Soluble urate-induced effects on cytokine production in vitro - Assessment of methodologies and cell types.

BACKGROUND: Hyperuricemia has been shown to be an inducer of pro-inflammatory mediators by human primary monocytes. To study the deleterious effects of hyperuricemia, a reliable and stable in vitro model using soluble urate is needed. One recent report showed different urate-dissolving methods resulted in either pro-inflammatory or anti-inflammatory properties. The aim of this study was to compare the effect of two methods of dissolving urate on both primary human peripheral blood mononuclear cells (PBMCs) and THP-1 cells. The two methods tested were 'pre-warming' and 'dissolving with NaOH'. METHODS: Primary human PBMCs and THP-1 cells were exposed to urate solutions, prepared using the two methodologies: pre-warming and dissolving with NaOH. Afterwards, cells were stimulated with various stimuli, followed by the measurement of the inflammatory mediators IL-1ß, IL-6, IL-1Ra, TNF, IL-8, and MCP-1. RESULTS: In PBMCs, we observed an overall pro-inflammatory effect of urate, both in the pre-warming and the NaOH dissolving method. A similar pro-inflammatory effect was seen in THP-1 cells for both dissolving methods after restimulation. However, THP-1 cells exhibited pro-inflammatory profile with exposure to urate alone without restimulation. We did not find MSU crystals in our cellular assays. CONCLUSIONS: Overall, the urate dissolving methods do not have critical impact on its inflammatory properties. Soluble urate prepared using either of the two methods showed mostly pro-inflammatory effects on human primary PBMCs and monocytic cell line THP-1. However, human primary PBMCs and the THP-1 differ in their response to soluble urate without restimulation.

Immunomodulatory assessment of Portulaca oleracea L. extract in a mouse model of colitis.

Ulcerative colitis (UC) is a gastrointestinal inflammatory disease with a multifactorial pathophysiology. This study aims to investigate the immunomodulatory effect of Portulaca oleracea leaf ethanolic extract (POE) on acetic acid (AA)-induced UC in mice. Experimental animals received oral doses of POE (200 mg/kg for 7 days) after an induction of colitis by intrarectal AA administration. In mice with AA-induced UC treated with POE, the results revealed a significant modulation in body weight and colon length. Moreover, treatment with POE downregulated the interleukin 1, 6, and 17, tumor necrosis factor-alpha, gamma interferon, and nuclear factor-kappa B levels compared with the colitis group. Furthermore, POE markedly inhibited histological damage, decreased myeloperoxidase activity and reduced fecal calprotectin level compared with the colitis group. These data are consistent with the reduction in total bacterial content in the colon. Taken together, treatment with POE may reduce colonic inflammation by alleviating the immune response and inhibiting the severity of colitis. The HPLC analysis of POE resulted in the identification of seven medicinal compounds comprising two phenolic acids (ferulic and caffeic acids) and five flavonoids (kaempferol, quercetin, rutin, narenginin and hesperidin). Subsequent analysis of POE by GC-MS revealed ten phytocomponents; the major percentages were hexadecenoic acid, methyl ester (29.8119%), α-linolenic acid (25.8431%), 16-octadecenoic acid, methyl ester (15.1578%) and α-tocopherol (10.7848%). Delta-lactams and alkanes were the minor components. Such natural plant-derived substances and their probable synergistic action appear to contribute to a promising therapeutic protocol for colitis.

Gender differences in Damp-Heat Syndrome: A review.

Gender differences have important biological significance for medical research. In this study, a bias towards males was identified in animal experiments of Damp-Heat Syndrome in traditional Chinese medicine, as was first proposed by a data mining method. Combined with the correlation between Damp-Heat Syndrome in traditional Chinese medicine and Gender differences, it was considered that Gender-related factors have a significant influence on the development of Damp-Heat Syndrome in traditional Chinese medicine. However, most traditional Chinese medicine studies ignore the key significance of Gender-related factors. This study emphasises that the development of modern traditional Chinese medicine research needs to pay full attention to the biological significance of Gender-related factors and to apply this concept to the research on the Gender equivalence strategy in basic research and the practice of personalised medical diagnosis and clinical treatment.

