Current Protein & Peptide Science

The incidence of neurological disorders is rising markedly with aging. Aged brains become highly prone to neurodegeneration owing to the formation of misfolded protein aggregates and lack of clearance mechanism. Earlier it was thought that accumulation and aggregation of amyloid β (Aβ) peptide is the main driver of Alzheimer’s disease (AD) pathogenesis. But the recent failure of Aβ-targeting clinical trials of drugs led to the mistrust that not only Aβ but also additional pathological mechanisms may play imperative roles. Furthermore, the economic burden of AD patients’ care represents a severe challenge in the health care system. Thus a more diaphanous understanding of AD pathogenesis in humans is essential. In the early stage of the disease, AD diagnosis is diligent and offers a challenging scientific frontline. Therefore, analysis of additional biological markers by using neuroproteomics for the brain aging process would be beneficial to detect disease-specific molecular changes. Similarly, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and other neurological disorders have been increasingly shown to be markedly associated with biologically significant proteomics biomarkers. Advanced neuroproteomics research can not only help in the emergence of new neuroproteomics biomarkers but can also address the qualitative and quantitative sketching as well as functional characterization of patients with neurological disorders. Therefore, this special thematic issue discusses and explores the inherent neuroproteomics aspects associated with various neurological disorders by addressing emerging diagnostic biomarkers and drug targets.

Khurana et al. [1] elucidated the importance of neuroproteomics against several neurological diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, epilepsy, as well as psychiatric disorders. The authors attempted to present the current successes and failures of the neuroproteomics approach on the results obtained from different clinical studies that targeted biomarkers associated with neurological disorders.

Narayanan et al. [2] explored the role of neuroproteomics in Alzheimer’s disease research. Elevated levels of amyloid β, total tau, and phosphorylated tau in cerebrospinal fluid have become an important biomarker for the identification of this neurodegenerative disease.

Puranik et al. [3] reviewed the profile of biomarkers, and techniques involved in the discovery of novel biomarkers for early diagnosis of neurodegenerative diseases. The authors stated that identifying the changes in novel protein levels and their functions under the disease conditions is necessary for early diagnosis.

Shaikh et al. [4] presented promising ways of developing competent Alzheimer’s disease therapeutic agents from antiamyloid aggregating gold nanoparticles. The review highlights some interesting landscapes that might effectively fill the gap in Alzheimer's disease research.

Mamun et al. [5] emphasized the relationship between the ubiquitin-proteasome system and Alzheimer's disease pathology. The authors also represented the recent therapeutic advancements targeting components of the ubiquitin-proteasome system to combat Alzheimer's disease pathogenesis.

Li et al. [6] focused on the application of iTRAQ and TMT labeling techniques for a better understanding of neurodegenerative diseases. The authors stated that proteomics can shed light on the mechanism by which neurodegeneration manifests as well as aid to establish diagnostic standards and discover new drug targets.

Kumar et al. [7] elucidated the current status of proteomic analysis of Huntington’s disease. This appraisal suggested that analysis of mutation in Huntington’s disease gene can be done efficiently by proteomic analysis, thereby enhancing the effectiveness of treatment. Bergantin [8] discussed the role of Ca2+/cAMP signaling in the interplay between depression and Parkinson´s disease, including the implications for the pharmacotherapy involving Ca2+ channel blockers. This appraisal also addressed the fact that Ca2+ channel blockers have been demonstrating off-label effects, such as alleviating both parkinsonism and depression symptoms.

With decades of effort, an increasing number of evidence have been reported which demonstrated that several bio-marks play several significant roles in medical diagnostics, pharmaceutical development, clinical trials and other related areas [1]. On one hand, these decades’ efforts have accumulated large amounts of data. These data may drive the development of information science. On the other hand, artificial intelligence can be treated as an emerging tool, which has been successfully utilized in several areas. Considering such a situation, the discovery of bio-marks with artificial intelligence has become an urgent mission in the modern world. Meanwhile, such tools seem to be a more effective conservative of resources and cheaper than some traditional ones.

A contribution by Ji Zhu’s group documents miRNAs has been shown to play critical roles in human fundamental physiological processes, such as proliferation, development, differentiation and others [2]. They also proposed the model of Decision Template-based MiRNA-Disease Association prediction (DTMDA) to prioritize potentially related miRNAs for diseases of interest. By integrating miRNA functional similarity network, miRNA Gaussian interaction profile kernel similarity network, two disease semantic similarity networks and disease Gaussian interaction profile kernel similarity network, we trained five multi-label K nearest neighbors-based core classifiers.

