Modified phages: novel antimicrobial agents to combat infectious diseases

Researchers increasingly believe that microbial, molecular and synthetic biology techniques along with genetic engineering will facilitate the treatment of persistent infectious diseases. However, such therapy has been plagued by the emergence of antibiotic-resistant bacteria, resulting in significant obstacles to treatment. Phage therapy is one promising alternative to antibiotics, especially now that recent modifications to ubiquitous phages have made them more controllable. Additionally, convincing in vitro and in vivo studies of genetically modified lytic phages and engineered non-lytic phages have confirmed the advantages of novel, specific bactericidal agents over antibiotics in some cases. There is still a need for a better understanding of phage therapy, however, before it can be adopted widely.     

China in action: national strategies to combat against emerging infectious diseases

正During the 2013–2016 Ebola epidemic in West Africa,there was a special team as part of an international effort working in field.This was the Chinese aid team deployed to West Africa as a multidisciplinary group composed of experienced virologists,epidemiologists and physicians.As part of an international effort,they participated in the control of Ebola virus disease from the very beginning until the end of the     

The effects of aggregation-inducing motifs on amyloid formation of model proteins related to neurodegenerative diseases

To examine the effects of aggregation-inducing motifs related to neurodegenerative diseases on amyloid formation of host protein, we prepared several chimera myoglobins, in which various aggregation-inducing motifs were inserted. The focused aggregation-inducing motifs included five (R5) or two (R2) oligopeptide repeats in yeast Sup35p, five octapeptide repeats (OPR) in the human prion protein, a nonamyloid beta component (NAC) in alpha-synuclein, and tandem repeats of 50 glutamines (Q50). Circular dichroism and infrared spectroscopies suggested that the OPR, R5, and Q50 motifs formed an antiparallel beta sheet as well as a random coil, whereas the R2 and NAC motifs mainly formed random coils. The OPR, R5, and Q50 mutants, but not the R2 and NAC mutants, readily formed the SDS-resistant aggregates under physiological condition, and electron microscopy revealed that the aggregates contained amyloid fibrils. The destabilization and increase in gyration radius of the OPR, R5, and Q50 mutants correlated with the tendency to form amyloid fibrils. A control mutant bearing a nonamyloidgenic sequence was also moderately destabilized but did not form amyloid fibrils. Therefore, we concluded that the OPR, R5, and Q50 motifs, even in a quite stable protein such as myoglobin, led the host protein to formation of amyloid fibrils under physiological condition.     

Hsp104: a weapon to combat diverse neurodegenerative disorders

Many of the fatal neurodegenerative disorders that plague humankind, including Alzheimer's and Parkinson's disease, are connected with the misfolding of specific proteins into a surprisingly generic fibrous conformation termed amyloid. Prior to amyloid fiber assembly, many proteins populate a common oligomeric conformation, which may be severely cytotoxic. Therapeutic innovations are desperately sought to safely reverse this aberrant protein aggregation and return proteins to normal function. Whether mammalian cells possess any such endogenous activity remains unclear. By contrast, fungi, plants and bacteria all express Hsp104, a protein-remodeling factor, which synergizes with the Hsp70 chaperone system to resolve aggregated proteins and restore their functionality. Surprisingly, amyloids can also be adaptive. In yeast, Hsp104 directly regulates the amyloidogenesis of several prion proteins, which can confer selective advantages. Here, I review the modus operandi of Hsp104 and showcase efforts to unleash Hsp104 on the protein-misfolding events connected to disparate neurodegenerative amyloidoses.     

Oxysterols and neurodegenerative diseases

In contrast to their parent molecule cholesterol, two of its side-chain oxidized metabolites are able to cross the blood–brain barrier. There is a concentration-driven flux of 24S-hydroxycholesterol (24S-OHC) from the brain into the circulation, which is of major importance for elimination of excess cholesterol from the brain. The opposite flux of 27-hydroxycholesterol (27-OHC) from the circulation into the brain may regulate a number of key enzymes within the brain. In vitro experiments suggest that the balance between the levels of these two molecules may be of importance for the generation of β-amyloid peptides. In primary cultures of rat hippocampal cells 27-OHC is able to suppress expression of the activity regulated cytoskeleton-associated protein (Arc), a protein important in memory consolidation which is reduced in patients with Alzheimer’s disease (AD). In the present work we explore the possibility that the flux of 27-OHC from the circulation into the brain represents the missing link between AD and hypercholesterolemia, and discuss the possibility that modification of this flux may be a therapeutic strategy. Lastly, we discuss the use of oxysterols as diagnostic markers in neurodegenerative disease.     

Functional genomics approaches to neurodegenerative diseases

Many of the neurodegenerative diseases that afflict humans are characterised by the protein aggregation in neurons. These include complex diseases like Alzheimer’s disease and Parkinson’s disease, and Mendelian diseases caused by polyglutamine expansion mutations [like Huntington’s disease (HD) and various spinocerebellar ataxias (SCAs), like SCA3]. A range of functional genomic strategies have been used to try to elucidate pathways involved in these diseases. In this minireview, I focus on how modifier screens in organisms from yeast to mice may be of value in helping to elucidate pathogenic pathways.     

