Inflammation In Different Diseases Research Articles

Takinib inhibits microglial M1 polarization and oxidative damage after subarachnoid hemorrhage by targeting TAK1-dependent NLRP3 inflammasome signaling pathway.

Transforming growth factor-β-activated kinase 1 (TAK1) positively regulates oxidative stress and inflammation in different diseases. Takinib, a novel and specific TAK1 inhibitor, has beneficial effects in a variety of disorders. However, the effects of takinib on early brain injury (EBI) after subarachnoid hemorrhage (SAH) and the underlying molecular mechanisms remain unknown. Our study showed that takinib administration significantly inhibited phosphorylated TAK1 expression after SAH. In addition, takinib suppressed M1 microglial polarization and promoted M2 microglial polarization. Furthermore, blockade of TAK1 by takinib reduced neuroinflammation, oxidative damage, brain edema, and neuronal apoptosis, and improved neurological behavior after SAH. Mechanistically, we revealed that TAK1 inhibition by takinib mitigated reactive oxygen species (ROS) production and ROS-mediated nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation. In contrast, NLRP3 activation by nigericin abated the neuroprotective effects of takinib against EBI after SAH. In general, our study demonstrated that takinib could protect against EBI by targeting TAK1-ROS-NLRP3 inflammasome signaling. Inhibition of TAK1 might be a promising option in the management of SAH.

P38γ modulates the lipid metabolism in non-alcoholic fatty liver disease by regulating the JAK-STAT signaling pathway.

Non-alcoholic fatty liver disease (NAFLD) is a major health problem in Western countries and has become the most common cause of chronic liver disease. Although NAFLD is closely associated with obesity, inflammation, and insulin resistance, its pathogenesis remains unclear. The disease begins with excessive accumulation of triglycerides in the liver, which in turn leads to liver cell damage, steatosis, inflammation, and so on. P38γ is one of the four isoforms of P38 mitogen-activated protein kinases (P38 MAPKs) that contributes to inflammation in different diseases. In this research, we investigated the role of P38γ in NAFLD. In vivo, a NAFLD model was established by feeding C57BL/6J mice with a methionine- and choline-deficient (MCD) diet and adeno-associated virus (AAV9-shRNA-P38γ) was injected into C57BL/6J mice by tail vein for knockdown P38γ. The results indicated that the expression level of P38γ was upregulated in MCD-fed mice. Furthermore, the downregulation of P38γ significantly attenuated liver injury and lipid accumulation in mice. In vitro, mouse hepatocytes AML-12 were treated with free fatty acid (FFA). We found that P38γ was obviously increased in FFA-treated AML-12 cells, whereas knockdown of P38γ significantly suppressed lipid accumulation in FFA-treated AML-12 cells. Furthermore, P38γ regulated the Janus Kinase-Signal transducers and activators of transcription (JAK-STAT) signaling pathway. Inhibition of P38γ can inhibit the JAK-STAT signaling pathway, thereby inhibiting lipid accumulation in FFA-treated AML-12 cells. In conclusion, our results suggest that targeting P38γ contributes to the suppression of lipid accumulation in fatty liver disease.

Blood Count Parameters as Inflammation Indicators in Children and Adolescents Diagnosed with Depressive Disorder.

There is increasing evidence that immunological and inflammatory dysfunctions play an essential role in the initiation and progression of major psychiatric disorders. Neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and mean platelet volume can be used as markers of systemic inflammation in different diseases. We aimed to investigate these blood count parameters in children and adolescents diagnosed with major depressive disorder. Designed as a case-control study, our sample consisted of patients aged 9-16 years referred to Child and Adolescent Psychiatry and pediatrics outpatient clinics for the first time and diagnosed with major depressive disorder according to Diagnostic and Statistical Manual of Mental Disorders, 5th edition diagnostic criteria, and healthy children and adolescents matched at a ratio of 1 to 2. Data of 58 cases and 90 healthy controls evaluated between 01.07.2019 and 01.07.2020 were included. Platelet-to-lymphocyte ratio values were significantly higher in the case group. No significant difference was found between patient and control groups regarding other blood count parameters. When depression group was compared in terms of all parameters as those who committed suicide and those did not, significant difference was found between the 3 groups in terms of platelet-to-lymphocyte ratio values. The intergroup difference in platelet-to-lymphocyte ratio was found between the depression group without suicide and the control group. No significant relationship was found between other parameters and Children's Depression Inventory Scale scores. We determined a cut-off value of 112.5 for platelet-to-lymphocyte ratio (with sensitivity of 70% and specificity of 63%). Platelet-to-lymphocyte ratio might be an important parameter in the clinical follow-up of major depressive disorder.