Bin Yang’s team reviews the Gene regulatory network inference based on differential equation models [3]. Reconstruction of gene regulatory networks (GRN) plays an important role in understanding the complexity, functionality and pathways of biological systems, supporting the design of new drugs for diseases. Because differential equation models are flexible and robust strong, these models have been utilized to identify biochemical reactions and gene regulatory networks. They investigate the differential equation models for reverse engineering gene regulatory networks. They introduce three kinds of differential equation models, including ordinary differential equation (ODE), time-delayed differential equation (TDDE) and stochastic differential equation (SDE). ODE models include linear ODE, nonlinear ODE and S-system model. They also discuss the evolutionary algorithms, which are utilized to search the optimal structures and parameters of differential equation models. This investigation could provide a comprehensive understanding of differential equation models, and lead to the discovery of novel differential equation models.

The contribution by Li Xu et al. provides that several computational prediction approaches have been designed to uncover disease-related miRNAs for further experimental validation [4]. Several algorithms integrated miRNA similarities of known miRNA-disease associations to enhance the miRNA functional similarity network and disease similarities of known miRNAdisease associations to enhance the disease semantic similarity network to improve the prediction accuracy. Xiaochao Sun’s group made a contribution on inter-chromosomal distribution of disease-related genes in human genome [5]. In this study, they explored these issues using the available genomic data of both human and model organisms. Moreover, they also analyzed the distribution pattern of protein-coding genes that have been associated with 14 common diseases and the insert/deletion mutations and single nucleotide polymorphisms detected by whole genome sequencing in an acute promyelocyte leukemia patient. They obtained the following novel findings. Firstly, inter-chromosomal distribution of genes displays a nonstochastic pattern and the gene densities in different chromosomes are heterogeneous. This kind of heterogeneity is observed in genomes of both lower and higher species. Secondly, protein-coding genes involved in certain biological processes tend to be enriched in one or a few chromosomes. Such findings have added new insights into our understanding of the spatial distribution of genome and disease-related genes across chromosomes. These results could be useful in improving the efficiency of diseaseassociated gene screening studies by targeting specific chromosomes.

Ruizhi Fan et al. proposed the EHAI model, which is Enhanced Human microbe-disease Association Identification [6]. EHAI employed the microbe-disease associations, and then Gaussian interaction profile kernel similarity has been utilized to enhance the basic microbe-disease association. Actually, some known microbe-disease associations and a large amount of associations are still unavailable among the datasets. The ‘super-microbe’ and ‘super-disease’ were employed to enhance the model. Computational results demonstrated that such super-classes have the ability to be helpful to the performance of EHAI. Therefore, it is anticipated that EHAI can be treated as an important biological tool in this field.

