Periodontitis exacerbation during pregnancy in mice: Role of macrophage migration inhibitory factor as a key inductor.

OBJECTIVE: The present study was designed to investigate the role of macrophage migration inhibitory factor (MIF) in the exacerbation of pregestational periodontal disease (PGPD). BACKGROUND: Periodontitis (PT) is a severe stage of periodontal disease characterized by inflammation of the supporting tissues of the teeth, which usually worsens during pregnancy. MIF is a proinflammatory cytokine that is significantly elevated in periodontitis, both at the beginning and at the end of pregnancy. Although periodontitis usually presents with greater severity during pregnancy, the participation of MIF in the evolution of periodontitis has not been established. METHODS: To analyze the relevance of MIF in the exacerbation of PGPD, we employed a model of PGPD in WT and Mif-/- mice, both with a BALB/c genetic background. PT was induced with nylon suture ligatures placed supramarginally around the second upper right molar. For PGPD, PT was induced 2 weeks before mating. We evaluated histological changes and performed histometric analysis of the clinical attachment loss, relative expression of MMP-2 and MMP-13 by immunofluorescence, and relative expression of the cytokines mif, tnf-α, ifn-γ, and il-17 by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Our data revealed that periodontal tissue from PGPD WT mice produced a twofold increase in MIF compared with PT WT mice. Moreover, the evolution of periodontitis in Mif-/- mice was less severe than in PGDP WT mice. Periodontal tissue from Mif-/- mice with PGPD produced 80% less TNF-α and no IFN-γ, as well as 50% lower expression of matrix metalloproteinase (MMP)-2 and 25% less MMP-13 compared to WT PGDP mice. CONCLUSIONS: Our study suggests that MIF plays an important role in the exacerbation of periodontitis during pregnancy and that MIF is partially responsible for the inflammation associated with the severity of periodontitis during pregnancy.

Investigating the association of physical and psychological problems with the levels of interleukin-1 and -6 in COVID-19 patients.

Introduction: The COVID-19 virus spreads at a high rate, exerting many physical, mental and psychological effects on patients. Patients with COVID-19 have been reported to have high levels of interleukin 1 and interleukin 6. Therefore, this study was conducted to determine the association of physical, mental, and psychological problems with the levels of interleukin-1 and -6 in COVID-19 patients. Methodology: This is cross-sectional descriptive-analytical research on 121 COVID-19 patients selected using simple random sampling method. The patients were hospitalized in university hospitals affiliated to Ahvaz Jundishapur University of Medical Sciences and Amir al-Momenin Hospital. Data collection tools included the depression anxiety stress scale (DASS), a demographic questionnaire, and a checklist of physical problems. Blood sampling was also done to perform an ELISA test and measure the level of interleukin-1 and -6. Data were analyzed based on independent t-tests, chi-square, regression, and Pearson's correlation coefficient, using SPSS ver. 22. Results: The average age of the 121 patients participating in this study was 53.31 ± 14.09. A direct and statistically significant correlation was observed between body temperature on the first day and interleukin 1 level. A statistically significant negative correlation was observed between blood oxygen saturation level and interleukin-1 and -6 on the first, third and fifth days. Shortness of breath and coughing had a statistically significant correlation with the level of interleukin 1 on the third and fifth days. A direct and statistically significant correlation was observed between body temperature on the first, third and fifth days and interleukin 6 level. Coughing on the third and fifth days had a statistically significant relationship with interleukin 6 level. No direct and non-significant statistical correlation was found between depression and stress and the serum level of interleukin 1, but a significant correlation was observed between anxiety and serum level of interleukin 1. Finally, the results showed that depression, anxiety and stress had a direct and statistically significant correlation with the serum level of interleukin 6. Conclusion: Given the relationship between interleukin-1 and -6 and most physical and psychological problems, level of the inflammatory biomarkers interleukin-1 and -6 can be used to estimate the severity of physical and psychological symptoms in COVID-19 patients.

Sympathoinhibitory electroacupuncture (EA) interacts positively with anti-inflammatory EA alleviating blood pressure in hypertensive rats.

