Pomelo peel oil suppresses TNF-α-induced necroptosis and cerebral ischaemia-reperfusion injury in a rat model of cardiac arrest.

CONTEXT: Pomelo peel oil (PPO) [Citrus maxima (Burm.) Merr. (Rutaceae)] is reported to possess antioxidant and antimelanogenic activities. OBJECTIVE: To investigate the effect of PPO [Citrus maxima (Burm.) Merr. cv. Shatian Yu] on tumour necrosis factor-α (TNF-α)-induced necroptosis in cerebral ischaemia-reperfusion injury (CIRI) after cardiac arrest (CA). MATERIALS AND METHODS: Male Sprague Dawley rats were randomly assigned to six groups: sham group, PP0-L (10 mg/kg), PPO-M (20 mg/kg), PPO-H (40 mg/kg) and two control groups (CA, 0.9% saline; Gly, 10% glycerol). All drugs were administered intravenously to the CA/CPR rats within 10 min after return of spontaneous circulation (ROSC). After 24 h, rats were assessed for neuronal injury via the neurological deficit score (NDS), cerebral cortex staining and transmission electron microscopy (TEM) and expression levels of TNF-α and necroptosis-related proteins by immunoreactivity staining and western blotting. RESULTS: Compared to those in the sham group (survival rate, 100% and NDS, 80), the survival rate and NDS were significantly reduced in the model groups (CA, 56.25%, 70; Gly, 62.5%, 71; PPO-L, 75%, 72; PPO-M, 87.5%, 75; PPO-H, 81.25%, 74). In the PPO-M group, Nissl bodies were significantly increased (43.67 ± 1.906 vs. 17 ± 1.732), the incidence of pathomorphological injury was lower and the necroptosis markers (TNF-α, RIPK1, RIPK3, p-MLKL/MLKL) expression was downregulated compared to those in the CA group (p < 0.05). DISCUSSION AND CONCLUSIONS: The neuroprotective effects of PPO in the CA rats suggested that PPO possibility as a health product enhances the resistance ability against brain injury for humans.

Isolated limb perfusion for soft tissue sarcoma: Current practices and future directions. A survey of experts and a review of literature.

Soft tissue sarcomas constitute 1% of adult malignant tumors. They are a heterogeneous group of more than 50 different histologic types. Isolated limb perfusion is an established treatment strategy for locally advanced sarcomas. Since its adoption for sarcomas in 1992, after the addition of TNFα, few modifications have been done and although indications for the procedure are essentially the same across centers, technical details vary widely. The procedures mainly involves a 60 min perfusion with melphalan and TNFα under mild hyperthermia, achieving a limb preservation rate of 72-96%; with an overall response rates from 72 to 82.5% and an acceptable toxicity according to the Wieberdink scale. The local failure rate is 27% after a median follow up of 14-31 months compared to 40% of distant recurrences after a follow up of 12-22 months. Currently there is no consensus regarding the benefit of ILP per histotype, and the value of addition of radiotherapy or systemic treatment. Further developments towards individualized treatments will provide a better understanding of the population that can derive maximum benefit of ILP with the least morbidity.

Topical Therapy with Antisense Tumor Necrosis Factor Alpha Using Novel ß-Glucan-Based Drug Delivery System Ameliorates Intestinal Inflammation.

Anti-tumor necrosis factor alpha (TNF-α) antibodies are effective in patients with inflammatory bowel disease (IBD). However, the effect is not optimal because a sufficient concentration of antibodies cannot be maintained at the site of inflammation. Thus, a macromolecular complex was developed with schizophyllan (SPG) and antisense oligonucleotides. In the present study, an SPG-antisense TNF-α complex was prepared, and its therapeutic efficacy was examined using a dextran sodium sulfate (DSS)-induced colitis model. The TNF-α production in CD11b+ macrophages significantly increased in the colon of DSS-treated mice. Dectin-1, a receptor of SPG, binds with SPG and is subsequently taken into the cells via phagocytosis. The expression of dectin-1 by CD11b+ macrophages significantly increased in DSS-treated mice. Flow cytometry revealed that the uptake of SPG-antisense TNF-α in the macrophages was efficient. TNF-α production was suppressed significantly by SPG-antisense TNF-α in vitro, which was administered via enema to evaluate its efficacy. The intrarectal administration of SPG-antisense TNF-α ameliorated the intestinal inflammation. In this study, we showed that the delivery system that conjugates SPG and antisense can have higher therapeutic efficacy. Thus, the new therapeutic approach presented in this study may be used in the management of IBD.