The metabolic derangements including diabetes mellitus is mediated by non-enzymatic glycation of proteome, lipidome and genome which plays a crucial role in the pathogenesis of secondary complications via the generation and accumulation of advanced glycation end products (AGEs). The metabolic disorders get accumulated over the due course of time as a result of the imbalance in the levels of reactive oxygen species (ROS) and reactive carbonyl species (RCS) [1]. Glycation initiates with nonenzymatic nucleophilic addition between free carbonyl groups (C=O) of reducing sugars and free amino groups (-NH2) of biological macromolecules. The initial stages of reaction proceed with the formation of reversible aldimines (Schiff’s bases) and irreversible ketoamines (Amadori products), whereas in the later stages ketoamines undergo rearrangement, dehydration and cyclization to give rise to AGEs [2]. During the course of glycation reaction, transition metal catalyzed autoxidation of reducing sugars and glycoxidation of glycation-adducts generate superoxide radicals and the later via Fenton’s reaction give rise to hydroxyl radicals, thereby mounting oxidative stress in physiological systems. This oxidative stress induces lipid peroxidation and oxidation of amino acids to give rise to highly electronegative aldehyde and/or ketone groups possessing dicarbonyls, called reactive carbonyl species (RCS) such as glyoxal (GO), methylglyoxal (MG) and 3-deoxyglucosone (3-DG), thus enhancing carbonyl stress [3]. Moreover, the triose phosphate intermediates glyceraldehydes-3-phospahate (G3P) and dihydroxyacetonephosphate (DHAP) of glycolysis also give rise to RCS. Furthermore, the hyperglycemic state also facilitates the dicarbonyls’ formation through the shunting of excess glucose in the polyol pathway. Dicarbonyls further react non-enzymatically with biological macromolecules via nucleophilic addition reaction in the similar fashion as that of reducing sugars, but this time more violently, to start glycationoxidation vicious cycle, thus exacerbating oxidative, carbonyl and glycative stress in the physiological system [4]. RCS mediated AGEs generation and accumulation result in the onset and progression of chronic disorders and metabolic syndromes via binding to receptors for advanced glycation end products (RAGE). AGE-RAGE axis induces generation of ROS by activating NADPH oxidases causing cellular oxidative damage. Moreover, AGE-RAGE axis activates Ras/extracellular signal regulated kinases (ERK) and Rac/CDC43 signalling pathways that are involved in carcinogenesis [5]. Furthermore, AGEs- RAGE interaction activates NF-κB, which in turn generates oxidative stress, vascular inflammation, thrombogenesis, angiogenesis and is responsible for diabetes associated complications [6]. AGEs have been implicated in the pathogenesis of type 2 diabetes by contributing in the development of insulin resistance and low-grade inflammation known to precede the condition. Accumulation of RCS induced AGEs in tissues cause micro- and macro-vascular complications including nephropathy, neuropathy, retinopathy and cardiovascular diseases (CVDs) [7]. RCS mediated glycation of proteins result in structural alterations and functional variations, thus derailing normal anabolic and catabolic pathways. Moreover, RCS induced glycation of DNA leads to depurination, strand breakage and mutation (insertions, deletions and transposition) that result in loss of genomic integrity. RCS mediated glycoxidation of DNA is also responsible for reduced gene expression, increased genotoxicity and immunogenicity [7]. Saeed et al. [8] review expects to display the assessment of thought concerning the GLO pathway, the current information on the GLO synthetics and their chronicled action in the control of glycation shapes while Badruddeen et al. [9] represents an overview on stroke including mechanisms involved. Dr. Choi and the group [10] in their review summarized the reported effects of dicarbonyl stress on skeletal muscle, associated extracellular proteins with emphasis on the impact of T2DM on skeletal muscle, and provided a brief introduction to the prevention/inhibition of dicarbonyl stress. Wajid and Alouffi [11] aim to provide a thoughtful understanding of the review by including in-depth information of past and current information about the formation of MG and glyoxal through multiple pathways with a focus on their biological functions and detoxifications. Ahmad and the co-workers [12] reviewed the hazards of glycation and its inhibition by natural antioxidants including polyphenols and plant extract. Dr. Ahmad and the co-workers [13] explained the physico-chemical changes induced in the serum proteins immunoglobulin g and fibrinogen mediated by methylglyoxal in in their research article while alterations in BSA structure via generation of carbonyl species by 2’-Deoxyribose mediated glycation has been well explained by Dr. Ahmad [14]. Thus, it may be concluded that RCS are more potent glycating agents than reducing sugars and hamper normal physiology and metabolism by altering native structures and normal functions of proteins, lipids and DNA, and play a critical role in the pathogenesis of diabetes associated secondary complications, neurological disorders via AGEs generation and activation of AGE-RAGE axis.

