Overexpression Of Proinflammatory Cytokines Research Articles

EPIGENETIC INTERPLAY BETWEEN H3K27ME3 AND MIR-146A/B ON THE PROTECTIVE ROLE OF THE NUTRACEUTICAL OLEOCANTHAL IN OSTEOARTHRITIS

Purpose: Osteoarthritis (OA) is a multifactorial, chronic disease that affects the joint by progressively degrading the extracellular matrix (ECM), compromising cartilage integrity. Traditionally, OA has not been considered an inflammatory condition, but recent research has elucidated the significant role of inflammation-related molecules on its pathogenesis. Proinflammatory cytokines overexpression can occur as a consequence of aberrant epigenetic modulation of their genes, which are implicated in the ECM catabolism.

Effect of Cerium Oxide on Kidney and Lung Tissue in Rats with Testicular Torsion/Detorsion.

Introduction Testicular torsion is a surgical emergency that results in testicular ischemia as a result of rotation of the spermatic cord around itself. Oxidative damage occurs in the testis and distant organs with the overproduction of free radicals and overexpression of proinflammatory cytokines by reperfusion after surgery. In this study, we aimed to investigate the effects of cerium oxide (CeO2), an antioxidant nanoparticle, on lung and kidney tissues in testicular torsion/detorsion (T/D) in rats. Materials and Methods After ethics committee approval, 24 rats were equally (randomly) divided into 4 groups. Left inguinoscrotal incision was performed in the control (C) group. In group CeO2, 0.5 mg/kg CeO2 was given intraperitoneally 30 minutes before inguinoscrotal incision. In group T/D, unilateral testicular T/D was achieved by performing an inguinoscrotal incision and rotating the left testis 720° clockwise, remaining ischemic for 120 minutes, followed by 120 minutes of reperfusion. In group CeO2-T/D, 0.5 mg/kg CeO2 was given intraperitoneally 30 minutes before testicular T/D. At the end of the experiment, lung and kidney tissues were removed for histopathological and biochemical examinations. Results Glomerular vacuolization (GV), tubular dilatation (TD), tubular cell degeneration and necrosis (TCDN), leukocyte infiltration (LI), and tubular cell spillage (TCS) in renal tissue were significantly different between groups (p = 0.012, p = 0.049, p < 0.003, p = 0.046, and p = 0.049, respectively). GV and TCDN were significantly decreased in group CeO2-T/D compared to group T/D (p = 0.042 and p = 0.029, respectively). Lung tissue neutrophil infiltration, alveolar thickening, and total lung injury score (TLIS) were significantly different between groups (p = 0.006, p = 0.001, and p = 0.002, respectively). Neutrophil infiltration and TLIS were significantly decreased in group CeO2-T/D compared to group T/D (p = 0.013 and p = 0.033, respectively). Lung and kidney tissue oxidative stress parameters were significantly different between groups (p < 0.05). Renal tissue glutathione-s-transferase (GST), catalase (CAT), and paraoxonase (PON) activities were significantly higher, and malondialdehyde (MDA) levels were significantly lower in group CeO2-T/D than in group T/D (p = 0.049, p = 0.012, p < 0.001, and p = 0.004, respectively). GST and PON activities were higher, and MDA levels were lower in group CeO2-T/D than in group T/D in the lung tissue (p = 0.002, p < 0.001, and p = 0.008, respectively). Discussion. In our study, cerium oxide was shown to reduce histopathological and oxidative damage in the lung and kidney tissue in a rat testis torsion/detorsion model.