Brain-specific chemokine FAM19A5 induces hypothalamic inflammation.

The cytokine-like protein FAM19A5 is highly expressed in the brain, but little is known about its functions there. Here, we found that FAM19A5 was expressed in mouse hypothalamic cells expressing proopiomelanocortin (POMC) and neuropeptide Y (NPY)/agouti-related peptide (AgRP), and in the microglia. Tumor necrosis factor-α (TNF-α), which induces inflammatory sickness responses, greatly increased hypothalamic expression of FAM19A5. Knockdown of FAM19A5 expression resulted in decreased TNF-α-induced anorexia, body weight loss and TNF-α-induced expression of inflammatory factors. In contrast, intracerebroventricular administration of FAM19A5 induced anorexia, body weight loss and hyperthermia, together with increased expression of inflammatory factors. FAM19A5 injection also induced increases in c-fos activation and POMC mRNA level in hypothalamic POMC neurons. Together, these results suggest that FAM19A5 plays an important role in hypothalamic inflammatory responses.

Secondary angiosarcoma: A fatal complication of chronic lymphedema.

Secondary Angiosarcoma (Stewart-Treves Syndrome) is a rare malignant cutaneous lesion, which arises in chronic lymphedema of the extremity, often observed after breast cancer treatment. We reviewed the history and the oncological outcome of two patients with this disease. Multimodal therapy including hyperthermic isolated limb perfusion with TNF-alpha and Melphalan, combined with radical resection of the affected skin and subcutaneous tissue including the fascia, with large safety margins may probably lead to better survival.

Neoadjuvant Hypertermic Isolated Limb Perfusion in Treatment of Undifferentiated Spindle Cell Sarcoma of Lower Limb with Achieved Complete Pathologic Response.

BACKGROUND: Hyperthermic isolated limb perfusion uses therapeutic effect of hyperthermia in the bounded compartment of the limb together with increased concentration of chemotherapy effect than what would be achieved in systemic application. Gold standard was melphalan (Alkeran) in combination with tasonermin (Beromun, tumor necrosis factor alpha). The efficacy of this combination has been demonstrated in limb soft tissue sarcomas and in patients with limb isolated bulky disease of malignant melanoma. CASE: We describe a case of a 65-year-old female patient with undifferentiated spindle-cell sarcoma treated by a multidisciplinary team at the 2nd Surgical Clinic of Cardiovascular Surgery and Clinic of Oncology General University Hospital in Prague and at the Department of Orthopaedics Na Bulovce Hospital with the aim of preserving the limb despite the advanced disease. The patient underwent hyperthermic isolated limb perfusion with tasonermin and melphalan with partial response on magnetic resonance imaging. Subsequent wide resection was done with complete pathological remission according to histological examination maintaining a fully functional limb. The patient is followed without signs of recurrence. CONCLUSION: Hyperthermic isolated limb perfusion with tasonermin and melphalan is an important part of a multimodal approach in the treatment of extremity sarcomas with a high percentage of responses that increase the percentage of limbs retaining resections. Multidisciplinary team should consider this option in patients with localized limb sarcomas and should be performed in specialized centers with experience in this procedure. This work was supported by project Progres Q28-LF1. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Tumour necrosis factor α induces neuroinflammation and insulin resistance in immortalised hypothalamic neurones through independent pathways.

