Anti-tumour necrosis factor-α therapy for severe enteropathy in patients with common variable immunodeficiency (CVID)

We present three common variable immunodeficiency (CVID) patients with
severe inflammatory bowel disease of unknown aetiology, resistant to steroid
treatment, treated with infliximab.After exclusion of any infection, infliximab
was given at a dose of 5 mg/kg every 4 weeks for a 3 month induction followed
by every 4–8 weeks depending on clinical response. Two of these patients had
predominantly small bowel disease; they both showed clinical response to
infliximab with weight gain and improvement of quality of life scores. The
third patient had large bowel involvement with profuse watery diarrhea; this
patient improved dramatically within 48 hours of having infliximab
treatment. All three patients have been maintained on infliximab treatment
for between 5 and 53 months (mean 37 months) with no evidence of increased
susceptibility to infections in the patients with small bowel disease, although
the third patient developed two urinary tract infections and a herpes zoster
infection following therapy. This is the first small case series to show that
infliximab is a useful addition to current therapy in this rare group of patients
with potentially life threatening enteritis.

Melatonin : an overlooked factor in schizophrenia and in the inhibition of anti-psychotic side effects

This paper reviews melatonin as an overlooked factor in the developmental etiology and maintenance of schizophrenia; the neuroimmune and oxidative pathophysiology of schizophrenia; specific symptoms in schizophrenia, including sleep disturbance; circadian rhythms; and side effects of antipsychotics, including tardive dyskinesia and metabolic syndrome. Electronic databases, i.e. PUBMED, Scopus and Google Scholar were used as sources for this review using keywords: schizophrenia, psychosis, tardive dyskinesia, antipsychotics, metabolic syndrome, drug side effects and melatonin. Articles were selected on the basis of relevance to the etiology, course and treatment of schizophrenia. Melatonin levels and melatonin circadian rhythm are significantly decreased in schizophrenic patients. The adjunctive use of melatonin in schizophrenia may augment the efficacy of antipsychotics through its anti-inflammatory and antioxidative effects. Further, melatonin would be expected to improve sleep disorders in schizophrenia and side effects of anti-psychotics, such as tardive dyskinesia, metaboilic syndrome and hypertension. It is proposed that melatonin also impacts on the tryptophan catabolic pathway via its effect on stress response and cortisol secretion, thereby impacting on cortex associated cognition, amygdala associated affect and striatal motivational processing. The secretion of melatonin is decreased in schizophrenia, contributing to its etiology, pathophysiology and management. Melatonin is likely to have impacts on the metabolic side effects of anti-psychotics that contribute to subsequent decreases in life-expectancy.

Fibroblast growth factor-2 over-rides insulin-like growth factor-I induced proliferation and cell survival in human neuroblastoma cells

The insulin-like growth factor (IGF) system is a key regulator of cell growth, survival and differentiation, and these functions are co-modulated by other growth factors including fibroblast growth factor-2 (FGF-2). To investigate IGF/FGF interactions in neuronal cells, we employed neuroblastoma cells (SK-N-MC). In serum free conditions proliferation of the SK-N-MC cells was promoted by IGF-I (25 ng/ml), but blunted by FGF-2 (50 ng/ml). IGF-I-induced proliferation was abolished in the presence of FGF-2 even when IGF-I was used at 100 ng/ml. In addition to our previously described FGF-2 induced proteolytic cleavage of IGFBP-2, we found that FGF-2 increased IGFBP-6 levels in conditioned medium (CM) without affecting IGFBP-6 mRNA abundance. Modulation of IGFBP-2 and -6 levels were not significant mechanisms involved in the blockade of IGF-I action since the potent IGF-I analogues [QAYL]IGF-I and des(1-3)IGF-I (minimal IGFBP affinity) were unable to overcome FGF-2 inhibition of cell proliferation. FGF-2 treated cells showed morphological differentiation expressing the TUJ1 neuronal marker while cells treated with IGF-I alone showed no morphological change. When IGF-I was combined with FGF-2, however, cell morphology was indistinguishable from that seen with FGF-2 alone. FGF-2 inhibited proliferation and enhanced differentiation was also associated with a 70% increase in cell death. Although IGF-I alone was potently anti-apoptotic (60% decreased), IGF-I was unable to prevent apoptosis when administrated in combination with FGF-2. Gene-array analysis confirmed FGF-2 activation of the intrinsic and extrinsic apoptotic pathways and blockade of IGF anti-apoptotic signaling. FGF-2, directly and indirectly, overcomes the proliferative and anti-apoptotic activity of IGF-I by complex mechanisms, including enhancement of differentiation and apoptotic pathways, and inhibition of IGF-I induced anti-apoptotic signalling. Modulation of IGF binding protein abundance by FGF-2 does not play a significant role in inhibition of IGF-I induced mitogenesis.