Prions and neurodegenerative diseases

The long-term, progressive decay of the central nervous system typifies prion diseases, a group of rare, transmissible maladies affecting humans, sheep, cattle and some other types of mammal. Little is known about the early molecular events in its pathogenesis but the diverse roles of PrP, the prion protein, in its destructive action have recently been re-emphasised.     

硫氧还蛋白与神经退行性病变

神经退行性病变与胞内氧化还原失衡诱发的神经元损伤,死亡有密切关系,硫氧还原白参与维持胞内氧化还原平衡,在氧化应激中起重要的氧还调节作用,因此成为对抗神经退行性病变的重要蛋白之一。硫氧还蛋白可能通过激活某些有氧还调节功能的酶,清除自由基和调节细胞内分子通道等发挥对神经元的保护作用,对转基因动物的研究,进一步提示硫氧还蛋白在神经退行性病变的防治中可能发挥重要作用。     

Treating the periphery to ameliorate neurodegenerative diseases

Abnormalities in the kynurenine pathway are associated with neurodegenerative disorders. Zwilling et?al. (2011) show that inhibition of kynurenine 3-monooxygenase in the body's periphery leads to an increase in kyneuric acid, a neuroprotective compound, in the brain. This intervention ameliorates neurodegeneration in mouse models of Alzheimer's disease and Huntington's disease.     

副监护子CHIP与神经退行性疾病

CHIP属于连接酶类,具有E3泛素连接酶活性,参与能量代谢途径和新陈代谢。包括阿尔茨海默病(Alzheimer'sdisease,AD)、帕金森病(Parkinson'sdisease,PD)、亨廷顿病(Huntington'sdisease,HD)等在内的神经退行性疾病的主要病理学特征之一——细胞中异常蛋白的聚集,如tau蛋白和α-突触核蛋白等,副监护子CHIP与分子伴侣,如Hsc70/Hsp70、Hsp90等相互作用对这些异常蛋白的产生具有调节作用。最近研究表明,CHIP改变了Hsc70和Hsp90介导调节的信号通路中蛋白折叠和降解的平衡,参与细胞内蛋白质的质量控制;Hsp70/CHIP伴侣系统在tau蛋白生物学和tau蛋白病理学机制中具有重要作用;CHIP可以作为α-突触核蛋白蛋白酶体降解途径和溶酶体降解途径的分子开关。这些研究进展对于进一步揭示神经退行性疾病的发病机制和研制新一代治疗药物具有重要的作用。     

Mechanisms of amyloid beta protein-induced modification in ion transport systems: implications for neurodegenerative diseases

1. Alzheimer's disease (AD) is a neurodegenerative disorder that affects the cognitive function of the brain. Pathological changes in AD are characterized by the formation of amyloid plaques and neurofibrillary tangles as well as extensive neuronal loss. Abnormal proteolytic processing of amyloid precursor protein (APP) is the central step that leads to formation of amyloid plaque, neurofibrillary tangles, and neuronal loss.2. The plaques, which accumulate extracellularly in the brain, are composed of aggregates and cause direct neurotoxic effects and/or increase neuronal vulnerability to excitotoxic insults. The aggregates consist of soluble pathologic amyloid beta peptides AP[1–42] and AP[1–43] and soluble nonpathologic AP[1–40]. Both APP and AP interact with ion transport systems. AP induces a wide range of effects as the result of activating a cascade of mechanisms.3. The major mechanisms proposed for AP-induced cytotoxicity involve the loss of Ca²⁺ homeostasis and the generation of reactive oxygen species (ROS). The changes in Ca²⁺ homeostasis could be the result of (1) changes in endogenous ion transport systems, e.g. Ca²⁺ and K⁺ channels and Na⁺/K⁺-ATPase, and membrane receptor proteins, such as ligand-driven ion channels and G-protein-driven releases of second messengers, and (2) formation of heterogeneous ion channels.4. The consequences of changes in Ca²⁺-homeostasis-induced generation of ROS are (a) direct modification of intrinsic ion transport systems and their regulatory mechanisms, and (b) indirect effects on ion transport systems via peroxidation of phospholipids in the membrane, inhibition of phosphorylation, and reduction of ATP levels and cytoplasmic pH.5. We propose that in AD, AP with its different conformations alters cell regulation by modifying several ion transport systems and also by forming heterogeneous ion channels. The changes in membrane transport systems are proposed as early steps in impairing neuronal function preceding plaque formation. We conclude that these changes damage the membrane by compromising its integrity and increasing its ion permeability. This mechanism of membrane damage is not only central for AD but also may explain other malfunctioned protein-processing–related pathologies.