Inhibition of NF-κB activation by diethylcarbamazine prevents alcohol-induced liver injury in C57BL/6 mice

Induction of NF-κB-mediated gene expression has been identified in the pathogenesis of alcoholic liver disease (ALD). Diethylcarbamazine (DEC) is a piperazine derivative drug with anti-inflammatory properties. The present study was designed to evaluate the effect of DEC on NF-κB pathways in mice undergoing alcoholism induced hepatic inflammation. Forty male C57BL/6 mice were divided equally into four groups: control group (C); DEC-treated group, which received 50 mg/kg (DEC50); alcoholic group (EtOH), submitted to chronic alcohol consumption and the alcohol-DEC treated group (EtOH50), submitted to chronic alcoholism consumption plus DEC treatment. Histological analysis of the alcoholic group showed evident hepatocellular damage which was reduced in EtOH50 group. Immunohistochemistry and western blot results showed elevated expression of inflammatory markers such as MDA, TNF-α, IL-1β, COX-2 and iNOS in hepatocytes of EtOH group. However, low immunopositivity for these markers was detected following DEC treatment. In the EtOH group the activation of NF-κB was observed by an increase in the expression of both NF-κB and pNF-κB in hepatocytes. This expression was significantly reduced in livers of EtOH50 group. Protein expression of Iκβα was measured to determine whether activation of NF-κB might be the result of Iκβα degradation. It was observed that expression of this protein was low in EtOH group, while animals treated with DEC had a high expression of Iκβα. The results of the present study indicate that DEC alleviates alcoholic liver injury, in part by the inhibiting activation of NF-κB and by suppressing the induction of NF-κB-dependent genes.     

T cells and intestinal commensal bacteria-ignorance,rejection, and acceptance

Trillions of commensal bacteria cohabit our bodies to mutual benefit. In the past several years, it has become clear that the adaptive immune system is not ignorant of intestinal commensal bacteria, but is constantly interacting with them. For T cells, the response to commensal bacteria does not appear uniform, as certain commensal bacterial species appear to trigger effector T cells to reject and control them, whereas other species elicit Foxp3⁺ regulatory T (Treg) cells to accept and be tolerant of them. Here, we review our current knowledge of T cell differentiation in response to commensal bacteria, and how this process leads to immune homeostasis in the intestine.     

Importance of Mast Cell Prss31/Transmembrane Tryptase/Tryptase-γ in Lung Function and Experimental Chronic Obstructive Pulmonary Disease and Colitis

Protease serine member S31 (Prss31)/transmembrane tryptase/tryptase-γ is a mast cell (MC)-restricted protease of unknown function that is retained on the outer leaflet of the plasma membrane when MCs are activated. We determined the nucleotide sequences of the Prss31 gene in different mouse strains and then used a Cre/loxP homologous recombination approach to create a novel Prss31^−/− C57BL/6 mouse line. The resulting animals exhibited no obvious developmental abnormality, contained normal numbers of granulated MCs in their tissues, and did not compensate for their loss of the membrane tryptase by increasing their expression of other granule proteases. When Prss31-null MCs were activated with a calcium ionophore or by their high affinity IgE receptors, they degranulated in a pattern similar to that of WT MCs. Prss31-null mice had increased baseline airway reactivity to methacholine but markedly reduced experimental chronic obstructive pulmonary disease and colitis, thereby indicating both beneficial and adverse functional roles for the tryptase. In a cigarette smoke-induced model of chronic obstructive pulmonary disease, WT mice had more pulmonary macrophages, higher histopathology scores, and more fibrosis in their small airways than similarly treated Prss31-null mice. In a dextran sodium sulfate-induced acute colitis model, WT mice lost more weight, had higher histopathology scores, and contained more Cxcl-2 and IL-6 mRNA in their colons than similarly treated Prss31-null mice. The accumulated data raise the possibility that inhibitors of this membrane tryptase may provide additional therapeutic benefit in the treatment of humans with these MC-dependent inflammatory diseases.     

