EGFR family: structure physiology signalling and therapeutic targets

There are four members of the EGFR family: EGFR, erbB2, erbB3 and erbB4. These receptors form ligand-activated oligomers which regulate intracellular processes via an oligomeric tyrosine kinase scaffold. The receptors are activated when the extracellular domain undergoes a conformational change which facilitates either homo- or hetero-oligomerization with other family members. The absence of one EGFR family member leads to embryonic or early post-natal death due to implantation, central nervous system or cardiac defects. Many mouse models of defective or deficient EGFR family members are available for studying physiology and/or pathology of EGFR family members. Sophisticated antibody and kinase inhibitors which target different family members have been designed, produced. EGFR and erbB2 are frequently activated, over expressed or mutated in many common cancers and the antagonists and/or inhibitors of EGFR and/or erbB2 signalling have already been shown to have therapeutic benefits for cancer patients.     

Immunosenescence in multiple sclerosis: the identification of new therapeutic targets

The number of elderly multiple sclerosis (MS) patients is growing, mainly due to the increase in the life expectancy of the general population and the availability of effective disease-modifying treatments. However, current treatments reduce the frequency of relapses and slow the progression of the disease, but they cannot stop the disability accumulation associated with disease progression. One possible explanation is the impact of immunosenescence, which is associated with the accumulation of unusual immune cell subsets that are thought to have a role in the development of an early ageing process in autoimmunity. Here, we provide a recent overview of how senescence affects immune cell function and how it is involved in the pathogenesis of autoimmune diseases, particularly MS. Numerous studies have demonstrated age-related immune changes in experimental autoimmune encephalomyelitis models, and the premature onset of immunosenescence has been demonstrated in MS patients. Therefore, potential therapeutic strategies based on rejuvenating the immune system have been proposed. Senolytics and regenerative strategies using haematopoietic stem cells, therapies based on rejuvenating oligodendrocyte precursor cells, microglia and monocytes, thymus cells and senescent B and T cells are capable of reversing the process of immunosenescence and could have a beneficial impact on the progression of MS.     

Maize stripe virus: characteristics of a member of a new virus class

An unusual filamentous nucleoprotein about 3 nm in diameter was consistently associated with maize stripe-diseased maize. Antiserum to purified nucleoprotein neutralized the infectivity of extracts from maize stripe-diseased plants suggesting that the nucleoprotein was the maize stripe virus (MStpV). The rate-zonal sedimentation pattern of the nucleoprotein on sucrose gradients was polydisperse between 51 and 70 S. CsCl isopycnic centrifugation of combined nucleoprotein zones from sucrose gradients resulted in a single band of 1.28 g/ml. The nucleoprotein consisted of 5.2% RNA and a single capsid protein of molecular weight 32,700 daltons. Large quantities of a noncapsid protein of molecular weight 16,300 daltons were also found in MStpV-infected tissue. MStpV was transovarially transmitted by its vector, Peregrinus maidis. Other species susceptible to MStpV in addition to Zea mays were Rottboellia exaltata and Sorghum bicolor. The similarities between MStpV and rice stripe virus are discussed. We conclude that these viruses represent a new virus class.     

Erythropoietin: elucidating new cellular targets that broaden therapeutic strategies

Given that erythropoietin (EPO) is no longer believed to have exclusive biological activity in the hematopoietic system, EPO is now considered to have applicability in a variety of nervous system disorders that can overlap with vascular disease, metabolic impairments, and immune system function. As a result, EPO may offer efficacy for a broad number of disorders that involve Alzheimer's disease, cardiac insufficiency, stroke, trauma, and diabetic complications. During a number of clinical conditions, EPO is robust and can prevent metabolic compromise, neuronal and vascular degeneration, and inflammatory cell activation. Yet, use of EPO is not without its considerations especially in light of frequent concerns that may compromise clinical care. Recent work has elucidated a number of novel cellular pathways governed by EPO that can open new avenues to avert deleterious effects of this agent and offer previously unrecognized perspectives for therapeutic strategies. Obtaining greater insight into the role of EPO in the nervous system and elucidating its unique cellular pathways may provide greater cellular viability not only in the nervous system but also throughout the body.     