Neutralization of interleukin-11 attenuates silica particles-induced pulmonary inflammation and fibrosis in vivo

Environmental exposure to crystalline silica particles can lead to silicosis, which is one of the most serious pulmonary interstitial fibrosis around the world. Unfortunately, the exact mechanism on silicosis is unclear, and the effective treatments are lacking to date. In this study, we aim to explore the molecular mechanism by which interleukin-11 (IL-11) affects silica particles-induced lung inflammation and fibrosis. We observed that IL-11 expressions in mouse lungs were significantly increased after silica exposure, and maintained at high levels across both inflammation and fibrosis phase. Immunofluorescent dual staining further revealed that the overexpression of IL-11 mainly located in mouse lung epithelial cells and fibroblasts. Using neutralizing anti-IL-11 antibody could effectively alleviate the overexpression of pro-inflammatory cytokines (i.e., interleukin-6 and tumor necrosis factor-α) and fibrotic proteins (i.e., collagen type I and matrix metalloproteinase-2) induced by silica particles. Most importantly, the expressions of IL-11 receptor subunit α (IL-11Rα), Glycoprotein 130 (GP130), and phosphorylated extracellular signal-regulated kinase (p-ERK) were significantly increased in response to silica, whereas blocking of IL-11 markedly reduced their levels. All findings suggested that the overexpression of IL-11 was involved in the pathological of silicosis, while neutralizing IL-11 antibody could effectively alleviate the silica-induced lung inflammation and fibrosis by inhibiting the IL-11Rα/GP130/ERK signaling pathway. IL-11 might be a promising therapeutic target for lung inflammation and fibrosis caused by silica particles exposure.

A Multitarget Therapeutic Peptide Derived From Cytokine Receptors Based on in Silico Analysis Alleviates Cytokine-Stimulated Inflammation.

Septicemia is a severe inflammatory response caused by the invasion of foreign pathogens. Severe sepsis-induced shock and multiple organ failure are the two main causes of patient death. The overexpression of many proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6, is closely related to severe sepsis. Although the treatment of sepsis has been subject to many major breakthroughs of late, the treatment of patients with septic shock is still accompanied by a high mortality rate. In our previous research, we used computer simulations to design the multifunctional peptide KCF18 that can bind to TNF-α, IL-1β, and IL-6 based on the binding regions of receptors and proinflammatory cytokines. In this study, proinflammatory cytokines were used to stimulate human monocytes to trigger an inflammatory response, and the anti-inflammatory ability of the multifunctional KCF18 peptide was further investigated. Cell experiments demonstrated that KCF18 significantly reduced the binding of proinflammatory cytokines to their cognate receptors and inhibited the mRNA and protein expressions of TNF-α, IL-1β, and IL-6. It could also reduce the expression of reactive oxygen species induced by cytokines in human monocytes. KCF18 could effectively decrease the p65 nucleus translocation induced by cytokines, and a mice endotoxemia experiment demonstrated that KCF18 could reduce the expression of IL-6 and the increase of white blood cells in the blood stimulated by lipopolysaccharides. According to our study of tissue sections, KCF18 alleviated liver inflammation. By reducing the release of cytokines in plasma and directly affecting vascular cells, KCF18 is believed to significantly reduce the risk of vascular inflammation.

Metabolic Syndrome and Its Components in Psoriatic Arthritis.

Psoriatic arthritis (PsA) is a well-known inflammatory disorder with a wide variety of phenotypes that extend beyond the joints. It has been defined as an immune-mediated disorder in which Th-1 and Th-17 cells play a key role. It has been associated with an elevated risk of metabolic syndrome (MetS), which is characterized by abdominal obesity, hypertension, hyperglycemia, and hyperlipidemia. While the exact pathophysiology of the link between PsA and MetS has yet to be precisely determined, persistence of inflammatory abnormalities, with overexpression of pro-inflammatory cytokines, might be the cause. Studies have consistently emphasized the strong association between elevated risk of developing cardiovascular disease and MetS in individuals with underlying PsA. The literature has also shown an association between the increased PsA severity and the increased frequency of MetS components. This association has important clinical consequences when treating patients with PsA. Therefore, screening programs should be implemented for PsA patients to evaluate whether they have MetS, and appropriate treatment should be given to manage cardiometabolic risk factors. Patients should also be closely monitored for potential adverse treatment effects on co-morbidities. This article summarizes the evidence of associations between several components of MetS and PsA and analyzes the impact of treatment on these factors.

