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CNS inflammation, including microglial activation, in response to peripheral infections are known to contribute to the pathology of both familial and sporadic neurodegenerative disease. The relationship between Fused-in-Sarcoma Protein (FUS)-mediated disease in the transgenic FUS[1–359] animals and the systemic inflammatory response have not been explored. Here, we investigated microglial activation, inflammatory gene expression and the behavioural responses to lipopolysaccharide-induced (LPS; 0.1 mg/kg) systemic inflammation in the FUS[1–359] transgenic mice. The pathology of these mice recapitulates the key features of mutant FUS-associated familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Here, pre-symptomatic 8-week-old mutant or wild type controls were challenged with LPS or with saline and sucrose intake, novel cage exploration, marble burying and swimming behaviours were analyzed. The level of pro-inflammatory gene expression was also determined, and microglial activation was evaluated. In chronic experiments, to discover whether the LPS challenge would affect the onset of ALS-like paralysis, animals were evaluated for clinical signs from 5 to 7 weeks post-injection. Compared to controls, acutely challenged FUS[1–359]-tg mice exhibited decreased sucrose intake and increased floating behaviours. The FUS[1–359]-tg mice exhibited an increase in immunoreactivity for Iba1-positive cells in the prefrontal cortex and ventral horn of the spinal cord, which was accompanied by increased expression of interleukin-1β, tumour necrosis factor, cyclooxygenase-(COX)-1 and COX-2. However, the single LPS challenge did not alter the time to development of paralysis in the FUS[1–359]-tg mice. Thus, while the acute inflammatory response was enhanced in the FUS mutant animals, it did not have a lasting impact on disease progression.

Coronavirus disease 2019 (COVID-19) has caused significant devastation globally. Despite the development of several vaccines, with uncertainty around global uptake and vaccine efficacy, the need for effective therapeutic agents remains. Increased levels of cytokines including tumour necrosis factor are significant in the pathogenesis of COVID-19 and associated with poor outcomes including ventilator requirement and mortality. Repurposing tumour necrosis factor blocker therapy used in conditions such as rheumatoid arthritis and inflammatory bowel disease seems promising, with early feasibility data showing a reduction in circulation of pro-inflammatory cytokines and encouraging the evaluation of such interventions in preventing disease progression and clinical deterioration in patients with COVID-19. Here, we examine the biological activities of tumour necrosis factor inhibitors indicative of their potential in COVID-19 and briefly outline the randomised control trials assessing their benefit-risk profile in COVID-19 therapy.

The apical inflammatory cytokine TNF regulates numerous important biological processes including inflammation and cell death, and drives inflammatory diseases. TNF secretion requires TACE (also called ADAM17), which cleaves TNF from its transmembrane tether. The trafficking of TACE to the cell surface, and stimulation of its proteolytic activity, depends on membrane proteins, called iRhoms. To delineate how the TNF/TACE/iRhom axis is regulated, we performed an immunoprecipitation/mass spectrometry screen to identify iRhom-binding proteins. This identified a novel protein, that we name iTAP (iRhom Tail-Associated Protein) that binds to iRhoms, enhancing the cell surface stability of iRhoms and TACE, preventing their degradation in lysosomes. Depleting iTAP in primary human macrophages profoundly impaired TNF production and tissues from iTAP KO mice exhibit a pronounced depletion in active TACE levels. Our work identifies iTAP as a physiological regulator of TNF signalling and a novel target for the control of inflammation.

CNS inflammation, including microglial activation, in response to peripheral infections are known to contribute to the pathology of both familial and sporadic neurodegenerative disease. The relationship between Fused-in-Sarcoma Protein (FUS)-mediated disease in the transgenic FUS[1-359] animals and the systemic inflammatory response have not been explored. Here, we investigated microglial activation, inflammatory gene expression and the behavioural responses to lipopolysaccharide-induced (LPS; 0.1 mg/kg) systemic inflammation in the FUS[1-359] transgenic mice. The pathology of these mice recapitulates the key features of mutant FUS-associated familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Here, pre-symptomatic 8-week-old mutant or wild type controls were challenged with LPS or with saline and sucrose intake, novel cage exploration, marble burying and swimming behaviours were analyzed. The level of pro-inflammatory gene expression was also determined, and microglial activation was evaluated. In chronic experiments, to discover whether the LPS challenge would affect the onset of ALS-like paralysis, animals were evaluated for clinical signs from 5 to 7 weeks post-injection. Compared to controls, acutely challenged FUS[1-359]-tg mice exhibited decreased sucrose intake and increased floating behaviours. The FUS[1-359]-tg mice exhibited an increase in immunoreactivity for Iba1-positive cells in the prefrontal cortex and ventral horn of the spinal cord, which was accompanied by increased expression of interleukin-1β, tumour necrosis factor, cyclooxygenase-(COX)-1 and COX-2. However, the single LPS challenge did not alter the time to development of paralysis in the FUS[1-359]-tg mice. Thus, while the acute inflammatory response was enhanced in the FUS mutant animals, it did not have a lasting impact on disease progression., Competing Interests: None of the authors involved in the work have any competing interests. We confirm that this manuscript has not been published elsewhere and is not under consideration by another journal., (© 2023 The Authors. Published by Elsevier Inc.)

In the past decade, interest in the century-old tuberculosis vaccine, bacillus Calmette-Guerin (BCG), has been revived for potential new therapeutic uses in type 1 diabetes and other forms of autoimmunity. Diverse clinical trials are now proving the value of BCG in prevention and treatment of type 1 diabetes, in the treatment of new onset multiple sclerosis and other immune conditions. BCG contains the avirulent tuberculosis strain Mycobacterium bovis, a vaccine originally developed for tuberculosis prevention. BCG induces a host response that is driven in part by tumour necrosis factor (TNF). Induction of TNF through BCG vaccination or through selective agonism of TNF receptor 2 (TNFR2) has 2 desired cellular immune effects: (1) selective death of autoreactive T cells and (2) expansion of beneficial regulatory T cells (Tregs). In human clinical trials in both type 1 diabetes and multiple sclerosis, administration of the BCG vaccine to diseased adults has shown great promise. In a Phase I trial in advanced type 1 diabetes (mean duration of diabetes 15 years), 2 BCG vaccinations spaced 4 weeks apart selectively eliminated autoreactive T cells, induced beneficial Tregs, and allowed for a transient and small restoration of insulin production. The advancing global clinical trials using BCG combined with mechanistic data on BCGs induction of Tregs suggest value in this generic agent and possible immune reversal of the type 1 diabetic autoimmune process. [ABSTRACT FROM AUTHOR]