Potassium channels: possible new therapeutic targets in Parkinson's disease

Parkinson's disease (PD) is one of the most common neurodegenerative disorders and still remains incurable. New targets for potential pharmacological intervention should be explored and evaluated in order to slow down, delay or reverse the progress of this disease, and/or to avoid the serious side effects of levodopa praeparatum. Potassium (K(+)) channels widely express in basal ganglia and play crucial roles in the pathophysiology of PD, thereby raising their therapeutic application. Based on data from some pilot studies, we propose that K(+) channels may provide possible new therapeutic targets for slowing down the progressive loss of dopamine neurons in PD. The most promising targets of K(+) channels, including Kv, K(ATP), Kir, SK, and K2P channels, etc. deserve further pursuit for making comprehensive use of their novel therapeutic potential. Attempts to confirm this hypothesis may lead to new therapeutic strategy of PD.     

Moving targets: cell migration inhibitors as new anti-inflammatory therapies

The pharmaceutical industry has targeted various types of molecules to subdue inflammatory diseases. Drugs that disrupt cell migration appear particularly promising in clinical trials and in many animal models of inflammatory disease. Cell migration inhibitors not only interfere with migration of cells to a tissue, but also can affect other necessary processes such as mediator release and angiogenesis. However, the question is whether drugs that target adhesion molecules or chemoattractant receptors will prove superior to drugs that target other molecular types. This review proclaims the virtues of targeting cell migration-related molecules for development of new anti-inflammatory and anti-tumor based drugs. It is likely that cell migration inhibitors will transform the way in which many human inflammatory diseases and cancers are treated.     

Orf virus: A promising new therapeutic agent

The orf virus (ORFV) is a zoonotic, epitheliotropic, DNA parapoxvirus that infects principally sheep and goats. Exposure of animals to the virus or immunization by an ORFV preparation can accentuate the severity of disease, which has provoked an interest in the underlying cellular, virological, and molecular mechanisms. The identified ORFV virulence genes and the fact that the virus can repeatedly infect a host, owing to its evasive mechanisms, contribute to the development of potent immune modulators in various animal species. ORFV has been developed as a vaccine in veterinary medicine. The unique host immune‐evasion ability of ORFV has made it an important candidate for vaccine vectors and biological agents (as an oncolytic virus). Genetic modifications using ORFV to obtain safe and efficient preparations and mechanistic studies are improvements to the currently available methods for disease treatment.     

Toward a complete cure for chronic hepatitis B: Novel therapeutic targets for hepatitis B virus

Hepatitis B virus (HBV) affects approximately 250 million patients worldwide, resulting in the progression to cirrhosis and hepatocellular carcinoma, which are serious public health problems. Although universal vaccination programs exist, they are only prophylactic and not curative. In the HBV life cycle, HBV forms covalently closed circular DNA (cccDNA), which is the viral minichromosome, in the nuclei of human hepatocytes and makes it difficult to achieve a complete cure with the current nucleos(t)ide analogs and interferon therapies. Current antiviral therapies rarely eliminate cccDNA; therefore, lifelong antiviral treatment is necessary. Recent trials for antiviral treatment of chronic hepatitis B have been focused on establishing a functional cure, defined by either the loss of hepatitis B surface antigen, undetectable serum HBV DNA levels, and/or seroconversion to hepatitis B surface antibody. Novel therapeutic targets and molecules are in the pipeline for early clinical trials aiming to cure HBV infection. The ideal strategy for achieving a long-lasting functional or complete cure might be using combination therapies targeting different steps of the HBV life cycle and immunomodulators. This review summarizes the current knowledge about novel treatments and combination treatments for a complete HBV cure.     

Siglec-8 and Siglec-F,the new therapeutic targets in asthma

The recruitment of eosinophils from the circulation into the airway is a prominent feature of allergic asthma. Persistent inflammatory responses may arise from inefficient mechanisms for resolution of inflammation, including delayed apoptosis. Several studies suggest that eosinophil apoptosis is delayed in asthma. Sialic acid-binding immunoglobulin-like lectins are characterized by their sequence similarities and abilities to bind sialic acids in glycoproteins and glycolipids. Siglec-8 is uniquely expressed on eosinophils, mast cells, and basophils. Engagement of Siglec-8 on blood eosinophils results in caspase- and mitochondria-dependent apoptosis. Eosinophil apoptosis is an important therapeutic target for the development of novel anti-asthma treatments that specifically target the eosinophil.     

Siglec-8 and Siglec-F, the new therapeutic targets in asthma

The recruitment of eosinophils from the circulation into the airway is a prominent feature of allergic asthma. Persistent inflammatory responses may arise from inefficient mechanisms for resolution of inflammation, including delayed apoptosis. Several studies suggest that eosinophil apoptosis is delayed in asthma. Sialic acid-binding immunoglobulin-like lectins are characterized by their sequence similarities and abilities to bind sialic acids in glycoproteins and glycolipids. Siglec-8 is uniquely expressed on eosinophils, mast cells, and basophils. Engagement of Siglec-8 on blood eosinophils results in caspase- and mitochondria-dependent apoptosis. Eosinophil apoptosis is an important therapeutic target for the development of novel anti-asthma treatments that specifically target the eosinophil.     