Deletion of p38γ attenuates ethanol consumption- and acetaminophen-induced liver injury in mice through promoting Dlg1.

Acetaminophen (APAP) is one of the major causes of drug-induced acute liver injury, and ethanol may aggravate APAP-induced liver injury. The problem of ethanol- and APAP-induced liver injury becomes increasingly prominent, but the mechanism of ethanol- and APAP-induced liver injury remains ambiguous. p38γ is one of the four isoforms of P38 mitogen activated protein kinases, that contributes to inflammation in different diseases. In this study we investigated the role of p38γ in ethanol- and APAP-induced liver injury. Liver injury was induced in male C57BL/6 J mice by giving liquid diet containing 5% ethanol (v/v) for 10 days, followed by gavage of ethanol (25% (v/v), 6 g/kg) once or injecting APAP (200 mg/kg, ip), or combined the both treatments. We showed that ethanol significantly aggravated APAP-induced liver injury in C57BL/6 J mice. Moreover, the expression level of p38γ was up-regulated in the liver of ethanol-, APAP- and ethanol+APAP-treated mice. Knockdown of p38γ markedly attenuated liver injury, inflammation, and steatosis in ethanol+APAP-treated mice. Liver sections of p38γ-knockdown mice displayed lower levels of Oil Red O stained dots and small leaky shapes. AML-12 cells were exposed to APAP (5 mM), ethanol (100 mM) or combined treatments. We showed that P38γ was markedly increased in ethanol+APAP-treated AML-12 cells, whereas knockdown of p38γ significantly inhibited inflammation, lipid accumulation and oxidative stress in ethanol+APAP-treated AML-12 cells. Furthermore, we revealed that p38γ could combine with Dlg1, a member of membrane-associated guanylate kinase family. Deletion of p38γ up-regulated the expression level of Dlg1 in ethanol+APAP-treated AML-12 cells. In summary, our results suggest that p38γ functions as an important regulator in ethanol- and APAP-induced liver injury through modulation of Dlg1.

Regulation of Inflammasomes by Application of Omega-3 Polyunsaturated Fatty Acids in a Spinal Cord Injury Model.

Omega-3 polyunsaturated fatty acids (PUFA n3) ameliorate inflammation in different diseases and potentially improve neurological function after neuronal injury. Following spinal cord injury (SCI), inflammatory events result in caspase-1 mediated activation of interleukin-1 beta (IL-1b) and 18. We aim to evaluate the neuroprotective potency of PUFA n3 in suppressing the formation and activation of inflammasomes following SCI. Male Wistar rats were divided into four groups: control, SCI, SCI+PUFA n3, and SCI+Lipofundin MCT (medium-chain triglyceride; vehicle). PUFA n3 or vehicle was intravenously administered immediately after SCI and every 24 h for the next three days. We analyzed the expression of NLRP3, NLRP1, ASC, caspase-1, IL-1b, and 18 in the spinal cord. The distribution of microglia, oligodendrocytes, and astrocytes was assessed by immunohistochemistry analysis. Behavioral testing showed significantly improved locomotor recovery in PUFA n3-treated animals and the SCI-induced upregulation of inflammasome components was reduced. Histopathological evaluation confirmed the suppression of microgliosis, increased numbers of oligodendrocytes, and the prevention of demyelination by PUFA n3. Our data support the neuroprotective role of PUFA n3 by targeting the NLRP3 inflammasome. These findings provide evidence that PUFA n3 has therapeutic effects which potentially attenuate neuronal damage in SCI and possibly also in other neuronal injuries.