Molecular mechanisms of inflammation : anti-inflammatory benefits of virgin olive oil and the phenolic compound oleocanthal

Chronic inflammation is a critical factor in the pathogenesis of many inflammatory disease states including cardiovascular disease, cancer, diabetes, degenerative joint diseases and neurodegenerative diseases. Chronic inflammatory states are poorly understood, however it is known that dietary habits can evoke or attenuate inflammatory responses. Popular methods to deal with inflammation and its associated symptoms involve the use of non steroidal anti-inflammatory drugs, however the use of these drugs are associated with severe side effects. Therefore, investigations concerned with natural methods of inflammatory control are warranted. A traditional Mediterranean diet has been shown to confer some protection against the pathology of chronic diseases through the attenuation of proinflammatory mediators and this has been partially attributed to the high intake of virgin olive oil accompanying this dietary regime. Virgin olive oil contains numerous phenolic compounds that exert potent anti-inflammatory actions. Of interest to this paper is the recently discovered phenolic compound oleocanthal. Oleocanthal is contained in virgin olive oil and possesses similar anti-inflammatory properties to ibuprofen. This pharmacological similarity has provoked interest in oleocanthal and the few studies conducted thus far have verified its anti-inflammatory and potential therapeutic actions. A review of the health benefits of the Mediterranean diet and antiinflammatory properties of virgin olive oil is presented with the additional emphasis on the pharmacological and anti-inflammatory properties of the phenolic compound oleocanthal.

Current protein-based anti-angiogenic therapeutics

 Angiogenesis is a complex multistep process of formation of new blood vessels. Interactions between several cellular factors including growth factors, cytokines and haematopoietic factors lead to activation of various cellular pathways, finally resulting in extracellular matrix (ECM) degradation, endothelial cell proliferation, survival and migration. Normally, angiogenesis is an essential requirement for vascular development in growing embryos as well as in adult tissues, where this process depends on the intricate balance between the activities of the pro- and anti-angiogenic factors. Abnormal angiogenesis results in aberrant vasculature leading to various pathological conditions. The most important factor implicated in angiogenic processes in vascular endothelial growth factor (VEGF) and its family of ligands and receptors. Several anti-angiogenic drugs have been developed and many more are currently in different phases of clinical trials, which target various angiogenesis-inducing agents, including VEGF, VEGF receptors, angiopoietins and ECM components such as integrins. Anti-angiogenic therapy can be divided into gene-based therapy and protein-based therapy. Gene-based therapies include use of antisense oligonucleotides, siRNA, aptamers, catalytic oligonucleotides including ribozymes and DNAzymes and transcription decoys. Protein-based therapeutics includes monoclonal antibodies, peptidomimetics, fusion proteins and decoy receptors. The later class of therapeutics has several advantages over gene-based and small molecule drugs, including specificity and complexity in functions, better tolerability, less interference with normal biological processes and lesser adverse effects due to decreased immune response by virtue of being mostly body's natural proteins. This review provides a comprehensive overview of angiogenesis and on the current protein-based anti-angiogenic therapeutics under research and in the clinic.