The Role of Molecular and Inflammatory Indicators in the Assessment of Cognitive Dysfunction in a Mouse Model of Diabetes.

The brain is the most vulnerable organ to glucose fluctuations, as well as inflammation. Considering that cognitive impairment might occur at the early stage of diabetes, it is very important to identify key markers of early neuronal dysfunction. Our overall goal was to identify neuroinflammatory and molecular indicators of early cognitive impairment in diabetic mice. To confirm cognitive impairment in diabetic mice, series of behavioral tests were conducted. The markers related to cognitive decline were classified into the following two groups: Neuroinflammatory markers: IL-1ß, IL-6, tumor necrosis factor-α (TNF-α) and genetic markers (Bdnf, Arc, Egr1) which were estimated in brain regions. Our studies showed a strong association between hyperglycemia, hyperinsulinemia, neuroinflammation, and cognitive dysfunction in T2DM mice model. Cognitive impairment recorded in diabetes mice were associated not only with increased levels of cytokines but also decreased Arc and Egr1 mRNA expression level in brain regions associated with learning process and memory formation. The results of our research show that these indicators may be useful to test new forms of treatment of early cognitive dysfunction associated not only with diabetes but other diseases manifesting this type of disorders. The significant changes in Arc and Egr1 gene expression in early stage diabetes create opportunities it possible to use them to track the progression of CNS dysfunction and also to differential disease diagnosis running with cognitive impairment.

Assessment of lesion-associated myocardial ischemia based on fusion coronary CT imaging - the FUSE-HEART study: A protocol for non-randomized clinical trial.

INTRODUCTION: Multimodality assessment of coronary artery lesions has demonstrated superior effectiveness compared to the conventional approach, for assessing both anatomical and functional significance of a coronary stenosis. Multiple imaging modalities can be integrated into a fusion imaging tool to better assess myocardial ischemia. MATERIAL AND METHODS: The FUSE-HEART trial is a single center, prospective, cohort study that will assess the impact of a coronary artery stenosis on myocardial function and viability, based on advanced fusion imaging technics derived from Cardiac Computed Tomography Angiography (CCTA). Moreover, the study will investigate the correlation between morphology and composition of the coronary plaques and myocardial ischemia in the territory irrigated by the same coronary artery. At the same time, imaging parameters will be correlated with inflammatory status of the subjects. The trial will include 100 subjects with coronary lesions found on CCTA examination. The study population will be divided into 2 groups: first group will consist of subjects with anatomically significant coronary lesions on native coronary arteries and the second one will include subjects surviving an acute myocardial infarction. The vulnerability score of the subjects will be calculated based on presence of CCTA vulnerability markers of the coronary plaques: napkin ring sign, positive remodeling, spotty calcifications, necrotic core, and low-density plaques. 3D fusion images of the coronary tree will be generated, integrating the images reflecting wall motion with the ones of coronary circulation. The fusion models will establish the correspondence between plaque composition and wall motion in the subtended myocardium of the coronary artery. The study primary outcome will be represented by the rate of major adverse cardiac events related to myocardial ischemia at 1-year post assessment, in correlation with the degree of coronary artery stenosis and myocardial ischemia or viability.The secondary outcomes are represented by the rate of re-hospitalization, rate of survival and rate of major adverse cardiovascular events (including cardiovascular death or stroke), in correlation with the morphology and composition of atheromatous plaques located in a coronary artery, and myocardial ischemia in the territory irrigated by the same coronary artery. CONCLUSION: In conclusion, FUSE-HEART will be a study based on modern imaging tools that will investigate the impact of a coronary artery stenosis on myocardial function and viability, using advanced fusion imaging technics derived from CCTA, sighting to validate plaque composition and morphology, together with inflammatory biomarkers, as predictors to myocardial viability.

Clinical disease activity and flare in SLE: Current concepts and novel biomarkers.