Proteins are known as the "building blocks of life" and are vital macromolecules in life science. They are essential not only for human health and associated diseases but also for the survival and homeostasis of the trillions of microbial residents. Among numerous nutrients, protein is a key component connecting host and microbes residing within the intestine. Protein resources, levels, and multiple metabolites all inextricably contribute to host physiological state and chronic metabolic conditions such as glucose homeostasis, colorectal cancer, type 2 diabetes, and cardiovascular disease. Via the implementation of 'omics' technologies, therapeutic regulations of these diseases by protein are expected to be developed. Li et al [1]. Reviewed how melatonin modulates lactation by regulating prolactin secretion via tuberoinfundibular dopaminergic neurons in Hypothalamus- Pituitary system. Shan et al. [2] summarized the physiological functions of heat shock proteins. Digestive system is a complex micro-ecological environment in animals. After hydrolyzing to various cleavage points to smaller polypeptides in the stomach, the remaining peptones and polypeptides are converted to the small intestine and mainly digested into peptides and free amino acids (FAAs) by proteases and peptidases, subsequently [3]. Xie et al. [4] concluded that amino acids regulate glycolipid metabolism and alter intestinal microbial composition. Although many low molecular-weight substances generated during this metabolic process do exert enormous physiological importance, excess protein that fermented by colonized microbes is somehow considered unfavorable. Consistently, recent research has indicated that moderate protein restriction can optimize the microbial structure, alter bacterial metabolites, and promote barrier function in both the ileum and colon of adult pigs [5] and only ileum of growing pig model [6]. The emergence of the gut microbiota as a key regulator of health and disease further complicates the function of the protein [7]. In this bidirectional relationship, dietary protein and amino acids regulate microbial composition and provide essential carbon and nitrogen to bacteria. Microbes, in turn, affect protein absorption and metabolism and generate numerous metabolites after deamination or decarboxylation reactions [8]. Peng et al. [9] summarized the regulation of probiotics on metabolism of dietary protein in intestine. Peng et al. [10] also reviewed the effect of Escherichia Coli infection on metabolism of dietary protein in intestine. Amino acid catabolism yields numerous metabolites that affect host physiology. Although short-chain fatty acids (SCFAs) are less produced from amino acids, they do contribute to colonocyte proliferation and differentiation and exert antiinflammatory effects via binding to G-protein coupled receptors (GPCRs) [11, 12] or inhibiting histone deacetylases [13]. Additional metabolites consist of phenols, ammonia, and amines can combine with nitric oxide to form genotoxic N-nitroso compounds that are related to gastrointestinal cancers [7]. Moreover, a range of active metabolites of tryptophan is generated involving in immune response [14]. Serotonin can be regulated by toll-like receptors (TLRs) to connect gut-brain axis [15]. Kynurenine serves as the ligand for aryl hydrocarbon receptor (AhR), which exert bidirectional functions in the crosstalk among tryptophan, microbiota, and the immune system [16]. AhR can also be regulated by cytochrome P450 1 enzymes via a feedback loop [17]. Furthermore, CARD9 was reported to impact colitis by altering gut microbiota metabolism of tryptophan into AhR ligands [18]. Jia et al. [19] summarized the effects of medium-chain fatty acids in intestinal health of monogastric animals. Sun et al. [20] reviewed gastrointestinal interaction between dietary amino acids and gut microbiota: with special emphasis on host nutrition. The source of dietary protein also determines the nature of microbiota-dependent metabolic outputs is thus involved in the pathogenesis of many diseases. Multiple epidemiological studies proved that excessive animal protein intake, especially red meat, could increase the risk of colorectal cancer resulting from reshaped microbial community and metabolites. Among them, butyrate acts as a favorable source for colonocytes, while bile acid that de-conjugates to protein fermentation causes damage to colonic cells through proinflammatory and preneoplastic ways [21]. An association between certain protein sources and obesity is also confirmed. Different protein sources such as beans, dairy, meat and so on differ in amino acid composition and further affect energy efficiency, obesity development, and the gut microbiota [22]. It is also demonstrated that animal proteins, especially the amino acid L-carnitine, are major nutrient precursors for gut microbiota-dependent generation of trimethylamine Noxide (TMAO) [23]. TMAO is predictive of cardiovascular events in various populations and has been implicated in the development of fatty liver disease [24], which is expected to be a therapy target. Zheng et al. [25] revealed the role of BCL-2 family proteins in apoptosis and its regulation by nutrients. Zhang et al. [26] concluded the fermentation and metabolism of dietary protein by intestinal microorganisms. Nie et al. [27] revealed the impacts of dietary protein from fermented cottonseed meal on lipid metabolism and metabolomic profiling in serum of broilers. In this theme issue, we focus on the up-to-date description of the dominant pathways involved in amino acid metabolism in gut bacteria, and metabolic intermediates derived from bacterial protein fermentation that may affect human health. Major progress in the area associate with protein metabolism is expected in the near future with the investigation of host-microbe omics profiles and the development of targeted therapeutic strategies for protein metabolites.