Effect of Hydroalcoholic Extract of Hyssop on Acute Pain in Male Rats Using Tail Flick Test

Background: Iranian traditional medicine uses hyssop (Hyssopus officinalis) as an effective medicinal plant to reduce pain and inflammation in different diseases. Although the anti-inflammatory effect of this plant is proved, there is no study into its analgesic effects. Thus, this study aimed to investigate the analgesic effect of the hydroalcoholic extract from hyssop flowers and upper branches. Methods: This experimental study was conducted on 66 male rats that were divided into several groups including a saline control group, the groups of different doses of hyssop extract, morphine positive control group, the groups of hyssop extract plus morphine, and the most effective dose of the hyssop extract plus naloxone. All injections were administered intraperitoneally, and the pain was measured through the tail flick test. Results: Based on the results, 600 mg/kg was the most effective analgesic hyssop extract dose, and the most analgesic effect was observed at 45 minutes after administration. In addition, the administration of the most effective extract dose (600 mg/kg) plus morphine significantly improved the analgesic effects of morphine (P<0.001). Finally, the administration of naloxone plus the most effective extract dose (600 mg/kg) significantly reduced the analgesic effect of the extract (P<0.05). Conclusion: Overall, the hydroalcoholic extract of hyssop has analgesic effects that are probably applied through opioid receptors.

Chitinase-3-like protein 1 is an independent risk factor for the early failure of forearm autologous arteriovenous fistulas in uremic patients.

Chitinase-3-like protein 1 (CHI3L1) has been introduced as a marker of inflammation in different diseases, which can promote cell proliferation and differentiation. It has also been demonstrated that elevated serum CHI3L1 concentration can independently predict all-cause mortality in uremic patients. However, the impact of CHI3L1 on the early failure of autologous arteriovenous fistulas (AVFs) in uremic patients remains unknown. We conducted a prospective observational cohort study of 109 uremic patients (mean age 53.2 ± 14.7 years, 67.9% males), who received forearm AVF surgery, and were consecutively enrolled with a median follow-up time of 15 months. The early failure was defined as a fistula that never developed adequately for dialysis or that failed within the first 3months of use. Serum CHI3L1 concentration was determined by the ELISA method. Among 109 uremic patients, 24 patients had AVF failure. The optimal cutoff value based on the receiver operating characteristics analysis of CHI3L1 was 122.6ng/mL, with the area under the curve of 0.73 (P=0.001). The Kaplan-Meier survival analysis demonstrated that patients with CHI3L1 < 122.6ng/mL had better AVF patency than patients with CHI3L1 ≥ 122.6ng/mL (Log-rank test, P=0.001). Multivariable Cox proportional hazards regression analysis showed that baseline CHI3L1 level (≥ 122.6ng/mL vs. < 122.6ng/mL) was significantly associated with AVF failure after adjustment for confounders (adjusted hazard ratio [HR], 3.67; 95% CI, 1.44-9.36). The study demonstrated that Increased baseline serum level of CHI3L1 is independently associated with higher risk of the early failure of forearm AVFs.

Hydrogen Sulfide in Inflammation: A Novel Mediator and Therapeutic Target.

Significance: Inflammation is a normal response to injury, but uncontrolled inflammation can lead to several diseases. In recent years, research has shown endogenously synthesized hydrogen sulfide (H2S) to be a novel mediator of inflammation. This review summarizes the current understanding and recent advances of H2S role with respect to inflammation in different diseases. Recent Advances: Promising early results from clinical studies suggest an important role of H2S in human inflammatory disease. Critical Issues: Defining the precise mechanism by which H2S contributes to inflammation is a complex challenge, and there is active ongoing research that is focused on addressing this question. Most of this work has been conducted on animal models of human disease and isolated/cultured cells, and its translation to the clinic is another challenge in the area of H2S research. Future Directions: Defining the mechanism by which H2S acts as an inflammatory mediator will help us better understand different inflammatory diseases and help develop novel therapeutic approaches for these diseases.

Cannabinoid control of neurogenic inflammation.