Elevated sympathetic activity and chronic inflammation are known contributory factors observed in hypertension. We have observed that sympathoinhibitory electroacupuncture (SI-EA) at acupoints ST36-37 alleviates sympathetic activity and hypertension. Additionally, EA at acupoints SP6-7 exerts anti-inflammatory (AI-EA) effects. However, it is not known whether simultaneous stimulation of this combination of acupoints attenuates or enhances individual effects. A 2 × 2 factorial design was used to test the hypothesis that combining SI-EA and AI-EA (cEA) leads to greater reduction of hypertension by decreasing sympathetic activity and inflammation in hypertensive rats than either set of acupoints alone. Dahl salt-sensitive hypertensive (DSSH) rats were treated with four EA regimens including cEA, SI-EA, AI-EA, and sham-EA twice weekly for five weeks. A group of normotensive (NTN) rats served as control. Systolic and diastolic BP (SBP and DBP) and heart rate (HR) were measured non-invasively by tail-cuff. Plasma norepinephrine (NE), high-sensitivity C-reactive protein (hs-CRP) and interleukin 6 (IL-6) concentrations were determined with ELISA at the completion of treatments. DSSH rats on high salt diet progressively developed moderate hypertension within five weeks. DSSH rats treated with sham-EA showed continuous increase in SBP and DBP and elevations in plasma NE, hs-CRP, and IL-6 levels relative to NTN control. Both SI-EA and cEA decreased SBP and DBP, and had corresponding changes in biomarkers (NE, hs-CRP, and IL-6) compared with sham-EA. AI-EA prevented SBP and DBP elevation and decreased IL-6 and hs-CRP relative to sham-EA. Importantly in DSSH rats that received repetitive cEA treatment, SI-EA interacted positively with AI-EA leading to greater reduction of SBP, DBP, NE, hs-CRP, and IL-6 than SI-EA or AI-EA alone. These data suggest that by targeting both elevated sympathetic activity and chronic inflammation, cEA regimen results in a greater reduction of BP effects in treating hypertension compared to using individual SI-EA or AI-EA alone.

Inflammation in pathogenesis of chronic pain: Foe and friend.

Chronic pain is a refractory health disease worldwide causing an enormous economic burden on individuals and society. Accumulating evidence suggests that inflammation in the peripheral nervous system (PNS) and central nervous system (CNS) is the major factor in the pathogenesis of chronic pain. The inflammation in the early- and late phase may have distinctive effects on the initiation and resolution of pain, which can be viewed as friend or foe. On the one hand, painful injuries lead to the activation of glial cells and immune cells in the PNS, releasing pro-inflammatory mediators, which contribute to the sensitization of nociceptors, leading to chronic pain; neuroinflammation in the CNS drives central sensitization and promotes the development of chronic pain. On the other hand, macrophages and glial cells of PNS and CNS promote pain resolution via anti-inflammatory mediators and specialized pro-resolving mediators (SPMs). In this review, we provide an overview of the current understanding of inflammation in the deterioration and resolution of pain. Further, we summarize a number of novel strategies that can be used to prevent and treat chronic pain by controlling inflammation. This comprehensive view of the relationship between inflammation and chronic pain and its specific mechanism will provide novel targets for the treatment of chronic pain.

Effects of histamine and antihistamine on the hard tick Haemaphysalis longicornis during blood sucking.

At the time of host attachment, ticks are very sensitive to histamine, but during rapid blood sucking they paradoxically require histamine. Using a rabbit model, we studied the effects of histamine and antihistamine during attachment and fast-feeding in different life stages of Haemaphysalis longicorns. We examined how they responded to histamine and antihistamine by analyzing the detachment rate, histology of feeding lesions, and post-feeding behavior. A significant difference (P<0.01) was found in the detachment rate between experimental and control treatments throughout the observation period. Ticks exhibited a higher detachment rate (30.1%) at 12 h after histamine application during attachment time and on antihistamine-treated skin (25.4%) at 96 h during fast-feeding. After feeding on histamine-treated rabbits, the fully engorged body weights of larvae and nymphs were 0.7±0.36 mg and 3.5±0.65 mg, respectively. An average increase in body weight of 0.6±0.05 mg and 3.2±0.30 mg was observed for larvae and nymphs compared to the respective control weights. Nymphs and adults engorged after antihistamine treatment had an average body weight of 1.3±0.54 mg and 54±0.81 mg, respectively. An average decrease in body weight was observed in antihistamine-treated H. longicornis compared with control nymphs (3.3±0.42 mg) and adults (174±1.78 mg). Skin biopsies were collected after treatment, and differential histopathological characteristics were found between the treatment and control groups. Tick-infested skin collected from rabbits in the antihistamine-treated group lacked erythrocytes in the feeding pool, indicating that antihistamine impaired tick fast-feeding stage.