The links between obesity, inflammation and insulin resistance, which are all key characteristics of type 2 diabetes mellitus, are yet to be delineated in the brain. One of the key neuroinflammatory proteins detected in the hypothalamus with over-nutrition is tumour necrosis factor (TNF)α. Using immortalised embryonic rat and mouse hypothalamic cell lines (rHypoE-7 and mHypoE-46) that express orexigenic neuropeptide Y and agouti-related peptide, we investigated changes in insulin signalling and inflammatory gene marker mRNA expression after TNFα exposure. A quantitative polymerase chain reaction array of 84 inflammatory markers (cytokines, chemokines and receptors) demonstrated an increase in the expression of multiple genes encoding inflammatory markers upon exposure to 100 ng mL-1 TNFα for 4 hours. Furthermore, neurones pre-exposed to TNFα (50 ng mL-1 ) for 6 or 16 hours exhibited a significant reduction in phosphorylated Akt compared to control after insulin treatment, indicating the attenuation of insulin signalling. mRNA expression of insulin signalling-related genes was also decreased with exposure to TNFα. TNFα significantly increased mRNA expression of IκBα, Tnfrsf1a and IL6 at 4 and 24 hours, activating a pro-inflammatory state. An inhibitor study using an inhibitor of nuclear factor kappa B kinase subunit ß (IKK-ß) inhibitor, PS1145, demonstrated that TNFα-induced neuroinflammatory marker expression occurs through the IKK-ß/nuclear factor-kappa B pathway, whereas oleate, a monounsaturated fatty acid, had no effect on inflammatory markers. To test the efficacy of anti-inflammatory treatment to reverse insulin resistance, neurones were treated with TNFα and PS1145, which did not significantly restore the TNFα-induced changes in cellular insulin sensitivity, indicating that an alternative pathway may be involved. In conclusion, exposure to the inflammatory cytokine TNFα causes cellular insulin resistance and inflammation marker expression in the rHypoE-7 and mHypoE-46 neurones, consistent with effects seen with TNFα in peripheral tissues. It also mimics insulin- and palmitate-induced insulin resistance in hypothalamic neurones. The present study provides further evidence that altered central energy metabolism may be caused by obesity-induced cytokine expression.

The Chinese Medicine Wu-Tou Decoction Relieves Neuropathic Pain by Inhibiting Hippocampal Microglia Activation.

The comorbidity between the nociceptive and mental syndromes adds to the refractoriness of neuropathic pain (NP). Wu-Tou decoction (WTD) has been prescribed for chronic pain for thousands of years in China. Recently, we reported that WTD was helpful for hippocampus and co-curative for the nociceptive, depressive and anxiety behaviors in the spinal cord ligation (SNL) mice. However, the mechanism underlying the rescue of hippocampus, as well as the roles hippocampus assumed in co-curation remain unexplored. In this study, we validated that in SNL mice, the long-lasting damages to limbic system were mainly limited to hippocampus. In addition, hippocampal neurons were proven sensitive to harms induced by microglia and rescued by WTD, which in sum indicated hippocampal microglia as the critical modulator of co-curation. To validate this hypothesis the hippocampal microglia were mal-activated in shamed mice, in which the atrophy of hippocampus and the development of NP syndromes were consolidated and proven rescued by WTD. On the contrary, in the SNL mice, the failure to control hippocampal microglia was sufficient to void all the rescues mediated by WTD. In sum, our study points out that the effective modulation of microglia in hippocampus is of pivotal importance for the co-curation by WTD.

No Benefit of Concomitant 5-Aminosalicylates in Patients With Ulcerative Colitis Escalated to Biologic Therapy: Pooled Analysis of Individual Participant Data From Clinical Trials.

OBJECTIVES: 5-aminosalicylates (5-ASA) are frequently continued in patients with moderate-severe ulcerative colitis (UC), even after escalation to biologic agents, without evaluation of the benefit of this approach. We conducted an individual participant data (IPD) pooled analysis of trials of infliximab and golimumab in UC, to evaluate whether concomitant use of 5-ASA modifies clinical outcomes among anti-tumor necrosis factor (TNF)-α-treated patients. METHODS: We included IPD from five trials of infliximab and golimumab in patients with moderate-severe UC (ACT-1 and -2, PURSUIT-SC, PURSUIT-M, NCT00336492). Patients treated with infliximab or golimumab were categorized as receiving concomitant 5-ASA or not at time of trial entry. Primary outcome was clinical remission (Mayo Clinic Score < 3) at last follow-up for each trial; secondary outcomes were clinical response and mucosal healing. Using multivariable logistic regression analysis, we evaluated association between concomitant 5-ASA and clinical remission, after adjusting for sex, smoking, baseline disease activity, disease extent, biochemical variables (C-reactive protein, albumin, hemoglobin), and concomitant prednisone and immunomodulators. RESULTS: We included 2183 infliximab-treated or golimumab-treated patients (1715 [78.6%] on 5-ASA). Concomitant use of 5-ASA was not associated with odds of achieving clinical remission (adjusted OR, 0.67 [95% CI, 0.45-1.01], p = 0.06), clinical response (aOR, 0.89 [0.60-1.33], p = 0.58) or mucosal healing (aOR, 1.12 [0.82-1.51], p = 0.48). These results were consistent in trials of induction and maintenance therapy, and in trials of infliximab and golimumab. CONCLUSIONS: Based on IPD pooled analysis, in patients with moderate-severe UC who are escalated to anti-TNF therapy, continuing 5-ASA does not improve clinical outcomes.

