Release Of Inflammatory Mediators Research Articles

Nonoptimal bacteria species induce neutrophil-driven inflammation and barrier disruption in the female genital tract

Neutrophil recruitment and activation within the female genital tract are often associated with tissue inflammation, loss of vaginal epithelial barrier integrity, and increased risk for sexually transmitted infections, such as HIV-1. However, the direct role of neutrophils on vaginal epithelial barrier function during genital inflammation in vivo remains unclear. Using complementary proteome and immunological analyses, we show high neutrophil influx into the lower female genital tract in response to physiological surges in progesterone, stimulating distinct stromal, immunological, and metabolic signaling pathways. However, despite the release of extracellular matrix-modifying proteases and inflammatory mediators, neutrophils contributed little to physiological mucosal remodeling events such as epithelial shedding or re-epithelialization during transition from diestrus to estrus phase. In contrast, the presence of bacterial vaginosis-associated bacteria resulted in a rapid and sustained neutrophil recruitment, resulting in vaginal epithelial barrier leakage and decreased cell-cell junction protein expression in vivo. Thus, neutrophils are important mucosal sentinels that rapidly respond to various biological cues within the female genital tract, dictating the magnitude and duration of the ensuing inflammatory response at steady state and during disease processes.

Protective Effect of Ferulic Acid on Lipopolysaccharide-Induced BV2 Microglia Inflammation via AMPK/mTOR Signaling Pathway

In neurodegenerative diseases, microglial activation and neuroinflammation are essential for the control and progression of neurodegenerative diseases. Mitigating microglium-induced inflammation is one strategy for hindering the progression of neurodegenerative diseases. Ferulic acid (FA) is an effective anti-inflammatory agent, but its potential role and regulation mechanism in neuroinflammatory reactions have not been fully studied. In this study, the neuroinflammation model was established by lipopolysaccharide (LPS), and the inhibitory effect of FA on neuroinflammation of BV2 microglia was studied. The results showed that FA significantly reduced the production and expression of reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), leukocyte-6 (IL-6) and interleukin-1β (IL-1β). We further studied the mechanism of FA's regulation of LPS-induced BV2 neuroinflammation and found that FA can significantly reduce the expression of mTOR in BV2 microglia induced by LPS, and significantly increase the expression of AMPK, indicating that FA may have an anti-inflammatory effect by activating the AMPK/mTOR signaling pathway to regulate the release of inflammatory mediators (such as NLRP3, caspase-1 p20 and IL-1β). We further added an autophagy inhibitor (3-MA) and an AMPK inhibitor (compound C, CC) for reverse verification. The results showed that FA's inhibitory effects on TNF-α, IL-6 and IL-1β and its regulatory effect on AMPK/mTOR were destroyed by 3-MA and CC, which further indicated that FA's inhibitory effect on neuroinflammation is related to its activation of the AMPK/mTOR autophagy signaling pathway. In a word, our experimental results show that FA can inhibit LPS-induced neuroinflammation of BV2 microglia by activating the AMPK/mTOR signaling pathway, and FA may be a potential drug for treating neuroinflammatory diseases.

Rosa davurica Inhibited Allergic Mediators by Regulating Calcium and Histamine Signaling Pathways

Rosa davurica Pall. exhibits antioxidant, antiviral, and anti-inflammatory properties; however, its pharmacological mechanism in allergy is yet to be understood. This study confirmed the effects of R. davurica Pall. leaf extract (RLE) on allergy as a new promising material. To evaluate the therapeutic potential of RLE against allergy, we investigated the effects of RLE on the regulatory β-hexosaminidase, histamine, histidine decarboxylase (HDC), Ca2+ influx, nitric oxide (NO), and cytokines induced by lipopolysaccharide (LPS) and DNP-IgE/BSA in Raw 264.7 and RBL-2H3 cells. Furthermore, we examined the effects of RLE on the signaling pathways of mitogen-activated protein kinase (MAPK) and Ca2+ pathways. After stimulating Raw 264.7 cells with LPS, RLE reduced the release of inflammatory mediators, such as NO, cyclooxygenase (COX)-2, inducible nitric oxygen synthase (iNOS), interleukin (IL)-1β, -6, and tumor necrosis factor (TNF)-α. Also, RLE reduced the β-hexosaminidase, histamine, HDC, Ca2+ influx, Ca2+ pathways, and phosphorylation of MAPK in DNP-IgE/BSA-stimulated RBL-2H3 cells. Our studies indicated that RLE is a valuable ingredient for treating allergic diseases by regulating cytokine release from macrophages and mast cell degranulation. Consequently, these results suggested that RLE may serve as a possible alternative promising material for treating allergies.

