NF-κB pathway activators as potential ageing biomarkers: targets for new therapeutic strategies

Chronic inflammation is a major biological mechanism underpinning biological ageing process and age-related diseases. Inflammation is also the key response of host defense against pathogens and tissue injury. Current opinion sustains that during evolution the host defense and ageing process have become linked together. Thus, the large array of defense factors and mechanisms linked to the NF-κB system seem to be involved in ageing process. This concept leads us in proposing inductors of NF-κB signaling pathway as potential ageing biomarkers. On the other hand, ageing biomarkers, represented by biological indicators and selected through apposite criteria, should help to characterize biological age and, since age is a major risk factor in many degenerative diseases, could be subsequently used to identify individuals at high risk of developing age-associated diseases or disabilities. In this report, some inflammatory biomarkers will be discussed for a better understanding of the concept of biological ageing, providing ideas on eventual working hypothesis about potential targets for the development of new therapeutic strategies and improving, as consequence, the quality of life of elderly population.     

The ADAMs family of proteases: new biomarkers and therapeutic targets for cancer?

The ADAMs are transmembrane proteins implicated in proteolysis and cell adhesion. Forty gene members of the family have been identified, of which 21 are believed to be functional in humans. As proteases, their main substrates are the ectodomains of other transmembrane proteins. These substrates include precursor forms of growth factors, cytokines, growth factor receptors, cytokine receptors and several different types of adhesion molecules. Although altered expression of specific ADAMs has been implicated in different diseases, their best-documented role is in cancer formation and progression. ADAMs shown to play a role in cancer include ADAM9, ADAM10, ADAM12, ADAM15 and ADAM17. Two of the ADAMs, i.e., ADAM10 and 17 appear to promote cancer progression by releasing HER/EGFR ligands. The released ligands activate HER/EGFR signalling that culminates in increased cell proliferation, migration and survival. Consistent with a causative role in cancer, several ADAMs are emerging as potential cancer biomarkers for aiding cancer diagnosis and predicting patient outcome. Furthermore, a number of selective ADAM inhibitors, especially against ADAM10 and ADAM17, have been shown to have anti-cancer effects. At least one of these inhibitors is now undergoing clinical trials in patients with breast cancer.     

Lipid-based biomarkers for CVD,COPD, and aging – A translational perspective

For many diseases, there is an unmet need for new or better biomarkers for improved disease risk assessment and monitoring, as available markers lack sufficient specificity. Lipids are drawing major interest as potential candidates for filling these gaps. This has recently been demonstrated by the identification of selective ceramides for prediction of cardiovascular mortality, enabling improved risk assessment of cardiovascular disease compared with conventional clinical markers. In this review, we discuss current lipid biomarker findings and the possible connection between cardiovascular disease, chronic obstructive pulmonary disease, and aging. Moreover, we discuss how to overcome the current roadblocks facing lipid biomarker research. We stress the need for improved quantification, standardization of methodologies, and establishment of initial reference values to allow for an efficient transfer path of research findings into the clinical landscape, and, ultimately, to put newly identified biomarkers into practical use.     

Cell-derived microparticles in atherosclerosis: biomarkers and targets for pharmacological modulation?

Cardiovascular diseases remain an important cause of morbi-mortality. Atherosclerosis, which predisposes to cardiovascular disorders such as myocardial infarction and stroke, develops silently over several decades. Identification of circulating biomarkers to evaluate cardiovascular event risk and pathology prognosis is of particular importance. Microparticles (MPs) are small vesicles released from cells upon apoptosis or activation. Microparticles are present in blood of healthy individuals. Studies showing a modification of their concentrations in patients with cardiovascular risk factors and after cardiovascular events identify MPs as potential biomarkers of disease. Moreover, the pathophysiological properties of MPs may contribute to atherosclerosis development. In addition, pharmacological compounds, used in the treatment of cardiovascular disease, can reduce plasma MP concentrations. Nevertheless, numerous issues remain to be solved before MP measurement can be applied as routine biological tests to improve cardiovascular risk prediction. In particular, prospective studies to identify the predictive values of MPs in pathologies such as cardiovascular diseases are needed to demonstrate whether MPs are useful biomarkers for the early detection of the disease and its progression.     

Heat shock proteins in oncology: Diagnostic biomarkers or therapeutic targets?

