Progress in vaccine development against Helicobacter pylori

Based on the very high prevalence of diseases caused by Helicobacter pylori, particularly in the developing world, and the rapid emergence of antibiotic resistance among clinical isolates, there is a strong rationale for an effective vaccine against H. pylori. In this review we describe recent promising candidate vaccines and prophylactic or therapeutic immunization strategies for use against H. pylori, as well as studies to identify immune responses that are related to protection in experimental animals. We also describe identification of different types of immune responses that may be related to protection against symptoms based on comparisons of H. pylori-infected patients with duodenal ulcers or gastric cancer and asymptomatic carriers. We conclude that there is still a strong need to clarify the main protective immune mechanisms against H. pylori as well as to identify a cocktail of strong protective antigens, or recombinant bacterial strains that express such antigens, that could be administered by a regimen that gives rise to effective immune responses in humans.     

Novel imidazole substituted 6-methylidene-penems as broad-spectrum beta-lactamase inhibitors

Beta-lactamases are serine and metallo-dependent enzymes produced by the bacteria in defense against beta-lactam antibiotics. Production of class-A, class-B, and class-C enzymes by the bacteria make the use of beta-lactam antibiotics ineffective in certain cases. To overcome resistance to beta-lactam antibiotics, several beta-lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam are widely used in the clinic in combination with beta-lactam antibiotics. However, single point mutations within these enzymes have allowed bacteria to overcome the inhibitory effect of the commercially approved beta-lactamase inhibitors. Although the commercially available beta-lactamase inhibitor/beta-lactam antibiotic combinations are effective against class-A producing bacteria and many extended spectrum beta-lactamase (ESBL's) producing bacteria they are less effective against class-C enzymes expressing bacteria. To circumvent this problem, based on modeling studies several novel imidazole substituted 6-methylidene-penem derivatives were synthesized and tested against various beta-lactamase producing isolates. The present paper deals with the synthesis and structure-activity relationships (SAR) of these compounds.     

Improved insights into the transcriptomes of the human hookworm Necator americanus--fundamental and biotechnological implications

Hookworms of humans are blood-feeding parasitic nematodes of major socio-economic significance in a wide range of countries. They cause a neglected tropical disease (NTD) called "hookworm disease" (=necatoriasis and/or ancylostomiasis). Necator americanus is the most widely distributed hookworm of humans and is a leading cause of iron deficiency anaemia, which can cause physical and mental retardation and deaths in children as well as adverse maternal-foetal outcomes. Currently, there is a significant focus on the development of new approaches for the prevention and control of hookworms in humans. Technological advances are underpinning the discovery of drug and vaccine targets through insights into the molecular biology and genomics of these parasites and their relationship with the human host. In spite of the widespread socio-economic impacts of human necatoriasis, molecular datasets for N. americanus are scant, limiting progress in molecular research. The present article explores all currently available EST datasets for adult and larval stages of N. americanus using a semi-automated bioinformatic pipeline. In the current repertoire of molecules now available, some have been or are being considered as candidate vaccines against N. americanus. Among others, the most abundant sets of molecules relate to the pathogenesis-related protein (PRP) superfamily, comprising various members, such as the Ancylostoma-secreted or activation-associated proteins (ASPs) and the kunitz-type proteins, both of which are inferred to play key roles in the interplay between N. americanus and the human host. Understanding the molecular biology of these and other novel molecules discovered could have important implications for finding new ways of disrupting the pathways that they are involved in, and should facilitate the identification of new drug and vaccine targets. Also, the bioinformatic prediction of the essentiality of genes and gene products as well as molecular network connectivity of nematode-specific genes, together with sequencing by 454 technology, are likely to assist in the genomic discovery efforts in the very near future, to also underpin fundamental, molecular research of hookworms.     

An old enzyme for current needs: adenosine deaminase and a dendritic cell vaccine for HIV

After nearly three decades of searching for a vaccine against HIV, a cure for this pandemic disease still remains elusive. The low immunogenicity of the surface proteins and the huge variability of the virus, together with the immunocompromised status of the host, have made developing an HIV vaccine an uphill battle. Over the past few years, both immunogen design and immunization strategies have improved, providing hope for future, although the anti-HIV responses achieved still remain modest. As developing a prophylactic vaccine seems unlikely nowadays, efforts have focused on alternative therapeutic immunization approaches, although these still need to be further optimized. Using an immunomodulator capable of restoring immune function in the context of infection, thereby boosting cell-mediated and humoral responses, could be critical in effectively improving current therapeutic approaches. Adenosine deaminase, a protein with a pivotal role in T-cell co-stimulation, has been shown to robustly enhance specific T-cell responses against HIV in vitro. Although its role in humoral responses has not yet been assessed, genetic defects in this enzyme are associated with impaired cellular and humoral responses. Importantly, this molecule is already commercially available pharmaceutically and, therefore, it fulfils all the requirements to be assayed as an anti-HIV vaccine adjuvant.     

