Therapeutic approaches to prion diseases

Prion diseases are unique in that they comprise sporadic, genetic, and iatrogenically or environmentally acquired forms. When disease is acquired by peripheral route, neuroinvasion occurs via at least two different neural pathways (vague and splanchnic nerves) and is usually preceded by prion propagation in secondary lymphoid organs. Conversely, in the other etiologic forms, PrPSc formation occurs within, and is apparently limited to, the CNS. Longitudinal studies on experimental scrapie indicate that substantial neuropathologic changes (i.e., glial activation and nerve cell degeneration) already are present before the onset of symptoms and are topographically related to PrPSc deposits. Accordingly, any effective intervention should start during the preclinical stage of disease, and be aimed at preventing neuroinvasion or PrPSc propagation in the CNS. Unfortunately, no tests are available currently to detect presymptomatic individuals, except for carriers of pathogenic mutations of the PRNP gene. Inhibition of PrPSc formation can be achieved through (1) abrogation of PrPC synthesis or prevention of its transport to the cell surface; (2) stabilization of the PrPC structure to make its conformational change unfavorable; (3) sequestration of PrPSc; (4) reversion of PrPSc to a protease-sensitive form; or (5) interference with the interaction between PrPC, PrPSc, and other macromolecules that feature in the conversion process. The compounds that have some effectiveness in in vitro, cell culture, or animal models of prion disease seem to operate through one of these mechanisms (see Table 1); however, even the most effective drugs only work when administered at the time of infection or very short thereafter, and these conditions are incurable at present. The heterogeneity and complexity of the etiopathogenesis of prion diseases suggest that various strategies and a combination of several compounds with different modes of actions are likely necessary for prevention and treatment. Major efforts should be focused on the development of preclinical diagnostic tests in conjunction with immunization strategies for diseases acquired by peripheral route and identification of more effective compounds for the other etiological forms.     

Clinical applications of glycomic approaches for the detection of cancer and other diseases

New glycomic approaches are being developed for clinical applications. Technologies that include microcapillary chromatography, lectin affinity chromatography, carbohydrate microarray and mass spectrometry (MS) enable better glycan analysis and are contributing to drug discovery, clinical assays and basic research efforts. More importantly, new glycomic approaches are contributing to our increased understanding of the underlying biology that is responsible for the development, progression and metastasis of cancer. In fact, disruption of part of the glycosylation process in mice has resulted in higher tumor formation in these animals. MS and lectin affinity methods are rapidly replacing traditional biochemical separation and enzymatic procedures for the analysis of oligosaccharides. These technologies are leading to faster and more clinically adaptable tests with greater sensitivity and specificity than currently used tests. Glycomics is also expected to be important in developing better analytical methods for the detection of cancer. It shows promise for personalized medicine since the heterogeneity and complexity of glycosylation reflect the genetic, environmental, lifestyle and nutritional states of each patient, as well as their ethnicity and age. A major challenge facing glycomics and any systems biology approach, will be the ability to accurately profile the glycosylation state of a patient and, based on this profile, to identify if a disease is present, the type of disease and determine the appropriate treatment for the individual patient. Therefore a comprehensive approach to personalized clinical medicine may include a glycomic analysis of clinical samples and could be used in addition to genetic, gene expression and proteomic analyses already being evaluated for clinical use.     

Immunotherapeutic approaches to inflammatory bowel diseases

For a long time corticosteroids, aminosalicylic acid preparations and antibiotics have represented the principal approaches in evidence-based drug therapy for chronic inflammatory bowel diseases (IBD), e.g., Crohn’s disease (CD) and ulcerative colitis (UC), and are able to suppress disease activity in most cases. However, there are cases that do not respond to conventional drug therapy or remain dependent on high doses of steroids associated with severe side effects in the long run. It is generally accepted now that IBD has an immunological basis and results from a hyper-responsive state of the intestinal immune system. Although the primary etiological defect respectively immunogenic agent still remains to be identified, substantial progress has been made in our understanding of regulatory mechanisms of the intestinal immune system and their alterations in IBD at the molecular level. Due to the concurrent advent of biotechnological processes it has been possible to utilise these insights for the development of novel immunomodulatory therapeutic strategies ranging from recombinant cytokines and blocking antibodies to oligonucleotide antisense strategies and gene therapeutic approaches. This review will present the current status of the development of these novel immunomodulatory therapeutic strategies in IBD and the status of their use in clinical practice. For a better understanding, it will be necessary to address the recent advances in the elucidation of pathogenetic mechanisms of IBD from studies in human specimen and experimental colitis models that have provided the basis for these novel therapeutic approaches.     

Novel genome-editing-based approaches to treat motor neuron diseases: Promises and challenges

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Nanotechnology-based approaches for food sensing and packaging applications

The rapid advancement of nanotechnology has provided opportunities for the development of new sensing and food packaging solutions, addressing long-standing challenges in the food sector to extend shelf-life, reduce waste, assess safety and improve the quality of food. Nanomaterials can be used to reinforce mechanical strength, enhance gas barrier properties, increase water repellence, and provide antimicrobial and scavenging activity to food packaging. They can be incorporated in chemical and biological sensors enabling the design of rapid and sensitive devices to assess freshness, and detect allergens, toxins or pathogenic contaminants. This review summarizes recent studies on the use of nanomaterials in the development of: (1) (bio)sensing technologies for detection of nutritional and non-nutritional components, antioxidants, adulterants and toxicants, (2) methods to improve the barrier and mechanical properties of food packaging, and (3) active functional packaging. The environmental, health and safety implications of nanomaterials in the food sector, along with an overview of regulation and consumer perception is also provided.