Systemic lupus erythematosus (SLE) is a complex and heterogeneous systemic autoimmune disease associated with innate and adaptive immune dysregulation. SLE occurs primarily in females of childbearing age, with increased prevalence and severity in minority populations. Despite improvements in treatment modalities, SLE patients frequently experience periods of heightened disease activity and flare that can lead to permanent organ damage, increased morbidity, and early mortality. Such outcomes impair quality of life and inflict a significant socioeconomic burden. Predicting changes in SLE disease activity could allow for closer monitoring and preemptive treatment, but existing clinical, demographic and serologic markers have been only modestly predictive. Novel, proactive approaches to clinical disease management are thus critically needed. Panels of blood biomarkers can detect a breadth of immune pathway dysregulation that captures SLE heterogeneity and disease activity. Alterations in the balance of pro-inflammatory and regulatory soluble mediators have been associated with changes in clinical disease activity and are detectable several weeks prior to clinical flare occurrence. A soluble mediator score has been highly predictive of impending flare in both European American and African American SLE patients, and this score does not require a priori knowledge of specific pathway activation in the patient. We review current concepts of disease activity and flare in SLE, focusing on the potential of novel blood biomarkers to characterize and predict changes in disease activity. Measuring the disordered immune response in SLE in this way promises to improve disease management and prevent organ damage in SLE.

Decreased pH in the aging brain and Alzheimer's disease.

Using publicly available data sets, we compared pH in the human brain and the cerebrospinal fluid (CSF) of postmortem control and Alzheimer's disease cases. We further investigated the effects of long-term acidosis in vivo in the APP-PS1 mouse model of Alzheimer's disease. We finally examined in vitro whether low pH exposure could modulate the release of proinflammatory cytokines and the uptake of amyloid beta by microglia. In the human brain, pH decreased with aging. Similarly, we observed a reduction of pH in the brain of C57BL/6 mice with age. In addition, independent database analyses revealed that postmortem brain and CSF pH is further reduced in Alzheimer's disease cases compared with controls. Moreover, in vivo experiments showed that low pH CSF infusion increased amyloid beta plaque load in APP-PS1 mice. We further observed that mild acidosis reduced the amyloid beta 42-induced release of tumor necrosis factor-alpha by microglia and their capacity to uptake this peptide. Brain acidosis is associated with aging and might affect pathophysiological processes such as amyloid beta aggregation or inflammation in Alzheimer's disease.

Health disparities: Intracellular consequences of social determinants of health.

Health disparities exist dependent on socioeconomic status, living conditions, race/ethnicity, diet, and exposures to environmental pollutants. Herein, the various exposures contributing to a person's exposome are collectively considered social determinants of health (SDOH), and the SDOH-exposome impacts health more than health care. This review discusses the extent of evidence of the physiologic consequences of these exposures at the intracellular level. We consider how the SDOH-exposome, which captures how individuals live, work and age, induces cell processes that modulate a conceptual "redox rheostat." Like an electrical resistor, the SDOH-exposome, along with genetic predisposition and age, regulate reductive and oxidative (redox) stress circuits and thereby stimulate inflammation. Regardless of the source of the SDOH-exposome that induces chronic inflammation and immunosenescence, the outcome influences cardiometabolic diseases, cancers, infections, sepsis, neurodegeneration and autoimmune diseases. The endogenous redox rheostat is connected with regulatory molecules such as NAD+/NADH and SIRT1 that drive redox pathways. In addition to these intracellular and mitochondrial processes, we discuss how the SDOH-exposome can influence the balance between metabolism and regulation of immune responsiveness involving the two main molecular drivers of inflammation, the NLRP3 inflammasome and NF-κB induction. Mitochondrial and inflammasome activities play key roles in mediating defenses against pathogens and controlling inflammation before diverse cell death pathways are induced. Specifically, pyroptosis, cell death by inflammation, is intimately associated with common disease outcomes that are influenced by the SDOH-exposome. Redox influences on immunometabolism including protein cysteines and ion fluxes are discussed regarding health outcomes. In summary, this review presents a translational research perspective, with evidence from in vitro and in vivo models as well as clinical and epidemiological studies, to outline the intracellular consequences of the SDOH-exposome that drive health disparities in patients and populations. The relevance of this conceptual and theoretical model considering the SARS-CoV-2 pandemic are highlighted. Finally, the case of asthma is presented as a chronic condition that is modified by adverse SDOH exposures and is manifested through the dysregulation of immune cell redox regulatory processes we highlight in this review.