A significant number of cannabinoids are known to have analgesic and anti-inflammatory properties in various diseases. Due to their presynaptic/terminal location, cannabinoid receptors can inhibit synaptic transmission and have the potential to regulate neurogenic inflammation. Neurogenic inflammation occurs when a noxious signal is detected in the periphery initiating an antidromic axon reflex in the same sensory neurone leading to depolarization of the afferent terminal. Neuropeptides are subsequently released and contribute to vasodilation, plasma extravasation and modulation of immune cells. Endocannabinoids, synthetic cannabinoids and phytocannabinoids can reduce neuroinflammation by inhibiting afferent firing and inflammatory neuropeptide release. Thus, in addition to a direct effect on vascular smooth muscle and inflammatory cells, cannabinoids can reduce inflammation by silencing small diameter neurones. This review examines the neuropharmacological processes involved in regulating antidromic depolarization of afferent nerve terminals by cannabinoids and the control of neurogenic inflammation in different diseases.

The enigmatic role of TIPE2 in asthma.

Unlike other members of the tumor necrosis factor (TNF)-α-induced protein 8 (TNFAIP8/TIPE) family that play a carcinogenic role and regulate apoptosis, TNFAIP8-like 2 (TIPE2) can not only maintain immune homeostasis but also regulate inflammation. TIPE2 mainly restrains the activation of T cell receptor (TCR) and Toll-like receptors (TLR), regulating its downstream signaling pathways, thereby regulating inflammation. Interestingly, TIPE2 is abnormally expressed in many inflammatory diseases and may promote or inhibit inflammation in different diseases. This review summarizes the molecular target and cellular function of TIPE2 in immune cells and inflammatory diseases and the underlying mechanism by which TIPE2 regulates inflammation. The function and mechanism of TIPE2 in asthma is also explained in detail. TIPE2 is abnormally expressed in asthma and participates in the pathogenesis of different phenotypes of asthma through regulating multiple inflammatory cells' activity and function. Considering the indispensable role of TIPE2 in asthma, TIPE2 may be an effective therapeutic target in asthma. However, the available data are insufficient to provide a full understanding of the complex role of TIPE2 in human asthma. Further study is still necessary to explore the possible mechanism and functions of TIPE2 in different asthma phenotypes.

The secreted protein DEL-1 activates a β3 integrin–FAK–ERK1/2–RUNX2 pathway and promotes osteogenic differentiation and bone regeneration

The integrin-binding secreted protein developmental endothelial locus-1 (DEL-1) is involved in the regulation of both the initiation and resolution of inflammation in different diseases, including periodontitis, an oral disorder characterized by inflammatory bone loss. Here, using a mouse model of bone regeneration and in vitro cell-based mechanistic studies, we investigated whether and how DEL-1 can promote alveolar bone regeneration during resolution of experimental periodontitis. Compared with WT mice, mice lacking DEL-1 or expressing a DEL-1 variant with an Asp-to-Glu substitution in the RGD motif ("RGE point mutant"), which does not interact with RGD-dependent integrins, exhibited defective bone regeneration. Local administration of DEL-1 or of its N-terminal segment containing the integrin-binding RGD motif, but not of the RGE point mutant, reversed the defective bone regeneration in the DEL-1-deficient mice. Moreover, DEL-1 (but not the RGE point mutant) promoted osteogenic differentiation of MC3T3-E1 osteoprogenitor cells or of primary calvarial osteoblastic cells in a β3 integrin-dependent manner. The ability of DEL-1 to promote in vitro osteogenesis, indicated by induction of osteogenic genes such as the master transcription factor Runt-related transcription factor-2 (Runx2) and by mineralized nodule formation, depended on its capacity to induce the phosphorylation of focal adhesion kinase (FAK) and of extracellular signal-regulated kinase 1/2 (ERK1/2). We conclude that DEL-1 can activate a β3 integrin-FAK-ERK1/2-RUNX2 pathway in osteoprogenitors and promote new bone formation in mice. These findings suggest that DEL-1 may be therapeutically exploited to restore bone lost due to periodontitis and perhaps other osteolytic conditions.