Patients with perianal Crohn's fistulas experience delays in accessing anti-TNF therapy due to slow recognition, diagnosis and integration of specialist services: lessons learned from three referral centres.

AIM: Crohn's anal fistula should be managed by a multidisciplinary team. There is no clearly defined 'patient pathway' from presentation to treatment. The aim of this study was to describe the patient route from presentation with symptomatic Crohn's anal fistula to starting anti-tumour necrosis factor (anti-TNF) therapy. METHOD: Case note review was undertaken at three hospitals with established inflammatory bowel disease services. Patients with Crohn's anal fistula presenting between 2010 and 2015 were identified through clinical coding and local databases. Baseline demographics were captured. Patient records were interrogated to identify route of access, and clinical contacts during the patient pathway. RESULTS: Seventy-nine patients were included in the study, of whom 54 (68%) had an established diagnosis of Crohn's disease (CD). Median time from presentation to anti-TNF therapy was 204 days (174 vs 365 days for existing and new diagnosis of CD, respectively; P = 0.019). The mean number of surgical outpatient attendances, operations and MRI scans per patient was 1.03, 1.71 and 1.03, respectively. Patients attended a mean of 1.49 medical clinics. Seton insertion was the most common procedure, accounting for 48.6% of all operations. Where care episodes ('clinical events per 30 days') were infrequent this correlated with prolongation of the pathway (r = -0.87; P < 0.01). CONCLUSION: This study highlights two key challenges in the treatment pathway: (i) delays in diagnosis of underlying CD in patients with anal fistula and (ii) the pathway to anti-TNF therapy is long, suggesting issues with service design and delivery. These should be addressed to improve patient experience and outcome.

The risk of cardiovascular events in psoriasis patients treated with tumor necrosis factor-α inhibitors versus phototherapy: An observational cohort study.

BACKGROUND: Psoriasis is a risk factor for cardiovascular events. OBJECTIVE: To assess the risk of major cardiovascular events and the effect of cumulative treatment exposure on cardiovascular event risk in patients with psoriasis treated with tumor necrosis factor-α inhibitors (TNFis) versus phototherapy. METHODS: Adult patients with psoriasis were selected from a large US administrative claims database (from the first quarter of 2000 through the third quarter of 2014) and classified in 2 mutually exclusive cohorts based on whether they were treated with TNFis or phototherapy. Cardiovascular event risk was compared between cohorts using multivariate Cox proportional hazards models. Cumulative exposure was defined based on treatment persistence. RESULTS: A total of 11,410 TNFi and 12,433 phototherapy patients (psoralen plus ultraviolet A light phototherapy, n = 1117; ultraviolet B light phototherapy, n = 11,316) were included in this study. TNFi patients had a lower risk of cardiovascular events compared to phototherapy patients (adjusted hazard ratio 0.77, P < .05). The risk reduction associated with 6 months of cumulative exposure was 11.2% larger for patients treated with TNFis compared to phototherapy (P < .05). LIMITATIONS: Information on psoriasis severity and mortality was limited/not available. CONCLUSIONS: Patients with psoriasis who were treated with TNFis exhibited a lower cardiovascular event risk than patients treated with phototherapy. Cumulative exposure to TNFis was associated with an incremental cardiovascular risk reduction compared to phototherapy.

Herbal prescription, Danggui-Sayuk-Ga-Osuyu-Senggang-Tang, inhibits TNF-α-induced epithelial-mesenchymal transition in HCT116 colorectal cancer cells.