Heat shock proteins (HSP) are a family of proteins induced in cells exposed to different insults. This induction of HSPs allows cells to survive stress conditions. Mammalian HSPs have been classified into six families according to their molecular size: HSP100, HSP90, HSP70, HSP60, HSP40 and small HSPs (15 to 30kDa) including HSP27. These proteins act as molecular chaperones either helping in the refolding of misfolded proteins or assisting in their elimination if they become irreversibly damaged. In recent years, proteomic studies have characterized several different HSPs in various tumor types which may be putative clinical biomarkers or molecular targets for cancer therapy. This has led to the development of a series of molecules capable of inhibiting HSPs. Numerous studies speculated that over-expression of HSP is in part responsible for resistance to many anti-tumor agents and chemotherapeutics. Hence, from a pharmacological point of view, the co-administration of HSP inhibitors together with other anti-tumor agents is of major importance in overcoming therapeutic resistance. In this review, we provide an overview of the current status of HSPs in autoimmune, cardiovascular, and neurodegenerative diseases with special emphasis on cancer.     

MSCs and hyaluronan: Sticking together for new therapeutic potential?

Research involving mesenchymal multipotent/stem/progenitor/stromal/marrow cells (MSCs) have translated to clinical trials at an extraordinary pace. By the time of this review, the public clinical trials database (http://clinicaltrials.gov) has 394 clinical trials listed using MSCs for a very wide range of therapeutic applications. Unexpectedly, the explanation for the increase in clinical trials using MSCs does not lie on a well-defined therapeutic mechanism – dramatic results have been demonstrated in a variety of studies involving different animal models of diseases, often describing discrete therapeutic mechanisms exerted by MSCs. This review will focus on recent data suggesting the involvement of hyaluronic acid (HA) in the beneficial effects of MSCs, evaluate the potential of MSC as modulators of HA and the implications of this modulation for disease therapy.     

ERα-negative and triple negative breast cancer: Molecular features and potential therapeutic approaches

Triple negative breast cancer (TNBC) is a type of aggressive breast cancer lacking the expression of estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor-2 (HER-2). TNBC patients account for approximately 15% of total breast cancer patients and are more prevalent among young African, African-American and Latino women patients. The currently available ER-targeted and Her-2-based therapies are not effective for treating TNBC. Recent studies have revealed a number of novel features of TNBC. In the present work, we comprehensively addressed these features and discussed potential therapeutic approaches based on these features for TNBC, with particular focus on: 1) the pathological features of TNBC/basal-like breast cancer; 2) E₂/ERβ-mediated signaling pathways; 3) G-protein coupling receptor-30/epithelial growth factor receptor (GPCR-30/EGFR) signaling pathway; 4) interactions of ERβ with breast cancer 1/2 (BRCA1/2); 5) chemokine CXCL8 and related chemokines; 6) altered microRNA signatures and suppression of ERα expression/ERα-signaling by micro-RNAs; 7) altered expression of several pro-oncongenic and tumor suppressor proteins; and 8) genotoxic effects caused by oxidative estrogen metabolites. Gaining better insights into these molecular pathways in TNBC may lead to identification of novel biomarkers and targets for development of diagnostic and therapeutic approaches for prevention and treatment of TNBC.     

Heat shock proteins in health and disease: therapeutic targets or therapeutic agents?

For many years, heat shock or stress proteins have been regarded as intracellular molecules that have a range of housekeeping and cytoprotective functions, only being released into the extracellular environment in pathological situations such as necrotic cell death. However, evidence is now accumulating to indicate that, under certain circumstances, these proteins can be released from cells in the absence of cellular necrosis, and that extracellular heat shock proteins have a range of immunoregulatory activities. The capacity of heat shock proteins to induce pro-inflammatory responses, together with the phylogenetic similarity between prokaryotic and eukaryotic heat shock proteins, has led to the proposition that these proteins provide a link between infection and autoimmune disease. Indeed, both elevated levels of antibodies to heat shock proteins and an enhanced immune reactivity to heat shock proteins have been noted in a variety of pathogenic disease states. However, further evaluation of heat shock protein reactivity in autoimmune disease and after transplantation has shown that, rather than promoting disease, reactivity to self-heat shock proteins can downregulate the disease process. It might be that self-reactivity to heat shock proteins is a physiological response that regulates the development and progression of pro-inflammatory immunity to these ubiquitously expressed molecules. The evolving evidence that heat shock proteins are present in the extracellular environment, that reactivity to heat shock proteins does not necessarily reflect adverse, pro-inflammatory responses and that the promotion of reactivity to self-heat shock proteins can downregulate pathogenic processes all suggest a potential role for heat shock proteins as therapeutic agents, rather than as therapeutic targets.     