Anti-inflammatory action of lipid nanocarrier-delivered myriocin: therapeutic potential in cystic fibrosis

Background

Sphingolipids take part in immune response and can initiate and/or sustain inflammation. Various inflammatory diseases have been associated with increased ceramide content, and pharmacological reduction of ceramide diminishes inflammation damage in vivo. Inflammation and susceptibility to microbial infection are two elements in a vicious circle. Recently, sphingolipid metabolism inhibitors were used to reduce infection. Cystic fibrosis (CF) is characterized by a hyper-inflammation and an excessive innate immune response, which fails to evolve into adaptive immunity and to eradicate infection. Chronic infections result in lung damage and patient morbidity. Notably, ceramide content in mucosa airways is higher in CF mouse models and in patients than in control mice or healthy subjects.

Methods

The therapeutic potential of myriocin, an inhibitor of the sphingolipid de novo synthesis rate limiting enzyme (Serine Palmitoyl Transferase, SPT),was investigated in CF cells and mice models.

Results

We treated CF human respiratory epithelial cells with myriocin, This treatment resulted in reduced basal, as well as TNFα-stimulated, inflammation. In turn, TNFα induced an increase in SPT in these cells, linking de novo synthesis of ceramide to inflammation. Furthermore, myriocin-loaded nanocarrier, injected intratrachea prior to P. aeruginosa challenge, enabled a significant reduction of lung infection and reduced inflammation.

Conclusions

The presented data suggest that de novo ceramide synthesis is constitutively enhanced in CF mucosa and that it can be envisaged as pharmacological target for modulating inflammation and restoring effective innate immunity against acute infection.

General significance

Myriocin stands as a powerful immunomodulatory agent for inflammatory and infectious diseases.     

Plant mating systems affect adaptive plasticity in response to herbivory

The fitness consequences of mating system variation (e.g. inbreeding) have been studied for at least 200 years, yet the ecological consequences of this variation remain poorly understood. Most plants are capable of inbreeding, and also exhibit a remarkable suite of adaptive phenotypic responses to ecological stresses such as herbivory. We tested the consequences of experimental inbreeding on phenotypic plasticity in resistance and growth (tolerance) traits in Solanum carolinense (Solanaceae). Inbreeding reduced the ability of plants to up‐regulate resistance traits following damage. Moreover, inbreeding disrupted growth trait responses to damage, indicating the presence of deleterious mutations at loci regulating growth under stress. Production of the phytohormones abscisic and indole acetic acid, and wounding‐induced up‐regulation of the defence signalling phytohormone jasmonic acid were all significantly reduced under inbreeding, indicating a phytohormonal basis for inbreeding effects on growth and defence trait regulation. We conclude that the plasticity of induced responses is negatively affected by inbreeding, with implications for fragmented populations facing mate limitation and stress as a consequence of environmental change.     

Identification of a selective inhibitor of murine intestinal alkaline phosphatase (ML260) by concurrent ultra-high throughput screening against human and mouse isozymes

Alkaline phosphatase (AP) isozymes are present in a wide range of species from bacteria to man and are capable of dephosphorylation and transphosphorylation of a wide spectrum of substrates in vitro. In humans, four AP isozymes have been identified—one tissue-nonspecific (TNAP) and three tissue-specific—named according to the tissue of their predominant expression: intestinal (IAP), placental (PLAP) and germ cell (GCAP) APs. Modulation of activity of the different AP isozymes may have therapeutic implications in distinct diseases and cellular processes. For instance, changes in the level of IAP activity can affect gut mucosa tolerance to microbial invasion due to the ability of IAP to detoxify bacterial endotoxins, alter the absorption of fatty acids and affect ectopurinergic regulation of duodenal bicarbonate secretion. To identify isozyme selective modulators of the human and mouse IAPs, we developed a series of murine duodenal IAP (Akp3-encoded dIAP isozyme), human IAP (hIAP), PLAP, and TNAP assays. High throughput screening and subsequent SAR efforts generated a potent inhibitor of dIAP, ML260, with specificity for the Akp3-, compared to the Akp5- and Akp6-encoded mouse isozymes.     