The molecular mechanism of Profilin for its tumour suppressor activity is still unknown. Nuclear transcription factor κB (NF-κB) is known to activate many target genes involved in cell proliferation. In the present study, we provide evidence that supports the involvement of Profilin in regulation of NF-κB, which might repress the tumorigenic response. Profilin overexpressing cells show low basal activity of IκBα kinase (IKK), high amounts of cytoplasmic inhibitory subunit of NF-κB (IκBα) and p65, and low nuclear NF-κB DNA binding activity. Co-localization and co-immunoprecipitation (Co-IP) studies suggest that Profilin interacts with a protein phosphatase, phosphatase and tension homologue (PTEN), and protects it from degradation. In turn, PTEN interacts physically and maintains a low phosphorylated state of the IKK complex and thereby suppresses NF-κB signalling. Thus, Profilin overexpressing cells show a decrease in NF-κB activation mediated by most of the inducers and potentiate cell death by repressing NF-κB-dependent genes involved in cell cycle progression. For the first time, we provide evidence, which suggests that Profilin increases tumour suppressor activity by regulating NF-κB. [ABSTRACT FROM AUTHOR]

Aims Pro-inflammatory cytokines, growth and angiogenic factors released by leukocytes are involved in carcinogenesis and cancer progression, but they are also crucial for fighting tumour growth and spreading. We have previously demonstrated that endocannabinoids modulate cell-to-cell crosstalk during inflammation. Here, we investigated the inflammatory and tumourigenic properties of endocannabinoids in a human urinary bladder carcinoma cell line. Main methods Endocannabinoid-treated ECV304 cells were checked for tumour necrosis factor (TNF)-α secretion (by ELISA assay) and surface exposure of selectins (by in situ ELISA and FACS analysis). ECV304/Jurkat T cell interaction was assessed by adhesion and live imaging experiments. Proliferation rate, cell death and cell cycle were determined by FACS analysis. Key findings By binding to type-1 (CB 1 ) and type-2 (CB 2 ) cannabinoid receptors, the endocannabinoid 2-arachidonoylglycerol (2-AG) exacerbates the pro-inflammatory status surrounding bladder carcinoma ECV304 cells, by: (i) enhancing TNF-α release, (ii) increasing surface exposure of P- and E-selectins, and (iii) allowing Jurkat T lymphocytes to adhere to treated cancer cells. We also found that the CB 1 inverse agonist AM281, unlike 2-AG, decreases cancer proliferation by delaying cell cycle progression. Significance Our data suggest that 2-AG modulates the inflammatory milieu of cancer cells in vitro, while AM281 plays a more specific role in proliferation. Collectively, these findings suggest that CB receptors may play distinct roles in cancer biology, depending on the specific ligand employed. Conclusions The in vivo assessment of the role of CB receptors in inflammation and cancer might be instrumental in broadening the understanding about bladder cancer biology. [ABSTRACT FROM AUTHOR]

Our immune system bears the tremendous task of mounting effective anti-microbial responses whilst maintaining immunoregulatory functions to avoid autoimmunity. In order to quickly respond to pathogens, Dendritic cells (DC) are armed with pattern recognition receptors (PRRs), allowing them to recognize highly conserved pathogen-associated molecular patterns (PAMPs) that are uniquely expressed by invading microbes. PRR activation can trigger DCs to release the pleiotropic cytokine, Type I IFN, which facilitates various biological functions in different immune cell types. In this review, we will discuss the classical PRR-induced Type I IFN response in DCs as well as describe a novel mechanism for Type I IFN induction by the Tumor-Necrosis Factor receptor superfamily (TNFRSF) members, TNFR-1 and Lymphotoxin-β receptor (LTβR). While PRR activation during viral infection, produces large amounts of Type I IFN in a relative short period of time, TNFRSF-induced Type I IFN expression is modest with gradual kinetics. Type I IFN can exert pro-inflammatory effects, but in some cases it also facilitates immune-regulatory functions. Therefore, DCs are important regulators of immune responses by carefully modulating Type I IFN expression.

Tumour necrosis factor and lipopolysaccharide can promote a regulated form of necrosis, called necroptosis, upon inhibition of caspase activity in cells expressing receptor-interacting serine/threonine kinase ( RIPK)3. Because inhibitors of RIPK1 kinase activity such as necrostatin-1 block necroptosis in many settings, RIPK1 is thought to be required for activation of RIPK3, leading to necroptosis. However, here we show that, although necrostatin potently inhibited tumour necrosis factor-induced, lipopolysaccharide-induced and poly IC-induced necroptosis, RIPK1 knockdown unexpectedly potentiated this process. In contrast, RIPK3 knockdown potently suppressed necroptosis under the same conditions. Significantly, necrostatin failed to block necroptosis in the absence of RIPK1, indicating that its ability to suppress necroptosis was indeed RIPK1-dependent. These data argue that RIPK1 is dispensable for necroptosis and can act as an inhibitor of this process. Our observations also suggest that necrostatin enhances the inhibitory effects of RIPK1 on necroptosis, as opposed to blocking its participation in this process. [ABSTRACT FROM AUTHOR]

Abstract: Background: Plasma levels of polyunsaturated fatty acids (PUFAs) are different before and after periodontal treatment. Asians and Westerners have significantly different baseline levels of plasma PUFAs. However, no Asian study has reported the effects of nonsurgical treatment on the correlation between periodontal condition and plasma levels of PUFAs. We analyzed whether recovery from periodontitis was correlated with the elevation of plasma fatty acids 3 months after the nonsurgical intervention and with no recommended supplements. Design: Thirty-five Taiwanese patients with periodontitis were recruited. Probing pocket depths (PPDs) and clinical attachment levels (CALs) were measured at baseline and 3 months after the nonsurgical treatment. Plasma levels of fatty acids were determined using gas chromatography. Differences and correlations between plasma fatty acid composition and periodontitis severity at baseline and 3 months after treatment were determined. Results: Twenty-six patients completed the study. At the baseline, PPDs were negatively correlated with plasma n-3 PUFAs (r =−0.52, p <0.01), but at 3 months post intervention, periodontitis severity had declined and the weight percentages of n-3 PUFAs, DPA, and DHA were significantly (p =0.019, 0.005, and 0.037, respectively) higher. The recovery percentages of CALs were positively and significantly correlated with plasma ΔPUFAs and the percentage of Δn-3 PUFAs in ΔPUFAs (r =0.42 and 0.45, respectively; p <0.05 for both). Conclusions: We conclude that a higher weight percentage of n-3 PUFAs in total PUFAs was related to the recovery of CALs 3 months after the nonsurgical periodontal treatment. However, no such relationship was found for PPDs. [Copyright &y& Elsevier]

Abstract: Background: Higher plasma plasminogen activator inhibitor-1 (PAI-1) levels have been reported in septic patients. However, some questions remain unanswered, such as whether there is an association between plasma PAI-1 levels and sepsis severity and mortality, and inflammation state during the first week. Methods: Multicenter, observational and prospective study carried out in six Spanish Intensive Care Units of 260 patients with severe sepsis. Circulating levels of PAI-1 and tumour necrosis factor (TNF)-α were measured at day 1, 4 and 8. End-point was 30-day mortality. Results: Nonsurviving septic patients (n=89) presented higher PAI-1 levels than surviving (n=171) at day 1 (58.4 (33.3-83.8) vs 36.5 (21.1-62.5) ng/mL; p<0.001), 4 (34.0 (14.7-53.3) vs 16.2 (10.2-27.4) ng/mL; p<0.001) and 8 (30.6 (16.2-47.8) vs 18.9 (10.4-29.5) ng/mL; p=0.004). We found a positive correlation of PAI-1 levels with SOFA, lactic acid, aPTT, INR and TNF-α, and negative with platelet count at day 1, 4 and 8. Logistic regression analyses showed that PAI-1 levels at day 1 (p<0.001), 4 (p<0.001) and 8 (p=0.001) were associated with 30-day mortality. On ROC curve analysis to predict 30- day survival, the area under the curve of PAI-1 levels at day 1, 4 and 8 were 0.65 (95% CI=0.58-0.72; p<0.001), 0.69 (95% CI=0.60-0.78; p<0.001) and 0.65 (95% CI=0.54-0.75; p=0.005) respectively. Conclusions: The most interesting findings of our study, to our knowledge the largest series reporting PAI-1 levels during follow-up in septic patients, were that plasma PAI-1 levels during the first week were associated with inflammation, severity and mortality. [Copyright &y& Elsevier]