Anti-Inflammatory Effect and Skin Toxicity of Aqueous Extract of Dorema ammoniacum Gum in Experimental Animals

Background and objectives: Dorema ammoniacum gum resin is used in Iranian traditional medicine for different indications including inflammatory diseases which are on the rise. Considering the important role of inflammation in different diseases, in the present study, we aimed to investigate the in vivo anti-inflammatory activity and skin toxicity of Dorema ammoniacum gum extract (DAGE) in rats and rabbits. Methods: The systemic anti-inflammatory effect ofDAGE (100, 200 and 300 mg/kg, i.p.) was assessed by carrageenan-induced paw edema method in 30 min, 1, 2, 3 and 4 h after the carrageenan injection to thirty male Wistar rats divided into five groups of six each. Control and standard groups received the vehicle and mefenamic acid (30 mg/kg, i.p.), respectively. To assess the topical anti-inflammatory effect ofthegum, eighteen rats were divided into three groups of six: standard, vehicle, and test groups which received topical diclofenac gel, distilled water and DAGE, respectively. The acute dermal toxicity of DAGEwas evaluated in nine white New Zealand rabbits. Results: The results showed significant anti-inflammatory effects of DAGE in systemic treatment.The findings also indicated that all doses of DAGE were more potent than mefenamic acid. However, the topical anti-inflammatory activity of DAGE (100 mg/kg) was comparable to that of diclofenac gel 2% and showed no skin toxicity. Conclusion: The results of the present study suggest that DAGE has significant anti-inflammatory effects without any erythema and edema in topical use. These effects might be partially or wholly due to possible inhibition of or interference with the production of some inflammatory mediators, especially prostaglandins, histamine, serotonin, and bradykinin.

Red Cell Distribution Width (RDW) at Diagnosis of Diffuse Large B-Cell Lymphoma (DLBCL) Is Associated to Higher Mortality and Worse Overall Survival

Red cell distribution width (RDW) is an indicator of the variability in the size of circulating erythrocytes (anisocytosis); different conditions can increase the RDW levels; such as hemolysis, ineffective erythropoiesis and blood transfusions. Recently, different studies have shown an association between increased levels of RDW and inflammation in different diseases, being proposed as a surrogate marker of inflammation and a strong predictor of adverse outcome. The proposed mechanism of this association departs from the finding that Inflammatory cytokines like TNFand IL-6 (part of the classic inflammatory cascade), have been found to inhibit erythropoietin-induced erythrocyte maturation, which is reflected in the RDW increase.Some reports have found a relationship between RDW and mortality related to age or several malignant or non-malignant conditions. However, there is no information about the role of RDW in overall survival (OS) of patients with DLBCL. We aim to evaluate the prognostic role of RDW levels in DLBCL patients at diagnosis.METHODSWe retrospectively evaluated 83 patients with DLBCL homogenously treated in frontline with R-CHOP from 2002 to 2013 in the Son Espases University Hospital. To avoid selection bias patients were obtained from Pharmacy and Pathology Departments registries. Main clinical and prognostic factors at diagnosis were obtained from medical records. Cheson criteria were used for response assessment. The RDW was collected from the hemogram at diagnosis. The IBM SPSS STADISTICS program was used for all statistical analyses. PFS (time to progression/relapse) and overall survival (OS) (time to death) were measured from the date of ABVD onset, and were estimated according to the Kaplan-Meier method. We performed the comparisons between those interest variables with the log-rank test. A comparison between categorical variables was made with the chi-square of Fisher’s exact test, as appropriate. All reported P-values were two-sided, and statistical significance was defined at P<0.05. For selecting cutoff values in RDW we used ROC curves.RESULTS:Main characteristics of patients were as follows: median age was 62 (20-86) years, 24% had ECOG PS>1, 64% advanced III-IV Ann Arbor (AA) stage, 39% B-symptoms, 51% adjusted-International Prognostic Index (a-IPI) and 39% belong to the high risk (3-5) subgroups of R-IPI Median RDW was 14.6 (11.1-21.1). Using ROC curves we selected the cutoff 14.05 for the death event. We evaluated the association of increased RDW with main prognostic factors at diagnosis. RDW >14.05 at diagnosis was associated with a more advanced age, worse ECOG PS, a more advanced AA stage, higher incidence of B symptoms and IPI>2. However, RDW was not related to disease control in terms of response to therapy (p=0.39) or relapse/progression (p=0.21) rates. Inversely, RDW>14.05 was in fact associated to a higher mortality (47%) compared to only 17% in patients with RDW≤14.05 (p=0.008). Median follow-up was 77 (20-137) months. Univariate survival analysis showed age>60 years (p=0.001), ECOG PS>1 (p=0.036), high risk R-IPI (p=0.005), a higher than 15% reduction in relative dose-intensity (RDI) (p=0.026) and RDW>14.05 (p=0.008) were significantly related to worse OS. By contrast, RDW did not significantly influence progression-free survival (p=0.19).CONCLUSIONS:Higher RDW at diagnosis in this series of DLBCL patients was related with older age, worse ECOG PS and more advanced disease but this was not translated into a worse control of disease in terms of only a small non statistically significant impact in response or PFS. By contrast higher RDW was linked to a significantly higher mortality and worse OS possibly related to a higher proinflammatory basal status and comorbidities. Patients with higher RDW may be at risk of reduction in RDI. These findings could justify including RDW in scores of comorbidities in DLBCL as well as in other malignant and non-malignant conditions. DisclosuresNo relevant conflicts of interest to declare.