Tumor necrosis factor­α­mediated (TNF­α) epithelial­mesenchymal transition (EMT) is associated with distant metastasis in patients with colorectal cancer with poor prognosis. Although traditional herbal medicines have long been used to treat colorectal cancer, the incidence and mortality in patients with colorectal cancer has continued to increase. Danggui­Sayuk­Ga­Osuyu­Saenggang­Tang (DSGOST) has long been used for treatment of chills, while few studies have reported its anticancer effect. This study aimed to demonstrate the inhibitory effect of DSGOST on TNF­α­mediated invasion and migration of colorectal cancer HCT116 cell lines. MTT was used to measure cell viability. Wound healing and Τranswell invasion assay were used to detect migration and invasion of cells, respectively. The intracellular localization of proteins of interest was assessed by immunocytochemistry. Western blotting was performed to determine the expression level of various proteins. A non­toxic dose of DSGOST (50 µg/ml) on HCT116 cells was determined by MTT assay. Furthermore, DSGOST prevented the TNF­α­induced invasive phenotype in HCT116 cells. DSGOST inhibition of the invasive phenotype was also associated with increased expression of EMT markers. Furthermore, DSGOST treatment blocked TNF­α­induced migration and invasion of HCT116 cells. In addition, DSGOST treatment inhibited TNF­α­mediated nuclear translocation of Snail. DSGOST treatment also downregulated TNF­α­induced phosphorylation of AKT and glycogen synthase kinase­3ß. Therefore, the findings of the current study suggest that DSGOST exhibits anti­migration and anti­invasion effects in TNF­α­treated HCT116 human colorectal cells.

Isolated limb perfusion with cytostatic drug leakage. / Perfusión aislada de extremidad inferior con fuga de quimioterapéutico.

Isolated limb perfusion is the treatment of stage III melanoma with in-transit metastasis. This technique allows the administration of cytostatics at an effective concentration and temperature, which could not be administered systemically because of their toxicity. The toxicity due to leakage of the chemotherapy agent from the limb into the systemic circulation is the most serious short-term complication, and is manifested by a systemic inflammatory response syndrome in the immediate post-intervention period. Early detection of this complication and its peri-operative management requires a multidisciplinary approach, in which the anaesthesiologist plays a key role. A case of isolated lower limb perfusion is reported in which the procedure had to be interrupted due to the passage of tumour necrosis factor into the systemic circulation, with severe intra-operative haemodynamic repercussions.

Eupatilin with PPARα agonistic effects inhibits TNFα-induced MMP signaling in HaCaT cells.

Eupatilin (5,7-dihydroxy-3,4,6-trimethoxyflavone) is a flavonoid compound exhibiting several beneficial biological activities, including neuroprotection, anti-cancer, antinociception, chondroprotection, anti-oxidation, and anti-inflammation. Our previous study demonstrated that eupatilin specifically activates peroxisome proliferator-activated receptor alpha (PPARα) through direct binding. The PPAR subfamily includes ligand-dependent transcription factors that consist of three isotypes: PPARα, PPARß/δ, and PPARγ. All isotypes are involved in inflammation, epidermal proliferation/differentiation and skin barrier function. Among them, PPARα regulates lipid and glucose metabolism and skin homeostasis. In this study, we confirm that the ability of eupatilin as a PPARα activator significantly inhibited tumor necrosis factor-alpha (TNFα)-induced matrix metalloproteinase (MMP)-2/-9 expression and proteolytic activity in HaCaT human epidermal keratinocytes. Furthermore, we found that eupatilin subsequently suppressed IκBα phosphorylation, blocked NF-κB p65 nuclear translocation and down-regulated MAPK/AP-1 signaling via PPARα activation. Taken together, our data suggest that eupatilin inhibits TNFα-induced MMP-2/-9 expression by suppressing NF-κB and MAPK/AP-1 pathways via PPARα. Our findings suggest the usefulness of eupatilin for preventing skin aging.

Electroacupuncture serum inhibits TNF­α­mediated chondrocyte inflammation via the Ras­Raf­MEK1/2­ERK1/2 signaling pathway.

The Ras­Raf­mitogen­activated protein kinase kinase (MEK)1/2­extracellular signal­regulated kinase (ERK)1/2 signaling pathway contributes to the release of chondral matrix­degrading enzymes and accelerates the degradation of articular cartilage. Electroacupuncture (EA) treatment has been widely used for the treatment of osteoarthritis (OA); however, the mechanism underlying the effects of EA on OA remains unclear. Therefore, the present study evaluated the anti­inflammatory effects and potential underlying mechanisms of EA serum (EAS) on tumor necrosis factor (TNF)­α­mediated chondrocyte inflammation. A total of 30 Sprague Dawley rats were randomly divided into three groups: The blank group; experimental group I, which received 15 min of EA treatment; and experimental group II, which received 30 min of EA treatment. Subsequently, serum samples were obtained. Chondrocytes were isolated from the knee cartilage of Sprague Dawley rats, and were identified using collagen type II immunohistochemistry. TNF­α­treated chondrocytes were used as a cell model, and subsequently the cells were treated with EAS from each group for various durations. The results demonstrated that EAS treatment significantly promoted the viability and inhibited the apoptosis of TNF­α­treated chondrocytes. In addition, interleukin (IL)­1ß concentration was significantly increased in the model group compared with in the control group, whereas EAS significantly reduced IL­1ß concentration in TNF­α­treated chondrocytes. Furthermore, the protein expression levels of Ras, Raf and MEK1/2 were reduced in the EAS groups compared with in the model group. EAS also significantly inhibited the phosphorylation of ERK1/2, and the expression of downstream regulators matrix metalloproteinase (MMP)­3 and MMP­13. In conclusion, these results indicated that EAS may inhibit TNF­α­mediated chondrocyte inflammation via the Ras­Raf­MEK1/2­ERK1/2 signaling pathway in vitro, thus suggesting that EAS may be considered a potential therapeutic strategy for the treatment of OA.