Abstract: Background and aims: The lectin pathway of the complement system is initiated through the recognition of pathogens or altered self-structures by mannan-binding lectin (MBL) or ficolins and subsequent activation of MBL-associated serine proteases (MASPs). Altered ficolin levels may contribute to a dysregulated immune response in Crohn's disease (CD). A complete analysis of the lectin pathway has not been performed in patients with CD. We hypothesised that the lectin pathway proteins exacerbate inflammation in CD. Methods: We assessed the lectin pathway proteins in 43 patients with active CD & 350 blood donors by measuring the serum levels of MBL; M-, H-, and L-ficolin; MASP-2; MASP-3; and MAp44. In patients with CD, the blood samples were obtained during induction treatment with infliximab or adalimumab. Results: Of 43 patients with CD, 32 (74%) were classified as responders. We observed a nearly 50% decrease in median M-ficolin levels between day 0 and weeks 1/7 in the responders (p<0.001), whereas there was no decrease in the non-responders. MASP-2 levels decreased from baseline to week 1 in both the responders (37%, p<0.0001) and the non-responders (29%, p=0.02). In the responders only, the level of the inhibitory serine protease MASP-3 increased by 26% from baseline to week 1 (p<0.001) and remained high at week 7. Conclusions: Our findings indicated that M-ficolin, MASP-2, and MASP-3 may act in concert to reduce the activity of the lectin pathway, in patients with CD who respond to biological therapy. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: A herbal formula (RL) consisting of Rosae Multiflorae Fructus (Yingshi) and Lonicerae Japonicae Flos (Jinyinhua) has been traditionally used to treat inflammatory disorders. This study aims to investigate the anti-inflammatory mode and mechanism of action of the ethanol extract of RL so as to provide a pharmacological basis for the use of RL in treating inflammatory diseases. Materials and method: RL consisting of Yingshi and Jinyinhua (in 5:3 ratio) was extracted using absolute ethanol. We investigated its effects on nitric oxide (NO), interleukin-6 (IL-6), tumour necrosis factor (TNF)-?, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), mitogen-activated protein kinases (MAPKs) and nuclear factor ?B (NF?B) in mouse RAW 264.7 macrophages activated with lipopolysaccharide (LPS). Results: RL could decrease the secretion of NO, IL-6 and TNF-? into the culture medium and the cellular protein levels of iNOS and COX-2, which were associated with the reduction of the phosphorylation/activation of JNK and p38, and the inhibition of the transcriptional activity of NF-?B. Conclusions: The present study demonstrated an inhibitory effect of RL on the inflammatory mediators regulated by the NF-?B and MAPK signalling pathways in LPS-stimulated RAW 264.7 macrophages, providing a pharmacological basis for RL in the control of inflammatory disorders. [Copyright &y& Elsevier]

Abstract: During chondrogenesis, complex intracellular signalling pathways regulate an intricate series of events including condensation of chondroprogenitor cells and nodule formation followed by chondrogenic differentiation. Reversible phosphorylation of key target proteins is of particular importance during this process. Among protein kinases known to be involved in these pathways, protein kinase C (PKC) subtypes play pivotal roles. However, the precise function of PKC isoenzymes during chondrogenesis and in mature articular chondrocytes is still largely unclear. In this review, we provide a historical overview of how the concept of PKC-mediated chondrogenesis has evolved, starting from the first discoveries of PKC isoform expression and activity. Signalling components upstream and downstream of PKC, leading to the stimulation of chondrogenic differentiation, are also discussed. Although it is evident that we are only at the beginning to understand what roles are assigned to PKC subtypes during chondrogenesis and how they are regulated, there are many yet unexplored aspects in this area. There is evidence that calcium signalling is a central regulator in differentiating chondroprogenitors; still, clear links between intracellular calcium signalling and prototypical calcium-dependent PKC subtypes such as PKCalpha have not been established. Exploiting putative connections and shedding more light on how exactly PKC signalling pathways influence cartilage formation should open new perspectives for a better understanding of healthy as well as pathological differentiation processes of chondrocytes, and may also lead to the development of novel therapeutic approaches. [Copyright &y& Elsevier]

Abstract: Concomitant immunity is a phenomenon in which a tumour-bearing host is resistant to the growth of an implanted secondary tumour. Metastases are considered to be secondary tumours that develop spontaneously during primary tumour growth, suggesting the involvement of concomitant immunity in controlling the rise of metastases. It has been demonstrated that B-1 cells, a subset of B-lymphocytes found predominantly in pleural and peritoneal cavities, not only increase the metastatic development of murine melanoma B16F10, but also are capable of differentiating into mononuclear phagocytes, modulating inflammatory responses in wound healing, in oral tolerance and in Paracoccidiose brasiliensis infections. Here, we studied B-1 cells’ participation in concomitant immunity during Ehrlich tumour progression. Our results show that B-1 cells obtained from BALB/c mice previously injected with Ehrlich tumour in the footpad were able to protect BALB/c and BALB/Xid mice against Ehrlich tumour challenge. In addition, it was demonstrated that BALB/Xid show faster tumour growth and have lost concomitant immunity, and that this state can be partially restored by reconstituting these animals with B-1 cells. However, further researches are required to establish the mechanism involving B-1 cells in Ehrlich tumour growth. [Copyright &y& Elsevier]

Abstract: There is considerable interest in sorghum, millets and pseudocereals for their phytochemical content, their nutritional potential and their use in gluten-free products. They are generally rich in a several phenolic phytochemicals. Research has indicated that the phenolics in these grains may have several important health-promoting properties: prevention and reduction of oxidative stress, anti-cancer, anti-diabetic, anti-inflammatory, anti-hypertensive and cardiovascular disease prevention. However, increased research on the actual health-promoting properties of foods made from these grains is required. Biofortified (macro and micronutrient enhanced) sorghum and millets are being developed through conventional breeding and recombinant DNA technology to combat malnutrition in developing countries. Enhanced nutritional traits include: high amylopectin, high lysine, improved protein digestibility, provitamin A rich, high iron and zinc, and improved mineral bioavailability through phytate reduction. Some of these biofortified cereals also have good agronomic characteristics and useful commercial end-use attributes, which will be important to their adoption by farmers. Knowledge of the structure of their storage proteins is increasing. Drawing on research concerning maize zein, which shows that it can produce a visco-elastic wheat-like dough, it appears that the storage proteins of these minor grains also have this potential. Manipulation of protein β-sheet structure seems critical in this regard. [Copyright &y& Elsevier]