Ultrasmall iron-quercetin metal natural product nanocomplex with antioxidant and macrophage regulation in rheumatoid arthritis.

Oxidative stress, due to the disruption of the balance between reactive oxygen species (ROS) generation and the antioxidant defense system, plays an important role in the pathogenesis of rheumatoid arthritis (RA). Excessive ROS leads to the loss of biological molecules and cellular functions, release of many inflammatory mediators, stimulate the polarization of macrophages, and aggravate the inflammatory response, thus promoting osteoclasts and bone damage. Therefore, foreign antioxidants would effectively treat RA. Herein, ultrasmall iron-quercetin natural coordination nanoparticles (Fe-Qur NCNs) with excellent anti-inflammatory and antioxidant properties were constructed to effectively treat RA. Fe-Qur NCNs obtained by simple mixing retain the inherent ability to remove ROS of quercetin and have a better water-solubility and biocompatibility. Invitro experiments showed that Fe-Qur NCNs could effectively remove excess ROS, avoid cell apoptosis, and inhibit the polarization of inflammatory macrophages by reducing the activation of the nuclear factor-κ-gene binding (NF-κB) pathways. Invivo experiments showed that the swollen joints of mice with rheumatoid arthritis treated with Fe-Qur NCNs significantly improved, with Fe-Qur NCNs largely reducing inflammatory cell infiltration, increasing anti-inflammatory macrophage phenotypes, and thus inhibiting osteoclasts, which led to bone erosion. This study demonstrated that the new metal-natural coordination nanoparticles could be an effective therapeutic agent for the prevention of RA and other diseases associated with oxidative stress.

Nanoemulsion of Turmeric in VCO Inhibit the Progressivity of Lung Fibrosis due to Cigarette Exposure

Pulmonary fibrosis is a form of lung damage caused by chronic inflammation. One of the causes is cigarette smoke exposure, which can damage cilia and epithelial cells, that is able to stimulate oxidative stress as well. The inflammatory response by inflammatory cells triggers release of inflammatory mediators, for example, TNF-α. Increased levels of TNF-α indicate a high inflammatory process and a high risk of pulmonary fibrosis. Nanoemulsion of turmeric extract in VCO contains curcumin, which can suppress the secretion and expression of TNF-α through several pathways. This study is aimed to analyze the inhibitory effect of turmeric extract nanoemulsion in VCO on pulmonary fibrosis in an inflammatory way. In this study, 40 white rats were used and divided into five groups; K0 was negative controls group, K1 was exposed to smoke from two cigarettes/day for 42 days, K2 received 0.3 mL dose of nanoemulsion + cigarette exposure, K3 received 0.6 mL dose of nanoemulsion + cigarette exposure and K4 received dexamethasone (0.2 mg/kgBW) + cigarette exposure. Furthermore, plasma TNF-α levels taken from cardiac blood and histopathological preparations (HE, MA) were made from the right lung. One-way ANOVA test was used to analyze plasma TNF-α levels, the Kruskal-Wallis test was used to analyze fibrosis degree scoring based on Aschroft Modification Scale and the correlation test was analyzed by Spearman test. The results showed that 0.3 mL of turmeric extract nanoemulsion in VCO had the best inhibitory effect on progressivity tissue damage and pulmonary fibrosis.

