Novel oxindole compounds inhibit the aggregation of amyloidogenic proteins associated with neurodegenerative diseases

Amyloidogenic proteins form aggregates in cells, thereby leading to neurodegenerative disorders, including Alzheimer's and prion's disease, amyotrophic lateral sclerosis (ALS) in humans, and degenerative myelopathy (DM) and cognitive dysfunction in dogs. Hence, many small-molecule compounds have been screened to examine their inhibitory effects on amyloidogenic protein aggregation. However, no effective drug suitable for transition to clinical use has been found. Here we examined several novel oxindole compounds (GIF compounds) for their inhibitory effects on aggregate formation of the canine mutant superoxide dismutase 1 (cSOD1 E40K), a causative mutation resulting in DM, using Thioflavin-T fluorescence. Most GIF compounds inhibited the aggregation of cSOD1 E40K. Among the compounds, GIF-0854-r and GIF-0890-r were most effective. Their inhibitory effects were also observed in cSOD1 E40K-transfected cells. Additionally, GIF-0890-r effectively inhibited the aggregate formation of human SOD1 G93A, a causative mutation of ALS. GIF-0827-r and GIF-0856-r also effectively inhibited aggregate formation of human prion protein (hPrP). Subsequently, the correlation between their inhibitory effects on cSOD1 and hPrP aggregation was shown, indicating GIF compounds inhibited the aggregate formation of multiple amyloidogenic proteins. Conclusively, the novel oxindole compounds (GIF-0827-r, GIF-0854-r, GIF-0856-r, and GIF-0890-r) are proposed as useful therapeutic candidates for amyloidogenic neurodegenerative disorders.     

Peptide‐based therapeutic cancer vaccine: Current trends in clinical application

The peptide‐based therapeutic cancer vaccines have attracted enormous attention in recent years as one of the effective treatments of tumour immunotherapy. Most of peptide‐based vaccines are based on epitope peptides stimulating CD8⁺ T cells or CD4⁺ T helper cells to target tumour‐associated antigens (TAAs) or tumour‐specific antigens (TSAs). Some adjuvants and nanomaterials have been exploited to optimize the efficiency of immune response of the epitope peptide to improve its clinical application. At present, numerous peptide‐based therapeutic cancer vaccines have been developed and achieved significant clinical benefits. Similarly, the combination of peptide‐based vaccines and other therapies has demonstrated a superior efficacy in improving anti‐cancer activity. We delve deeper into the choices of targets, design and screening of epitope peptides, clinical efficacy and adverse events of peptide‐based vaccines, and strategies combination of peptide‐based therapeutic cancer vaccines and other therapies. The review will provide a detailed overview and basis for future clinical application of peptide‐based therapeutic cancer vaccines.     

Liposomes in immunology

Liposomes, the artificial phospholipid vesicles, have the capacity of entrapping water soluble substances in their aqueous compartments. Of the many possible potentials of liposomes their application in immunology is most significant. Recent studies have shown an adjuvant and a carrier effect of liposomes to a number of antigens. Liposomes used in these studies are generally multilamellar vesicles with the antigen encapsulated in the aqueous phase. Some antigens may also be associated with the lipid lamellae covalently or noncovalently. The adjuvant property of liposomes is greatly affected by the surface charge of the vesicle as well as the site of association of the antigen. The other factors which may have a role in immunopotentiation by liposomes are the size and structure of the vesicles, the lipid composition, route of administration and their surface sugars. In addition, liposomes may function as carriers to haptens and other antigens. In association with liposomes the nature of the immune response may be modulated. For a further enhancement of the adjuvant activity of liposomes use has been made of immunomodulators.     

Expression of CD55 and CD59 on peripheral blood cells from systemic lupus erythematosus (SLE) patients

CD55 and CD59 are glycosylphosphatidylinositol-anchored proteins with complement inhibitory properties. CD55 inhibits the formation of C3 convertases, and CD59 prevents the terminal polymerisation of the membrane attack complex. It has been reported that SLE patients seems to have an acquired deficiency of these proteins associated with secondary autoimmune haemolytic anaemia and lymphopenia. The aim of this study was to evaluate the presence of altered CD55 and CD59 expression on peripheral blood cells from SLE patients. Flow cytometric analyses were performed on red and white blood cells from 23 SLE patients and 23 healthy controls. We observed more CD55- and CD59-lymphocytes (p = 0.005 and p = 0.019, respectively), and CD59-granulocytes (p = 0.045) in SLE patients than in controls. These results suggest there is an altered pattern of CD55 and CD59 expression on the peripheral blood cells of SLE patients, and it may play a role in the cytopenias in these patients.     