The advancement of nanotechnology has provided opportunities for the development of new sensing and food packaging solutions, addressing long-standing challenges to extend shelf-life, reduce waste, assess safety and improve the quality of food.     

Diagnosis and approaches to therapy of emotional disorders in patients with infectious diseases

AIM: To examine psychological and emotional disorders in patients with infectious diseases, to specify indications for their pharmacological correction. MATERIAL AND METHODS: Clinicopsychological, clinicofunctional and laboratory tests were made to examine 30 patients with infectious mononucleosis (19 females and 11 males) and 30 patients with serous meningitis (16 females and 14 males) aged 16-35 admitted to hospital on the disease day 2-14. RESULTS: Shmishek's questionnaire revealed various types of personality accentuations with dominating hyperthymic (30%) and cyclothymic (20%). According to the data of the clinical scale SCL-90, the greatest number of cases with values over normal was in patients with serous meningitis. Beck's questionnaire revealed clinical depression in 12 patients (40%) with acute serous meningitis, subdepression in 14(46.7%) patients, severe depression in 6(20%) patients with infectious mononucleosis. In convalescence, emotional disorders persisted in 4 patients with serous meningitis. CONCLUSION: Affective disorders in the above patients require consultation of the psychiatrist to decide on psychopharmacotherapy inclusion in combined treatment of infectious diseases to prevent lingering course.     

Gene transfer approaches for gynecological diseases.

Gene transfer presents a potentially useful approach for the treatment of diseases refractory to conventional therapies. Various preclinical and clinical strategies have been explored for treatment of gynecological diseases. Given the direst need for novel treatments, much of the work has been performed with gynecological cancers and ovarian cancer in particular. Although the safety of many approaches has been demonstrated in early phase clinical trials, efficacy has been mostly limited so far. Major challenges include improving gene transfer vectors for enhanced and selective delivery and achieving effective penetration and spread within advanced and complex tumor masses. This review will focus on current and developmental gene transfer applications for gynecological diseases.     

Metabolomic profiling,biological evaluation of Aspergillus awamori,the river Nile-derived fungus using epigenetic and OSMAC approaches

LC-HRMS-based metabolomics approach was applied to the river Nile-derived fungus Aspergillus awamori after its fermentation on four different media and using four epigenetic modifiers as elicitors. Thereafter, a comprehensive multivariate statistical analysis such as PCA, PLS-DA and OPLS-DA were employed to explain the generated metabolomic data (1587 features). PCA showed that the fungus displayed a unique chemical profile in each medium or elicitor. Additionally, PLS-DA results revealed the upregulated metabolites under each of these conditions. Results indicated that both rice and malt dextrose agar were recognized as the best media in terms of secondary metabolites diversity and showed better profiles than the four applied epigenetic modifiers, of which nicotinamide was the best secondary metabolite elicitor. Testing the antibacterial and cytotoxic effects of all A. awamori-derived extracts revealed that using epigenetic modifiers can induce antimicrobial metabolites against S. aureus and E. coli, whereas using rice, malt dextrose or nicotinamide can induce groups of cytotoxic metabolites. OPLS-DA results assisted in the putative identification of the induced metabolites that could be responsible for these observed inhibitory activities. This study highlighted how powerful the OSMAC approach in maximizing of the chemical diversity of a single organism. Furthermore, it revealed the power of metabolomics in tracing, profiling and categorizing such chemical diversity and even targeting the possible bioactive candidates which require further scaling up studies in the future.

LC-HRMS-based metabolomics approach was applied to the river Nile-derived fungus Aspergillus awamori after its fermentation on four different media and using four epigenetic modifiers as elicitors.     

The histocompatibility complex and rheumatic diseases.

Histocompatibility typing has assumed an increasingly important role as a clinical and research tool in rheumatic diseases. The HLA antigens which are serologically defined (A and B series) are being used most extensively for clinical work, but the role of other immunologic determinants in the HLA complex is being evaluated. These include D-locus (MLC) determinants, several complement components, and immune response genes which have been well characterized in the mouse, but not in man. The products of the major histocompatibility complex are inherited in a simple Mendelian fashion as a series of co-dominant alleles. Large population studies have characterized the frequencies of various alleles, and family studies have allowed tentative mapping of the various loci within the complex on the sixth chromosome in man. A number of diseases which are considered to be autoimmune in nature are now known to be associated with specific HLA antigens. Of these disease associations, the strongest and best studied are the seronegative spondyloarthropathies which are highly associated with the B27 antigen. Included in this group are ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, colitic arthropathy, Yersinia arthritis and a small group of juvenile rheumatoid arthritis patients with features of ankylosing spondylitis. The clinical application of tissue typing or B27 testing is most helpful in regard to difficult diagnostic problems in patients with early or atypical seronegative spondyloarthropathy. Its value as an indicator of prognosis, and its value in counselling family members is not well established. There are many interesting hypotheses regarding pathogenetic mechanisms of these rheumatic diseases based on susceptibility factors related to the major histocompatibility complex. An abnormal immune response gene within the complex is probably a key feature of the mechanism, but the exact details are little more than speculative at this point.     

Contemporary approaches to evaluation of psychosomatic status in patients with alimentary tract diseases

The authors present the results of psychosomatic status evaluation performed in 159 patients with biliary dyskinesia, chronic gastritis, and somatoform disturbances. The examination was done using questionnaires, scales, and computer methods. Computer diagnostic methods were proved to be most effective and allowed for quantitative evaluation of psychosomatic disturbances in patients with gastrointestinal diseases.