Trimethylamine N-Oxide (TMAO) Mediates Increased Inflammation and Colonization of Bladder Epithelial Cells during a Uropathogenic E. coli Infection In Vitro.

Urinary tract infections (UTIs) are among the most common infections in humans and are often caused by uropathogenic E. coli (UPEC). Trimethylamine N-oxide (TMAO) is a proinflammatory metabolite that has been linked to vascular inflammation, atherosclerosis, and chronic kidney disease. As of today, no studies have investigated the effects of TMAO on infectious diseases like UTIs. The aim of this study was to investigate whether TMAO can aggravate bacterial colonization and the release of inflammatory mediators from bladder epithelial cells during a UPEC infection. We found that TMAO aggravated the release of several key cytokines (IL-1β and IL-6) and chemokines (IL-8, CXCL1 and CXCL6) from bladder epithelial cells during a CFT073 infection. We also found that CFT073 and TMAO mediate increased release of IL-8 from bladder epithelial cells via ERK 1/2 signaling and not bacterial growth. Furthermore, we showed that TMAO enhances UPEC colonization of bladder epithelial cells. The data suggest that TMAO may also play a role in infectious diseases. Our results can be the basis of further research to investigate the link between diet, gut microbiota, and urinary tract infection.

Role of NLRP3 in the pathogenesis and treatment of gout arthritis.

Gout arthritis (GA) is a common and curable type of inflammatory arthritis that has been attributed to a combination of genetic, environmental and metabolic factors. Chronic deposition of monosodium urate (MSU) crystals in articular and periarticular spaces as well as subsequent activation of innate immune system in the condition of persistent hyperuricemia are the core mechanisms of GA. As is well known, drugs for GA therapy primarily consists of rapidly acting anti-inflammatory agents and life-long uric acid lowering agents, and their therapeutic outcomes are far from satisfactory. Although MSU crystals in articular cartilage detected by arthrosonography or in synovial fluid found by polarization microscopy are conclusive proofs for GA, the exact molecular mechanism of NLRP3 inflammasome activation in the course of GA still remains mysterious, severely restricting the early diagnosis and therapy of GA. On the one hand, the activation of Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome requires nuclear factor kappa B (NF-κB)-dependent transcriptional enhancement of NLRP3, precursor (pro)-caspase-1 and pro-IL-1β, as well as the assembly of NLRP3 inflammasome complex and sustained release of inflammatory mediators and cytokines such as IL-1β, IL-18 and caspase-1. On the other hand, NLRP3 inflammasome activated by MSU crystals is particularly relevant to the initiation and progression of GA, and thus may represent a prospective diagnostic biomarker and therapeutic target. As a result, pharmacological inhibition of the assembly and activation of NLRP3 inflammasome may also be a promising avenue for GA therapy. Herein, we first introduced the functional role of NLRP3 inflammasome activation and relevant biological mechanisms in GA based on currently available evidence. Then, we systematically reviewed therapeutic strategies for targeting NLRP3 by potentially effective agents such as natural products, novel compounds and noncoding RNAs (ncRNAs) in the treatment of MSU-induced GA mouse models. In conclusion, our present review may have significant implications for the pathogenesis, diagnosis and therapy of GA.

Female with peritonitis and abdominal distention.