Red Cell Distribution Width (RDW) at Diagnosis Is Associated to Advanced Stage, Worse Response and Poor Prognosis in Hodgkin Lymphoma

Red cell distribution width (RDW) is an indicator of the variability in the size of circulating erythrocytes (anisocytosis); different conditions can increase the RDW levels; such as hemolysis, ineffective erythropoiesis and blood transfusions. Recently, different studies have shown an association between increased levels of RDW and inflammation in different diseases, being proposed as a surrogate marker of inflammation and astrong predictor of adverse outcome. The proposed mechanism of this association departs from the finding that Inflammatory cytokines like TNFand IL-6 (part of the classic inflammatory cascade), have been found to inhibit erythropoietin-induced erythrocyte maturation, which is reflected in the RDW increase.Hodgkin lymphoma (HL) is a B cell neoplasm which originates in the germinal or post-germinal center B cells and is characterized by the presence of clonal malignantHodgkin/Reed-Sternbergcells (HRS) in an inflammatory background. The presence of autocrine or paracrine cytokines signaling loops drive proliferation and survival of HRS cells, making HL a lymphoma where the inflammatory status is important. We aim to evaluate the prognostic role of RDW levels in HL patients at diagnosis.METHODSWe retrospectively evaluated 119 patients with HL homogenously treated in frontline with ABVD from 2001 to 2015 in the Son Espases University Hospital. To avoid selection bias patients were obtained from Pharmacy and Pathology Departments registries. Main clinical and prognostic factors at diagnosis were obtained from medical records. Cheson criteria were used for response assessment. The RDW was collected from the hemogram at diagnosis. The IBM SPSS STADISTICS program was used for all statistical analyses. PFS (time to progression/relapse) and overall survival (OS) (time to death) were measured from the date of ABVD onset, and were estimated according to the Kaplan-Meier method. We performed the comparisons between those interest variables with the log-rank test. A comparison between categorical variables was made with the chi-square of Fisher’s exact test, as appropriate. All reported P-values were two-sided, and statistical significance was defined at P<0.05. For selecting cutoff values in RDW we used ROC curves.RESULTS:Main characteristics of patients were as follows: median age was 37 (15-75) years, 61% were males, 13% had ECOG PS>1, 47% advanced III-IV Ann Arbor (AA) stage, 42% B-symptoms and 29% IPS>2 Median RDW was14.1 (11-23.9).Using ROC curves we selected the cutoff 16.6 for relapse/progression event. We evaluated the association of increased RDW with main prognostic factors at diagnosis. RDW >16.6 at diagnosis was associated with a worse ECOG PS, a more advanced AA stage, higher incidence of B symptoms, IPS>2, higher Erythrocyte sedimentation rate (ESR) and unfavorable lymphocyte/monocyte rate (LMR) (Table 1). Patients with RDW>16.6 were associated with worse responses compared to those with RDW≤16.6: 29% versus 6% of stable/progressive disease and lower complete or partial responses: 67% and 5% versus 93% and 1%, respectively (p=0.004).Univariate survival analysis is shown in Table 2. Age, ECOG PS, AA stage, IPS, LMR and RDW were related to PFS. Age, ECOG PS, IPS and LMR were associated with OS. Multivariate analysis showed age>60 years (HR 7.66; p=0.002), RDW>16.6 (HR=3.41; p=0.005) and advanced AA stage (HR=2.55;p=0.044) as independently associated to worse PFS (Figure 1) while only age>60 years (HR=11.5; p<0.001) and ECOG PS>1 (HR=4.15; p=0.008) independently influenced a worse OS.CONCLUSION:Higher RDW at diagnosis was related with more aggressive and advanced disease in HL and lower response rates, probably reflecting a higher inflammatory activity of the lymphoma and its microenvironment. RDW>16.6 was independently associated with a worse PFS. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