Abstract: Patients with Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) have a significantly increased risk of cardiovascular disease (CVD). The reason for this is unclear but may be due, at least in part, to the failure of endothelial repair mechanisms. Over the last 15years there has been much interest in the mechanisms of endothelial renewal and its potential as a therapy for CVD. In the circulation there are two distinct populations of cells; myeloid angiogenic cells (MACs) which augment repair by the paracrine secretion of angiogenic factors, and outgrowth endothelial cells (OECs) which are true endothelial progenitor cells (EPCs) and promote vasculogenesis by differentiating into mature endothelium. There are marked abnormalities in the number and function of these cells in patients with RA and SLE. Inflammatory cytokines including interferon-alpha (IFNα) and tumour-necrosis factor alpha (TNFα) both impair MAC and OEC function ex vivo and may therefore contribute to the CVD risk in these patients. Whilst administration of mononuclear cells, MACs and other progenitors has improved cardiovascular outcomes in the acute setting, this is not a viable option in chronic disease. The pharmacological manipulation of MAC/OEC function in vivo however has the potential to significantly improve endothelial repair and thus reduce CVD in this high risk population. [Copyright &y& Elsevier]

Highlights: [•] IL-18 mediates the inflammatory response during acute pneumococcal meningitis. [•] IL-18 deficiency improves survival of mice during brain infection with pneumococci. [•] IL-18 deficiency diminishes behavioural sequelae due to pneumococcal meningitis. [•] IL-18 is not responsible for cognition impairment caused by pneumococcal meningitis. [•] IL-18-mediated cytokine dysfunction may contribute to mortality and/or morbidity. [Copyright &y& Elsevier]

Abstract: Tumour necrosis factor (p55 or p60) receptor (TNFR) 1 is the major receptor that activates pro-inflammatory signalling and induces gene expression in response to TNF. Consensus is lacking for the function of (p75 or p80) TNFR2 but experiments in mice have suggested neuro-, cardio- and osteo-protective and anti-inflammatory roles. It has been shown in various cell types to be specifically required for the induction of TNFR-associated factor-2 (TRAF2) degradation and activation of the alternative nuclear factor (NF)-kappaB pathway, and to contribute to the activation of mitogen-activated protein kinases (MAPK) and the classical NF-kappaB pathway. We have investigated the signalling functions of TNFR2 in primary human and murine macrophages. We find that in these cells TNF induces TRAF2 degradation, and this is blocked in TNFR2−/− macrophages. TRAF2 has been previously reported to be required for TNF-induced activation of p38 MAPK. However, TRAF2 degradation does not inhibit TNF-induced tolerance of p38 MAPK activation. Neither TNF, nor lipopolysaccharide treatment, induced activation of the alternative NF-kappaB pathway in macrophages. Activation by TNF of the p38 MAPK and NF-kappaB pathways was blocked in TNFR1−/− macrophages. In contrast, although TNFR2−/− macrophages displayed robust p38 MAPK activation and IkappaBα degradation at high concentrations of TNF, at lower doses the concentration dependence of signalling was weakened by an order of magnitude. Our results suggest that, in addition to inducing TRAF2 protein degradation, TNFR2 also plays a crucial auxiliary role to TNFR1 in sensitising macrophages for the ligand-induced activation of the p38 MAPK and classical NF-kappaB pro-inflammatory signalling pathways. [Copyright &y& Elsevier]

Abstract: Cancer is a major public health issue and, despite recent advances, effective clinical management remains elusive due to intra-tumoural heterogeneity and therapeutic resistance. Iron is a trace element integral to a multitude of metabolic processes, including DNA synthesis and energy transduction. Due to their generally heightened proliferative potential, cancer cells have a greater metabolic demand for iron than normal cells. As such, iron metabolism represents an important “Achilles' heel” for cancer that can be targeted by ligands that bind and sequester intracellular iron. Indeed, novel thiosemicarbazone chelators that act by a “double punch” mechanism to both bind intracellular iron and promote redox cycling reactions demonstrate marked potency and selectivity in vitro and in vivo against a range of tumours. The general mechanisms by which iron chelators selectively target tumour cells through the sequestration of intracellular iron fall into the following categories: (1) inhibition of cellular iron uptake/promotion of iron mobilisation; (2) inhibition of ribonucleotide reductase, the rate-limiting, iron-containing enzyme for DNA synthesis; (3) induction of cell cycle arrest; (4) promotion of localised and cytotoxic reactive oxygen species production by copper and iron complexes of thiosemicarbazones (e.g., Triapine® and Dp44mT); and (5) induction of metastasis and tumour suppressors (e.g., NDRG1 and p53, respectively). Emerging evidence indicates that chelators can further undermine the cancer phenotype via inhibiting the epithelial–mesenchymal transition that is critical for metastasis and by modulating ER stress. This review explores the “expanding horizons” for iron chelators in selectively targeting cancer cells. [Copyright &y& Elsevier]

Abstract: Macrophages, and more broadly inflammation, have been considered for a long time as bad markers of tissue homeostasis. However, if it is indisputable that macrophages are associated with many diseases in a deleterious way, new roles have emerged, showing beneficial properties of macrophages during tissue repair and regeneration. This discrepancy is likely due to the high plasticity of macrophages, which may exhibit a wide range of phenotypes and functions depending on their environment. Therefore, regardless of their role in immunity, macrophages play a myriad of roles in the maintenance and recovery of tissue homeostasis. They take a major part in the resolution of inflammation. They also exert various effects of parenchymal cells, including stem and progenitor cell, of which they regulate the fate. In the present review, few examples from various tissues are presented to illustrate that, beyond their specific properties in a given tissue, common features have been described that sustain a role of macrophages in the recovery and maintenance of tissue homeostasis. [Copyright &y& Elsevier]

Highlights: [•] Smac mimetic BV6 and cytarabine synergize to trigger apoptosis in AML cells. [•] Synergistic apoptosis involves autocrine/paracrine TNFα signaling. [•] BV6 and cytarabine trigger necroptosis in apoptosis-resistant AML cells. [Copyright &y& Elsevier]

Abstract: Omega-3 (n−3) polyunsaturated fatty acids (n−3 PUFAs) have well documented anti-inflammatory properties, and consequently therapeutic potential in chronic inflammatory diseases. Here we discuss the effects of n−3 PUFAs on various inflammatory pathways and how this leads to alterations in the function of inflammatory cells, most importantly endothelial cells and leukocytes. Strong evidence indicates n−3 PUFAs are beneficial as a dietary supplement in certain diseases such as rheumatoid arthritis; however for other conditions such as asthma, the data are less robust. A clearer understanding of the pharmacology of n−3 PUFAs will help to establish targets to modulate chronic inflammatory diseases. [Copyright &y& Elsevier]

Highlights: [•] Neuroinflammation is central to the common pathology of diseases/disorders. [•] Neuroinflammation causes acute brain cell death. [•] Neuroinflammation causes and accelerates long-term neurodegenerative disease. [•] Preventative and therapeutic approaches are needed to dampen-down neuroinflammation. [Copyright &y& Elsevier]