Multivalent peptide dendrimers inhibit the fusion of viral-cellular membranes and the cellular NF-κB signaling pathway

The binding of the influenza A virus (IAV) to host cells is multivalent interactions between the hemagglutinin (HA) trimer and sialic acid residues on the cell surface, which present a challenge for the development of efficient antiviral drugs interfering with the entry of IAV into host cells. In this study, a number of multivalent peptide dendrimers targeting the HA2 subunit of HA to block the fusion between viral-cellular membranes have been created, of which FMOC-4-KKWK showed the lowest cytotoxicity, while in the nanomolar concentration range of antiviral effects. In addition to being active against a panel of various subtypes of influenza viruses, these dendrimers reduced the levels of NF-κB in RAW 264.7 cells and inhibited the overexpression of proinflammatory cytokines of TNF-α, IL-1β, and IL-6 that are associated with the influenza infection. Further tests in mice infected with a lethal dose of PR8 virus showed that these dendrimers increased the survival rate of mice, and reduced the viral load in the lungs. Significantly, this is the first report describing peptide dendrimers that target the HA2 subunit of IAV, differing from those using carbohydrates as ligands to block the adsorption of viruses to host cells.

Increased circulating levels of High Mobility Group Box 1 (HMGB1) in acute-phase Chikungunya virus infection: Potential disease biomarker.

Chikungunya virus (CHIKV) causes a febrile syndrome with intense and debilitating arthralgia that can persist for several months or years after complete virus clearance. As there is no specific antiviral treatment or vaccine against CHIKV, identification of serological markers that help clinical management of CHIKV patients is urgent. The High Mobility Group Box 1 (HMGB1) protein is secreted to extracellular milieu and triggers an intense inflammatory process by inducing the overexpression of pro-inflammatory cytokines. HMGB1 plays an important role in several virus diseases as well as in rheumatoid arthritis. This study focus on the investigation of HMGB1 serum levels in a sera panel from CHIKV-infected patients in an attempt to assess its potential as a biomarker for chikungunya clinical management. Eighty CHIKV-positive samples and 32 samples from healthy donors were subjected to a quantitative HMGB1 ELISA assay to assess the HMGB1 circulating levels. HMGB1 levels were significantly higher in CHIKV-positive samples (516.12ng/mL, SEM±48.83ng/mL) compared to negative control (31.20ng/mL, SEM±3.24ng/mL, p<0.0001). Circulating levels of HMGB1 persisted elevated during the whole acute-phase of disease and correlated with virus titer (p<0.05). The present study is the first to describe increased serum levels of HMGB1 in CHIKV infection and its positive correlation with virus titer, suggesting its potential use as a biomarker for diagnosis and treatment of chikungunya fever.

Ingestion of Sudan IV-adulterated palm oil impairs hepato-renal functions and induces the overexpression of pro-inflammatory cytokines: A sub-acute murine model

ABSTRACT Palm oil (PO), the most utilized vegetable oil, continues to be the object of adulteration, especially with Sudan-IV dye (S4D), notwithstanding the health implications of such acts. This study investigated the effects of S4D-adulterated PO on tissue damage/function and inflammatory status. Thirty male albino rats were grouped into five (- n=6); Control, PO, PO+S4D (100 mg/kg), PO+S4D (250 mg/kg), and S4D (250 mg/kg) and treated for 21 days. Exposure to S4D occasioned significant (p < 0.05) elevations in the serum activities of ALT, AST, ALP, and LDH. Contrastingly, the activities of these enzymes were reduced in the liver and kidneys. Serum levels of uric acid, BUN, and creatinine were also elevated in the serum of S4D-exposed rats. Gene expression analyses revealed upregulated expression of CRP and COX-2 in the liver of S4D-exposed rats, while the expression of IL-10 and BAX were downregulated compared to the control group. In the kidneys, exposure to S4D upregulated the expressions of TNFα, IL-1β, and KIM-1 compared to control. Our resultspresent empirical evidence of the adverse effects of adulterating PO with S4D, highlighted by the impaired hepatic and renal function, as well as pro-inflammatory responses elicited in rats exposed to S4D, via PO and alone.