The Role of Cellular Metabolism in Maintaining the Function of the Dentine-Pulp Complex: A Narrative Review.

The cellular metabolic processes ensure the physiological integrity of the dentine-pulp complex. Odontoblasts and odontoblast-like cells are responsible for the defence mechanisms in the form of tertiary dentine formation. In turn, the main defence reaction of the pulp is the development of inflammation, during which the metabolic and signalling pathways of the cells are significantly altered. The selected dental procedures, such as orthodontic treatment, resin infiltration, resin restorations or dental bleaching, can impact the cellular metabolism in the dental pulp. Among systemic metabolic diseases, diabetes mellitus causes the most consequences for the cellular metabolism of the dentine-pulp complex. Similarly, ageing processes present a proven effect on the metabolic functioning of the odontoblasts and the pulp cells. In the literature, several potential metabolic mediators demonstrating anti-inflammatory properties on inflamed dental pulp are mentioned. Moreover, the pulp stem cells exhibit the regenerative potential essential for maintaining the function of the dentine-pulp complex.

Understanding the mechanisms underlying obesity in remodeling the breast tumor immune microenvironment: from the perspective of inflammation.

Obesity is a well-known modifiable risk factor for breast cancer and is considered a poor prognostic factor in pre- and post-menopausal women. While the systemic effects of obesity have been extensively studied, less is known about the mechanisms underlying obesity-associated cancer risk and the local consequences of obesity. Thus, obesity-induced inflammation has become the focus of research interest. Biologically, the development of cancer involves a complex interaction with numerous components. As the tumor immune microenvironment changes due to obesity-triggered inflammation, an increase in infiltration occurs for proinflammatory cytokines and adipokines, as well as adipocytes, immune cells, and tumor cells in the expanded adipose tissue. Complicated cellular-molecular crosstalk networks change critical pathways, mediate metabolic and immune function reprogramming, and have a significant role in tumor metastasis, proliferation, resistance, angiogenesis, and tumorigenesis. This review summarizes recent research findings on how inflammatory mediators in the in situ tumor microenvironment regulate the occurrence and development of breast cancer in the context of obesity. We analyzed the heterogeneity and potential mechanisms of the breast cancer immune microenvironment from the perspective of inflammation to provide a reference for the clinical transformation of precision targeted cancer therapy.

Triphenyl phosphate-induced macrophages dysfunction by activation TLR4-mediated ERK/NF-κB pathway.

Triphenyl phosphate (TPHP) is one of the most widely used organic phosphorus flame retardants and is ubiquitous in the environment. Studies have been reported that TPHP may lead to obesity, neurotoxicity and reproductive toxicity, but its impact on the immune system is almost blank. The present study was aimed to investigate the potential immunotoxicity of TPHP on macrophages and its underlying mechanism. The results demonstrated for the first time that TPHP (12.5, 25, and 50 µM)-induced F4/80+ CD11c+ phenotype of RAW 264.7 macrophages, accompanied by increased mRNA levels of inflammatory mediators, antigen-presenting genes (Cd80, Cd86, and H2-Aa), and significantly enhanced the phagocytosis of macrophage. Meanwhile, TPHP increased the expression of Toll-like receptor 4 (TLR4), and its co-receptor CD14, leading to significant activation of the downstream ERK/NF-κB pathway. However, co-exposure of cells to TAK-242, a TLR4 inhibitor, suppressed TPHP-induced F4/80+ CD11c+ phenotype, and down-regulated inflammatory mediators and antigen-presentation related genes, via blocked the TLR4/ERK/NF-κB pathway. Taken together, our results suggested that TPHP could induce macrophage dysfunction through activating TLR4-mediated ERK/NF-κB signaling pathway, and it may be the potential reason for health-threatening consequences.