Abstract: Apoptotic cell death is critical for maintaining integrity of the epithelia as well as for removal of the virus infected cells. We assessed the role of Fas/FasL-dependent pathway in apoptosis of genital epithelium during HSV-2 infection using a murine model of HSV-2 infection applied to C57BL6, MRL-Fas lpr /J (Fas−/−) and C3-Fasl gld /J (FasL−/−) mice and an in vitro model of HSV-2 infection in monocyte RAW 264.7 and keratinocyte 291.03C cell cultures and peritoneal macrophages. In contrast to keratinocyte in vitro cultures, HSV-2 infection of the monocytic cell cultures led to early induction of apoptosis. HSV-2 infection of peritoneal macrophages isolated from Fas- and FasL-deficient mice showed decreased activation of apoptosis, which could be further blocked by caspase-9 inhibitor. Infection of Fas and FasL-deficient mice increased the percentage of apoptotic cells and activation of caspase-9 in the vaginal tissue in comparison to C57BL6 wild type strain. Furthermore, Fas and FasL-deficient mice showed increased infiltration of neutrophiles in the vaginal mucosal epithelium at 3 and 7 day of infection in contrast to HSV-2 infected wild-type mice. Our results show that while the Fas/FasL pathway during HSV-2 infection of the vaginal epithelium plays an important role in controlling early local inflammatory response, mitochondrial apoptotic pathway also becomes activated by the inflammatory reaction. [Copyright &y& Elsevier]

Abstract: Fishermen who had participated in clean-up activities of the Prestige oil spill showed increased bronchial responsiveness and higher levels of respiratory biomarkers 2years later. We aimed to evaluate the persistence of these functional and biological respiratory health effects 6years after clean-up work. In 2008/2009 a follow-up study was done in 230 never-smoking fishermen who had been exposed to clean-up work in 2002/2003 and 87 non-exposed fishermen. Lung function and bronchial responsiveness testing and the determination of respiratory biomarkers in exhaled breath condensate were done identically as in the baseline survey in 2004/2005. Associations between participation in clean-up work and respiratory health parameters were assessed using linear and logistic regression analyses adjusting for sex and age. Information from 158 exposed (69%) and 57 non-exposed (66%) fishermen was obtained. Loss to follow-up in the non-exposed was characterised by less respiratory symptoms at baseline. During the 4-year follow-up period lung function, bronchial hyperresponsiveness and the levels of respiratory biomarkers of oxidative stress and growth factors had deteriorated notably more among non-exposed than among exposed. At follow-up, respiratory health indices were similar or better in clean-up workers than in non-exposed. No clear differences between highly exposed and moderately exposed clean-up workers were found. In conclusion, we could not detect long-term respiratory health effects in clean-up workers 6years after the Prestige oil spill. Methodological issues that need to be considered in this type of studies include the choice of a non-exposed control group and limitation of follow-up to subgroups such as never smokers. [Copyright &y& Elsevier]

Abstract: Bonamiosis and disseminated neoplasia (DN) are the most important diseases affecting cultured flat oysters (Ostrea edulis) in Galicia (NW Spain). Previous research of the response of O. edulis against bonamiosis by suppression subtractive hybridisation yielded a partial expressed sequence tag of tumour necrosis factor (TNF) and allograft inflammatory factor (AIF), as well as the whole open reading frame for dermatopontin and vesicle-associated membrane (VAMP). Herein, the complete open reading frames of TNF and AIF genes were determined by the rapid amplification of cDNA, and the deduced amino acid sequences of the four genes were characterised. Phylogenetic relationships for each gene were studied using maximum likelihood parameters. Quantitative-PCR assays were also performed in order to analyse the modulation of the expression of these genes by bonamiosis and disseminated neoplasia. Gene expression profiles were studied in haemolymph cells and in various organs (gill, gonad, mantle and digestive gland) of oysters affected by bonamiosis, DN, and both diseases with regard to non-affected oysters (control). TNF expression in haemolymph cells was up-regulated at heavy stage of bonamiosis but its expression was not affected by DN. AIF expression was up-regulated at heavy stage of bonamiosis in haemolymph cells and mantle, which is associated with heavy inflammatory response, and in haemolymph cells of oysters affected by DN. AIF expression was, however, down-regulated in other organs as gills and gonads. Dermatopontin expression was down-regulated in haemolymph cells and digestive gland of oysters affected by bonamiosis, but DN had no significant effect on its expression. Gills and gonads showed up-regulation of dermatopontin expression associated with bonamiosis. There were significant differences in the expression of TNF and VAMP depending on the bonamiosis intensity stage whereas no significant differences were detected between light and heavy severity degrees of DN for the studied genes. VAMP expression showed also differences among haemolymph cells and the organs studied. The occurrence of both diseases in oysters involved haemolymph cell gene expression patterns different from those associated to each disease separately: no significant effect was observed in TNF expression, dermatopontin was up-regulated and marked up-regulation of AIF and VAMP was recorded, which suggests a multiplier effect of the combination of both diseases for the latter two genes. [Copyright &y& Elsevier]

Abstract: Biomarkers are regularly used in medicine to provide objective indicators of normal biological processes, pathogenic processes or pharmacological responses to therapeutic interventions, and have proved invaluable in expanding our understanding and treatment of medical diseases. In the field of psychiatry, assessment and treatment has, however, primarily relied on patient interviews and questionnaires for diagnostic and treatment purposes. Biomarkers in psychiatry present a promising addition to advance the diagnosis, treatment and prevention of psychiatric diseases. This review provides a summary on the potential of peripheral biomarkers in major depression with a specific emphasis on those related to inflammatory/immune and oxidative stress/antioxidant defences. The complexities associated with biomarker assessment are reviewed specifically around their collection, analysis and interpretation. Focus is placed on the potential of peripheral biomarkers to aid diagnosis, predict treatment response, enhance treatment-matching, and prevent the onset or relapse of major depression. [Copyright &y& Elsevier]

Programmed necrosis or necroptosis is controlled by the action of two serine/threonine kinases, RIP1 (receptor-interacting serine/threonine protein kinase 1; also known as RIPK1) and RIP3. The phosphorylation of RIP1 and RIP3 is critical for assembly of the necrosome, an amyloid-like complex that initiates transmission of the pro-necrotic signal. In the present study, we used site-directed mutagenesis to systematically examine the effects of putative phosphoacceptor sites on RIP1 and RIP3 on TNF (tumour necrosis factor)-induced programmed necrosis. We found that mutation of individual serine residues in the kinase domain of RIP1 had little effect on RIP1 kinase activity and TNF-induced programmed necrosis. Surprisingly, an alanine residue substitution for Ser89 enhanced RIP1 kinase activity and TNF-induced programmed necrosis without affecting RIP1-RIP3 necrosome formation. This indicates that Ser89 is an inhibitory phosphoacceptor site that can dampen the pro-necrotic function of RIP1. In addition, we show that a phosphomimetic mutant of RIP3, S204D, led to programmed necrosis that was refractory to RIP1 siRNA and insensitive to necrostatin-1 inhibition. Our results show that programmed necrosis is regulated by positive and inhibitory phosphorylation events. [ABSTRACT FROM AUTHOR]