In 1992 Edwin G. Krebs and Edmond H. Fischer were awarded the Nobel Prize in medicine for their research regarding reversible protein phosphorylation as a biochemical switch that turns on and off the activities of cell proteins regulating fundamental biological processes. However, it was not long from its discovery that it has become apparent that phosphorylation is only one of a wide variety of post-translational modifications, which include acetylation, methylation, addition of proteins such as ubiquitylation and sumoylation, modifications by complex molecules such as AMPylation, ADP-ribosylation etc. Protein methylation, the topic of this special issue, was first discovered in 1959 on flagellin from the bacterium Salmonella typhimurium [1], only five years after the discovery of protein phosphorylation (1954), but was long overlooked due to the difficulty in identifying the biological functions of this post-translational modification. Only in the late 1990s with the discovery of the functional role of histone methylation, this post-translational modification takes the centre of the stage as one of the most important epigenetic mechanisms that cells use to control gene expression. In particular, a precise combination of different post-translational modifications, i.e. methylation, acetylation, and phosphorylation encodes the so-called ‘histone code’ for the regulation of chromatin accessibility and gene expression. In 2010, with technical advancements in mass spectrometry and the development of new enrichment strategies, it was realized that protein methylation is more common than expected, not limited to epigenetic regulation (the vast majority of lysine methylations are actually found on non-histone proteins), and elevating it as a major post-translational modification in cell. To date, PhosphoSitePlus database (www.phosphosite.org), the most comprehensive resource of post-translational modifications, collected 5231 unique methylation events in lysine (2824 proteins), 11156 unique methylation events in arginine (4214 proteins), 3 unique methylation events in histidine (3 proteins) (dataset Dec 4 2019). More importantly, a steadily rising number of publications are shedding light on the physiological and pathophysiological relevance of protein methylation in a wide array of biological processes including cell growth, cell cycle, apoptosis, DNA repair etc. The aim of this thematic issue is to provide an overview of our current understanding of the role of non-histone protein methylation in cell physiology and pathology. Biggar’g group provides a very interesting link between methylysine signalling and hypoxic response. On one side indeed, lysine methylation, directly or indirectly, affects the regulation of HIF-1α signalling by regulating its stability, transcription, association with binding partners, etc. From the other side, the activity of lysine demethylases belonging to the Jumonji C (JmjC) family (JmjC KDMs) can be in turn regulated by oxygen [2]. The contribution by Reynoird’s group provides a comprehensive overview of the lysine methyltransferases (KMTs) signalling in non-histone proteins [3]. KMTs belong to two protein families: the SET domain and the 7β-strand family. In this review, Lukinovic et al. starting from the SET-KMTs and then moving to the 7β-strand-KMTs, describe specific substrates and functional significance of their modification. The major cellular signalling pathways regulated by these two group of KMTs [3] with a particular reference to their relevance in cancer, are disclosed. A contribution by Kwiatkowski and Drozak documents the significant progress made in understanding methylation on histidine residues [4]. The authors provide a full picture of the functional significance of histidine methylation up to date. In specific they describe biochemical properties and posttranslational modifications of histidine, give us an historical perspective on histidine methylation research, and finally deepen the role and biological functions of the only two, so far, identified histidine methyltransferases (Hpm1 and SETD3). Jethmalani and Green in their paper highlight that yeast can be an excellent in vivo model to study protein lysine methylation. Lysine methyltransferases enzymes, substrates and biological functions are described giving us a whole picture of this type of modification in yeast [5]. Switching from lysine to arginine methylation, Al-Hamashi et al., give us an overview of recent advances and updates focusing on arginine methyltransferases (PRMTs) enzymes. A detailed description of each PRMT and their non-histone substrates is provided. Finally, the role of these enzymes in human diseases and a summary of the PRMT inhibitors in clinical trials are presented [6]. In human, nine arginine methyl transferases have been identified (PRMT1-9). A deeper understanding of how arginine methyl transferases recognize their substrates is provided by Price and Havel [7]. The different approaches to define the substrate specificity of individual PRMTs are here summarized: structural analysis of active site and the use of peptide/protein library to define a possible consensus sequence, and large-scale approaches to identify PRMT specific substrates, i.e. the use of biorthogonal chemistry and mass spectrometry [7]. As mentioned above, advances in mass spectrometry technologies and improved protocols for sample processing and purification have been crucial to highlight the widespread occurrence of protein methylation in non-histone proteins. In this issue, Musani et al. provide an excellent summary of current status and advances in biochemical and computational approaches for large scale analysis of arginine methylation by mass spectrometry-based proteomics [8].