Anti-swelling and Analgesic Mechanism of Jianpi Tongluo Prescription from MAPKs Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo observe the anti-swelling and analgesic effects of Jianpi Tongluo prescription （JPTL） and to explore its mechanism initially. MethodA total of 120 ICR mice were divided into normal group， model group， JPTL low-， medium- and high-dose groups （5， 10， 20 g·kg-1） and positive drug （celecoxib， 0.03 g·kg-1） group， with 10 in each group （po，once a day）. Complete freund's adjuvant （CFA） was used to induce the model of chronic inflammatory pain， and xylene-induced ear swelling test， hot plate test and acetic acid writhing test were performed to observe the anti-swelling and analgesic effects of different doses of JPTL in these four acute and chronic models. Further， enzyme-linked immunosorbent assay （ELISA） was used to detect the expressions of prostaglandin E2 （PGE2）， interleukin-1β （IL-1β）， interleukin-6 （IL-6） and tumor necrosis factor-α （TNF-α） in serum and inflammatory paw of mice with chronic inflammatory pain， and the expressions of aquaporin 1 （AQP1）， aquaporin 3 （AQP3）， cyclooxygenase 1 （COX1）， cyclooxygenase 2 （COX2） and mitogen-activated protein kinases （MAPKs） in inflammatory paw were detected by Western blot， to explore the preliminary mechanism of JPTL. ResultCompared with the conditions in the normal group， there was a significant increase in the ear swelling of xylene-induced model mice， a shortened paw withdrawal latency in the hot plate test （P<0.01）. Compared with the model group， JPTL remarkably increased the inhibition rate of xylene-induced ear swelling （P<0.05， P<0.01）， prolonged the latency period of writhing caused by acetic acid and reduced the number of writhing （P<0.05， P<0.01）. Compared with normal group, the degree of feet swelling in chronic inflammatory pain mice was significantly increased， the threshold of mechanical pain was decreased and the threshold of cold pain was increased （P<0.05， P<0.01）， the protein contents of AQP1 and AQP3 in inflammatory feet were increased， and the contents of IL-1β， IL-6， TNF-α， PGE2 and COX2 in inflammatory feet were increased in serum and/or inflammatory feet. The protein expression levels of p-p38 MAPK， p-JNK and p-ERK in inflammatory feet were increased （P<0.01）. Compared with the model group， JPTL relieved paw swelling of mice with chronic inflammatory pain， elevated mechanical withdrawal threshold while decreased cold withdrawal threshold， with analgesia lasting for 4 h and the optimal time point for analgesia being 2 h after administration （P<0.05， P<0.01）. Moreover， JPTL down-regulated AQP1， AQP3， COX2， p-p38 MAPK， p-JNK and p-ERK in inflammatory paw of mice with chronic inflammatory pain and reduced IL-1β， IL-6， TNF-α， and PGE2 in serum and/or inflammatory paw， but it had no significant effect on COX1 （P<0.05， P<0.01）. ConclusionJPTL has anti-swelling and analgesic effects， and its mechanism is related to inhibiting the production of cytokines and inflammatory mediators via the down-regulation of MAPKs signaling pathway， which provides an experimental basis for the clinical application of JPTL.

Value of inflammatory mediator profiles and procalcitonin in predicting postoperative infection in patients with hypertensive cerebral hemorrhage.