A G0 35-year-old female with a body mass index (BMI) of 21 and history of antibiotic allergies presented to the emergency department with diffuse abdominal pain. Two days prior, she had a transvaginal ultrasound-guided oocyte retrieval for mature oocyte cryopreservation and 36 hours before the procedure received a human chorionic gonadotropin (hCG) “trigger shot.” She was tachycardic, but otherwise hemodynamically stable. On abdominal examination, she had a distended abdomen with diffuse tenderness to percussion and rebound tenderness. A point-of-care ultrasound demonstrated free fluid and a computed tomography (CT) of the abdomen/pelvis with intravenous contrast was obtained after consultation with surgery and obstetrics (Figures 1-3). CT revealed bilateral enlarged ovaries with follicles, the largest at 17 × 15 × 10 cm, with ascites and bilateral pleural effusions. No free air or active hemorrhage was identified. She underwent paracentesis of 2.5 L with administration of albumin and anticoagulation. Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of assisted reproduction technology, described as cystic enlargement of the ovaries and fluid shifts from the intravascular space to the third space.1, 2 It can occur in 1%–5% of cycles with risk factors of low BMI, polycystic ovarian syndrome, allergy history, high doses of hCG, and large number of follicles.2, 3 Peritonitis can occur because of the release of inflammatory mediators or rupture of follicular cysts.3 Severe OHSS is characterized by ascites, pleural effusions, and hemoconcentration. In addition to OHSS, complications of oocyte retrieval, albeit rare, must also be considered as intraperitoneal hemorrhage, bowel perforation, or infection.4

Comparing the Effects of Rocaglates on Energy Metabolism and Immune Modulation on Cells of the Human Immune System.

A promising new approach to broad spectrum antiviral drugs is the inhibition of the eukaryotic translation initiation factor 4A (elF4A), a DEAD-box RNA helicase that effectively reduces the replication of several pathogenic virus types. Beside the antipathogenic effect, modulation of a host enzyme activity could also have an impact on the immune system. Therefore, we performed a comprehensive study on the influence of elF4A inhibition with natural and synthetic rocaglates on various immune cells. The effect of the rocaglates zotatifin, silvestrol and CR-31-B (-), as well as the nonactive enantiomer CR-31-B (+), on the expression of surface markers, release of cytokines, proliferation, inflammatory mediators and metabolic activity in primary human monocyte-derived macrophages (MdMs), monocyte-derived dendritic cells (MdDCs), T cells and B cells was assessed. The inhibition of elF4A reduced the inflammatory potential and energy metabolism of M1 MdMs, whereas in M2 MdMs, drug-specific and less target-specific effects were observed. Rocaglate treatment also reduced the inflammatory potential of activated MdDCs by altering cytokine release. In T cells, the inhibition of elF4A impaired their activation by reducing the proliferation rate, expression of CD25 and cytokine release. The inhibition of elF4A further reduced B-cell proliferation, plasma cell formation and the release of immune globulins. In conclusion, the inhibition of the elF4A RNA helicase with rocaglates suppressed the function of M1 MdMs, MdDCs, T cells and B cells. This suggests that rocaglates, while inhibiting viral replication, may also suppress bystander tissue injury by the host immune system. Thus, dosing of rocaglates would need to be adjusted to prevent excessive immune suppression without reducing their antiviral activity.

Alterations in gut immunological barrier in SARS-CoV-2 infection and their prognostic potential.

Although coronavirus disease 2019 (COVID-19) is primarily associated with mild respiratory symptoms, a subset of patients may develop more complicated disease with systemic complications and multiple organ injury. The gastrointestinal tract may be directly infected by SARS-CoV-2 or secondarily affected by viremia and the release of inflammatory mediators that cause viral entry from the respiratory epithelium. Impaired intestinal barrier function in SARS-CoV-2 infection is a key factor leading to excessive microbial and endotoxin translocation, which triggers a strong systemic immune response and leads to the development of viral sepsis syndrome with severe sequelae. Multiple components of the gut immune system are affected, resulting in a diminished or dysfunctional gut immunological barrier. Antiviral peptides, inflammatory mediators, immune cell chemotaxis, and secretory immunoglobulins are important parameters that are negatively affected in SARS-CoV-2 infection. Mucosal CD4+ and CD8+ T cells, Th17 cells, neutrophils, dendritic cells, and macrophages are activated, and the number of regulatory T cells decreases, promoting an overactivated immune response with increased expression of type I and III interferons and other proinflammatory cytokines. The changes in the immunologic barrier could be promoted in part by a dysbiotic gut microbiota, through commensal-derived signals and metabolites. On the other hand, the proinflammatory intestinal environment could further compromise the integrity of the intestinal epithelium by promoting enterocyte apoptosis and disruption of tight junctions. This review summarizes the changes in the gut immunological barrier during SARS-CoV-2 infection and their prognostic potential.