Cytokine storm and histopathological findings in 60 cases of COVID-19-related death: from viral load research to immunohistochemical quantification of major players IL-1\u03b2, IL-6, IL-15 and TNF-\u03b1

This study involves the histological analysis of samples taken during autopsies in cases of COVID-19 related death to evaluate the inflammatory cytokine response and the tissue localization of the virus in various organs. In all the selected cases, SARS-CoV-2 RT-PCR on swabs collected from the upper (nasopharynx and oropharynx) and/or the lower respiratory (trachea and primary bronchi) tracts were positive. Tissue localization of SARS-CoV-2 was detected using antibodies against the nucleoprotein and the spike protein. Overall, we tested the hypothesis that the overexpression of proinflammatory cytokines plays an important role in the development of COVID-19-associated pneumonia by estimating the expression of multiple cytokines (IL-1β, IL-6, IL-10, IL-15, TNF-α, and MCP-1), inflammatory cells (CD4, CD8, CD20, and CD45), and fibrinogen. Immunohistochemical staining showed that endothelial cells expressed IL-1β in lung samples obtained from the COVID-19 group (p < 0.001). Similarly, alveolar capillary endothelial cells showed strong and diffuse immunoreactivity for IL-6 and IL-15 in the COVID-19 group (p < 0.001). TNF-α showed a higher immunoreactivity in the COVID-19 group than in the control group (p < 0.001). CD8 + T cells where more numerous in the lung samples obtained from the COVID-19 group (p < 0.001). Current evidence suggests that a cytokine storm is the major cause of acute respiratory distress syndrome (ARDS) and multiple organ failure and is consistently linked with fatal outcomes.

Redox nanomedicine ameliorates chronic kidney disease (CKD) by mitochondrial reconditioning in mice

Targeting reactive oxygen species (ROS) while maintaining cellular redox signaling is crucial in the development of redox medicine as the origin of several prevailing diseases including chronic kidney disease (CKD) is linked to ROS imbalance and associated mitochondrial dysfunction. Here, we have shown that a potential nanomedicine comprising of Mn3O4 nanoparticles duly functionalized with biocompatible ligand citrate (C-Mn3O4 NPs) can maintain cellular redox balance in an animal model of oxidative injury. We developed a cisplatin-induced CKD model in C57BL/6j mice with severe mitochondrial dysfunction and oxidative distress leading to the pathogenesis. Four weeks of treatment with C-Mn3O4 NPs restored renal function, preserved normal kidney architecture, ameliorated overexpression of pro-inflammatory cytokines, and arrested glomerulosclerosis and interstitial fibrosis. A detailed study involving human embryonic kidney (HEK 293) cells and isolated mitochondria from experimental animals revealed that the molecular mechanism behind the pharmacological action of the nanomedicine involves protection of structural and functional integrity of mitochondria from oxidative damage, subsequent reduction in intracellular ROS, and maintenance of cellular redox homeostasis. To the best of our knowledge, such studies that efficiently treated a multifaceted disease like CKD using a biocompatible redox nanomedicine are sparse in the literature. Successful clinical translation of this nanomedicine may open a new avenue in redox-mediated therapeutics of several other diseases (e.g., diabetic nephropathy, neurodegeneration, and cardiovascular disease) where oxidative distress plays a central role in pathogenesis.

COVID-19 and Obesity: Role of Ectopic Visceral and Epicardial Adipose Tissues in Myocardial Injury.