BACKGROUND: Hypertensive cerebral hemorrhage (HICH) is a common clinical cerebrovascular disease and one of the most serious complications of hypertension. Early warning of the occurrence of infection during treatment and timely anti-infective treatment are of great significance for the early prevention and treatment of postoperative infection in patients with HICH. Changes in the levels of inflammatory mediators, which are closely related to the occurrence and development of postoperative infection, and procalcitonin (PCT), which is a sensitive indicator for diagnosing bacterial infections, are widely used in clinical practice. AIM: To explore the application value of inflammatory mediator profiles and PCT in predicting postoperative infection in patients with HICH. METHODS: A total of 271 patients who underwent HICH surgery at our hospital between March 2019 and March 2021 were selected and divided into the infection (n = 80) and non-infection (n = 191) groups according to whether postoperative infection occurred. The postoperative infection status and etiological characteristics of the infective pathogens in the infection group were analyzed. Changes in inflammatory mediator profile indices and PCT levels were compared between the two groups, pre- and postoperatively. RESULTS: A total of 109 strains of pathogenic bacteria were detected in the infection group, including 67 strains (61.47%) of gram-negative bacteria, 32 strains (29.36%) of gram-positive bacteria, and 10 strains (9.17%) of fungi. The main infection site of the patients in the infection group was the respiratory system (63.75%). Preoperative interleukin (IL)-4, IL-6, IL-10, tumor necrosis factor-α, interferon-γ, and PCT levels were higher in the infection group than in the non-infection group (P < 0.05), and there were no significant differences in the IL-2 Levels between the two groups (P > 0.05). The inflammatory mediator profile indices and PCT levels were higher in the two groups of patients on the first postoperative day than preoperatively (P < 0.05), and were higher than those in the non-infection group (P < 0.05). Logistic regression analysis showed that preoperative IL-6 and PCT levels correlated with postoperative infection (P < 0.05). Operating characteristic curve analysis results showed that the area under the curve (AUC) values of preoperative IL-6 and PCT levels in predicting postoperative infection in patients with HICH were 0.755 and 0.824, respectively. The AUC value of joint detection was 0.866, which was significantly higher than that of the single index (P < 0.05). CONCLUSION: Preoperative IL-6 and PCT levels are correlated with postoperative infection in patients with HICH. Their detection is clinically significant for early identification of patients at high risk for postoperative infection.

Network analysis and experimental pharmacology study explore the protective effects of Isoliquiritigenin on 5-fluorouracil-Induced intestinal mucositis.

5-fluorouracil (5-FU) is one of the most widely used chemotherapy drugs for malignant tumors. However, intestinal mucositis caused by 5-FU is a severe dose-limiting toxic effect and even leads to treatment interruption. Isoliquiritigenin (ISL) is one of the main active compounds of licorice, which is a traditional Chinese herbal medicine commonly used in inflammation and gastrointestinal diseases. It is speculated that ISL have protective effects on intestinal mucositis. However, no such studies have been reported. Therefore, to investigate the impact of ISL on 5-Fu-induced intestinal mucositis, a strategy based on network prediction and pharmacological experimental validation was proposed in this study. Firstly, the targets and mechanism of ISL in alleviating 5-Fu-induced gastrointestinal toxicity were predicted by network analysis. And the results were further confirmed by molecular docking. Then, a mouse model of intestinal mucositis was established by intraperitoneal injection of 5-FU (384 µmol/kg) to verify the prediction of network analysis. The network analysis results suggested that PTGS2 (Prostaglandin G/H synthase 2) and NOS2 (Nitric oxide synthase, inducible) might be the critical targets of ISL for reducing the intestinal toxicity of 5-FU. In addition, KEGG and GO enrichment analysis revealed that the HIF-1, TNF, MAPK, IL-17, PI3K-Akt, Ras, NF-kappa B signaling pathway, and biological processes of the inflammatory response, apoptosis regulation, NO production and NF-kappa B transcription factor activity might be involved in the mechanism of ISL against intestinal mucositis. Subsequent animal experiments showed that ISL could reduce the weight loss, leukopenia and mucosal damage caused by 5-FU. Compared with the intestinal mucositis model, the protein expressions of PTGS2, NOS2, TNFα (Tumor necrosis factor-alpha) and NF-κB p65 (nuclear factor kappa-B P65) were decreased after ISL treatment. In conclusion, this study is the fist time to find that ISL can attenuate 5-FU-induced intestinal mucositis in mice. Its anti-mucositis effect may be through regulating TNF/NF-κB pathway and inhibiting inflammatory mediators PTGS2 and NOS2. It will provide a potential candidate for the prevention and treatment of chemotherapy-induced intestinal mucositis.