Abstract: Mesenchymal stem cells (MSCs) are multipotent cells with a substantial potential in human regenerative medicine due to their ability to migrate to sites of injury, capability to suppress immune response and accessibility in large amount from patient's own bone marrow or fat tissue. It has been increasingly observed that the transplanted MSCs did not necessarily engraft and differentiate at the site of injury but might exert their therapeutic effects through secreted trophic signals. The MSCs secrete a variety of autocrine/paracrine factors, called secretome, that support regenerative processes in the damaged tissue, induce angiogenesis, protect cells from apoptotic cell death and modulate immune system. The cell culture medium conditioned by MSCs or osteogenic, chondrogenic as well as adipogenic precursors derived from MSCs has become a subject of intensive proteomic profiling in the search for and identification of released factors and microvesicles that might be applicable in regenerative medicine. Jointly with the methods for MSC isolation, expansion and differentiation, proteomic analysis of MSC secretome was enabled recently mainly due to the extensive development in protein separation techniques, mass spectrometry, immunological methods and bioinformatics. This review describes proteomic techniques currently applied or prospectively applicable in MSC secretomics, with a particular focus on preparation of the secretome sample, protein/peptide separation, mass spectrometry and protein quantification techniques, analysis of posttranslational modifications, immunological techniques, isolation and characterisation of secreted vesicles and exosomes, analysis of cytokine-encoding mRNAs and bioinformatics. [Copyright &y& Elsevier]

The p38 MAPK (mitogen-activated protein kinase)/MK2 [MAPKAP (MAPK-activated protein) kinase-2] signalling pathway is a major regulator of stress- and cytokine-induced gene expression at the transcriptional and post-transcriptional level. Using phosphoproteomics we identified the ER (endoplasmic reticulum)-associated ubiquitin-conjugating enzyme Ube2j1 as a potential substrate of MK2. We demonstrate that Ube2j1 is phosphorylated in a cytokine-, cytosolic stress- and LPS (lipopolysaccharide)-induced manner. The cytosolic stressinduced phosphorylation of Ube2j1 proceeds at Ser184, a site described previously to be phosphorylated in response to ER stress, which is located in a perfect MK2 consensus motif. The cytosolic stress-induced phosphorylation of Ube2j1, but not its ER-stressinduced phosphorylation is sensitive to p38/MK2 inhibitors and abrogated in MK2/MK3-deficient cells. In a pull-down assay we demonstrate the interaction of MK2 with Ube2j1 in HEK (human embryonic kidney)-293T cells. Furthermore, MK2 is able to phosphorylate recombinant Ube2j1, but not the S184A mutant in an in vitro kinase assay. These findings strongly suggest that MK2 directly phosphorylates Ube2j1 at Ser184 upon p38- activating stress in vivo. However, ectopically expressed Ube2j1- S184A mutant displays ubiquitinating activity towards the model substrate ER-synthesized T-cell receptor-a similar to that of the wild-type protein. Interestingly, Ube2j1 is phosphorylated in response to LPS also in macrophages and contributes to MK2- dependent TNFa biosynthesis by a so far unknown mechanism [ABSTRACT FROM AUTHOR]

Summary: Ischemia-reperfusion injury is an important cause of liver damage occurring during surgical procedures including hepatic resection and liver transplantation, and represents the main underlying cause of graft dysfunction post-transplantation. Cellular and biochemical processes occurring during hepatic ischemia-reperfusion are diverse and complex, and include the deregulation of the healthy phenotype of all liver cellular components. Nevertheless, a significant part of these processes are still unknown or unclear. The present review aims at summarizing the current knowledge in liver ischemia-reperfusion, but specifically focusing on liver cell phenotype and paracrine interaction deregulations. Moreover, the most updated therapeutic strategies including pharmacological, genetic and surgical interventions, as well as some of the scientific controversies in the field will be described. Finally, the importance of considering the subclinical situation of liver grafts when translating basic knowledge to the bedside is discussed. [Copyright &y& Elsevier]

Abstract: Death receptors are members of the tumour necrosis factor (TNF) receptor superfamily characterised by an ~80 amino acid long alpha-helical fold, termed the death domain (DD). Death receptors diversified during early vertebrate evolution indicating that the DD fold has plasticity and specificity that can be easily adjusted to attain additional functions. Eight members of the death receptor family have been identified in humans, which can be divided into four structurally homologous groups or clades, namely: the p75NTR clade (consisting of ectodysplasin A receptor, death receptor 6 (DR6) and p75 neurotrophin (NTR) receptor); the tumour necrosis factor receptor 1 clade (TNFR1 and DR3), the CD95 clade (CD95/FAS) and the TNF-related apoptosis-inducing ligand receptor (TRAILR) clade (TRAILR1 and TRAILR2). Receptors in the same clade participate in similar processes indicating that structural diversification enabled functional specialisation. On the surface of nearly all human cells multiple death receptors are expressed, enabling the cell to respond to a plethora of external signals. Activation of different death receptors converges on the activation of three main signal transduction pathways: nuclear factor-κB-mediated differentiation or inflammation, mitogen-associated protein kinase-mediated stress response and caspase-mediated apoptosis. While the ability to induce cell death is true for nearly all DRs, the FAS and TRAILR clades have specialised in inducing cell death. Here we summarise recent discoveries about the molecular regulation and structural requirements of apoptosis induction by death receptors and discuss how this information can be used to better explain the biological functions, similarities and distinguishing features of death receptors. [Copyright &y& Elsevier]

Highlights: [•] Knock-down of syntaxin-4 in U266 plasma cells resulted in reduction of IgE secretion. [•] Knock-down of syntaxin-4 also leads to the accumulation of IgE in the cell. [•] Immuno-fluorescence staining shows co-localisation of IgE and syntaxin-4 in U266 cells. [•] Findings suggest a critical requirement for syntaxin-4 in IgE secretion from plasma cells. [Copyright &y& Elsevier]

Abstract: Metastatic melanoma monotherapies with drugs such as dacarbazine, cisplatin or paclitaxel (PXT) are associated with significant toxicity and low efficacy rates. These facts reinforce the need for development of novel agents or combinatory strategies. Cl-IB-MECA is a small molecule, orally bioavailable, well tolerated and currently under clinical trials as an anticancer agent. Our aim was to investigate a possible combinatory therapeutic strategy using PXT and Cl-IB-MECA on human C32 melanoma cells and its underlying mechanisms. Cytotoxicity was evaluated using MTT reduction, lactate dehydrogenase leakage and neutral red uptake assays, for different concentrations and combinations of both agents, at 24 and 48h. Apoptosis was also assessed using fluorescence microscopy and through the evaluation of caspases 8, 9, and 3 activities. We demonstrated, for the first time, that combination of PXT and Cl-IB-MECA significantly increases cytotoxicity for clinically relevant concentrations. This combination seems to act synergistically in disrupting membrane integrity, but also causing lysosomal and mitochondrial dysfunction. When using the lowest PTX concentration (10ng/mL), co-incubation with CI-IB-MECA (micromolar concentrations) potentiated overall cytotoxic effects and morphological signs of apoptosis. All combinations studied enhanced caspase 8, 9, and 3 activities, suggesting the involvement of both intrinsic and extrinsic apoptotic pathways. The possibility that cytotoxicity elicited by Cl-IB-MECA, alone or in combination with PXT, involves adenosine receptor activation was discarded and results confirmed that oxidative stress is only involved in cytotoxicity after treatment with PXT, alone. Being melanoma a very apoptosis-resistance cancer, this combination seems to hold promise as a new therapeutic strategy for melanoma. [Copyright &y& Elsevier]