In March 2020, the WHO declared coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a global pandemic. Obesity was soon identified as a risk factor for poor prognosis, with an increased risk of intensive care admissions and mechanical ventilation, but also of adverse cardiovascular events. Obesity is associated with adipose tissue, chronic low-grade inflammation, and immune dysregulation with hypertrophy and hyperplasia of adipocytes and overexpression of pro-inflammatory cytokines. However, to implement appropriate therapeutic strategies, exact mechanisms must be clarified. The role of white visceral adipose tissue, increased in individuals with obesity, seems important, as a viral reservoir for SARS-CoV-2 via angiotensin-converting enzyme 2 (ACE2) receptors. After infection of host cells, the activation of pro-inflammatory cytokines creates a setting conducive to the “cytokine storm” and macrophage activation syndrome associated with progression to acute respiratory distress syndrome. In obesity, systemic viral spread, entry, and prolonged viral shedding in already inflamed adipose tissue may spur immune responses and subsequent amplification of a cytokine cascade, causing worse outcomes. More precisely, visceral adipose tissue, more than subcutaneous fat, could predict intensive care admission; and lower density of epicardial adipose tissue (EAT) could be associated with worse outcome. EAT, an ectopic adipose tissue that surrounds the myocardium, could fuel COVID-19-induced cardiac injury and myocarditis, and extensive pneumopathy, by strong expression of inflammatory mediators that could diffuse paracrinally through the vascular wall. The purpose of this review is to ascertain what mechanisms may be involved in unfavorable prognosis among COVID-19 patients with obesity, especially cardiovascular events, emphasizing the harmful role of excess ectopic adipose tissue, particularly EAT.

Mast Cell Cytokines IL-1, IL-33, and IL-36 Mediate Skin Inflammation in Psoriasis: A Novel Therapeutic Approach with the Anti-Inflammatory Cytokines IL-37, IL-38, and IL-1Ra.

Psoriasis (PS) is a skin disease with autoimmune features mediated by immune cells, which typically presents inflammatory erythematous plaques, and is associated with many comorbidities. PS exhibits excessive keratinocyte proliferation, and a high number of immune cells, including macrophages, neutrophils, Th1 and Th17 lymphocytes, and mast cells (MCs). MCs are of hematopoietic origin, derived from bone marrow cells, which migrate, mature, and reside in vascularized tissues. They can be activated by antigen-provoking overexpression of proinflammatory cytokines, and release a number of mediators including interleukin (IL)-1 and IL-33. IL-1, released by activated keratinocytes and MCs, stimulates skin macrophages to release IL-36—a powerful proinflammatory IL-1 family member. IL-36 mediates both innate and adaptive immunity, including chronic proinflammatory diseases such as psoriasis. Suppression of IL-36 could result in a dramatic improvement in the treatment of psoriasis. IL-36 is inhibited by IL-36Ra, which binds to IL-36 receptor ligands, but suppression can also occur by binding IL-38 to the IL-36 receptor (IL-36R). IL-38 specifically binds only to IL-36R, and inhibits human mononuclear cells stimulated with IL-36 in vitro, sharing the effect with IL-36Ra. Here, we report that inflammation in psoriasis is mediated by IL-1 generated by MCs—a process that activates macrophages to secrete proinflammatory IL-36 inhibited by IL-38. IL-37 belongs to the IL-1 family, and broadly suppresses innate inflammation via IL-1 inhibition. IL-37, in murine models of inflammatory arthritis, causes the suppression of joint inflammation through the inhibition of IL-1. Therefore, it is pertinent to think that IL-37 can play an inhibitory role in inflammatory psoriasis. In this article, we confirm that IL-38 and IL-37 cytokines emerge as inhibitors of inflammation in psoriasis, and hold promise as an innovative therapeutic tool.

How the Gut Microbiome Links to Menopause and Obesity, with Possible Implications for Endometrial Cancer Development.

Background: Interest is growing in the dynamic role of gut microbiome disturbances in human health and disease. No direct evidence is yet available to link gut microbiome dysbiosis to endometrial cancer. This review aims to understand any association between microbiome dysbiosis and important risk factors of endometrial cancer, high estrogen levels, postmenopause and obesity. Methods: A systematic search was performed with PubMed as primary database. Three separate searches were performed to identify all relevant studies. Results: Fifteen studies were identified as highly relevant and included in the review. Eight articles focused on the relationship with obesity and eight studies focused on the menopausal change or estrogen levels. Due to the heterogeneity in patient populations and outcome measures, no meta-analysis could be performed. Both the menopausal change and obesity were noted to enhance dysbiosis by reducing microbiome diversity and increasing the Firmicutes to Bacteroidetes ratio. Both also incurred estrobolome changes, leading to increased systemic estrogen levels, especially after menopause. Furthermore, microbiome dysbiosis was reported to be related to systemic inflammation through toll-like receptor signaling deficiencies and overexpression of pro-inflammatory cytokines. Conclusions: This review highlights that the female gut microbiome is intrinsically linked to estrogen levels, menopausal state and systemic inflammation, which indicates gut microbiome dysbiosis as a potential hallmark for risk stratification for endometrial cancer. Studies are needed to further define the role the gut microbiome plays in women at risk for endometrial cancer.