Regulation of granulocyte colony-stimulating factor and its receptor in skeletal muscle is dependent upon the type of inflammatory stimulus

The cytokine granulocyte colony-stimulating factor (G-CSF) binds to its receptor (G-CSFR) to stimulate hematopoietic stem cell mobilization, myelopoiesis, and the production and activation of neutrophils. In response to exercise-induced muscle damage, G-CSF is increased in circulation and G-CSFR has recently been identified in skeletal muscle cells. While G-CSF/G-CSFR activation mediates pro- and anti-inflammatory responses, our understanding of the role and regulation in the muscle is limited. The aim of this study was to investigate, in vitro and in vivo, the role and regulation of G-CSF and G-CSFR in skeletal muscle under conditions of muscle inflammation and damage. First, C2C12 myotubes were treated with lipopolysaccharide (LPS) with and without G-CSF to determine if G-CSF modulates the inflammatory response. Second, the regulation of G-CSF and its receptor was measured following eccentric exercise-induced muscle damage and the expression levels we investigated for redox sensitivity by administering the antioxidant N-acetylcysteine (NAC). LPS stimulation of C2C12 myotubes resulted in increases in G-CSF, interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNFα) messenger RNA (mRNA) and an increase in G-CSF, IL-6, and MCP-1 release from C2C12 myotubes. The addition of G-CSF following LPS stimulation of C2C12 myotubes increased IL-6 mRNA and cytokine release into the media, however it did not affect MCP-1 or TNFα. Following eccentric exercise-induced muscle damage in humans, G-CSF levels were either marginally increased in circulation or remain unaltered in skeletal muscle. Similarly, G-CSFR levels remained unchanged in response to damaging exercise and G-CSF/G-CSFR did not change in response to NAC. Collectively, these findings suggest that G-CSF may cooperate with IL-6 and potentially promote muscle regeneration in vitro, whereas in vivo aseptic inflammation induced by exercise did not change G-CSF and G-CSFR responses. These observations suggest that different models of inflammation produce a different G-CSF response.

Antimanic-like activity of candesartan in mice: possible involvement of antioxidant, anti-inflammatory and neurotrophic mechanisms

Activation of the brain angiotensin II type 1 receptor (AT1R) triggers pro-oxidant and pro-inflammatory mechanisms which are involved in the neurobiology of bipolar disorder (BD). Candesartan (CDS) is an AT1 receptor antagonist with potential neuroprotective properties. Herein we investigated CDS effects against oxidative, neurotrophic inflammatory and cognitive effects of amphetamine (AMPH)-induced mania. In the reversal protocol adult mice were given AMPH 2mg/kg i.p. or saline and between days 8 and 14 received CDS 0.1, 0.3 or 1mg/kg orally, lithium (Li) 47.5mg/kg i.p., or saline. In the prevention treatment, mice were pretreated with CDS, Li or saline prior to AMPH. Locomotor activity and working memory performance were assessed. Glutathione (GSH), thiobarbituric acid-reactive substance (TBARS) and TNF-α levels were evaluated in the hippocampus (HC) and cerebellar vermis (CV). Brain-derived neurotrophic factor (BDNF) and glycogen synthase kinase 3-beta (GSK-3beta) levels were measured in the HC. CDS and Li prevented and reversed the AMPH-induced increases in locomotor activity. Only CDS prevented and reversed AMPH-induced working memory deficits. CDS prevented AMPH-induced alterations in GSH (HC and CV), TBARS (HC and CV), TNF-α (HC and CV) and BDNF (HC) levels. Li prevented alterations in BDNF and phospho-Ser9-GSK3beta. CDS reversed AMPH-induced alterations in GSH (HC and CV), TBARS (HC), TNF-α (CV) and BDNF levels. Li reversed AMPH-induced alterations in TNF-α (HC and CV) and BDNF (HC) levels. CDS is effective in reversing and preventing AMPH-induced behavioral and biochemical alterations, providing a rationale for the design of clinical trials investigating CDS׳s possible therapeutic effects.