Effects of hypoxia on bronchial and alveolar epithelial cells linked to pathogenesis in chronic lung disorders.

Introduction: Chronic lung disorders involve pathological alterations in the lung tissue with hypoxia as a consequence. Hypoxia may influence the release of inflammatory mediators and growth factors including vascular endothelial growth factor (VEGF) and prostaglandin (PG)E2. The aim of this work was to investigate how hypoxia affects human lung epithelial cells in combination with profibrotic stimuli and its correlation to pathogenesis. Methods: Human bronchial (BEAS-2B) and alveolar (hAELVi) epithelial cells were exposed to either hypoxia (1% O2) or normoxia (21% O2) during 24h, with or without transforming growth factor (TGF)-β1. mRNA expression of genes and proteins related to disease pathology were analysed with qPCR, ELISA or immunocytochemistry. Alterations in cell viability and metabolic activity were determined. Results: In BEAS-2B and hAELVi, hypoxia significantly dowregulated genes related to fibrosis, mitochondrial stress, oxidative stress, apoptosis and inflammation whereas VEGF receptor 2 increased. Hypoxia increased the expression of Tenascin-C, whereas both hypoxia and TGF-β1 stimuli increased the release of VEGF, IL-6, IL-8 and MCP-1 in BEAS-2B. In hAELVi, hypoxia reduced the release of fibroblast growth factor, epidermal growth factor, PGE2, IL-6 and IL-8, whereas TGF-β1 stimulus significantly increased the release of PGE2 and IL-6. TGF-β1 stimulated BEAS-2B cells showed a decreased release of VEGF-A and IL-8, while TGF-β1 stimulated hAELVi cells showed a decreased release of PGE2 and IL-8 during hypoxia compared to normoxia. Metabolic activity was significantly increased by hypoxia in both epithelial cell types. Discussion: In conclusion, our data indicate that bronchial and alveolar epithelial cells respond differently to hypoxia and profibrotic stimuli. The bronchial epithelium appears more responsive to changes in oxygen levels and remodelling processes compared to the alveoli, suggesting that hypoxia may be a driver of pathogenesis in chronic lung disorders.

Neuroprotective effect of tangeretin against chromium-induced acute brain injury in rats: targeting Nrf2 signaling pathway, inflammatory mediators, and apoptosis

Potassium dichromate (PD) is an environmental xenobiotic commonly recognized as teratogenic, carcinogenic, and mutagenic in animals and humans. The present study was conducted to investigate the role of tangeretin (TNG) as a neuro-protective drug against PD-induced brain injury in rats. Thirty-two male adult Wistar rats were blindly divided into four groups (8 rats/group). The first group received saline intranasally (i.n.). The second group received a single dose of PD (2 mg/kg, i.n.). The third group received TNG (50 mg/kg; orally), for 14 days followed by i.n. of PD on the last day of the experiment. The fourth group received TNG (100 mg/kg; orally) for 14 days followed by i.n. of PD on the last day of the experiment. Behavioral indices were evaluated 18 h after PD administration. Neuro-biochemical indices and histopathological studies were evaluated 24 h after PD administration. Results of the present study revealed that rats intoxicated with PD induced- oxidative stress and inflammation via an increase in malondialdehyde (MDA) and a decrease in nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and glutathione(GSH) levels with an increase in brain contents of tumor necrosis factor-alpha (TNF-α) and interleukin (IL-6). Pre-treatment with TNG (100 mg/kg; orally) ameliorated behavior, cholinergic activities, and oxidative stress and decreased the elevated levels of pro-inflammatory mediators; TNF-α and IL-6 with a decrease in brain content of chromium residues detected by Plasma–Optical Emission Spectrometer. Also, the histopathological picture of the brain was improved significantly in rats that received TNG (100 mg/kg). Additionally, TNG decreased caspase-3 expression in the brain of PD rats. In conclusion, TNG possesses a significant neuroprotective role against PD-induced acute brain injury via modulating the Nrf2 signaling pathway and quenching the release of inflammatory mediators and apoptosis in rats.Graphical abstract

Alterations in the gut microbiome and metabolome profiles of septic mice treated with Shen FuHuang formula.