Increased platelet activation and platelet-inflammasome engagement during chikungunya infection.

Chikungunya fever is a viral disease transmitted by mosquitoes of the genus Aedes. The infection is usually symptomatic and most common symptoms are fever accompanied by joint pain and swelling. In most cases symptoms subside within a week. However, severe prolonged and disabling joint pain, that may persist for several months, even years, are reported. Although the pathogenesis of Chikungunya infection is not fully understood, the evolution to severe disease seems to be associated with the activation of immune mechanisms and the action of inflammatory mediators. Platelets are recognized as inflammatory cells with fundamental activities in the immune response, maintenance of vascular stability and pathogenicity of several inflammatory and infectious diseases. Although the involvement of platelets in the pathogenesis of viral diseases has gained attention in recent years, their activation in Chikungunya has not been explored. The aim of this study was to analyze platelet activation and the possible role of platelets in the amplification of the inflammatory response during Chikungunya infection. We prospectively included 132 patients attended at the Quinta D'Or hospital and 25 healthy volunteers during the 2016 epidemic in Rio de Janeiro, Brazil. We observed increased expression of CD62P on the surface of platelets, as well as increased plasma levels of CD62P and platelet-derived inflammatory mediators indicating that the Chikungunya infection leads to platelet activation. In addition, platelets from chikungunya patients exhibit increased expression of NLRP3, caspase 4, and cleaved IL-1ß, suggestive of platelet-inflammasome engagement during chikungunya infection. In vitro experiments confirmed that the Chikungunya virus directly activates platelets. Moreover, we observed that platelet activation and soluble p-selectin at the onset of symptoms were associated with development of chronic forms of the disease. Collectively, our data suggest platelet involvement in the immune processes and inflammatory amplification triggered by the infection.

Stimuli-responsive polypeptide nanogels for trypsin inhibition.

A new type of hydrophilic, biocompatible, and biodegradable polypeptide nanogel depots loaded with the natural serine protease inhibitor α1-antitrypsin (AAT) was applied for the inhibition of the inflammatory mediator trypsin. Two types of nanogels were prepared from linear synthetic polypeptides based on biocompatible and biodegradable poly[N 5-(2-hydroxyethyl)-ʟ-glutamine-ran-N 5-propargyl-ʟ-glutamine-ran-N 5-(6-aminohexyl)-ʟ-glutamine]-ran-N 5-[2-(4-hydroxyphenyl)ethyl)-ʟ-glutamine] (PHEG-Tyr) or biocompatible N α-ʟ-lysine-grafted α,ß-poly[(2-propyne)-ᴅ,ʟ-aspartamide-ran-(2-hydroxyethyl)-ᴅʟ-aspartamide-ran-(2-(4-hydroxyphenyl)ethyl)-ᴅʟ-aspartamide] (N α-Lys-NG). Both nanogels were prepared by HRP/H2O2-mediated crosslinking in inverse miniemulsions with pH and temperature-stimuli responsive behavior confirmed by dynamic light scattering and zeta potential measurements. The loading capacity of PHEG-Tyr and N α-Lys-NG nanogels and their release profiles were first optimized with bovine serum albumin. The nanogels were then used for loading and release of AAT. PHEG-Tyr and N α-Lys-NG nanogels showed different loading capacities for AAT with the maximum (20%) achieved with N α-Lys-NG nanogel. In both cases, the nanogel depots demonstrated a burst release of AAT during the first 6 h, which could be favorable for quick inhibition of trypsin. A consequent pilot in vitro inhibition study revealed that both PHEG-Tyr and N α-Lys-NG nanogels loaded with AAT successfully inhibited the enzymatic activity of trypsin. Furthermore, the inhibitory efficiency of the AAT-loaded nanogels was higher than that of only AAT. Interestingly, also non-loaded PHEG-Tyr and N α-Lys-NG nanogels were shown to effectively inhibit trypsin because they contain suitable amino acids in their structures that effectively block the active site of trypsin.

A Systematic Review of Keratinocyte Secretions: A Regenerative Perspective.

