Toxicity of extracellular secreted alpha-synuclein: Its role in nitrosative stress and neurodegeneration

It has been demonstrated that both oligomerisation and accumulation of α-synuclein (ASN) are the key molecular processes involved in the pathophysiology of neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease and other synucleinopathies. Alterations of ASN expression and impairment of its degradation can lead to the formation of intracellular deposits of this protein, called Lewy bodies. Overexpressed or misfolded ASN could be secreted to the extracellular space. Today the prion-like transmission of ASN oligomers to neighbouring cells is believed to be responsible for protein modification and propagation of neurodegeneration in the brain. It was presented that oxidative/nitrosative stress may play a key role in ASN secretion and spread of ASN pathology. Moreover, ASN-evoked protein oxidation, nitration and nitrosylation lead to disturbances in synaptic transmission and cell death. The interaction of secreted ASN with other amyloidogenic proteins and its involvement in irreversible mitochondrial disturbances and oxidative stress were also described. A better understanding of the mechanisms of ASN secretion and dysfunction may help to explain the molecular mechanisms of neurodegeneration and may be the basis for the development of novel therapeutic strategies.     

Dual effect of chemokine CCL7/MCP-3 in the development of renal tubulointerstitial fibrosis

Most end-stage renal disease kidneys display accumulation of extracellular matrix (ECM) in the renal tubular compartment (tubular interstitial fibrosis – TIF) which is strongly correlated with the future loss of renal function. Although inflammation is a key event in the development of TIF, it can also have a beneficial anti-fibrotic role depending in particular on the stage of the pathology. Chemokines play an important role in monocyte extravasation in the inflammatory process. CCL2 has already been shown to be involved in the development of TIF but CCL7, a close relative of CCL2 and able to bind to similar receptors, has not been studied in renal disease. We therefore studied chemokine CCL7 in a model of unilateral ureteral obstruction (UUO)-induced TIF. We observed that the role of CCL7 differs depending on the stage of the pathology. In early stages (0–8 days), CCL7 deficient (CCL7-KO) mice displayed attenuated TIF potentially involving two mechanisms: an early (0–3 days) decrease of inflammatory cell infiltration followed (3–8 days) by a decrease in tubular ECM production independent of inflammation. In contrast, during later stages of obstruction (10–14 days), CCL7-KO mice displayed increased TIF which was again associated with reduced inflammation. Interestingly, the switch between this anti- to profibrotic effect was accompanied by an increased influx of immunosuppressive regulatory T cells. In conclusion, these results highlight for the first time a dual role for CCL7 in the development of renal TIF, deleterious in early stages but beneficial during later stages.     

Discovery of new PPARγ agonists based on arylopeptoids

In this study we present the design, synthesis and biological evaluation of a small, first-generation library of small molecule aromatic amides based on the arylopeptoid skeleton. The compounds were efficiently synthesized using a highly convenient submonomer solid-phase methodology which potentially allows for access to great product diversity. The synthesized compounds were tested for their ability to activate peroxisome proliferator-activated receptors (PPARs) and they all acted as PPARγ agonists in the μM range spanning from 2.5- to 14.7-fold activation of the receptor. This is the first discovery of bioactive molecules based on the arylopeptoid architecture.     

Raf激酶抑制蛋白的研究进展

Raf激酶抑制蛋白(RKIP)是磷脂酰乙醇胺结合蛋白家族的成员。RKIP通过与Raf-1结合,抑制了Ras/Raf-1/MEK/ERK信号转导通路,并在NF-κB及G蛋白偶联受体(GPCR)信号转导通路中也起重要调节作用。RKIP参与细胞凋亡、肿瘤转移、神经发育以及精子发生等病理生理过程,通过研究RKIP能为治疗相关疾病提供新思路新靶点。本文主要介绍RKIP的生物功能,着重于其在神经系统、肿瘤和生殖系统中的研究进展。     

Identification of Fungal Species Associated with Cladode Spot of Prickly Pear and Their Sensitivity to Chitosan

México is the most important producer of prickly pear (Opuntia ficus‐indica) in the world. There are several fungal diseases that can have a negative impact on their yields. In this study, there was a widespread fungal richness on cladodes spot of prickly pears from México. A total of 41 fungi isolates were obtained from cladodes spot; 11 of them were morphologically different. According to the pathogenicity test, seven isolates caused lesions on cladodes. The morphological and molecular identification evidenced the isolation of Colletotrichum gloeosporioides, Alternaria alternata, Fusarium lunatum, Curvularia lunata. All these species caused similar symptoms of circular cladodes spot. However, it is noticeable that some lesions showed perforation and detachment of affected tissues by Fusarium lunatum. To our knowledge, this is the first report of the Fusarium lunatum as phytopathogenic fungus of cladodes of prickly pear. The chitosan inhibited the mycelium growth in the seven isolates of phytopathogenic fungi. Chitosan applications diminished the disease incidence caused by C. gloeosporioies and F. lunatum in 40 and 100%, respectively. Likewise, the lesion severity index in cladodes decreased. There are no previous reports about the application of chitosan on cladodes of prickly pears for the control of phytopathogenic fungi. Therefore, this research could contribute to improve the strategies for the management of diseases in prickly pear.     