Inhibiting Brd4 alleviated PTSD-like behaviors and fear memory through regulating immediate early genes expression and neuroinflammation in rats.

Post-traumatic stress disorder (PTSD) is characterized by depression/anxiety and memory failure, primarily fear memory. According to the reports, neuroinflammation and synaptic plasticity can play a role in the neurophysiological mechanisms underlying PTSD. Bromodomain-containing protein 4 (Brd4) intriguingly affects regulating of inflammatory responses and learning and memory. This study aimed to explore the effect of inhibiting Brd4 on depression/anxiety-like behaviors, spatial and fear memory, and underlying mechanisms in a model of PTSD. Inescapable foot shocks (IFS) with a sound reminder in 6days were used to induce PTSD-like behaviors which were tested using contextual and cue fear tests, sucrose preference test, open-field test, elevated plus maze test, and Y-maze test. Meanwhile, the Brd4 inhibitor JQ1 was used as an intervention. The results found that IFS induced PTSD-like behaviors and indicated obvious Brd4 expression in microglia of the prefrontal cortex (PFC), hippocampus, and amygdala, pro-inflammatory cytokines over-expression, microglial activation, and nuclear factor-kappa B over-expression in PFC and hippocampus but not in amygdala. Meanwhile, the alterations of immediate early genes (IEGs) were found in PFC, hippocampus, and amygdala. Besides, dendritic spine density was reduced in PFC and hippocampus but was elevated in amygdala of rats with IFS. In addition, treatment with JQ1 significantly reduced freezing time in the contextual and cue fear test, reversed the behavioral impairment, decreased the elevated neuroinflammation, and normalized the alteration in IEGs and dendritic spine densities. The results suggested that Brd4 was involved in IFS-induced PTSD-like behaviors through regulating neuroinflammation, dynamics of IEGs, and synaptic plasticity.

The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible RNA virus that is the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic. Patients with severe COVID-19 may develop acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) and require mechanical ventilation. Key features of SARS-CoV-2 induced pulmonary complications include an overexpression of pro-inflammatory chemokines and cytokines that contribute to a ‘cytokine storm.’ In the current study an inflammatory state in Calu-3 human lung epithelial cells was characterized in which significantly elevated transcripts of the immunostimulatory chemokines CXCL9, CXCL10, and CXCL11 were present. Additionally, an increase in gene expression of the cytokines IL-6, TNFα, and IFN-γ was observed. The transcription of CXCL9, CXCL10, IL-6, and IFN-γ was also induced in the lungs of human transgenic angiotensin converting enzyme 2 (ACE2) mice infected with SARS-CoV-2. To elucidate cell signaling pathways responsible for chemokine upregulation in SARS-CoV-2 infected cells, small molecule inhibitors targeting key signaling kinases were used. The induction of CXCL9, CXCL10, and CXCL11 gene expression in response to SARS-CoV-2 infection was markedly reduced by treatment with the AKT inhibitor GSK690693. Samples from COVID-19 positive individuals also displayed marked increases in CXCL9, CXCL10, and CXCL11 transcripts as well as transcripts in the AKT pathway. The current study elucidates potential pathway specific targets for reducing the induction of chemokines that may be contributing to SARS-CoV-2 pathogenesis via hyperinflammation.

In Vivo Cigarette Smoke Exposure to Examine the Expression of Genes Involved in the Inflammatory Response in the Mouse Uterus.