Cell regenerative therapy is a modern solution for difficult-to-heal wounds. Keratinocytes, the most common cell type in the skin, are difficult to obtain without the creation of another wound. Stem cell differentiation towards keratinocytes is a challenging process, and it is difficult to reproduce in chemically defined media. Nevertheless, a co-culture of keratinocytes with stem cells usually achieves efficient differentiation. This systematic review aims to identify the secretions of normal human keratinocytes reported in the literature and correlate them with the differentiation process. An online search revealed 338 references, of which 100 met the selection criteria. A total of 80 different keratinocyte secretions were reported, which can be grouped mainly into cytokines, growth factors, and antimicrobial peptides. The growth-factor group mostly affects stem cell differentiation into keratinocytes, especially epidermal growth factor and members of the transforming growth factor family. Nevertheless, the reported secretions reflected the nature of the involved studies, as most of them focused on keratinocyte interaction with inflammation. This review highlights the secretory function of keratinocytes, as well as the need for intense investigation to characterize these secretions and evaluate their regenerative capacities.

Factors influencing the blood-brain barrier permeability.

The blood-brain barrier (BBB) is a dynamic structure that protects the brain from harmful blood-borne, endogenous and exogenous substances and maintains the homeostatic microenvironment. All constituent cell types play indispensable roles in the BBB's integrity, and other structural BBB components, such as tight junction proteins, adherens junctions, and junctional proteins, can control the barrier permeability. Regarding the need to exchange nutrients and toxic materials, solute carriers, ATP-binding case families, and ion transporter, as well as transcytosis regulate the influx and efflux transport, while the difference in localisation and expression can contribute to functional differences in transport properties. Numerous chemical mediators and other factors such as non-physicochemical factors have been identified to alter BBB permeability by mediating the structural components and barrier function, because of the close relationship with inflammation. In this review, we highlight recently gained mechanistic insights into the maintenance and disruption of the BBB. A better understanding of the factors influencing BBB permeability could contribute to supporting promising potential therapeutic targets for protecting the BBB and the delivery of central nervous system drugs via BBB permeability interventions under pathological conditions.

Inflammatory Mediators in Atherosclerotic Vascular Remodeling.

Atherosclerotic vascular disease remains the most common cause of ischemia, myocardial infarction, and stroke. Vascular function is determined by structural and functional properties of the arterial vessel wall, which consists of three layers, namely the adventitia, media, and intima. Key cells in shaping the vascular wall architecture and warranting proper vessel function are vascular smooth muscle cells in the arterial media and endothelial cells lining the intima. Pathological alterations of this vessel wall architecture called vascular remodeling can lead to insufficient vascular function and subsequent ischemia and organ damage. One major pathomechanism driving this detrimental vascular remodeling is atherosclerosis, which is initiated by endothelial dysfunction allowing the accumulation of intimal lipids and leukocytes. Inflammatory mediators such as cytokines, chemokines, and modified lipids further drive vascular remodeling ultimately leading to thrombus formation and/or vessel occlusion which can cause major cardiovascular events. Although it is clear that vascular wall remodeling is an elementary mechanism of atherosclerotic vascular disease, the diverse underlying pathomechanisms and its consequences are still insufficiently understood.

Tongbixiao Pills Improve Gout by Reducing Uric Acid Levels and Inhibiting Inflammation.

Gout is a chronic disease. Gout symptoms are often experienced in the middle of the night. The onset of gout in the middle of the night is closely related to abnormal liver and gallbladder meridian. The purpose of this study was to investigate the clinical efficacy and possible mechanism of action of Tongbixiao pills in the treatment of hyperuricemia and gouty arthritis. The Tongbixiao pills we used included several traditional Chinese medicines, most of which tonify the spleen; strengthen the liver; benefit the kidney; and reduce heat, dampness, and blood stasis. In this randomized clinical study of 105 patients, we found that Tongbixiao pills can reduce uric acid levels in hyperuricemia patients. Additionally, the efficacy was similar to that of allopurinol and the level of uric acid did not increase significantly at eight weeks after withdrawal. In the absence of notable adverse reactions, Tongbixiao pills can also increase uric acid excretion, reduce serum creatinine and lipid levels, and reduce inflammation and relieve gout symptoms. In addition, we used SD rats to simulate gout and arthritis and divided them into five groups: normal group, model group, low-dose group, medium-dose group, and high-dose group. The inflammatory indices of the 40 SD rats were observed. After seven days, ankle swelling in rats in the treatment group was significantly reduced. The indices of uric acid, creatinine, and urea nitrogen in the treatment group were significantly lower than those in the model group, which proved that Tongbixiao pills could inhibit hyperuricemia in rats, thus treating gout. This study demonstrates that Tongbixiao pills can treat gout, provide more treatment options for gouty arthritis, and improve the quality of life of patients.