Modulation of MMP-2 and -9 secretion by cytokines, inducers and inhibitors in human melanoma A-2058 cells.

Melanoma, an extremely aggressive cancer, causes the most skin cancer-related deaths, due to metastasis to other areas of the body, such as lymph nodes, lungs, liver, brain or bone. It is characterized by high levels of matrix metalloproteinase (MMP)-2 and -9 secretions that degrade the extracellular matrix and basement membrane, allowing cancer cells to spread to distal organs. Various cytokines, mitogens, growth factors, inducers and inhibitors control MMP activities. We investigated the roles of these in regulation of MMP-2 and -9 in human melanoma A-2058 cells. Human A-2058 cells were grown in DMEM supplemented with 15% FBS and antibiotics in 24-well tissue culture plates. At near confluence, the cells were washed with PBS and incubated in serum-free media with phorbol 12-myristate 13-acetate (PMA) at 10, 25, 50 and 100 ng/ml; TNF-α and IL-1ß at 0.1, 1, 10 and 25 ng/ml; LPS at 10, 25, 50 and 100 µg/ml; epigallocatechin gallate (EGCG) and doxycycline (Dox) at 10, 25, 50 and 100 µM without and with PMA; a nutrient mixture (NM) containing lysine, proline, ascorbic acid and green tea extract without and with PMA at 10, 50, 100, 500 and 1,000 µg/ml; actinomycin D and cyclohexamide at 2 and 4 µM; retinoic acid and dexamethasone at 50 µM. After 24 h the media were removed and analyzed for MMP-2 and MMP-9 by zymography and densitometry. Melanoma A-2058 demonstrated strong expression of MMP-2 and slight expression of MMP-9. PMA at 100 ng/ml showed no effect on MMP-2 secretion but potently upregulated MMP-9 secretion to 400% that of control. TNF-α showed no significant overall effect on expression of MMP-2 but potent dose-dependent increased MMP-9 secretion with 200% of control at 25 ng/ml. IL-1ß showed no significant effect on MMP-2 or MMP-9 secretion by A-2058 cells, except at 25 ng/ml where MMP-2 level was reduced by ~40% and MMP-9 secretion ~50%. LPS treatment showed no significant effect on MMP-2 secretion and enhanced MMP-9 secretion up to 25 µg/ml followed by decreased level. EGCG, NM and doxycycline, without and with PMA, downregulated the expression of MMP-2 and MMP-9 in a dose-dependent manner. Actinomycin D, cyclohexamide and retinoic acid had inhibitory effects on MMP-2, while dexamethasone showed slight stimulatory effect on MMP-2 secretion. Our results showed that select cytokines, mitogens and inhibitors modulated A-2058 MMP-2 and MMP-9 expression. They suggest the clinical potential of MMP inhibitors, especially the non-toxic ones, such as the nutrient mixture and its component EGCG in management of melanoma.

Terapias biológicas y manifestaciones neurológicas. ¿Qué sabemos? / Biological therapy and neurological manifestations. What do we know?