In the last century, drug discovery has led to the commercialization of thousands of molecules of different chemical structure, for treatment of most varied diseases [1]. However, due to the increasing emergence of resistance to these compounds, and to their intrinsic limitations encompassing a high toxicity at active concentrations or a limited delivery to the target site, many medical treatments are destined to fail [2]. Notwithstanding, the advent of nanotechnology has shed new light on those molecules that were previously abandoned or poorly characterized and has made it possible to overcome the aforementioned disadvantages for their therapeutic development [3-6]. This special issue focuses on peptide-based drugs and the employment of nanotechnological approaches to improve the peptides’ pharmacological profile. Nowadays, more than 60 peptides have been approved since 1980, while ~120 peptide-based formulations have entered into clinical development since 2010 [7]. In the first manuscript, Dr. Xiang and co-workers present a brief analysis of peptide-combined nanoparticles, highlighting their advantages and disadvantages from a mechanistic point of view and list several examples of application [8]. The following two reviews by Dr. Avesani and Dr. Willcox describe two different types of application of peptides in the immunological field; Dr. Avesani and collaborators show the potential of engineered plant virus nanoparticles (pVNPs), coated with peptides and proteins from different types of pathogens, for active immunization. The usage of such pVNPs for the delivery of peptide antigens to the host immune system in order to stimulate lasting systemic immunity is also discussed [9]. Dr. Willcox and his team instead describe their recent progress in the development of an antimicrobial peptide-coated contact lens for fighting microbial keratitis. They deal with all processes for drug development, from conception to laboratory and preclinical tests as well as to the latest information on clinical testing of the designed antimicrobial contact lenses [10]. The subsequent three authors focus on strategies for the delivery of peptide drugs at the target site. In particular, Dr. Verma and colleagues describe the pharmacological efficacy of host defense peptides and the various strategies for designing inhalable formulations to enhance the peptide activity for treatment of pulmonary ailments [11]. The review article from Dr. Bossmann and coworkers summarizes the state-of-the-art of nanosized delivery systems for therapeutic peptides and antibodies with particular attention to different nanoplatforms, e.g. liposome-, hydrogel-, polymer-, silica nanosphere-, or nanosponge-based delivery systems [12]. Dr. Laverty and his group discuss the capability of self-assembled peptides to form well-defined nanostructures with outstanding characteristics for many biomedical applications and for controlled drug delivery. The manuscript focuses on different types of self-assembling nanostructures, the mechanism underlying their formation along with their applications for drug delivery [13]. The last two papers describe different nanotechnological approaches to improve the biological profile of antimicrobial peptides (AMPs). Dr. Bhunia’s group discusses the current progress and implementation of different nanoparticles as well as quantum dots conjugated AMPs in terms of biostability, drug delivery, and therapeutic tools [14]. Finally, Dr. Casciaro and coworkers summarize examples of conjugation of AMPs to inorganic gold nanoparticles and biodegradable polymeric nanoparticles made of poly(lactide-co-glycolide), highlighting their promising potential as new antimicrobial nanoformulations [15]. Overall, we hope that this special issue provides knowledge on how nanotechnologies have revolutionized pharmaceutical research on peptide-based drugs. We express our gratitude to all authors for their excellent contribution. We also like to thank Prof. Ben M. Dunn for giving us the opportunity to edit this issue and to Bentham Science Publishers for their assistance. Finally, we would like to dedicate this special issue to Professor Emeritus Francesco Bossa, for his devotion and valuable contribution to the biochemistry and peptide science.