Cigarette smoke may impair uterine function, but the underlying mechanisms are poorly characterized. In this article, we describe the methodology for whole-body exposure to cigarette smoke together with assessment of the impact of this exposure on the expression of a panel of genes related to stress and toxicity pathways in mouse uteri using an in vivo model. C57BL/6 mice are whole-body-exposed to three cigarettes daily, 7 days/week, for 2 months using a specific rodent ventilator. Uteri are then collected and subjected to qRT-PCR analysis using the Stress & Toxicity PathwayFinder RT2 Profiler PCR Array (Qiagen). Cigarette smoke was found to be associated with an upregulation (≥2-fold) of C-reactive protein (Crp; 2.65-fold, p-value = 0.02), growth arrest and DNA-damage-inducible45γ (Gadd45γ; 2.11-fold, p-value = 0.04), interferon γ (Ifnγ; 2.05-fold, p-value = 0.01), and interleukin1α (Il1α; 7.74-fold, p-value = 0.003) and downregulation of matrix metallopeptidase-9 (Mmp9; -2.42-fold, p-value = 0.01). The protocol used in this study may represent a new experimental model of mouse in vivo mainstream exposure to cigarette smoke. In addition, the resulting overexpression of pro-inflammatory cytokines and genes involved in cell cycle proliferation, together with the downregulation of extracellular matrix metallopeptidases, may represent a toxicological response to cigarette smoke exposure, with potential repercussion for the processes of uterine remodeling and growth that are essential for uterine receptiveness. A recommendation to expand upon this research area is made. © 2021 Wiley Periodicals LLC.

Cynandione A and PHA-543613 inhibit inflammation and stimulate macrophageal IL-10 expression following α7 nAChR activation

Cynandione A, an acetophenone isolated from Cynanchum Wilfordii Radix, attenuates inflammation. The present study aimed to study the mechanisms underlying cynandione A-induced antiinflammation. Treatment with cynandione A and the specific α7 nicotinic acetylcholine receptor (α7 nAChR) agonist PHA-543613 remarkably reduced overexpression of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β in lipopolysaccharide (LPS)-treated RAW264.7 cells and primary peritoneal macrophages, and endotoxemic mice. Both cynandione A and PHA-543613 also stimulated IL-10 expression in naïve and LPS-treated macrophages and endotoxemic mice. Cynandione A- and PHA-543613-inhibited proinflammatory cytokine expression was completely blocked by the α7 nAChR antagonist methyllycaconitine and the IL-10 antibody. The stimulatory effect of cynandione A and PHA-543613 on IL-10 expression were suppressed by methyllycaconitine and knockdown of α7 nAChRs using siRNA/α7 nAChR. Cynandione A significantly stimulated STAT3 phosphorylation, which was attenuated by methyllycaconitine and the IL-10 neutralizing antibody. The STAT3 activation inhibitor NSC74859 also blocked cynandione A-inhibited proinflammatory cytokine expression. Taken together, our results, for the first time, demonstrate that cynandione A and PHA-543613 inhibit inflammation through macrophageal α7 nAChR activation and subsequent IL-10 expression.

4R-cembranoid confers neuroprotection against LPS-induced hippocampal inflammation in mice