Abstract: Both chronic cough and chronic pain are critical clinical issues in which a large number of patients remain unsatisfied with available treatments. These conditions have considerable effects on sufferers' quality of life, who often show co-morbidities such as anxiety and depression. There is therefore a pressing need to find new effective therapies. The basic neurobiological mechanisms and pathologies of these two conditions show substantial homologies. However, whilst chronic pain has received a great deal of attention over the last few decades, the same cannot be said for the neurological underpinnings of chronic cough. There is a substantial literature around mechanisms of chronic pain which is likely to be useful in advancing knowledge about the pathologies of chronic cough. Here we compare the basic pain and cough pathways, in addition to the clinical features and possible pathophysiologies of each; including mechanisms of peripheral and central sensitisation which may underlie symptoms such as hyperalgesia and allodynia, and hypertussitvity and allotussivity. Due to the substantial overlap that emerges, it is likely that therapies may be effective over both areas. [Copyright &y& Elsevier]

Abstract: Skeletal muscle loss appears to be the most significant clinical event in cancer cachexia and is associated with a poor outcome. With regard to such muscle loss, despite extensive study in a range of models, there is ongoing debate as to whether a reduction in protein synthesis, an increase in degradation or a combination of both is the more relevant. Each model differs in terms of key mediators and the pathways activated in skeletal muscle. Certain models do suggest that decreased synthesis accompanied by enhanced protein degradation via the ubiquitin proteasome pathway (UPP) is important. Murine models tend to involve rapid development of cachexia and may represent more acute muscle atrophy rather than the chronic wasting observed in humans. There is a paucity of human data both at a basic descriptive level and at a molecular/mechanism level. Progress in treating the human form of cancer cachexia can only move forwards through carefully designed large randomised controlled clinical trials of specific therapies with validated biomarkers of relevance to underlying mechanisms. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. [Copyright &y& Elsevier]

Abstract: Background and aims: Extraintestinal manifestations of inflammatory bowel disease (IBD) can involve the orbit and the optic nerve. Although these manifestations are rare, they can be particularly serious as they can lead to permanent loss of vision. The aim of the review is to present the existing literature on IBD-related optic nerve and orbital complications. Methods: A literature search identified the publications reporting on incidence, clinical features and management of IBD patients with optic nerve and orbital manifestations. Results: Posterior scleritis and orbital inflammatory disease (orbital pseudotumor) are the most commonly encountered entities affecting the structures of the orbit. On the other hand, the optic nerve of IBD patients can be affected by conditions such as optic (demyelinating) neuritis (“retrobulbar” neuritis), or ischaemic optic neuropathy. Other neuro-ophthalmic manifestations that can be encountered in patients with IBD are related to increased intracranial pressure or toxicity secondary to anti tumour necrosis factor (anti-TNF) agents. Conclusions: IBD-related optic nerve and orbital complications are rare but potentially vision-threatening. Heightened awareness and close cooperation between gastroenterologists and ophthalmologists are warranted. [Copyright &y& Elsevier]

Highlights: [•] We mimic a relapse of MS by a single transfer of encephalitogenic T cells in rats. [•] Marked degeneration of pyramidal neurons was found already 5days post injection. [•] Hippocampal damage aggravated and inflammation persisted 90days post injection. [•] No memory disturbances were revealed by the Morris water maze test 30 and 90days post injection. [•] The data suggest that hippocampus may be targeted during any relapse of MS. [ABSTRACT FROM AUTHOR]

Abstract: In November 2002 the oil tanker Prestige spilled 63,000tonnes of heavy oil off the northwest coast of Spain, impacting more than 1000km of coastline. A general concern led to a huge mobilization of human and technical resources, and more than 300,000 people participated in cleanup activities, which lasted up to 10months. Some endocrine and immunological alterations were reported in Prestige oil exposed subjects for several months. Therefore, the objective of this study was to evaluate if these alterations are still present seven years after the exposure. Fifty-four individuals exposed for at least 2months were compared to 50 matched referents. Prolactin and cortisol plasma concentrations, percentages of lymphocyte subsets (CD3+, CD4+, CD8+, CD19+, and CD56+16+), plasma levels of circulating cytokines (interleukin (IL) 2, IL4, IL6, IL10, tumour necrosis factor α, and interferon γ), and serum concentrations of neopterin, tryptophan and kynurenine were determined in peripheral blood samples. Results showed significant differences in exposed individuals vs. referents only in cortisol (increase), kynurenine and %CD16+56+ lymphocytes (both decrease). Time of exposure to the oil or using protective clothes did not influence the results, but effect of using protective mask was observed on neopterin, %CD8+, CD4+/CD8+ ratio and IL4. Surveillance of the exposed individuals for early detection of possible health problems related to the endocrine or immunological systems is recommended. [Copyright &y& Elsevier]

Abstract: Management of Crohn's disease has traditionally placed high value on subjective symptom assessment; however, it is increasingly appreciated that patient symptoms and objective parameters of inflammation can be disconnected. Therefore, strategies that objectively monitor inflammatory activity should be utilised throughout the disease course to optimise patient management. Initially, a thorough assessment of the severity, location and extent of disease is needed to ensure a correct diagnosis, identify any complications, help assess prognosis and select appropriate therapy. During follow-up, clinical decision-making should be driven by disease activity monitoring, with the aim of optimising treatment for tight disease control. However, few data exist to guide the choice of monitoring tools and the frequency of their use. Furthermore, adaption of monitoring strategies for symptomatic, asymptomatic and post-operative patients has not been well defined. The Annual excHangE on the ADvances in Inflammatory Bowel Disease (IBD Ahead) 2011 educational programme, which included approximately 600 gastroenterologists from 36 countries, has developed practice recommendations for the optimal monitoring of Crohn's disease based on evidence and/or expert opinion. These recommendations address the need to incorporate different modalities of disease assessment (symptom and endoscopic assessment, measurement of biomarkers of inflammatory activity and cross-sectional imaging) into robust monitoring. Furthermore, the importance of measuring and recording parameters in a standardised fashion to enable longitudinal evaluation of disease activity is highlighted. [Copyright &y& Elsevier]