Electronic nicotine delivery system-induced alterations in oral health via saliva assessment.

IMPACT STATEMENT: The use of traditional tobacco products is a known risk factor for the development of diseases including periodontal disease. To date, the potential oral health effects related to electronic nicotine delivery systems (ENDS) use is unknown. This study collected saliva from ENDS users and never tobacco users to examine differences in the oral cavity of inflammatory cytokines and metabolites. The identification and measurement of these ENDS-related changes provide insight into disease pathways potentially associated with ENDS use. The utilization of saliva samples collected from human participates enhances the application of the findings compared to the majority of studies using cell culture and animal models. In addition, these foundational findings can inform future studies to examining specific pathways identified, interventional approaches, and application of translatable biomarkers of ENDS use.

Use of a common European approach for nanomaterials' testing to support regulation: a case study on titanium and silicon dioxide representative nanomaterials.

The European Union (EU) continuously takes ensuring the safe use of manufactured nanomaterials (MNMs) in consumer products into consideration. The application of a common approach for testing MNMs, including the use of optimized protocols and methods' selection, becomes increasingly important to obtain reliable and comparable results supporting the regulatory framework. In the present study, we tested four representative MNMs, two titanium dioxides (NM100 and NM101) and two silicon dioxides (NM200 and NM203), using the EU FP7-NANoREG approach, starting from suspension and dispersion preparations, through to their characterization and final evaluation of biological effects. MNM dispersions were prepared following a refined NANOGENOTOX protocol and characterized by dynamic light scattering (DLS) in water/bovine serum albumin and in media used for in vitro testing. Potential genotoxic effects were evaluated on human bronchial BEAS-2B cells using micronucleus and Comet assays, and pro-inflammatory effects by cytokines release. Murine macrophages RAW 264.7 were used to detect potential innate immune responses using two functional endpoints (pro-inflammatory cytokines and nitric oxide [NO] production). The interaction of MNMs with RAW 264.7 cells was studied by electron microscopy. No chromosomal damage and slight DNA damage and an oxidative effect, depending on MNMs, were observed in bronchial cells. In murine macrophages, the four MNMs directly induced tumor necrosis factor α or interleukin 6 secretion, although at very low levels; lipopolysaccharide-induced NO production was significantly decreased by the titania and one silica MNM. The application of this approach for the evaluation of MNM biological effects could be useful for both regulators and industries.

T-Cell Dependent Immunogenicity of Protein Therapeutics Pre-clinical Assessment and Mitigation-Updated Consensus and Review 2020.

Immune responses to protein and peptide drugs can alter or reduce their efficacy and may be associated with adverse effects. While anti-drug antibodies (ADA) are a standard clinical measure of protein therapeutic immunogenicity, T cell epitopes in the primary sequences of these drugs are the key drivers or modulators of ADA response, depending on the type of T cell response that is stimulated (e.g., T helper or Regulatory T cells, respectively). In a previous publication on T cell-dependent immunogenicity of biotherapeutics, we addressed mitigation efforts such as identifying and reducing the presence of T cell epitopes or T cell response to protein therapeutics prior to further development of the protein therapeutic for clinical use. Over the past 5 years, greater insight into the role of regulatory T cell epitopes and the conservation of T cell epitopes with self (beyond germline) has improved the preclinical assessment of immunogenic potential. In addition, impurities contained in therapeutic drug formulations such as host cell proteins have also attracted attention and become the focus of novel risk assessment methods. Target effects have come into focus, given the emergence of protein and peptide drugs that target immune receptors in immuno-oncology applications. Lastly, new modalities are entering the clinic, leading to the need to revise certain aspects of the preclinical immunogenicity assessment pathway. In addition to drugs that have multiple antibody-derived domains or non-antibody scaffolds, therapeutic drugs may now be introduced via viral vectors, cell-based constructs, or nucleic acid based therapeutics that may, in addition to delivering drug, also prime the immune system, driving immune response to the delivery vehicle as well as the encoded therapeutic, adding to the complexity of assessing immunogenicity risk. While it is challenging to keep pace with emerging methods for the preclinical assessment of protein therapeutics and new biologic therapeutic modalities, this collective compendium provides a guide to current best practices and new concepts in the field.