BackgroundChronic brain inflammation has been implicated in the pathogenesis of various neurodegenerative diseases and disorders. For example, overexpression of pro-inflammatory cytokines has been associated with impairments in hippocampal-dependent memory. Lipopolysaccharide (LPS) injection is a widely used model to explore the pathobiology of inflammation. LPS injection into mice causes systemic inflammation, neuronal damage, and poor memory outcomes if the inflammation is not controlled. Activation of the alpha-7 nicotinic receptor (α7) plays an anti-inflammatory role in the brain through vagal efferent nerve signaling. 4R-cembranoid (4R) is a natural compound that crosses the blood-brain barrier, induces neuronal survival, and has been shown to modulate the activity of nicotinic receptors. The purpose of this study is to determine whether 4R reduces the deleterious effects of LPS-induced neuroinflammation and whether the α7 receptor plays a role in mediating these beneficial effects.MethodsEx vivo population spike recordings were performed in C57BL/6J wild-type (WT) and alpha-7-knockout (α7KO) mouse hippocampal slices in the presence of 4R and nicotinic receptor inhibitors. For in vivo studies, WT and α7KO mice were injected with LPS for 2 h, followed by 4R or vehicle for 22 h. Analyses of IL-1β, TNF-α, STAT3, CREB, Akt1, and the long-term novel object recognition test (NORT) were performed for both genotypes. In addition, RNA sequencing and RT-qPCR analyses were carried out for 12 mRNAs related to neuroinflammation and their modification by 4R.Results4R confers neuroprotection after NMDA-induced neurotoxicity in both WT and α7KO mice. Moreover, hippocampal TNF-α and IL-1β levels were decreased with 4R treatment following LPS exposure in both strains of mice. 4R restored LPS-induced cognitive decline in NORT. There was a significant increase in the phosphorylation of STAT3, CREB, and Akt1 with 4R treatment in the WT mouse hippocampus following LPS exposure. In α7KO mice, only pAkt levels were significantly elevated in the cortex. 4R significantly upregulated mRNA levels of ORM2, GDNF, and C3 following LPS exposure. These proteins are known to play a role in modulating microglial activation, neuronal survival, and memory.ConclusionOur results indicate that 4R decreases the levels of pro-inflammatory cytokines; improves memory function; activates STAT3, Akt1, and CREB phosphorylation; and upregulates the mRNA levels of ORM2, GDNF, and C3. These effects are independent of the α7 nicotinic receptor.

Small molecule natural compound targets the NF-κB signaling and ameliorates the development of osteoarthritis.

Osteoarthritis (OA) is a multifactorial and chronic disease describing the destruction of cartilage that can lead to defects in the elderly. There is currently no practical strategy that can reverse the OA process. Here, we describe nepetin, a small natural compound with extracellular matrix (ECM) and inflammation regulating functions. In this study, we investigated the therapeutic effects of nepetin on interleukin-1β (IL-1β)-induced inflammation in mice chondrocyte and OA model. In chondrocytes, treatment with nepetin inhibited the overexpression of pro-inflammatory cytokines and mediators induced by IL-1β. Moreover, pretreatment or posttreatment with nepetin also reduced the ECM catabolism and enhanced the ECM anabolism. Mechanistically, nepetin suppressed NF-κB signaling pathway in IL-1β stimulated chondrocyte. Meanwhile, our molecular docking studies indicated nepetin had a powerful binding capacity to p65. Furthermore, nepetin showed a protective and therapeutic effect on the mouse OA model. To sum up, this study indicated nepetin had a new potential therapeutic option in OA.

Fibrinogen Interaction with Astrocyte ICAM-1 and PrPC Results in the Generation of ROS and Neuronal Death

Many neuroinflammatory diseases, like traumatic brain injury (TBI), are associated with an elevated level of fibrinogen and short-term memory (STM) impairment. We found that during TBI, extravasated fibrinogen deposited in vasculo-astrocyte interfaces, which was associated with neurodegeneration and STM reduction. The mechanisms of this fibrinogen-astrocyte interaction and its functional role in neurodegeneration are still unclear. Cultured mouse brain astrocytes were treated with fibrinogen in the presence or absence of function-blocking antibody or peptide against its astrocyte receptors intercellular adhesion molecule-1 (ICAM-1) or cellular prion protein (PrPC), respectively. Fibrinogen interactions with astrocytic ICAM-1 and PrPC were characterized. The expression of pro-inflammatory markers, generations of reactive oxygen species (ROS) and nitric oxide (NO) in astrocytes, and neuronal death caused by astrocyte-conditioned medium were assessed. Data showed a strong association between fibrinogen and astrocytic ICAM-1 or PrPC, overexpression of pro-inflammatory cytokines and overproduction of ROS and NO, resulting in neuronal apoptosis and death. These effects were reduced by blocking the function of astrocytic ICAM-1 and PrPC, suggesting that fibrinogen association with its astrocytic receptors induce the release of pro-inflammatory cytokines, resulting in oxidative stress, and ultimately neuronal death. This can be a mechanism of neurodegeneration and the resultant STM reduction seen during TBI.