Sepsis has a high mortality rate, and treating sepsis remains a significant challenge worldwide. In former studies, our group found that traditional Chinese medicine, Shen FuHuang formula (SFH), is a promising medicine in treating coronavirus disease 2019 (COVID-19) patients with the septic syndrome. However, the underlying mechanisms remain elusive. In the present study, we first investigated the therapeutic effects of SFH on septic mice. To investigate the mechanisms of SFH-treated sepsis, we identified the gut microbiome profile and exploited untargeted metabolomics analyses. The results demonstrated that SFH significantly enhanced the mice's 7-day survival rate and hindered the release of inflammatory mediators, i.e., TNF-α, IL-6, and IL-1β. 16S rDNA sequencing further deciphered that SFH decreased the proportion of Campylobacterota and Proteobacteria at the phylum level. LEfSe analysis revealed that the treatment of SFH enriched Blautia while decreased Escherichia_Shigella. Furthermore, serum untargeted metabolomics analysis indicated that SFH could regulate the glucagon signaling pathway, PPAR signaling pathway, galactose metabolism, and pyrimidine metabolism. Finally, we found the relative abundance of Bacteroides, Lachnospiraceae_NK4A136_group, Escherichia_Shigella, Blautia, Ruminococcus, and Prevotella were closely related to the enrichment of the metabolic signaling pathways, including L-tryptophan, uracil, glucuronic acid, protocatechuic acid, and gamma-Glutamylcysteine. In conclusion, our study demonstrated that SFH alleviated sepsis by suppressing the inflammatory response and hence reduced mortality. The mechanism of SFH for treating sepsis may be ascribed to the enrichment of beneficial gut flora and modulation in glucagon signaling pathway, PPAR signaling pathway, galactose metabolism, and pyrimidine metabolism. To sum up, these findings provide a new scientific perspective for the clinical application of SFH in treating sepsis.

Management of Hemorrhagic Pancreatitis: Review of the Current Literature

Pancreatitis is the disease that affects the organ of the pancreas and should be given early attention, since its complications are quite lethal and can involve other organs. This research work provides a compilation of important information that expresses, through its development, the most common complications associated with pancreatitis, especially in its hemorrhagic presentation, as well as the necessary treatments used in this condition. In the course of pancreatitis, the first two to four days of symptoms are the most important because this is the period during which 15% to 25% of patients progress to its severe form. According to clinical and experimental data, this period is characterized by an initial state of hypovolemia. The morbidity of severe acute pancreatitis is known to occur in two stages. The first two weeks are characterized by a systemic inflammatory response syndrome (SIRS), which results from the release of inflammatory mediators. Organ failure is common and usually occurs even in the absence of infection. The early mortality rate is 42 to 60%. The second stage begins approximately two weeks after symptom onset and is characterized by sepsis-related complications resulting from infection of pancreatic necrosis. Therefore, there is an association with systemic complications, such as pulmonary failure, renal failure, and cardiovascular failure, known as multiple organ failure syndrome (MOFS).

Molecular Mechanisms of Neurogenic Inflammation of the Skin.