DDD-028: A potent potential non-opioid,non-cannabinoid analgesic for neuropathic and inflammatory pain

DDD-028 (4), a novel pentacyclic pyridoindolobenzazepine derivative was evaluated in vitro for receptor binding affinity and in vivo for analgesic activity using rodent models of neuropathic and inflammatory pain. DDD-028 does not bind to opioid, cannabinoid, dopamine, or histamine receptors. DDD-028 is very active even at the low oral dose of 1–5 mg/kg in both neuropathic, (spinal nerve ligation and chronic constriction injury) and inflammatory (Complete Freund’s Adjuvant Induced) models of pain. DDD-028 appears to be about 6-fold more potent than pregabalin and indomethacin. Visual observation of all the animals used in these studies indicated that DDD-028 is well tolerated without any sedation. Thus, DDD-028 seems to be a promising candidate for the treatment of neuropathic and inflammatory pain without the possible side effects or abuse potential associated with opioid or cannabinoid activities.     

不同品种油橄榄离体叶片对渗透胁迫的生理响应及其抗旱机制

以油橄榄3个主栽品种(‘戈达尔’、‘城固32’、‘弗奥’)离体叶片为研究对象,在实验室条件下考察了30%PEG溶液模拟渗透胁迫对叶片相关生理生化指标的影响,探讨不同品种间的响应差异及其生理机制。结果显示:(1)随着渗透胁迫时间的延长,各油橄榄品种离体叶片含水量和叶绿素含量呈下降趋势,相对电导率和MDA含量大幅度升高,即渗透胁迫造成了油橄榄离体叶片水分状况恶化、叶绿素分解、脂质过氧化和细胞膜损伤程度加重;同时,3个品种油橄榄叶片的束缚水与自由水相对含量、超氧阴离子产生速率、SOD活性及渗透调节物质含量表现出升高的趋势。(2)品种间相比较,随着胁迫时间的延长,‘城固32’叶片脂质过氧化产物MDA含量相对较低、细胞膜损伤较小,‘戈达尔’的表现则相反,‘弗奥’介于二者之间;同期各品种间叶片束缚水与自由水相对含量、超氧阴离子产生速率、SOD活性及渗透调节物质含量的变化表现相似。研究表明,3个油橄榄主栽品种中‘城固32’对30%PEG溶液渗透胁迫的抗性最强,‘弗奥’次之,‘戈达尔’最差;在30%PEG溶液渗透胁迫下,‘城固32’叶片具有较高的束缚水与自由水含量比值、较低的超氧阴离子产生速率、较高的SOD活性及较高渗透调节物质含量,这在一定程度上保证其叶片具有较强的抗脱水能力、抗氧化能力和渗透调节能力,从而在整体上表现出对渗透胁迫的较强抗性。     

双歧杆菌三联活菌胶囊对非酒精性脂肪性肝炎患者血清内毒素和炎症因子的影响

目的探讨双歧杆菌三联活菌胶囊对非酒精性脂肪性肝炎患者血清内毒素和炎症因子的影响。方法将84例非酒精性脂肪性肝炎患者随机分为对照组和观察组。两组患者均予以常规保肝治疗,观察组患者加用双歧杆菌三联活菌胶囊420mg,2次／d,连用4周。对照组除不使用双歧杆菌三联活菌胶囊外,余治疗同观察组。观察两组患者治疗前后肝功能、血清内毒素、白介素（IL）-6和肿瘤坏死因子（TNF）-α水平的变化。结果治疗4周后,两组患者ALT、AST和GGT水平较前均明显下降（P〈0．05或P〈0．01）,且观察组下降幅度比对照组更明显（P〈0．05）;同时两组患者血清内毒素、IL-6和TNF-＆水平均较前明显下降（P〈0．05或P〈0．01）,且观察组下降幅度比对照组更明显（P〈0．05）。结论双歧杆菌三联活菌胶囊对非酒精性脂肪性肝炎具有良好辅助治疗作用,能降低血清内毒素、IL-6和TNF—α水平,减轻肠源性内毒素血症,抑制肝细胞炎症及免疫损伤,改善肝功能指标。