Plasmid-only rescue of influenza A virus vaccine candidates.

The potential threat of another influenza virus pandemic stimulates discussion on how to prepare for such an event. The most reasonable prophylactic approach appears to be the use of effective vaccines. Since influenza and other negative-stranded RNA viruses are amenable to genetic manipulation using transfection by plasmids, it is possible to outline new reverse genetics-based approaches for vaccination against influenza viruses. We suggest three approaches. First, we use a plasmid-only rescue system that allows the rapid generation of high-yield recombinant vaccine strains. Second, we propose developing second-generation live influenza virus vaccines by constructing an attenuated master strain with deletions in the NS1 protein, which acts as an interferon antagonist. Third, we suggest the use of Newcastle disease virus recombinants expressing influenza virus haemagglutinin proteins of pandemic (epizootic) strains as novel vaccine vectors for use in animals and possibly humans.     

Anti-Ebola therapies based on monoclonal antibodies: current state and challenges ahead

The 2014 Ebola outbreak, the largest recorded, took us largely unprepared, with no available vaccine or specific treatment. In this context, the World Health Organization declared that the humanitarian use of experimental therapies against Ebola Virus (EBOV) is ethical. In particular, an experimental treatment consisting of a cocktail of three monoclonal antibodies (mAbs) produced in tobacco plants and specifically directed to the EBOV glycoprotein (GP) was tested in humans, apparently with good results. Several mAbs with high affinity to the GP have been described. This review discusses our current knowledge on this topic. Particular emphasis is devoted to those mAbs that have been assayed in animal models or humans as possible therapies against Ebola. Engineering aspects and challenges for the production of anti-Ebola mAbs are also briefly discussed; current platforms for the design and production of full-length mAbs are cumbersome and costly.     

埃博拉病毒疫苗研究进展

埃博拉病毒是一种可引起人和非人灵长类动物出血热传染病的最为致命的烈性病毒,致死率可达90%。2014年在西非爆发的埃博拉疫情引起了全世界的关注。疫苗接种是预防和控制传染病最为常规和有效的方法,尽管目前还没有正式获得批准上市的埃博拉病毒疫苗,但是已有多个尚处于研究阶段的疫苗在非人灵长类动物上取得了很好的保护效果,并有几个已进入临床Ⅰ期试验阶段,有望尽快用于本次埃博拉疫情的防控。本文对目前处于研究阶段的多个类型的埃博拉病毒疫苗进行了综述,为相关研究人员提供参考。     

Compounds Derived from the Bhutanese Daisy,Ajania nubigena,Demonstrate Dual Anthelmintic Activity against Schistosoma mansoni and Trichuris muris

BackgroundWhipworms and blood flukes combined infect almost one billion people in developing countries. Only a handful of anthelmintic drugs are currently available to treat these infections effectively; there is therefore an urgent need for new generations of anthelmintic compounds. Medicinal plants have presented as a viable source of new parasiticides. Ajania nubigena, the Bhutanese daisy, has been used in Bhutanese traditional medicine for treating various diseases and our previous studies revealed that small molecules from this plant have antimalarial properties. Encouraged by these findings, we screened four major compounds isolated from A. nubigena for their anthelmintic properties.Conclusions/SignificanceAmong the four compounds tested, luteolin demonstrated the best broad-spectrum activity against two different helminths—T. muris and S. mansoni—and was effective against juvenile schistosomes, the stage that is refractory to the current gold standard drug, praziquantel. Medicinal chemistry optimisation including cytotoxicity analysis, analogue development and structure-activity relationship studies are warranted and could lead to the identification of more potent chemical entities for the control of parasitic helminths of humans and animals.     

Zebrafish as a model for infectious disease and immune function

The zebrafish, Danio rerio, has come to the forefront of biomedical research as a powerful model for the study of development, neurobiology, and genetics of humans. In recent years, use of the zebrafish system has extended into studies in behaviour, immunology and toxicology, retaining the concept that it will serve as a model for human disease. As one of the most thoroughly studied teleosts, with a wealth of genetic and genomic information available, the zebrafish is now being considered as a model for pathogen studies in finfishes. Its genome is currently being sequenced and annotated, and gene microarrays and insertional mutants are commercially available. The use of gene-specific knockdown of translation through morpholino oligonucleotides is widespread. As a result, several laboratories have developed bacterial and viral disease models with the zebrafish to study immune responses to infection. Although many of the zebrafish pathogen models were developed to address human infectious disease, the results of these studies should provide important clues for the development of effective vaccines and prophylactic measures against bacterial and viral pathogens in economically important fishes. In this review, the capabilities and potential of the zebrafish model system will be discussed and an overview of information on zebrafish infectious disease models will be presented.     

