Current Protein and Peptide Science - Volume 19, Issue 11, 2018

Substance P (SP) is associated with pain and inflammatory processes and is released from terminals of specific sensory nerves. This undecapeptide that mediates its effects through the neurokinin type 1 (NK1) receptor, is rapidly degraded in vivo to smaller fragments. The heptapeptide SP(1-7) with a hitherto unknown receptor, is a major bioactive fragment and displays often opposite actions to those induced by SP. Hence, SP(1-7) elicits anti-nociceptive and anti-hyperalgesic effects. These observations have attracted a substantial interest and in this mini-review the efforts to transform the heptapeptide SP(1-7) into more drug-like small-molecule SP(1-7) peptidomimetics as a potential new class of analgesics are summarized. Structure-activity relationship studies and subsequent amidation of the C-terminal and truncations from the N-terminal of the heptapeptide delivered the bioactive dipeptide amide Gln- Phe-NH2 showing a high affinity at the SP(1-7) binding site. Similarly, endomorphin-2, an endogenous opioid ligand containing a C-terminal carboxamide group, demonstrated a high affinity at the SP(1-7) binding site. Endomorphin-2 subjected to truncations yielded the potent dipeptide amide Phe-Phe-NH2. Structural optimization of the latter furnished more drug-like high affinity ligands and among those a constrained cis-3-phenylpyrrolidine derivative that after peripheral administration produced a significant anti-allodynic effect in a mouse SNI model of neuropathic pain. This SP(1-7) peptidomimetic was as effective as SP(1-7) in alleviating mechanical allodynia in mice. Although, additional structural modifications are needed to achieve compounds exhibiting high/fair bioavailability after oral administration, the examples presented herein demonstrate that the bioactive peptides SP(1-7) and endomorphin-2 can be converted into low molecular weight compounds that are able to mimic the in vivo actions of the heptapeptide SP(1-7).

Connexins are a family of gap junction proteins widely distributed in human organs and tissues. Gap junctions are organized systems of intercellular protein channels that allow the exchange of ions, chemical signals, and energy substrates between two adjacent cells. Connexin43 (Cx43) is the most abundant isoform of connexins in the heart which play an important role in myocardium disease. Numerous studies have shown that Cx43 was involved in tumor migration and invasion by mediating gap junctions between tumor cells and normal cells. Changes in the expression and distribution of Cx43 contribute to heart disease and cancer. This review discusses current knowledge on the functional and structural abnormalities in Cx43 associated with heart disease and cancer, aiming to highlight the importance of this connexin as an emerging therapeutic target. Here, the current knowledge on the pharmacology of Gap Junction Channels and Hemichannels were also summarized. Finally, we propose that these knowledges can be exploited to identify new diagnostic and effective therapeutic approaches for ischemic heart disease and cancer.

Celiac disease (CD) is an inflammatory syndrome that affects mainly the intestine, but also other organs. This ailment is also affected by the physicochemical behavior of gluten as such. From the medical standpoint, this pathology results from a combination of genetic and environmental factors. At the same time, gliadin (the alcohol-soluble fraction of gluten) along with other related oligomers, such as 33-gliadin, present high immunogenicity and are responsible for triggering of this disease. Within CD characterization, there are mainly two different approaches to carry out this study; one focuses on its chronic phase, while the other deals with its initial stages. Although the chronic phase of CD has been well characterized, the initiation of the inflammatory process is still unclear. As this process is apparently related to the aggregation of the oligomers involved in CD, the initiation of the disease could be explained by means of clarifying their self-assembly behavior. Thus, this work addresses the clinical explanation, within the chronic approach, attempting to combine it with the physicochemical techniques used for characterization of proteins aggregates as well.

There are two vertebrate talin genes, TLN1 and TLN2, which encode talin1 and talin2. Talin1 governs integrin activation, thus regulating focal adhesion (FA) assembly, cell migration and invasion, but the biological function of talin2 remains to be elucidated and not too long ago talin2 was presumed to function redundantly with talin1. Recent studies have shown distinct differences between talin2 and talin1. The promoter of TLN2 is different from that of TLN1 in their size and binding to different transcription factors. Talin2 has a higher affinity to β -integrins than talin1. Talin2 regulates traction force generation, focal adhesion dynamics and invadopodium formation, thus controlling tumor cell migration, invasion and metastasis. Also, talin2 is enriched in the myotendinous junction (MTJ) in striated muscle, costameres and intercalated disks (ICDs) of cardiac myofibrils, and atherosclerotic plaques of blood vessels, thus regulating cardiovascular integrity. In this review, we discuss the differences between talin1 and talin2, in genome, protein expression pattern, affinity with integrins, traction force generation, and provide a glance at the roles of talin2 in cancer cell invasion and cardiovascular function.

Cardiovascular (CV) diseases are caused by vascular dysfunction. The enhanced sensitivity to vasoconstrictors, reduced endothelium-derived vasodilators nitric oxide (NO) and prostacyclin (PGI2), and endothelium-derived hyperpolarization (EDH) indicate CV dysfunction. In recent years, recombinant human relaxin, known as serelaxin, has emerged as a new vasoactive drug that is useful in acute heart failure. First part of this review article encompasses the role of endogenous relaxin in CV homeostasis. Subsequently, vascular effects of serelaxin and the underlying modes of action in comparison to other vasodilators are discussed. Finally, the usefulness of treatment with serelaxin in vascular dysfunction in different CV diseases, particularly due to oxidative stress, is explained.