COVID-19 vaccine development and the way forward.

The whole globe is reeling under the COVID-19 pandemic now. With the scale and severity of infection, number of deaths and lack of any definite therapeutic armamentarium, the vaccine development has been accelerated at a never-before pace. A wide variety of vaccine technologies and platforms are being attempted. Out of the over 108 efforts, 100 are in preclinical and eight in Phase 1 or 2 trial stage. While the availability of newer technologies has facilitated development, there are several challenges on the way including limited understanding of the pathophysiology, targeting humoral or mucosal immunity, lack of suitable animal model, poor success of human severe acute respiratory syndrome/Middle East Respiratory Syndrome vaccines, limited efficacy of influenza vaccines, and immune exaggeration with animal coronavirus vaccines. With the current scenario with political, funding, research, and regulatory supports, if everything sails through smoothly, the successful vaccine is expected in 12-18 months. Modestly efficacious vaccine may be also a good achievement.

Multicellular Human Alveolar Model Composed of Epithelial Cells and Primary Immune Cells for Hazard Assessment.

A human alveolar cell coculture model is described here for simulation of the alveolar epithelial tissue barrier composed of alveolar epithelial type II cells and two types of immune cells (i.e., human monocyte-derived macrophages [MDMs] and dendritic cells [MDDCs]). A protocol for assembling the multicellular model is provided. Alveolar epithelial cells (A549 cell line) are grown and differentiated under submerged conditions on permeable inserts in two-chamber wells, then combined with differentiated MDMs and MDDCs. Finally, the cells are exposed to an air-liquid interface for several days. As human primary immune cells need to be isolated from human buffy coats, immune cells differentiated from either fresh or thawed monocytes are compared in order to tailor the method based on experimental needs. The three-dimensional models, composed of alveolar cells with either freshly isolated or thawed monocyte-derived immune cells, show a statistically significant increase in cytokine (interleukins 6 and 8) release upon exposure to proinflammatory stimuli (lipopolysaccharide and tumor necrosis factor α) compared to untreated cells. On the other hand, there is no statistically significant difference between the cytokine release observed in the cocultures. This shows that the presented model is responsive to proinflammatory stimuli in the presence of MDMs and MDDCs differentiated from fresh or thawed peripheral blood monocytes (PBMs). Thus, it is a powerful tool for investigations of acute biological response to different substances, including aerosolized drugs or nanomaterials.

Evaluation of goserelin effectiveness based on assessment of inflammatory cytokines and symptoms in uterine leiomyoma.