Fungal infections cause significant losses in the agronomic field, with tons of crops and ornamental plants affected every year. Similarly, infections caused by members of the kingdom Fungi are among the most prevalent in humans, and systemic candidiasis, aspergillosis, and cryptococcosis are associated with high morbidity and mortality rates. The lack of a vast repertoire of antifungal drugs to attack phytopathogens and medically relevant fungi has led to the search for new potential targets to develop novel compounds to fight these diseases. The search of virulence factors that confer the ability of these organisms to cause damage to the cells, and the identification of the mechanisms of sensing by the host immunity and evasion of this by the fungus, are among the main aspects currently under study to find new therapeutic targets. The synthesis of pigments like melanins, the capsule, the cell wall, secreted and membrane-bound proteins, along with the secretion of extracellular vesicles are the first lines of contact with the host cells and these contribute to adhesion, colonization, and ultimately to cell and tissue damage. Since most of these components are not synthesized by host cells, they are also part of the elements that the defense mechanisms recognize to establish a protective immune response. Therefore, the balance between the effector role of these fungal components and its recognition by the host will define the outcome of the interaction: control and clearance of the fungal population or establishment of the disease. Here, we offer a collection of comprehensive review papers dealing with the current progress in the study of virulence factors in phytopathogens and medically relevant fungi, the mechanisms behind their immune sensing and the current strategies they have to avoid the host’s defense mechanisms. When a capsule is absent, the cell wall is the outermost structure of the fungal cell and is the first in establishing contact with the host. This interaction will be key to the development of the disease, as reported by Plaza et al. [1]. They present a thorough revision on the relevance of glucans, chitin, chitosan, and cell wall glycoproteins in the interaction of both human and plant pathogens with the host, highlighting the molecular bases and the signaling pathways involved in the synthesis of these wall components [1]; while García-Carnero et al. describe the relevance of these polysaccharides and proteins during recognition by the host immunity [2]. Fabri et al. offer an analysis of the Aspergillus fumigatus cell wall integrity and the high osmolarity glycerol signaling pathways, which regulate the synthesis of plasma membrane sphingolipids, ergosterol, and phospholipids [3]. By comparative analysis with better studied fungal models, they proposed that the study of these pathways could unveil targets for the development of new therapeutic options to control invasive pulmonary aspergillosis [3]. Another strategy that is currently under study to find new sources of molecules that could assist in the therapy against fungal pathogens is the identification and characterization of plant lectins with antifungal properties [4]. Del Rio et al. gathered the most relevant information on this subject and highlighted lectins that have shown an effect on the cell wall, viability, biofilms, membrane permeabilization, and inhibition of morphological transition of causative agents of mycoses in humans [4]. Sporotrichosis is a subcutaneous or deep-seated infection that affects mammals, including the human being. It is caused by members of the pathogenic clade of genus Sporothrix and thus far, the most studied species is Sporothrix schenckii. At present, the virulence factors this organism uses to establish interaction with the host and to cause damage are not well documented. Here, Tamez- Castrellón et al. performed a comparative analysis of the S. schenckii genome with well-described virulence factors in Candida albicans, Cryptococcus neoformans, and A. fumigatus [5]. They generated a list of S. schenckii genes likely to encode proteins involved in morphological change, cell wall synthesis, immune evasion, thermotolerance, adhesion, biofilm formation, melanin production, nutrient uptake, response to stress, extracellular vesicle formation, and toxin production [5]. One of the most thoroughly studied fungal models in medical mycology is C. albicans, and there is a vast amount of information on virulence factors and how the fungal proteins provide advantages to the pathogen to cause disease and at the same time, how the recognition by the host could help to establish strategies to control C. albicans cells [6]. Here, Staniszewska summarized the most recent and relevant information not only on virulence factors found in C. albicans but also in other medically relevant species, like Candida parapsilosis, Candida tropicalis, Candida glabrata, and Candida krusei [6]. Finally, Metarhizium is a fungal genus that includes organisms with the ability to colonize and cause an entomopathogenic interaction with more than 200 insect species [7]. González-Hernández et al., present here a revision of the molecular mechanisms behind the conidia attachment, appressorium formation, penetration, and colonization of insects by Metarhizium spp [7].

More than two thousand molecules, mostly proteins, have been characterized as allergens, which bind to IgE antibodies subsequently eliciting allergic responses. Household allergens play an essential role in respiratory allergy. Multiple allergens are found throughout the house but the level of an individual allergen may differ by room and area. A dose-dependent association between allergen density and allergic symptoms has been established. Exposure to the allergens in the bedroom and living room are commonly relevant to trigger sensitization and morbidity. Component-resolved diagnosis, which utilizes purified native or recombinant allergens may predict symptom prognosis, is a hot topic in the field of molecular allergology [1]. With industrialization and westernization of Asian countries, allergic disorders are being increased. Allergen science originated from western countries and most of the allergens imported to Asian countries, which do not reflect the differences between continents, are produced from Europe and American companies. However, there are some differences in the flora, fauna, custom, and culture including cooking, clothing, and habitats. Interestingly, it has been proposed that the natural history of allergic disorders in Asia might fundamentally differ from western countries. Thus, main causes of allergic diseases are peculiar in Asia. For example, pollens (from the tree, weed, and grass), and domestic or stinging or biting insects, as well as various foods from plants and animals are often native to Asian countries and are not found or are rare in western countries. Sometimes, different breeds and polymorphism may endow different allergenicity even among the same species. Hence, some of the allergy diagnosis in Asian countries depends inevitably on crossreactivity with similar allergens. Therefore, this series of reviews summarized the molecular properties of indoor allergens with an emphasis on the differences between western and Asian countries. Household arthropods are a major source of indoor aeroallergens. Firstly, house dust mite, Dermatophagoides farinae and not D. pteronyssinus, is the major producer of allergens [2]. Secondly, storage mite, Blomia tropicalis, is a major source of dust allergens in subtropical and tropical regions [2]. Among the common household pests, the cockroach is a potent producer of inhalant insect allergens [3]. Other domiciliary insects such as ant, mosquito, mayfly, housefly, silkworm moth, silverfish and termite have been documented as the source of indoor allergens [4]. Sensitization to insects can be elicited not only by stinging but also by biting [5,6]. Many different species of worms and bugs are being consumed and serve as an important source of protein. However, some of the edible insects cause allergic responses [7]. Some proteins from companion animals are also of allergenic importance. However, there are some differences in the preferred breeds among countries. Housing features, microenvironments with excess moisture and occupants’ behavior are the main facilitating factors not only for the growth and persistence of residential fungi but also its exposure profiles. Fungal allergens are distributed by airborne spores and fungal fragments, which are to be investigated in more detail [8]. Topics on IgE reactive molecules from parasites and perspectives on recombinant allergen vaccines were included to provide better insight on the molecular properties of allergens [9, 10]. We hope the next issue would cover the topics on the outdoor allergens in Asia. Hopefully, this series of reviews can provide an insight into molecular properties which endow allergenicity to certain antigens. In addition, understanding of allergenic properties can facilitate the development of improved allergy diagnostic and therapeutic reagents.