Pro-inflammatory dietary intake as a risk factor for CVD in men: a 5-year longitudinal study

Convincing evidence has identified inflammation as an initiator of atherosclerosis, underpinning CVD. We investigated (i) whether dietary inflammation, as measured by the 'dietary inflammatory index (DII)', was predictive of 5-year CVD in men and (ii) its predictive ability compared with that of SFA intake alone. The sample consisted of 1363 men enrolled in the Geelong Osteoporosis Study who completed an FFQ at baseline (2001-2006) (excluding participants who were identified as having previous CVD). DII scores were computed from participants' reported intakes of carbohydrate, micronutrients and glycaemic load. DII scores were dichotomised into a pro-inflammatory diet (positive values) or an anti-inflammatory diet (negative values). The primary outcome was a formal diagnosis of CVD resulting in hospitalisation over the 5-year study period. In total, seventy-six events were observed during the 5-year follow-up period. Men with a pro-inflammatory diet at baseline were twice as likely to experience a CVD event over the study period (OR 2·07; 95 % CI 1·20, 3·55). This association held following adjustment for traditional CVD risk factors and total energy intake (adjusted OR 2·00; 95 % CI 1·03, 3·96). This effect appeared to be stronger with the inclusion of an age-by-DII score interaction. In contrast, SFA intake alone did not predict 5-year CVD events after adjustment for covariates (adjusted OR 1·40; 95 % CI 0·73, 2·70). We conclude that an association exists between a pro-inflammatory diet and CVD in Australian men. CVD clinical guidelines and public health recommendations may have to expand to include dietary patterns in the context of vascular inflammation.

An anti-biodegradable hydrophobic sulfonate-based acrylamide copolymer containing 2,4-dichlorophenoxy for enhanced oil recovery

We report here a novel anti-biodegradable hydrophobic acrylamide copolymer that was prepared from acrylamide, acrylic acid, sodium 3-(allyloxy)-2-hydroxypropane-1-sulfonate and N-allyl-2-(2,4-dichlorophenoxy) acetamide using the 2,2'-azobis(2-methylpropionamide) dihydrochloride initiation system. Subsequently, the copolymer was characterized by FT-IR, 1H NMR, TG-DTG and water-solubility. And the biodegradability test indicated that the copolymer was not deemed to be readily biodegradable via a closed bottle test established by the Organization for Economic Co-operation and Development (OECD 301 D). Meanwhile the copolymer could significantly enhance the viscosity of the aqueous solution in comparison with partially hydrolyzed polyacrylamide. A viscosity retention of 51.9% indicated the result of a dramatic improvement of temperature tolerance. And then the excellent salt resistance, shear resistance, viscoelasticity, long-term stability of the copolymer could be obtained, which provides a good theoretical foundation for the application in enhanced oil recovery. In addition, this copolymer exerted stronger mobility control ability with a resistance factor of 22.1 and a residual resistance factor of 5.0, and superior ability for enhanced oil recovery of 12.9%. Hence, the copolymer has potential application for enhanced oil recovery in high-temperature and high-salinity reservoirs.

Anti-inflammatory activity and mechanisms of a lipid extract from hard-shelled mussel (mytilus coruscus) in mice with dextran sulphate sodium-induced colitis

The anti-inflammatory effect of a lipid extract from hard-shelled mussel (HMLE) on dextran sulphate sodium (DSS)-induced colitis in mice was investigated. Salicylazosulphapyridine (SASP) and different doses of HMLE were administered by gastric gavage. HMLE significantly attenuated DSS-induced colitis disease activity index scores, tissue damage, splenic enlargement and colon myeloperoxidase accumulation. In addition, HMLE improved colon oxidative stress and production and expression of anti-inflammatory cytokine, interleukin (IL)-10, while HMLE inhibited the abnormal productions and mRNA expressions of pro-inflammatory cytokines, namely tumour necrosis factor-α, IL-1β, and IL-6, as well as the expression of key molecules in the toll-like receptor (TLR)-4/nuclear factor (NF)-κB signalling pathway. These findings suggest that HMLE has an anti-inflammatory effect on DSS-induced colitis, equivalent to that of SASP, and this effect might be related to the regulation of inflammatory mediators and key molecules in the TLR-4/NF-κB pathway.