Background Uterine leiomyoma is a benign tumour of the uterine smooth muscles associated with an elevated level of inflammatory cytokines. Goserelin, a synthetic gonadotropin-releasing hormone analogue, suppresses the production of sex hormones and release of inflammatory cytokines in uterine leiomyoma cells. Objective The primary objective of this study was to find out the effectiveness of subcutaneous goserelin therapy on lowering serum levels of inflammatory cytokines and improving uterine leiomyoma-related symptoms in female patients diagnosed with uterine leiomyoma. The secondary objective was to assess the tolerability to goserelin therapy used in the management of this tumour. Setting Outpatient gynaecological clinic of the medical consultation department of Baghdad Teaching Hospital, Baghdad province, Iraq. Methods A single centre, prospective, longitudinal, cohort study was carried out on female patients diagnosed with uterine leiomyoma. Goserelin 3.6 mg subcutaneous injection was given in a consecutive monthly dose for the total time duration of three months. Serum levels of inflammatory cytokines, tumour necrosis factor-α and monocyte chemotactic protein-1 were detected before and after goserelin therapy in a consecutive monthly assessment. The study also assessed the improvement in uterine leiomyoma-related symptoms, including pelvic pain alongside the incidence of goserelin-related side effects during therapy schedules. Main Outcome Measures Assessment of serum levels of tumour necrosis factor-α and monocyte chemotactic protein-1 alongside uterine leiomyoma-related symptoms, including pelvic pain and goserelin-related side effects. Results There was a significant decrease in serum levels of tumour necrosis factor-α and monocyte chemotactic protein-1 compared to the baseline level over the 3-month duration of goserelin therapy (0.11 ± 0.02 vs. 0.74 ± 0.19) pg/mL; (0.07 ± 0.00 vs. 0.44 ± 0.18) pg/mL respectively. Patients showed a clinical improvement regarding uterine leiomyoma-related symptoms following each of the consecutive monthly doses of goserelin therapy (n = 11, 55%, P < 0.0001; n = 15, 75%, P < 0.0001; n = 18, 90%, P < 0.0001) respectively. This also includes a significant decrease in the intensity of leiomyoma-related pelvic pain before and after goserelin therapy (7.2 ± 1.43 vs. 3.05 ± 1.14, P < 0.0001). The majority of patients reported vaginal dryness (60%) as the main goserelin-related side effect. Conclusion Goserelin therapy reduces serum levels of inflammatory cytokines, tumour necrosis factor- α and monocyte chemotactic protein-1, improving leiomyoma-related symptoms with good tolerability in patients with uterine leiomyoma.

Harnessing radiation to improve immunotherapy: better with particles?

The combination of radiotherapy and immunotherapy is one of the most promising strategies for cancer treatment. Recent clinical results support the pre-clinical experiments pointing to a benefit for the combined treatment in metastatic patients. Charged particle therapy (using protons or heavier ions) is considered one of the most advanced radiotherapy techniques, but its cost remains higher than conventional X-ray therapy. The most important question to be addressed to justify a more widespread use of particle therapy is whether they can be more effective than X-rays in combination with immunotherapy. Protons and heavy ions have physical advantages compared to X-rays that lead to a reduced damage to the immune cells, that are required for an effective immune response. Moreover, densely ionizing radiation may have biological advantages, due to different cell death pathways and release of cytokine mediators of inflammation. We will discuss results in esophageal cancer patients showing that charged particles can reduce the damage to blood lymphocytes compared to X-rays, and preliminary in vitro studies pointing to an increased release of immune-stimulating cytokines after heavy ion exposure. Pre-clinical and clinical studies are ongoing to test these hypotheses.

Establishment of rapid risk assessment model for cigarette smoke extract exposure in chronic obstructive pulmonary disease.

Rapid risk assessment models for different types of cigarette smoke extract (CSE) exposure are critical to understanding the etiology of chronic obstructive pulmonary disease. The present study investigated inflammation of cultured tracheal tissues with CSE exposure. Rat trachea rings were isolated, cultured, then exposed to various concentrations of CSE from 3R4 F reference cigarettes for 4 h. Tissue/cellular morphology, ultrastructure, viability and damage, inflammatory cell infiltration, and inflammatory protein levels were measured and compared to untreated controls. Human bronchial epithelial cells (BEAS-2B) exposed to 0 or 300 µg/mL CSE were cocultured with macrophages to assess extent of mobilization and phagocytosis. Endotracheal epithelium cilia densities were significantly reduced with increasing CSE concentrations, while mucous membranes became increasingly disordered; both eventually disappeared. Macrophages became larger as the CSE concentration increased, with microvilli and extended pseudopodium covering their surface, and many primary and secondary lysosomes present in the cytoplasm. Inflammatory cell infiltration also increased with increasing CSE dose, as did intracellular adhesion molecule-1(ICAM-1), interleukin-6(IL-6). The method described here may be useful to qualitatively characterized the effects of the compound under study. Then, we use BEAS-2B cell line system to strength the observation made in the cultured tissues. Probably, an approach to integrate results from both experiments will facilitate its application. These results demonstrate that cultured rat tracheal rings have a whole-tissue structure that undergoes inflammatory processes similar to in vivo tissues upon CSE exposure.