The role of tumour necrosis factor-alpha in the pathogenesis of complicated falciparum malaria

Plasmodium falciparum malaria is the most important parasitic infection of humans and is one of the most serious health problems facing the inhabitants of developing countries. It is responsible for about 2 million deaths every year. To date there is no specific treatment for the disease apart from anti-malarials. The declining sensitivity to these drugs is a serious therapeutic problem, while no safe and effective vaccine is likely to be available for general use in the near future. There is now abundant laboratory and clinical evidence to suggest that tumour necrosis factor-alpha (TNF-alpha) plays a major role in the pathogenesis of complicated falciparum malaria. Modulation of TNF-alpha response in combination with the current anti-malarial drugs, may represent a novel approach to the treatment of the serious complications associated with the disease.     

Evolutionary aspects of lipoxygenases and genetic diversity of human leukotriene signaling

Leukotrienes are pro-inflammatory lipid mediators, which are biosynthesized via the lipoxygenase pathway of the arachidonic acid cascade. Lipoxygenases form a family of lipid peroxidizing enzymes and human lipoxygenase isoforms have been implicated in the pathogenesis of inflammatory, hyperproliferative (cancer) and neurodegenerative diseases. Lipoxygenases are not restricted to humans but also occur in a large number of pro- and eucaryotic organisms. Lipoxygenase-like sequences have been identified in the three domains of life (bacteria, archaea, eucarya) but because of lacking functional data the occurrence of catalytically active lipoxygenases in archaea still remains an open question. Although the physiological and/or pathophysiological functions of various lipoxygenase isoforms have been studied throughout the last three decades there is no unifying concept for the biological importance of these enzymes. In this review we are summarizing the current knowledge on the distribution of lipoxygenases in living single and multicellular organisms with particular emphasis to higher vertebrates and will also focus on the genetic diversity of enzymes and receptors involved in human leukotriene signaling.     

Immunoprophylaxis of respiratory infections

Anti-infective antibody-based immunotherapy has gained renewed interest since the crisis of antibiotic resistance and because there is no therapy against various viral infections. The immunoprophylaxis of respiratory infections aims to utilize the ability of local antibodies to neutralize inhaled micro-organisms and their cytopathic products. Immunoglobulins for intravenous use (i.v.i.g.) have a wide spectrum of specificities. Hyperimmune i.v.i.g. containing high titers of specific antibodies have demonstrated efficacy in clinical trials, notably against the respiratory syncytial virus. Monoclonal antibodies have the advantage to be homogenous and specific for one selected epitope and several studies have demonstrated their efficacy to neutralize several infectious agents. Moreover, antibodies can be administered topically and are effective at lower doses than those needed for systemic administration. The mechanism of action could be the agglutination of bacteria or viruses at the epithelial surfaces of the respiratory tract inhibiting the early steps of the infectious process. Thanks to new technologies of humanized monoclonal antibodies, immunotherapy offers real promising perspectives for prophylactic and therapeutic therapies against a variety of current or emerging infectious diseases.     

Neurotoxic mechanisms of triclosan: The antimicrobial agent emerging as a toxicant

Several scientific studies have suggested a link between increased exposure to pollutants and a rise in the number of neurodegenerative disorders of unknown origin. Notably, triclosan (an antimicrobial agent) is used in concentrations ranging from 0.3% to 1% in various consumer products. Recent studies have also highlighted triclosan as an emerging toxic pollutant due to its increasing global use. However, a definitive link is missing to associate the rising use of triclosan and the growing number of neurodegenerative disorders or neurotoxicity. In this article, we present systematic scientific evidence which are otherwise scattered to suggest that triclosan can indeed induce neurotoxic effects, especially in vertebrate organisms including humans. Mechanistically, triclosan affected important developmental and differentiation genes, structural genes, genes for signaling receptors and genes for neurotransmitter controlling enzymes. Triclosan-induced oxidative stress impacting cellular proteins and homeostasis which triggers apoptosis. Though the scientific evidence collated in this article unequivocally indicates that triclosan can cause neurotoxicity, further epidemiological studies may be needed to confirm the effects on humans.     