Bioecology of some key cashew insect pests and diseases in diverse habitats and landscapes in Tanzania

Cashew (Anacardium occidentale) is an economically important cash crop for many rural households in Tanzania. However, its production is constrained by some insect pests and diseases. As a prerequisite for the development of a more sustainable integrated insect pest and disease management strategy for cashew, information on the biology and ecology of the key insect pests and diseases in a changing environment, and on influencing biotic and abiotic factors, is needed. Surveys were conducted in the major cashew nut‐producing areas of Tanzania for two seasons: August to December, 2009, and August to December, 2010. Data on number of infested and infected shoots by key insect pests and diseases, natural enemies and associated farmer practices, namely synthetic pesticide use and intercropping systems, were collected from different subzones within agroecological zones. Our data showed that abundance and diversity of key cashew insect pests and diseases were influenced by agroecological zones and subzones. Intercropping was more commonly practised in the northern than in the southern zone. Agrochemicals were most frequently used in the southern agroecological zone and affected the occurrence of natural enemies, notably the weaver ant that was more abundant in the northern zone. Furthermore, our findings revealed that Helopeltis sp. and the powdery mildew remained the major constraints to cashew nut production in Tanzania.     

TOR-centric view on insulin resistance and diabetic complications: perspective for endocrinologists and gerontologists

This article is addressed to endocrinologists treating patients with diabetic complications as well as to basic scientists studying an elusive link between diseases and aging. It answers some challenging questions. What is the link between insulin resistance (IR), cellular aging and diseases? Why complications such as retinopathy may paradoxically precede the onset of type II diabetes. Why intensive insulin therapy may initially worsen retinopathy. How nutrient- and insulin-sensing mammalian target of rapamycin (mTOR) pathway can drive insulin resistance and diabetic complications. And how rapamycin, at rational doses and schedules, may prevent IR, retinopathy, nephropathy and beta-cell failure, without causing side effects.     

Yeast-based automated high-throughput screens to identify anti-parasitic lead compounds

We have developed a robust, fully automated anti-parasitic drug-screening method that selects compounds specifically targeting parasite enzymes and not their host counterparts, thus allowing the early elimination of compounds with potential side effects. Our yeast system permits multiple parasite targets to be assayed in parallel owing to the strains’ expression of different fluorescent proteins. A strain expressing the human target is included in the multiplexed screen to exclude compounds that do not discriminate between host and parasite enzymes. This form of assay has the advantages of using known targets and not requiring the in vitro culture of parasites. We performed automated screens for inhibitors of parasite dihydrofolate reductases, N-myristoyltransferases and phosphoglycerate kinases, finding specific inhibitors of parasite targets. We found that our ‘hits’ have significant structural similarities to compounds with in vitro anti-parasitic activity, validating our screens and suggesting targets for hits identified in parasite-based assays. Finally, we demonstrate a 60 per cent success rate for our hit compounds in killing or severely inhibiting the growth of Trypanosoma brucei, the causative agent of African sleeping sickness.     

Pseudomonas fluorescens,a potential bacterial antagonist to control plant diseases

Abstract

Fluorescent Pseudomonads belong to plant Growth Promoting Rhizobacteria (PGPR), the important group of bacteria that play a major role in the plant growth promotion, induced systemic resistance, biological control of pathogens etc. Many strains of Pseudomonas fluorescens are known to enhance plant growth promotion and reduce severity of various diseases. The efficacy of bacterial antagonists in controlling fungal diseases was often better as alone, and sometimes in combination with fungicides. The present review refers to occurrence, distribution, mechanism, growth requirements of P. fluorescens and diseases controlled by the bacterial antagonist in different agricultural and horticultural crops were discussed. The literature in this review helps in future research programmes that aim to promote P. fluorescens as a potential bio-pesticide for augmentative biological control of many diseases of agriculture and horticultural importance.     

Quantitative analysis of site-specific N-glycans on sera haptoglobin βchain in liver diseases

The site-specific characterization of N-glycans in glycopro- teins with the potential of clinical application is important. In our previous report, the overall N-glycans of sera haptoglobin （Hp） β chain were found to be different in liver diseases. Hp β chain contains four potential sites of N-glycosylation. In this study, we investigated the potential change of N-glycans on Hp β chain in a site-specific fashion. Sera Hp β chain in healthy individuals as well as patients with hepatitis B virus （HBV）, liver cirrhosis （LC） and hepatocellular carcinoma （HCC） were purified, digested and subjected to liquid chromatography-electro- spray ionization-higher energy collision dissociation mass spectrometry, which allowed identification and structure determination of the glycopeptide, as well as the relative quantification of glycans present on each glycopeptide. The quantitative results revealed that the sialylation of NLFLN207HSEN211 ATAK and the fucosylated structure at all glycopeptides increased significantly in LC and HCC patients compared with those in HBV patients and healthy individuals. A set of different N-glycan patterns of Hp β chain in various liver diseases has been determined. Thus, the sialylated and fucosylated glycoforms of Hp β chain might be related to early hepatocarcinogenesis and also might be useful as novel differential markers for LC and HCC patients.