Abstract: Rates of obesity are higher than normal across a range of psychiatric disorders, including major depressive disorder, bipolar disorder, schizophrenia and anxiety disorders. While the problem of obesity is generally acknowledged in mental health research and treatment, an understanding of their bi-directional relationship is still developing. In this review the association between obesity and psychiatric disorders is summarised, with a specific emphasis on similarities in their disturbed biological pathways; namely neurotransmitter imbalances, hypothalamus–pituitary–adrenal axis disturbances, dysregulated inflammatory pathways, increased oxidative and nitrosative stress, mitochondrial disturbances, and neuroprogression. The applicability and effectiveness of weight-loss interventions in psychiatric populations are reviewed along with their potential efficacy in ameliorating disturbed biological pathways, particularly those mediating inflammation and oxidative stress. It is proposed that weight loss may not only be an effective intervention to enhance physical health but may also improve mental health outcomes and slow the rate of neuroprogressive disturbances in psychiatric disorders. Areas of future research to help expand our understanding of the relationship between obesity and psychiatric disorders are also outlined. [Copyright &y& Elsevier]

Highlights: [•] Striking similarities exist between vertebrate and non-vertebrate mucosal defenses. [•] ROS and antimicrobial peptides are a key feature of non-vertebrate gut immunity. [•] Mechanisms of non-vertebrate gut immunity are modulated by a resident microbiota. [Copyright &y& Elsevier]

Abstract: Age-related macular degeneration (AMD) is a complex, degenerative and progressive disease involving multiple genetic and environmental factors. It can result in severe visual loss e.g. AMD is the leading cause of blindness in the elderly in the western countries. Although age, genetics, diet, smoking, and many cardiovascular factors are known to be linked with this disease there is increasing evidence that long-term oxidative stress, impaired autophagy clearance and inflammasome mediated inflammation are involved in the pathogenesis. Under certain conditions these may trigger detrimental processes e.g. release of vascular endothelial growth factor (VEGF), causing choroidal neovascularization e.g. in wet AMD. This review ties together these crucial pathological threads in AMD. [Copyright &y& Elsevier]

Abstract: Objective: Hemophagocytic lymphohistiocytosis (HLH) is a severe immunological disorder that leads to a massive inflammatory reaction that may prove rapidly fatal. We show that HLH may present by masquerading as surgical disease or as a postoperative complication leading to delays in diagnosis and treatment. Study design: A case series of four children with acute surgical presentation and prolonged unexplained postoperative sepsis, who were diagnosed with HLH. Results: Four children with different clinical presentations (1. neonatal abdominal distension, 2. ileostomy closure and Hirschsprung's disease, 3. iatrogenic sigmoid perforation and Crohn's disease, and 4. streptococcal toxic shock syndrome with primary peritonitis) were diagnosed with HLH at our regional pediatric surgical centre in the last two years. All developed signs of prolonged postoperative sepsis with hepatosplenomegaly and pancytopenia, requiring intensive care support. In the absence of explanation for their symptoms and deteriorating clinical condition, a total of six ‘negative’ exploratory laparotomies were performed. Eventually, HLH was diagnosed with bone marrow aspiration after an average of 23days (range 17–40), following the finding of significantly elevated ferritin (up to 293150ng/ml) and triglyceride levels. All children improved with initiation of high-dose steroid treatment followed by etoposide and cyclosporin. Conclusion: HLH may rarely present with symptoms and signs of surgical disease or complicate post-operative recovery. This diagnosis should be considered in children with unexplained prolonged fever, hepatosplenomegaly and pancytopenia, especially if associated with high ferritin levels. HLH can prove rapidly fatal without appropriate treatment. [Copyright &y& Elsevier]

Abstract: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) exert pleiotropic effects on the cardiovascular system, in part through a decrease in reactive oxygen species (ROS) formation and reduction of vascular inflammation. To elucidate the molecular mechanisms involved in these effects, we investigated the effect of statins on TNF-α-induced ROS production, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression in human aortic endothelial cells (HAECs). Exposure of HAECs to TNF-α caused production of ROS via Rac-1 membrane translocation and activation. The Rac-1 activation and ROS liberation mediated TNF-stimulated NF-κB activation and the subsequent VCAM-1 and ICAM-1 expression. Extracellular-signal-regulated kinase 5 (ERK5) plays a central role in inhibiting endothelial inflammation. Immune complex kinase assay of protein extracts from HAECs treated with atorvastatin revealed increased ERK5 activity in a time- and dose-dependent manner. In addition, pretreatment with atorvastatin inhibited TNF-α-induced ROS production and VCAM-1 and ICAM-1 expression. Chemical or genetic inhibition of ERK5 ablated the statins inhibition of Rac-1 activation, ROS formation, NF-κB, VCAM-1 and ICAM-1 expression induced by TNF-α. Taken together, statins, via ERK5 activation, suppress TNF-stimulated Rac-1 activation, ROS generation, NF-κB activation and VCAM-1 and ICAM-1 expression in human ECs, which provides a novel explanation for the pleiotropic effects of statins that benefit the cardiovascular system. [Copyright &y& Elsevier]

Abstract: The Yangtze finless porpoise (Neophocaena phocaenoides asiaorientalis) is listed on the First Order of Protected Animals in China and was identified as an endangered species by the International Union for Conservation of Nature and Natural Resources (IUCN) in 2011. A proliferation inducing ligand (APRIL), belonging to the tumour necrosis factor (TNF) family, is critical for immune regulation. In this study, we identified a finless porpoise APRIL cDNA (fAPRIL) by RACE (rapid amplification of cDNA ends) strategies, from the Yangtze finless porpoise (fAPRIL). This gene encodes 247 amino acids containing a predicted transmembrane domain and a TNF domain, and phylogenetic analysis of the APRIL sequence indicated that finless porpoises are closely related to Artiodactyla. In vitro, soluble fAPRIL (fsAPRIL) not only promoted the survival/proliferation of the mouse spleen lymphocytes, but also bound specifically to the surface of the B cells. The results of this study contribute to our understanding of the immune mechanisms in the finless porpoise and other aquatic mammals. [Copyright &y& Elsevier]

Abstract: The many features that link autoimmune disorders (AD) and lymphoma are reviewed herein. Firstly, the epidemiology indicates the increased risk of non-Hodgkin's lymphoma (NHL) development in many AD, and especially in Sjögren's syndrome, rheumatoid arthritis and systemic lupus erythematosus. In these AD, the relative risk of NHL occurrence varies between 2 and 4 up to 40 fold higher than in the general population, according to various surveys. Factors favouring or predicting NHL have been reported in detail. B-cell activation and proliferation are part of AD and are essential factors for the onset of malignant cell clones in a deregulated immunological environment. Targeting deregulated or malignant B-cells is the goal of some newly developed treatments. The prototype is anti-CD20 rituximab that has substantially modified the prognosis of B-cell NHL and is also an effective new treatment opportunity for some AD. Similarly, intensified treatments with autologous haematopoietic stem cell transplant (ASCT) that were developed for high-risk lymphoma are now under advanced investigation for use in some refractory AD. Thus, the successful use of rituximab and ASCT in both AD and NHL further emphasizes the close link between these two entities. This review provides details on the main epidemiological features regarding NHL incidence in AD, the pathogenetic factors that favour lymphoma onset and some recent advances in therapeutic approaches that are effective in both autoimmune and malignant lymphoproliferative disorders. [Copyright &y& Elsevier]