新型冠状病毒肺炎感染病例中鼻咽拭子与咽拭子标本的病毒核酸检验结果分析

新型冠状病毒(SARS-CoV-2)主要通过飞沫和密切接触传播,传染性强,目前在全球蔓延,给人的身体健康及世界公共卫生安全造成了严重的损害。病毒核酸检验是新型冠状病毒肺炎(COVID-19)病例确诊的金标准。本研究分别采集武汉江夏方舱医院67例确诊为COVID-19病例的鼻咽拭子与咽拭子标本送检,进行SARS-CoV-2核酸检验。其中28例患者鼻咽拭子病毒核酸呈阳性,13例患者咽拭子病毒核酸呈阳性,26例患者鼻咽拭子与咽拭子病毒核酸均为阴性。本研究结果提示,鼻咽拭子送检标本病毒核酸检验结果优于咽拭子标本(P<0.05)。     

Synthetic and therapeutic perspectives of nitrogen containing heterocycles as anti-convulsants

Epilepsy is one of the commonly prevailing neurological disorders. According to the reports, it is evident that about 80% of the epileptic cases have been observed in developing countries. Although there are many drugs with significant potency available in the market; still there is an issue of selectivity and toxicity. Therefore, continuous attempts have been made by the researchers to develop newer therapeutic agents against epilepsy. Many synthetic strategies have been available in the literature to synthesize various classes of anticonvulsants with promising activity. In the presented review, authors have summarized some newer synthetic routes being used for the synthesis of nitrogen-containing anticonvulsants taking a cue from the reported established anticonvulsant drugs viz. vigabatrin, sodium valproate, oxcarbazepine, felbamate, retigabine, and gabapentin. Various derivatives with the substitution for better anticonvulsant profile have been described in the figures for easy comparative study. The structure–activity relationship (SAR) of compounds with maximum potency has also been discussed. This article may serve as a boost for the researchers to modify the pre-existing synthetic routes as well as to improve potency and yield of the compounds.     

Proteases involved in cartilage matrix degradation in osteoarthritis

Osteoarthritis is a common joint disease for which there are currently no disease-modifying drugs available. Degradation of the cartilage extracellular matrix is a central feature of the disease and is widely thought to be mediated by proteinases that degrade structural components of the matrix, primarily aggrecan and collagen. Studies on transgenic mice have confirmed the central role of Adamalysin with Thrombospondin Motifs 5 (ADAMTS-5) in aggrecan degradation, and the collagenolytic matrix metalloproteinase MMP-13 in collagen degradation. This review discusses recent advances in current understanding of the mechanisms regulating expression of these key enzymes, as well as reviewing the roles of other proteinases in cartilage destruction. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.     

The Chemotherapy of Protozoal Infections of Veterinary Importance1

The use of drugs in domestic animals is dominated by considerations of cost-effectiveness and profitability. They are extensively used against coccidial infections of poultry where they are an important factor in intensive husbandry. Ionophore antibiotics, which dominate this field, may have applications in ruminants. Imidocarb is of therapeutic and prophylactic value against babesial infections and there are new prospects for control of theileriasis. Effective drugs for the control of African trypanosomiasis are limited and attention is being given to alternative uses of available compounds.     

Neutralizing antibodies against oncogenic human papillomavirus as a possible determinant of the fate of low-grade cervical intraepithelial neoplasia

To determine whether neutralizing antibodies (NAs) against HPV16 is responsible for a higher regression rate of low-grade cervical intraepithelial neoplasia (CIN1), we investigated an association between the presence of the NAs and the fate of the HPV16-related CIN1. All the women examined in this study had HPV16 positive cervix. The women were allocated into four groups by their cervical pathology, i.e., non-pathological (n:7), CIN1 (n:37), CIN2/3 (n:19), and cervical cancer (n:13). Their sera were tested for the presence of NAs against HPV16 by an in vitro assay using HPV16-pseudovirions. As for the CIN1 cases, clinical regression of the lesions were compared between NA-positive and NA-negative groups. Copy number of HPV16-DNA in smear samples was measured by quantitative PCR. The incidence of the presence of the NAs in the women with a non-pathological cervix (85.7%) was significantly higher than in the CIN1 cases (21.5%), the CIN2/3 cases (15.7%), and the cervical cancer cases (0%) (p<0.0001). The regression of the CIN1 lesion was closely associated with the presence of the N As (p=0.0002). The presence of the NAs was associated with low-level copy number of the viral DNA relative to the NA-negative group (p=0.05). The presence of the NAs against HPV16 was associated with a higher regression rate of HPV-related CIN1 lesions. The NAs seem to have a role in deterring HPV-related cervical lesions from progressing to CIN2/3 by inhibiting the infection with de novo replicated HPV. This study further suggests that HPV vaccine to induce the NAs may be effective in eliminating CIN lesions, especially in the NA-negative cases.