Acute changes of pro-inflammatory markers and corticosterone in experimental subarachnoid haemorrhage: A prerequisite for severity assessment.

Many details of the pathophysiology of subarachnoid haemorrhage (SAH) still remain unknown, making animal experiments an indispensable tool for assessment of diagnostics and therapy. For animal protection and project authorization, one needs objective measures to evaluate the severity and burden in each model. Corticosterone is described as a sensitive stress parameter reflecting the acute burden, and inflammatory markers can be used for assessment of the extent of the brain lesion. However, the brain lesion itself may activate the hypothalamic-pituitary-adrenal-axis early after SAH, as shown for ischemic stroke, probably interfering with early inflammatory processes, thus complicating the assessment of severity and burden on the basis of corticosterone and inflammation. To assess the suitability of these markers in SAH, we evaluated the courses of corticosterone, IL-6 and TNF-α up to 6h in an acute model simulating SAH in continuously anaesthetized rats, lacking the pain and stress induced impact on these parameters. Animals were randomly allocated to sham or SAH. SAH was induced by cisterna magna blood-injection, and intracranial pressure and cerebral blood flow were measured under continuous isoflurane/fentanyl anaesthesia. Withdrawn at predetermined time points, blood was analysed by commercial ELISA kits. After 6h the brain was removed for western blot analysis of IL-6 and TNF-α. Serum corticosterone levels were low with no significant difference between sham and SAH. No activation of the HPA-axis was detectable, rendering corticosterone a potentially useful parameter for stress assessment in future chronic studies. Blood IL-6 and TNF-α increased in both groups over time, with IL-6 increasing significantly more in SAH compared to sham towards the end of the observation period. In the basal cortex, IL-6 and TNF-α increased only in SAH. The pro-inflammatory response seems to start locally in the brain, reflected by an increase in peripheral blood. An additional surgery-induced systemic inflammatory response should be considered.

In vitro and in vivo assessment of the proresolutive and antiresorptive actions of resolvin D1: relevance to arthritis.

BACKGROUND: Resolvin D1 (RvD1), an important member of resolvins, exerts a wide spectrum of biological effects, including resolution of inflammation, tissue repair, and preservation of cell viability. The aim of the present study is to investigate the anti-arthritic potential and clarify the bone protective actions of RvD1 in vitro and in vivo. METHODS: RAW264.7 cells were treated with 50 ng/ml LPS for 72 h in the presence or absence of RvD1 (0-500 nM). Primary human monocytes were treated with M-CSF + RANKL for 14 days ± RvD1 (0-500 nM) with or without siRNA against RvD1 receptor FPR2. Expressions of inflammatory mediators, degrading enzymes, osteoclasts (OC) formation, and bone resorption were analyzed. The therapeutic effect of RvD1 (0-1000 ng) was carried out in murine collagen antibody-induced arthritis. Arthritis scoring, joint histology, and inflammatory and bone turnover markers were measured. RESULTS: RvD1 is not toxic and inhibits OC differentiation and activation. It decreases bone resorption, as assessed by the inhibition of TRAP and cathepsin K expression, hydroxyapatite matrix resorption, and bone loss. In addition, RvD1 reduces TNF-α, IL-1ß, IFN-γ, PGE2, and RANK and concurrently enhances IL-10 in OC. Moreover, in arthritic mice, RvD1 alleviates clinical score, paw inflammation, and bone and joint destructions. Besides, RvD1 reduces inflammatory mediators and markedly decreases serum markers of bone and cartilage turnover. CONCLUSION: Our results provide additional evidence that RvD1 plays a key role in preventing bone resorption and other pathophysiological changes associated with arthritis. The study highlights the clinical relevance of RvD1 as a potential compound for the treatment of inflammatory arthritis and related bone disorders.