The thermodynamic analyses of proteins, protein-ligands and protein-nucleic acid complexes involves the entropy–enthalpy (S-H) compensation phenomenon. We have examined the question whether the observed compensation is artificial or reflects anything more than the well-known laws of statistical thermodynamics (so-called extra-thermodynamic compensation). We have shown that enthalpy− entropy compensation (EEC) is mainly the trivial consequence of the basic thermodynamic laws and there are no experimental evidences for existence of the extra-thermodynamic compensation. In most cases EEC obtained in the experiments through the plot enthalpies (ΔH) and entropies (TΔS) versus one another is meaningless due to the large correlated errors in ΔH and TΔS, unless special measures are taken to minimize, quantify and propagate these errors. Van't Hoff equation can be used for entropy calculation in limited cases when enthalpy is measured in independent experiments. Eyring equation cannot be used for calculation of entropy in any case and should be excluded from scientific use. Both equation, Van't Hoff and Eyring cannot be used for simultaneous calculation of the enthalpy and entropy values using one set of data. All the data obtained in this way should be recognized as erroneous.

The concept of Cell-Mediated Immunity (CMI) monitoring in transplantation has gained popularity over time and is now a reality. Significant technological advances have enabled us to test for multiple molecules and cells implicated in inflammatory or suppressive reactions to the graft. The main challenge nowadays is whether clinicians can use the information provided by the measurement of such markers to predict post-transplant outcome. To date a wide range of markers have been identified as promising biomarkers in the monitoring of individual responses to immunosuppression or in the determination of patient alloreactivity to the graft, which could prove helpful in the assessment of the occurrence of an adverse/side effect. Before these biomarkers are deemed suitable, standardisation of the methodology and validation of its feasibility in clinical outcome remains an ongoing challenge. The research community is currently facing a large effort towards the implementation of a standard methodology that is both highly reproducible and can reduce inter-laboratory variability, therefore generating consistency with data. The aim of this manuscript is to review the current literature regarding CMI monitoring in the field of solid organ transplantation (SOT), undertaking a comprehensive study of the latest findings. In addition, based upon current literature, we aim to propose a comprehensive classification of biomarkers to further aid our current understanding, taking in to account the type of transplantation, when its measurement should be applied and which would be the most suitable biomarker to assess.

Background: The co-stimulatory B7 family members are cell-surface protein ligands, binding to receptors on lymphocytes to regulate immune responses. One of them is the inducible co-stimulatory molecule ligand (ICOS-L). This protein is expressed on professional antigen-presenting cells (APCs), including B cells, macrophages, and dendritic cells (DCs), but it can also be expressed by endothelial cells, lung epithelium and in tumour microenvironment cells. ICOS-L is important for memory and effector T cells during the specific humoral immune responses, but its role in cancer is not yet understood. Objective: To discuss the role of ICOS/ICOS-L in cancer, given importance of identifying selective targets for cancer treatment, and knowing the mechanism of immune evasion by tumour. Main Findings: ICOS/ICOS-L signal has opposite effects on the T-cell response. ICOS-L is activated in several types of cancers to maintain immunosuppressive CD4+ T cell subsets, such as regulatory T cells (Tregs). ICOS-L over-expression is associated with tumour progression and poor overall survival. In colon cancer, activation of this co-stimulatory signal is associated with improved survival suggesting a dualistic effect of the ICOS/ICOs-L signal pathway. Interestingly, following anti-cancer vaccine or anti- CTLA-4 treatment, ICOS+ T cells increased significantly in both the CD4+ and CD8+ population and the ratio Teff/Treg increased in tumour microenvironment. This suggests a potential role of ICOS/ICOS-L in improving effectiveness of cancer therapy. Conclusion: ICOS/ICOS-L signal pathway has the potential to improve cancer treatment. However, studies in other models are needed to understand whether inhibition of ICOS expression or the blockage of its co-stimulation could be a potential therapeutic target or adjuvant treatment for immunotherapy.

Plants, being sessile organisms, are challenged by variety of stresses in the form of abiotic and biotic components of environment. In such adverse conditions, plants evolve various adaptive strategies in order to survive. Among these strategies, accumulation of polyamines in plants helps to combat stress. Polyamines are ubiquitous low molecular weight compounds, which are now known to be involved in stress tolerance as suggested by various pieces of evidence during abiotic and biotic stress. The anti-stress properties of polyamines in plants are illustrated by their roles in modulation of morphological growth parameters, elevation of photosynthetic pigments, as well as declined content of stress indices, antioxidative enzymes, and non-enzymatic antioxidants content. The emerging role of polyamines in plant stress tolerance has been discussed in the present review.

The incidence of cardiovascular disorders, especially coronary artery disease and atherosclerosis, is increasing alarmingly. Clarifying the underlying causes is of the utmost importance and should be elucidated in order to reduce this growing trend. Periodontitis is known as a chronic destructive disease with sophisticated pathophysiological mechanisms that slowly impose negative effects not only on the oral tissues but also on distant organs. Additionally, it has been shown in many studies that atherosclerosis and periodontitis utilized common inflammatory signaling pathways and mediators. Several lines of evidence have demonstrated the signatures of periodontitis-related bacteria in atherosclerotic plaque specimens. It is proposed that virulent proteins of these bacteria probably accelerate the initiation or development of plaque formation on the inner walls of the coronary arteries. Proteomics techniques are very sensitive and have a global point of view. They can help to discover host factors and pathogenrelated biomarkers. This review summarizes the studies focused on the three most important bacterial species involved in both diseases and presents recent findings about the proteomic evaluation of virulence factors of these bacteria. The known mechanisms of action of the virulence factors are also described.