The skin, including the hypodermis, is the largest body organ and is in constant contact with the environment. Neurogenic inflammation is the result of the activity of nerve endings and mediators (neuropeptides secreted by nerve endings in the development of the inflammatory reaction in the skin), as well as interactions with other cells such as keratinocytes, Langerhans cells, endothelial cells and mast cells. The activation of TRPV-ion channels results in an increase in calcitonin gene-related peptide (CGRP) and substance P, induces the release of other pro-inflammatory mediators and contributes to the maintenance of cutaneous neurogenic inflammation (CNI) in diseases such as psoriasis, atopic dermatitis, prurigo and rosacea. Immune cells present in the skin (mononuclear cells, dendritic cells and mast cells) also express TRPV1, and their activation directly affects their function. The activation of TRPV1 channels mediates communication between sensory nerve endings and skin immune cells, increasing the release of inflammatory mediators (cytokines and neuropeptides). Understanding the molecular mechanisms underlying the generation, activation and modulation of neuropeptide and neurotransmitter receptors in cutaneous cells can aid in the development of effective treatments for inflammatory skin disorders.

Airport smoking zones: a prospective public health hazard.

Airport smoking zones: a prospective public health hazard.

Effect of different retreatment files using different kinematics on the release of inflammatory mediators in root canal retreatment of single-rooted teeth: a randomized clinical trial.

This randomized clinical trial aimed to evaluate the effect of two rotaries (ProTaper Universal Retreatment (PTUR)), D-Race (DR) + XP-Endo Finisher R (XPFR) and one reciprocating (Reciproc Blue (RB) retreatment techniques on the release of neuropeptides (Substance P, calcitonin gene-related peptide (CGRP)), and cytokines (IL-6 and IL-10) in periapical fluid in root canal retreatment of single-rooted teeth. In this randomized clinical trial (ClinicalTrials.gov ID: NCT05039502), seventy-five patients scheduled for retreatment were randomly divided into 3 groups according to the file system used to remove root canal filling materials (n = 25): PTUR, RB, and DR + XPFR. After reshaping and disinfection of the root canals, periapical fluid samples were taken, and the levels of Substance P, CGRP, IL-6, and IL-10 were measured by enzyme-linked immunosorbent assay (ELISA) test. Data were analyzed using the Kruskal-Wallis and chi-square tests. The level of significance was set as p = 0. 05. All the allocated participants received the intervention and were analyzed. There was no statistically significant difference among groups in terms of gender, age, tooth localization, and the distribution of analgesic use after treatment (p values 0.799, 0.095, 0.637, 1.000, respectively). No statistically significant difference was found in terms of the levels of Substance P, CGRP, and IL-10 among groups (p > .05), except IL-6. PTUR, RB, and DR + XPFR files have comparable results in the expression of inflammatory mediators. Retreatment files powered with rotary or reciprocating motion produced similar neuropeptide and cytokine levels in patients.

Two Ferulic Acid Derivatives Inhibit Neuroinflammatory Response in Human HMC3 Microglial Cells via NF-κB Signaling Pathway.

Various physiological and pathological changes are related to the occurrence and development of neurodegenerative diseases. Neuroinflammation is a major trigger and exacerbation of neurodegenerative diseases. One of the main symptoms of neuritis is the activation of microglia. Thus, to alleviate the occurrence of neuroinflammatory diseases, an important method is to inhibit the abnormal activation of microglia. This research evaluated the inhibitory effect of trans-ferulic acid (TJZ-1) and methyl ferulate (TJZ-2), isolated from Zanthoxylum armatum, on neuroinflammation, by establishing the human HMC3 microglial cell neuroinflammation model induced by lipopolysaccharide (LPS). The results showed both compounds significantly inhibited the production and expression of nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) contents, and increased the level of anti-inflammatory factor β-endorphin (β-EP). Furthermore, TJZ-1 and TJZ-2 can inhibit LPS-induced activation of nuclear factor kappa B (NF-κB). It was found that of two ferulic acid derivatives, both had anti-neuroinflammatory effects by inhibiting the NF-κB signaling pathway and regulating the release of inflammatory mediators, such as NO, TNF-α, IL-1β, and β-EP. This is the first report that demonstrates that TJZ-1 and TJZ-2 had inhibitory effects on LPS-induced neuroinflammation in human HMC3 microglial cells, which indicates that two ferulic acid derivates from Z. armatum could be used as potential anti-neuroinflammatory agents.