[Coactivator p300-induced H3K27 acetylation mediates lipopolysaccharide-induced inflammatory mediator synthesis].

OBJECTIVE: To investigate the role of acetylated modification induced by coactivator p300 in lipopolysaccharide (LPS)- induced inflammatory mediator synthesis and its molecular mechanism. METHODS: Agilent SurePrint G3 Mouse Gene Expression V2 microarray chip and Western blotting were used to screen the molecules whose expression levels in mouse macrophages (RAW246.7) were correlated with the stimulation intensity of LPS. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (chip-qPCR) were used to verify the binding of the molecules to the promoters of IL-6 and TNF-α genes. The effects of transfection of RAW246.7 cells with overexpression or interfering plasmids on IL-6 and TNF-α synthesis were evaluated with ELISA, and the binding level of the target molecules and acetylation level of H3K27 in the promoter region of IL-6 and TNF-α genes were analyzed by chromatin immunoprecipitation sequencing technique (chip-seq). RESULTS: Gene microarray chip data and Western blotting both confirmed a strong correlation of p300 expression with the stimulation intensity of LPS. Immunocoprecipitation confirmed the binding between p300 and c-myb. The results of EMSA demonstrated that c-myb (P < 0.05), but not p300, could directly bind to the promoter region of IL-6 and TNF-α genes; p300 could bind to the promoters only in the presence of c-myb (P < 0.05). The expressions of p65, p300 and c-myb did not show interactions. Both p300 overexpression and LPS stimulation could increase the level of promoter-binding p300 and H3K27 acetylation level, thus promoting p65 binding and inflammatory gene transcription; such effects were obviously suppressed by interference of c-myb expression (P < 0.05). Interference of p65 resulted in inhibition of p65 binding to the promoters and gene transcription (P < 0.05) without affecting p300 binding or H3K27 acetylation level. CONCLUSION: LPS can stimulate the synthesis of p300, whose binding to the promoter region of inflammatory genes via c-myb facilitates the cohesion of p65 by inducing H3K27 acetylation, thus promoting the expression of the inflammatory genes.

Paraquat modulates immunological function in bone marrow-derived macrophages.

The herbicide paraquat (PQ) is known to affect the immune system. Many reports have indicated that PQ impacts on the viability and functions of the immune cells, however, the underlying mechanism in detail is still unknown. The aim of this study was to evaluate the effects of PQ on the free radical production, oxidative stress, cell death and pro-inflammatory gene expression of murine bone marrow-derived macrophages (BMDMs) from C57BL/6NJcl mice in vitro. BMDMs were incubated with PQ at 0, 200 and 400 µM concentrations for 24 h. Intracellular reactive oxygen species (ROS) production, apoptosis, cell viability, nitric oxide, inducible nitric oxide synthase (iNOS), and IL-6 expression levels were measured. The results revealed that PQ treatments led to a decrease in the cell viability and induced apoptotic cell death in a dose-dependent manner. Additionally, PQ also induced the generation of ROS. The mRNA level of the pro-inflammatory mediator genes iNOS and IL-6 were also elevated, while the level of lipid peroxide (malondialdehyde) production remained unaltered. Interestingly, the PQ treatment led to a decrease in the nitric oxide production. These results indicate that the increased cellular ROS production, due to the PQ treatment, induces apoptosis and the herbicide triggers production of iNOS and IL-6 in BMDMs.