La terapia biológica ha cambiado el curso de las enfermedades reumáticas inflamatorias. La seguridad de la misma está más que documentada en diferentes estudios nacionales e internacionales. La baja frecuencia de las manifestaciones neurológicas dificulta en muchas ocasiones el establecer una relación causal clara entre el tratamiento biológico y la clínica neurológica propiamente dicha. Los síntomas y signos neurológicos que pueden aparecer son múltiples, y en ocasiones simulan enfermedades neurológicas desmielinizantes y/o neurodegenerativas. El conocimiento y el reporte de los mismos es fundamental para realizar un manejo exhaustivo de la terapia biológica en nuestros pacientes (AU)

Biological therapy has changed the course of inflammatory rheumatic diseases. The safety is well documented in national and international studies. Neurological manifestations are uncommon and it is difficult to establish a clear causal relationship. The neurological signs and symptoms that may appear are multiple and sometimes mimic demyelinating neurological diseases and/or neurodegenerative diseases. Knowledge and disclosure of these cases is essential for a comprehensive management of biological therapy in our patients (AU)

Systemic TNF-α produces acute cognitive dysfunction and exaggerated sickness behavior when superimposed upon progressive neurodegeneration.

Inflammation influences chronic neurodegeneration but its precise roles are not yet clear. Systemic inflammation caused by infection, trauma or co-morbidity can alter the brain's inflammatory status, produce acute cognitive impairments, such as delirium, and drive new pathology and accelerated decline. Consistent with this, elevated systemic TNF-α is associated with more rapid cognitive decline over 6months in Alzheimer's disease patients. In the current study we challenged normal animals and those with existing progressive neurodegeneration (ME7 prion disease) with TNF-α (i.p.) to test the hypothesis that this cytokine has differential effects on cognitive function, sickness behavior and features of underlying pathology contingent on the animals' baseline condition. TNF-α (50µg/kg) had no impact on performance of normal animals (normal brain homogenate; NBH) on working memory (T-maze) but produced acute impairments in ME7 animals similarly challenged. Plasma TNF-α and CCL2 levels were equivalent in NBH and ME7 TNF-challenged animals but hippocampal and hypothalamic transcription of IL-1ß, TNF-α and CCL2 and translation of IL-1ß were higher in ME7+TNF-α than NBH+TNF-α animals. TNF-α produced an exaggerated sickness behavior response (hypothermia, weight loss, inactivity) in ME7 animals compared to that in NBH animals. However a single challenge with this dose was not sufficient to produce de novo neuronal death, synaptic loss or tau hyperphosphorylation that was distinguishable from that arising from ME7 alone. The data indicate that acutely elevated TNF-α has robust acute effects on brain function, selectively in the degenerating brain, but more sustained levels may be required to significantly impact on underlying neurodegeneration.

Impacto del grosor del tejido celular subcutáneo en el sitio de la inyección medido por ecografía sobre la respuesta terapéutica a fármacos antifactor de necrosis tumoral subcutáneos / Impact of the thickness of the subcutaneous tissue at the site of injection as measured by ultrasound on the therapeutic response to subcutaneous anti-tumour necrosis factor drugs

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In vitro assessment of the combined effect of eicosapentaenoic acid, green tea extract and curcumin C3 on protein loss in C2C12 myotubes.

EPA has been clinically shown to reduce muscle wasting during cancer cachexia. This study investigates whether curcumin or green tea extract (GTE) enhances the ability of low doses of eicosapentaenoic acid (EPA) to reduce loss of muscle protein in an in vitro model. A low dose of EPA with minimal anti-cachectic activity was chosen to evaluate any potential synergistic effect with curcumin or GTE. Depression of protein synthesis and increase in degradation was determined in C2C12 myotubes in response to tumour necrosis factor-α (TNF-α) and proteolysis-inducing factor (PIF). EPA (50 µM) or curcumin (10 µg ml(-1)) alone had little effect on protein degradation caused by PIF but the combination produced complete inhibition, as did the combination with GTE (10 µg ml(-1)). In response to TNF-α (25 ng ml(-1))-induced protein degradation, EPA had a small, but not significant effect on protein degradation; however, when curcumin and GTE were combined with EPA, the effect was enhanced. EPA completely attenuated the depression of protein synthesis caused by TNF-α, but not that caused by PIF. The combination of EPA with curcumin produced a significant increase in protein synthesis to both agents. GTE alone or in combination with EPA had no effect on the depression of protein synthesis by TNF-α, but did significantly increase protein synthesis in PIF-treated cells. Both TNF-α and PIF significantly reduced myotube diameter from 17 to 13 µm for TNF-α (23.5%) and 15 µm (11.8%) for PIF However the triple combination of EPA, curcumin and GTE returned diameters to values not significantly different from the control. These results suggest that either curcumin or GTE or the combination could enhance the anti-catabolic effect of EPA on lean body mass.