Surface sensing and stress-signalling in Ulva and fouling diatoms – potential targets for antifouling: a review

Understanding the underlying signalling pathways that enable fouling algae to sense and respond to surfaces is essential in the design of environmentally friendly coatings. Both the green alga Ulva and diverse diatoms are important ecologically and economically as they are persistent biofoulers. Ulva spores exhibit rapid secretion, allowing them to adhere quickly and permanently to a ship, whilst diatoms secrete an abundance of extracellular polymeric substances (EPS), which are highly adaptable to different environmental conditions. There is evidence, now supported by molecular data, for complex calcium and nitric oxide (NO) signalling pathways in both Ulva and diatoms being involved in surface sensing and/or adhesion. Moreover, adaptation to stress has profound effects on the biofouling capability of both types of organism. Targets for future antifouling coatings based on surface sensing are discussed, with an emphasis on pursuing NO-releasing coatings as a potentially universal antifouling strategy.     

The activins and their binding protein,follistatin—Diagnostic and therapeutic targets in inflammatory disease and fibrosis

The activins, as members of the transforming growth factor-β superfamily, are pleiotrophic regulators of cell development and function, including cells of the myeloid and lymphoid lineages. Clinical and animal studies have shown that activin levels increase in both acute and chronic inflammation, and are frequently indicators of disease severity. Moreover, inhibition of activin action can reduce inflammation, damage, fibrosis and morbidity/mortality in various disease models. Consequently, activin A and, more recently, activin B are emerging as important diagnostic tools and therapeutic targets in inflammatory and fibrotic diseases. Activin antagonists such as follistatin, an endogenous activin-binding protein, offer considerable promise as therapies in conditions as diverse as sepsis, liver fibrosis, acute lung injury, asthma, wound healing and ischaemia–reperfusion injury.     

Impaired mitochondrial homeostasis and neurodegeneration: towards new therapeutic targets?

Journal of Bioenergetics and Biomembranes - The sustained integrity of the mitochondrial population of a cell is critical for maintained cell health, and disruption of that integrity is linked...     

Corticotropin-releasing factor family and its receptors: tumor therapeutic targets?

Urocortin (UCN) and corticotropin-releasing factor (CRF) are members of CRF family. Though CRF is mainly distributed in central nervous system (CNS), UCN has been reported to play biologically diverse roles in several systems such as cardiovascular, respiratory, digestive, reproductive, stress, immunologic system, etc. UCN and CRF bind to two known receptors, CRFR1 and CRFR2, to function. Both CRF receptors are distributed in CNS and periphery tissues, and their expression in cancer tissues has been reported. Now there are many documents indicating UCN/CRF play an important role in the regulation of carcinogenesis. There is also evidence indicating UCN/CRF have anticancer effects via CRFRs. This paper will review the effects of CRF family in cancers.     

The metabolic potential of plastics as biotechnological carbon sources – Review and targets for the future

The plastic crisis requires drastic measures, especially for the plastics’ end-of-life. Mixed plastic fractions are currently difficult to recycle, but microbial metabolism might open new pathways. With new technologies for degradation of plastics to oligo- and monomers, these carbon sources can be used in biotechnology for the upcycling of plastic waste to valuable products, such as bioplastics and biosurfactants. We briefly summarize well-known monomer degradation pathways and computed their theoretical yields for industrially interesting products. With this information in hand, we calculated replacement scenarios of existing fossil-based synthesis routes for the same products. Thereby, we highlight fossil-based products for which plastic monomers might be attractive alternative carbon sources. Notably, not the highest yield of product on substrate of the biochemical route, but rather the (in-)efficiency of the petrochemical routes (i.e., carbon, energy use) determines the potential of biochemical plastic upcycling. Our results might serve as a guide for future metabolic engineering efforts towards a sustainable plastic economy.     

The “A Disintegrin And Metalloproteases” ADAM10 and ADAM17: Novel drug targets with therapeutic potential?

Proteolytic ectodomain release, a process known as "shedding", has been recognised as a key mechanism for regulating the function of a diversity of cell surface proteins. A Disintegrin And Metalloproteinases (ADAMs) have emerged as the major proteinase family that mediates ectodomain shedding. Dysregulation of ectodomain shedding is associated with autoimmune and cardiovascular diseases, neurodegeneration, infection, inflammation and cancer. Therefore, ADAMs are increasingly regarded as attractive targets for novel therapies. ADAM10 and its close relative ADAM17 (TNF-alpha converting enzyme (TACE)) have been studied in particular in the context of ectodomain shedding and have been demonstrated as key molecules in most of the shedding events characterised to date. Whereas the level of expression of ADAM10 may be of importance in cancer and neurodegenerative disorders, ADAM17 mainly coordinates pro- and anti-inflammatory activities during immune response. Despite the high therapeutical potential of ADAM inhibition, all clinical trials using broad-spectrum metalloprotease inhibitors have failed so far. This review will cover the emerging roles of both ADAM10 and ADAM17 in the regulation of major physiological and developmental pathways and will discuss the suitability of specifically modulating the activities of both proteases as a feasible way to inhibit inflammatory states, cancer and neurodegeneration.