P38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration.

Non-alcoholic fatty liver disease (NAFLD) is a major health problem and the main cause of liver disease in Western countries. Although NAFLD is strongly associated with obesity and insulin resistance, its pathogenesis remains poorly understood. The disease begins with an excessive accumulation of triglycerides in the liver, which stimulates an inflammatory response. Alternative p38 mitogen-activated kinases (p38γ and p38δ) have been shown to contribute to inflammation in different diseases. Here we demonstrate that p38δ is elevated in livers of obese patients with NAFLD and that mice lacking p38γ/δ in myeloid cells are resistant to diet-induced fatty liver, hepatic triglyceride accumulation and glucose intolerance. This protective effect is due to defective migration of p38γ/δ-deficient neutrophils to the damaged liver. We further show that neutrophil infiltration in wild-type mice contributes to steatosis development by means of inflammation and liver metabolic changes. Therefore, p38γ and p38δ in myeloid cells provide a potential target for NAFLD therapy.

Immunolocalization of CCL2-expressing cells in EAE and EAE-MSC cerebral cortex

The chemokine CCL2 has been considered as a mediator of inflammation in different diseases of the central nervous system, including experimental autoimmune encephalomyelitis (EAE), where the chemokine mediates extravasation of mononuclear leukocytes and loss of microvessel barrier function [1]. Previous studies have demonstrated that cellular sources of CCL2 during both EAE and multiple sclerosis (MS) are astrocytes and microvessel endothelial cells (ECs). Initially, we have demonstrated that in a MOG-induced model of EAE in C57BL/6 mice, 6 hrs after the intravenous treatment with bone marrow derived mesenchymal stem cells (MSCs) [2], the junctional staining patter of blood-brain barrier (BBB) microvessels and their functional effectiveness to permeability tracers seem to be restored. We have subsequently analysed, in the same experimental models, EAE and EAE-MSC mice, expression and immunolocalization of chemokine CCL2 by double immmunolabelling with cell-specific markers: endothelial PECAM-1 (CD31), OPCs (oligodendrocyte precursor cells) proteoglycan NG2, astrocytic GFAP, and Iba1 for microglia cells. Surprisingly, in the adopted model of cerebral cortex EAE, astrocytes and ECs do not show any detectable CCL2 expression, instead a strong staining is observed on activated parenchymal and perivascular microglia. Astrogliosis, microglia activation, and CCL2 overexpression appearing strongly reduced in EAE mice after MSC treatment. These observations identify microglia cells as the major source of CCL2 in EAE mice, whose barrier is damaged, and suggest the downregulation of the chemokine in perivascular microglia as a possible mechanism involved in BBB protection after MSC administration.