Inhibition of CaMKK2 Decreases Progression of Post-traumatic Osteoarthritis in a Rabbit ACL Transection Model

Background and Hypothesis:Post-traumatic osteoarthritis (PTOA) is a multifactorial degenerative disease of the joint affecting 20-50% of all joint injuries with a total annual cost of $15 billion. There are no current disease-modifying therapies for PTOA. Mechanical stress due to ligament tear or impact injury triggers the release of inflammatory mediators in the joint. Resulting collagen damage, loss of proteoglycans, and cell death triggers further release of inflammatory mediators and reactive oxygen species. This cycle of inflammation leads to PTOA. We hypothesize that inhibition of Ca2+/CaM dependent protein kinase kinase 2 (CaMKK2), a kinase associated with the inflammatory effects in PTOA, will mitigate the disease-propagating mechanisms.
 Methods:We utilized a rabbit model of PTOA which involved surgical transection of the anterior cruciate ligament (ACL) to generate joint instability. Rabbits were then treated tri-weekly with either STO-609 (CaMKK2 inhibitor, 0.033 mg/kg) or saline (control) for 16 weeks. Rabbits were sacrificed at 16 weeks post-surgery. Tibiofemoral joints were harvested for staining with safranin O fast green (SO) and PTOA grading via Osteoarthritis Research Society International (OARSI) guidelines. Apoptosis was assessed with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). RNA isolation of cartilage and subchondral bone tissue was conducted for qRT-PCR. Gene expression of MMP-13, IL-6, IL-1B, ACAN, COL2A1 was quantified and normalized to GAPDH.
 Results:Histology and gross morphology showed increased PTOA severity in saline controls compared to STO-609 treated rabbits. There was no significant difference in chondrocyte apoptosis in STO-609 treated rabbits compared to saline controls based on TUNEL staining. Gene expression analyses are in progress.
 Potential Impact:This study addresses the unmet clinical need for novel disease-modifying therapeutics for PTOA. Preliminary results show that inhibition of CaMKK2 has the potential to decrease cartilage degradation after joint injuries.

Dengue fever ophthalmic manifestations: A review and update.

Dengue fever, the most common arbovirus disease, affects an estimated 390 million people annually. Dengue virus (DENV) is an RNA virus of the Flaviviridae family with four different serotypes. Dengue haemorrhagic fever is the deadliest form of dengue infection and is characterised by thrombocytopaenia, hypotension, and the possibility of multi-system organ failure. The mechanism hypothesised for DENV viral replication is intrinsic antibody-dependent enhancement, which refers to Fcγ receptor-mediated viral amplification. This hypothesis suggests that the internalisation of DENV through the Fcγ receptor inhibits antiviral genes by suppressing type-1 interferon-mediated antiviral responses. DENV NS1 antibodies can promote the release of various inflammatory mediators in the nuclear transcription factor pathway (NF-κB-dependent), including monocyte chemoattractant protein (MCP)-1, interleukin (IL)-6, and IL-8. As a result, MCP-1 increases ICAM-1 expression and facilitates leukocyte transmigration. In addition, anti-DENV NS1 antibodies induce endothelial cell apoptosis via a nitric oxide-regulated pathway. A chain reaction involving pre-existing DENV heterotypic antibodies and innate immune cells causes dysfunction in complement system activity and contributes to the action of autoantibodies and anti-endothelial cells, resulting in endothelial cell dysfunction, blood-retinal barrier breakdown, haemorrhage, and plasma leakage. A spectrum of ocular diseases associated with DENV infection, ranging from haemorrhagic to inflammatory manifestations, has been reported in the literature. Although rare, ophthalmic manifestations can occur in both the anterior and posterior segments and are usually associated with thrombocytopenia. The most common ocular complication is haemorrhage. However, ophthalmic complications, such as anterior uveitis and vasculitis, suggest an immune-mediated pathogenesis.