Assessment of alcohol consumption in depression follow-up using self-reports and blood measures including inflammatory biomarkers.

AIMS: Alcohol consumption has been suggested a major role in the pathogenesis and prognosis of depression. However, reliable identification of hazardous drinking continues to be problematic. We compared the accuracy of different biomarkers and self-reports of alcohol consumption in the follow-up study of depression. METHODS: Data from 202 patients with major depressive disorder were obtained through self-reports, AUDIT and AUDIT-C questionnaires and biomarker analyses. The clinical assessments and measurements of biomarkers (GT, CDT, GT-CDT-combination, MCV, ALT, AST, hs-CRP, IL-6) were performed at baseline and after six months of treatment. Based on self-reported alcohol intake at baseline the patients were classified to three subgroups. RESULTS: About 27.2% of patients were categorized to high-risk drinkers, 26.3% low-risk drinkers and 46.5% abstainers. High-risk drinkers showed significantly higher mean values of GT, CDT, GT-CDT-combination and IL-6 than abstainers, diagnostic accuracy being highest with the combined marker of GT-CDT. The accuracy of AUDIT and AUDIT-C to detect high-risk drinking was also significant. During follow-up, the differences observed in the biomarkers at baseline disappeared together with recovery from depression. CONCLUSIONS: Our data suggest the combined use of GT-CDT and AUDIT questionnaires to improve the identification of drinking of patients with depression. This approach could be useful for improving treatment adherence and outcome in depressed patients.

Effect of photobiomodulation on the severity of oral mucositis and molecular changes in head and neck cancer patients undergoing radiotherapy: a study protocol for a cost-effectiveness randomized clinical trial.

BACKGROUND: Oral mucositis (OM) is the most frequent and debilitating acute side effect associated with head and neck cancer (HNC) treatment. When present, severe OM negatively impacts the quality of life of patients undergoing HNC treatment. Photobiomodulation is a well-consolidated and effective therapy for the treatment and prevention of severe OM, and is associated with a cost reduction of the cancer treatment. Although an increase in the quality of life and a reduction in the severity of OM are well described, there is no study on cost-effectiveness for this approach considering the quality of life as a primary outcome. In addition, little is known about the photobiomodulation effects on salivary inflammatory mediators. Thus, this study aimed to assess the cost-effectiveness of the photobiomodulation therapy for the prevention and control of severe OM and its influence on the salivary inflammatory mediators. METHODS/DESIGN: This randomized, double-blind clinical trial will include 50 HNC patients undergoing radiotherapy or chemoradiotherapy. The participants will be randomized into two groups: intervention group (photobiomodulation) and control group (preventive oral care protocol). OM (clinical assessment), saliva (assessment of collected samples) and quality of life (Oral Health Impact Profile-14 and Patient-Reported Oral Mucositis Symptoms questionnaires) will be assessed at the 1st, 7th, 14th, 21st and 30th radiotherapy sessions. Oxidative stress and inflammatory cytokine levels will be measured in the saliva samples of all participants. The costs are identified, measured and evaluated considering the radiotherapy time interval. The incremental cost-effectiveness ratio will be estimated. The study will be conducted according to the Brazilian public health system perspective. DISCUSSION: Photobiomodulation is an effective therapy that reduces the cost associated with OM treatment. However, little is known about its cost-effectiveness, mainly when quality of life is the effectiveness measure. Additionally, this therapy is not supported by the Brazilian public health system. Therefore, this study widens the knowledge about the safety of and strengthens evidence for the use of photobiomodulation therapy, providing information for public policy-makers and also for dental care professionals. This study is strongly encouraged due to its clinical relevance and the possibility of incorporating new technology into public health systems. TRIAL REGISTRATION: Brazilian Registry of Clinical Trials-ReBEC, RBR-5h4y4n . Registered on 13 June 2017.