to conventional anti-TNF-alpha drugs, which are not devoid of side effects feared by patients.

Langerhans Cells Correlate With Macrophages for Defense Mechanisms in the Atrophic Epithelium of Radicular Cysts.

Langerhans cells (LCs) play important roles in cell-mediated immune reactions, as well as in the pathogenesis of periapical lesions. The aim of this study is to evaluate the role of LCs in the proliferative epithelium of radicular cysts (RCs) and the release of the proinflammatory cytokine tumor necrosis factor α (TNF-α) associated with epithelial thickness. Thirty cases of RCs and 30 cases of residual RCs were randomly selected. Morphologic analysis was performed to evaluate the association between the inflammatory infiltrate, cystic epithelial thickness and lesion size, in addition to immunohistochemical assessment of CD1a, CD68, and TNF-α. The highest macrophage percentages and TNF-α scores were found in RCs (P=0.038 and 0.017, respectively). The largest number of LCs was observed in RCs (P=0.021), especially those exhibiting atrophic epithelium (P=0.05). In addition, LCs were positively correlated with the number of macrophages in both RCs and residual RCs (P=0.033 and 0.002, respectively). In contrast to LCs, the largest number of macrophages was detected in cases with an intense inflammatory infiltrate (P=0.022). In addition, the highest TNF-α scores were associated with an intense inflammatory infiltrate (P=0.024) when analyzed in the capsule of RCs (P=0.017). In conclusion, LCs participate in defense mechanisms and were present in all cases evaluated. Along with macrophages, these cells release proinflammatory cytokines such as TNF-α, which is responsible for inducing the continued proliferation of cystic epithelium.

Induction of Krüppel-Like Factor 4 Mediates Polymorphonuclear Neutrophil Activation in Streptococcus pneumoniae Infection.

The recruitment and activation of polymorphonuclear neutrophils (PMNs) are of central importance for the elimination of pathogens in bacterial infections. We investigated the Streptococcus pneumoniae-dependent induction of the transcription factor Krüppel-like factor (KLF) 4 in PMNs as a potential regulator of PMN activation. We found that KLF4 expression is induced in human blood-derived PMNs in a time- and dose-dependent manner by wild-type S. pneumoniae and capsule knockout mutants. Unencapsulated knockout mutants induced stronger KLF4 expression than encapsulated wild types. The presence of autolysin LytA-competent (thus viable) pneumococci and LytA-mediated bacterial autolysis were required for KLF4 induction in human and murine PMNs. LyzMcre-mediated knockdown of KLF4 in murine blood-derived PMNs revealed that KLF4 influences pneumococci killing and increases the release of the proinflammatory cytokines tumor necrosis factor α and keratinocyte chemoattractant and decreases the release of the anti-inflammatory cytokine interleukin-10. Thus, S. pneumoniae induces KLF4 expression in PMNs, which contributes to PMN activation in S. pneumoniae infection.

Influence of Nanoparticle-Loaded Edaravone on Postoperative Effects in Patients with Cerebral Hemorrhage.

In order to explore the influence of nanoparticle-loaded edaravone on postoperative effects in patients with cerebral hemorrhage, a total of 120 patients who were diagnosed as cerebral hemorrhage and underwent minimally invasive hematoma removal at the designated hospital by the study from December 2014 to December 2018 were selected as research objects and divided into three groups according to the random number table method: edaravone treatment (ET) group, nanoparticle-loaded edaravone treatment (NET) group, and combined treatment (CT) group with 40 patients in each group. Three groups of patients underwent routine treatments based on their conditions, including regulating blood sugar, regulating blood pressure, anti-infection, nutritional support, and managing complications, in which 25 mg edaravone injection and 100 ml saline were added for patients in NET and CT group on the basis of the routine treatment of patients in ET group. The results showed that, after 15 days of standard treatment, the 40 patients in NET group had significantly improved neurological function than that before the treatment; the secretion of inflammatory factors in peripheral serum increased on the 7th day of treatment and decreased on the 14th day of treatment; there was no statistically significant difference in edema volume before treatment and the edema volume in the NET group was (11.56±0.44) mL after treatment, which was significantly smaller than that in ET group of (14.63±1.15) mL and the difference between the three groups was statistically significant (P <0.05). Therefore, it is believed that nanoparticle-loaded edaravone has an important effect on the postoperative effect of patients with cerebral hemorrhage; it can significantly improve the neurological function of patients with cerebral hemorrhage after minimally invasive drainage, and obviously reduce the production and release of interleukin and tumor necrosis factor, which is beneficial to protect healthy brain tissue and other organs throughout the body, and is conducive to the recovery and healing of cerebral hemorrhage. The results of this study provide a reference for further research on the influence of nanoparticle-loaded edaravone on postoperative effects in patients with cerebral hemorrhage.

The Threshold Effect: Lipopolysaccharide-Induced Inflammatory Responses in Primary Macrophages Are Differentially Regulated in an iRhom2-Dependent Manner.

A well-controlled innate immune response is characterized by a rapid yet self-limiting inflammatory response. Although much is known about the range of inflammatory stimuli capable of triggering an innate immune response, the mechanisms which govern the degree of inflammation induced by inflammatory insults and the mechanisms in place to reset or maintain homeostasis are poorly understood. Tumor necrosis factor (TNF) is a potent early response pro-inflammatory cytokine produced by immune cells following a broad range of insults spanning autoimmunity and metabolic diseases to pathogenic infections. Previous studies have shown that a disintegrin and metalloproteinase (ADAM) 17 controls the release of soluble TNF and epidermal growth factor receptor signaling. Utilizing a genetic model of ADAM17 deficiency through the deletion of its regulator, the inactive rhomboid 2 (iRhom2), we show that loss of ADAM17 activity in innate immune cells leads to decreased expression of various cytokines in response to low levels of pathogen-associated molecular pattern (PAMP) stimulation but not at high-dose stimulation. In addition, TNF receptor (TNFR) 1/2-deficient bone marrow-derived macrophages yielded significantly reduced TNF expression following low levels of PAMP stimulation, suggesting that signaling through the TNFRs in immune cells drives a feed-forward regulatory mechanism wherein low levels of TNF allow sustained enhancement of TNF expression in an iRhom2/ADAM17-dependent manner. Thus, we demonstrate that inflammatory expression of TNF and IL1β is differentially regulated following high or low doses of PAMP stimulation, invoking the activation of a previously unknown regulatory mechanism of inflammation.