Hepatitis B virus core protein interacts with CD59 to promote complement-mediated liver inflammation during chronic hepatitis B virus infection

The inflammatory response mediated by the immune system is the major cause of hepatitis B virus (HBV)-associated liver injury. Here, we identified CD59, as a novel HBc-interacting protein in hepatocytes by tandem affinity purification (TAP) screening. The expression of CD59 was markedly down-regulated in HBc-transfected HepG2 or HepG2.215 cells, which resulted in an upshift of hepatocyte sensitivity to membrane attack complex (MAC)-induced cell lysis. These results were consistent with the accumulation of MACs in the liver of HBV-infected patients. Additional analyses using laser confocal microscopy, quantitative PCR and flow cytometry revealed that CD59 was specifically translocated to the nucleus upon binding to HBc, which induced the down-regulation of CD59 on both the mRNA and protein levels.     

NMR relaxation studies of intracellular Na in red blood cells

The state of intracellular Na⁺ in human and dog erythrocytes was characterized by ²³Na-NMR using dysprosium complexes as shift reagents. Intracellular Na⁺ concentrations were determined using integration of the inner Na⁺ NMR signals and measurements of the intracellular volume using ⁵⁹Co-NMR of extracellular Co(CN)³⁻₆. T₂ was found to be significantly shorter than T₁, indicating some binding to macromolecules. While the longitudinal magnetization decay follows a single exponential the transverse magnetization could be fitted with a double-exponential function. It was shown that neither the binding to the inner side of the membrane nor binding to hemoglobin contributes to the relaxation enhancement.     

The effect of adjuvants on vaccine-induced antibody response against influenza in aged mice

While influenza remains a major threat to public health, researchers continue to search for a universal solution to improving the efficacy of the influenza vaccine. Even though influenza affects people of all different ages, it can be extremely hazardous to people of 65 years of age or older since that is the population that makes up the high majority of the death toll caused by influenza-related diseases. Elderly individuals suffer the effects of immunosenescence as they age, which is the diminishing of the overall immune response. Immunosenescence occurs by specifically affecting the adaptive immune response which controls the establishment of immunity after vaccination or infection. There are many studies under way that are trying to find a resolution to the problem of the influenza vaccine not providing enough protection in the elderly population. One of the possible strategies is to seek the use of an optimal adjuvant, an immunological agent that can enhance immune responses, with the current vaccine formulation. Here, we used the murine model to review the effects of adjuvants on the antibody response to influenza vaccines in aged mice. Since adjuvants can enhance the production of important inflammatory cytokines and activation of dendritic cells, the stimulation of these cells are boosted to increase the effectiveness of the influenza vaccine in aged mice which would hopefully translate to the elderly.     

Field larvicidal and oviposition repellent efficacy of three essential oil formulations for the control of filaria vector mosquito Culex quinquefasciatus Say (Diptera: Culicidae): A kill and push concept

Biological control of larval mosquitoes is in great demand due to the development of resistance against synthetic insecticides, environmental toxicity and the inability to protect habitats from further oviposition. In the present study, three botanical essential oils (BEOs) – citronella, eucalyptus, and pine oils – were formulated for the assessment of larvicidal and oviposition repellent efficacies against Culex quinquefasciatus Say, the filaria vector. The GC–MS profiling of BEOs showed the presence of 16 – 19 compounds covering 87.7–93% of oil composition. The resistance status of Culex quinquefasciatus population was evaluated with temephos (LC₅₀ = 0.001 ppm, LC₉₀ = 0.01 ppm). Larval bioassay of emulsifiable concentrate (EC) formulations prepared from eucalyptus and pine oils showed promising efficacy (LC₅₀ = 22.7 and 23.2 ppm) and LC₉₀ (63.8 and 62.4 ppm) compared to citronella oil EC (LC₅₀ = 43.4 ppm and LC₉₀ = 199.0 ppm). The field trials of eucalyptus + pine (1:1 ratio) EC showed 100% larval mortality for 3 weeks at 300 ppm compared to 2 weeks of individual oils. Further, the oviposition attraction index (OAI) for ECs of eucalyptus, pine, and their combination showed complete protection of breeding habitats from oviposition at 1st week and ?0.9 to ?1.0 OAI at 2nd week with slight reduction to ?0.5 at 3rd week. Citronella EC provided shortest larvicidal and oviposition repellent efficacy under the field conditions. The promising mosquitocidal activities of EC formulations of eucalyptus and pine or their combination suggest them as potential biocontrol vector control candidates over citronella oil.