Inflammation in Disease: Mechanism and Therapies

Inflammation in the face of harming stimuli protects the organism; as a result, it is an essential process for survival, in which both innate and adaptive immunity are involved. This process must be tightly controlled and terminated in order to warrant the reestablishment of body homeostasis. Therefore, activation of resident inflammatory cells and the recruitment and modulation of migrating inflammatory cells must be ceased. When failure in neutralising acute inflammation occurs, there is augmented risk for the development of chronic inflammation, leading to several metabolic consequences. In the present special issue, original research studies as well as review articles address the inflammatory process as a key contributor to the development of disease. In addition, pharmacological and nonpharmacological therapies are examined and the molecular and physiological mechanisms of the treatments are discussed. Among the 24 accepted articles, 5 focus on nutritional therapy and inflammation (D. Estadella et al.; L. Ma et al.; M. J. Kim et al.; S. Scolleta et al.; C. Cunha et al.). The selected articles discuss the effects of the consumption of saturated and trans fatty acids upon tissue lipotoxicity, the influence of resveratrol on lung injury, the beneficial effect of genistein on renal damage, the role of vitamin D in the resolution of inflammation, and finally the capacity of green tea extract to counteract the consequences of obesity. The ability of exercise to modulate chronic inflammation is the focus of two articles, the first of which discusses the adaptive response of skeletal muscle to inflammation as induced by eccentric overload resistance training (B. N. Ide et al.), while the other considers exercise effects upon spinal cord injury-associated low grade inflammation (E. S. Alves et al.). Pulmonary diseases and inflammation are the subject debated in 8 from the total of 24 articles selected for this issue, with special emphasis on the possible triggers of inflammation onset in the scenario (Y. Yang et al.; G. Karakiulakis et al.; M. S. Duan et al.; Geve et al.; I. T. Lee et al.; P. Seidel et al.; Y. Shimizu et al.; A. D. Yalcin et al.). In fact, asthma, emphysema, and COPD are extensively discussed in this issue, and studies concerning the effects of treatment with dimethyl fumarate, anti-IgE; activation of muscarinic receptors of immune cells; and proinflammatory signalling are reviewed. Sleep disorders are also contemplated in articles (V. A. Lemos et al.; D. Rosa et al.; Y. Jin et al.) that demonstrate that sleep apnea contributes to the increased inflammatory cytokine content, a response to hypoxia induced by high altitude. Finally, 3 studies investigate the role of PPAR, 41BB/4 1 BBL, and mitochondrial dysfunction in metabolic disease (T. H. Tu et al.; F. Monsalve et al.; A. Hernandez-Aguilera et al.). In addition, inflammation is discussed in the presence of periodontal disease and endotoxaemic shock (J. D. Correa et al.; A. Sampaio et al.). Collectively, this issue aims at providing insight on the role of acute and chronic inflammation in different diseases, as well as at presenting recently proposed treatment strategies. Gustavo Duarte Pimentel Marilia Seelaender Fabio Santos Lira

Protease-Activated Receptor 2 Deficiency Reduces Cardiac Ischemia/Reperfusion Injury

To investigate the effect of protease-activated receptor (PAR) 2 deficiency on ischemia/reperfusion (I/R) injury-induced infarct size, inflammation, heart remodeling, and cardiac function. PAR-2 signaling enhances inflammation in different diseases. The effect of PAR-2 deficiency in cardiac I/R injury is unknown. PAR-2(-/-) mice and wild-type littermates were subjected to 30 minutes of ischemia and up to 4 weeks of reperfusion. Infarct size, oxidative/nitrative stress, phosphorylation of mitogen-activated protein kinases, and inflammatory gene expression were assessed 2 hours after reperfusion. Changes in heart size and function were measured by echocardiography up to 4 weeks after reperfusion. Infarct size was significantly reduced in hearts of PAR-2(-/-) mice compared with wild-type littermates. In addition, oxidative/nitrative stress, phosphorylation of mitogen-activated protein kinase, and expression of proinflammatory genes were significantly attenuated in injured hearts of PAR-2(-/-) mice. Finally, PAR-2(-/-) mice were protected from postinfarction remodeling and showed less impairment in heart function compared with wild-type littermates up to 4 weeks after I/R injury. PAR-2 deficiency reduces myocardial infarction and heart remodeling after I/R injury.