Endogenous tumor lectins: a new class of tumor markers and targets for therapy?

Endogenous lectins of normal tissues can play a functional role in recognition processes and cell adhesion. These functions are areas of particular relevance to tumor growth and metastasis. Our initial results on endogenous lectins of different tumors lead to the working hypothesis that the pattern of endogenous lectins is qualitatively and quantitatively different between different types of tumors and between tumors and normal, nonmalignant tissues. The endogenous lectins may thus prove to be potentially important in establishing a new concept for a rational lectin-based type of diagnosis and therapy of various tumors.     

Molecular biology of bone remodeling: Implications for new therapeutic targets for osteoporosis

Osteoporosis is a major public health problem for adults over age 55 years costing billions of euros/dollars. Over the last 20 years anti-resorptive drugs were the treatment of choice for osteoporosis and most were derived from the bisphosphonate molecule.     

Platelet proteomics: identification of potential therapeutic targets

The integration of proteomics into biochemical and biological investigation has proved a powerful tool in understanding the anucleate platelet. Over the past few years, various approaches have been used to document platelet proteins and here, we describe our efforts to analyse specific platelet subproteomes so as to capture biologically relevant proteins of low abundance. These include characterisation of the phosphotyrosine proteome, the platelet releasate and more recently, the proteome of membrane lipid rafts. These approaches have revealed a wealth of relevant platelet proteins, which may in the future prove suitable as therapeutic targets in atherothrombosis.     

New therapeutic targets for osteoporosis: Beyond denosumab

Treatments for osteoporosis over the last few decades have largely focused on antiresorptive agents that effectively prevent bone loss. Beginning with hormone therapy, a variety of new potent antiresorptive agents were developed, including oral and intravenous bisphosphonates, raloxifene and other selective estrogen receptor modulators, nasal spray calcitonin, and denosumab. Teriparatide and PTH 1–84 are the only approved anabolic agents to date that primarily build new bone density. A variety of new biologic agents that focus on molecular targets important for the stimulation of new bone formation are being developed. Cathepsin K inhibitors appear to have mixed antiresorptive and anabolic actions because they inhibit one of the major osteoclast digestive enzymes without suppressing bone formation, thereby leading to anabolic effects on bone. New biologic agents in clinical trials include anti-sclerostin and anti-dickkopf antibodies that stimulate the Wnt/β-catenin pathway in osteoblasts, leading to new bone formation. These new agents will effectively stimulate new bone formation by different mechanisms, leading to improved bone mineral density and reduced fractures.     

Entry of hepatitis B virus: Mechanism and new therapeutic target

Entry of hepatitis B virus (HBV) into human hepatocytes constitutes the initial step in viral infection. The study of HBV entry had long been hampered by the lack of efficient cell culture systems and small animal models. The situation was greatly improved in the last decade with the development of HBV-infectible HepaRG cell line and primary Tupaia hepatocyte culture. Armed with these new tools, marked progresses have been achieved in the elucidation of the mechanism of HBV entry. Plenty of evidences indicate that the viral large surface protein (LHBs) is essential for HBV entry. Several regions in the PreS1 domain of LHBs have been verified to contribute directly to the viral attachment. In addition, a myristate moiety linked to the N-terminal glycine of PreS1 appears critical for HBV infectivity. Recently, the cysteine-rich antigenic loop of the S domain was identified as another crucial determinant for HBV infectivity. On the other hand, several cellular proteins were implicated in HBV attachment to hepatic cells, though definitive proofs are required in support to their functional involvement in HBV infection. Aiming to blocking viral entry, a couple of approaches based on acylated PreS1-derived peptides and short PreS1-binding peptides are currently under investigation, which have the potential to become novel antiviral therapeutics.     

Core structure in a new virus,XBM/67

Summary Electron microscopic studies on thin sections of BHK-21 cells infected with XBM/67 virus, a new spherical RNA virus, have demonstrated a core substructure in the virus. This has been confirmed in negatively stained preparations of the virus. The icosahedral core consists of 12 spherical subunits, each having a diameter of approximately 14.3 nm. The overall diameter of the virus particle is 67 nm. It is suggested that the core subunits may contain segments of the virus genome and that this may hold for other members of the bluetongue-type group of viruses.