The Central European Conference series "Chemistry towards Biology" was initiated in 2002 in Portoroz, Slovenia, to promote the exchange of scientific results, methods and ideas and encourage cooperation between researchers working in the interconnecting fields of chemistry and biology primarily, but not exclusively, in Central Europe. The events welcome chemists working on biology-related problems, biologists using chemical methods, students and other researchers of the respective areas that fall within the common scope of chemistry and biology. In 2018 the theme of the conference was “Biomolecules as potential drugs”. Topics included the study of chemicals and chemical reactions involved in biological processes that incorporate the disciplines of bioorganic chemistry, biochemistry, cell biology, medical biochemistry, pathology, microbiology, evolutionary biotechnology, structural biology, molecular and cellular biology, molecular medicine, pharmacology as well as experimental methodologies. Subjects cover chemical substances, which are of interest since they provide insight into biological problems. The methodology of the field uses the tools of chemical synthesis, biophysical and biochemical measurements, structure determination to understand functional biology and disease pathways at a molecular level. This Special Issue is dedicated to the work and research field of some of the outstanding researchers who presented a lecture at the conference. A wide variety of topics is addressed by the authors. A Zagreb group, lead by Professor Piantanida discusses advances in cyanine-amino acid conjugates for sensing nucleic acid and protein structures [1]. They present their recent advances in the development of novel amino acid-fluorophore probes, with the unique characteristic of free N- and C-terminus available for incorporation at any peptide backbone position. Polish authors, lead by Professor Brindell, treat strategies for oral delivery of metal-saturated lactoferrin [2]. They focus on presenting recent scientific efforts towards the elucidation of the role and therapeutic potential of lactoferrin saturated with iron(III) or manganese(III) ions and discuss strategies for oral delivery of lactoferrin. In their second paper [3] it is shown that interaction of Ru(II) polypyridyl complexes with proteins can result in significant changes in their photophysical properties, which can be crucial to their potential application in diagnostic or photodynamic therapy. A study by Dr. Fehér deals with single stranded DNA immune modulators with unmethylated CpG motifs [4]. Her observations support the existence of a second binding site on toll-like receptor 9, which is characterized in crystal structures and delivers further insights to the nucleic acid recognition of the innate immune system by this receptor. Polanski and coworkers discuss ligand potency, efficiency and drug-likeness [5]. The concept of ligand potency is briefly discussed, as well the meaning of ligand efficiency, its understanding requires the complex interpretation of the potency concept. Structural aspects of proteins are studied in three papers from the Budapest structural biology and chemistry group. Perczel and co-workers summarize amyloid characteristics and discuss the basic morphologies, sequential requirements and 3D-structure that are required for the understanding of the protein structure [6]. This is a prerequisite for developing either inhibitors or promoters of amyloidforming processes. Menyhárd et al. describe structure and size selection of serine oligopeptidases [7]. They show that the most important features contributing to selectivity and efficiency are the potential absence of two domains, which play a role in deactivation, and whether the β-edge of the hydrolase domain can guide a multimerization process that creates shielded entrance or intricate inner channels for the size-based selection of substrates. Dürvanger and Harmat give an outline of the different types of calmodulin-peptide complexes, providing an overview of recently determined 3D structures [8]. They discuss factors defining the orientations of peptides within the complexes, as well as role of anchoring residues. They found that the activity against Mycobacterium kansasii was positively influenced by higher lipophilicity and electron-donor properties of the substituent. Ježova et al. have shown a decrease in testosterone concentrations in saliva of children undergoing a school exam compared to values on a non-exam school day [9]. The group of Professor Jampilek prepared ten new 1-(4-nitrophenyl)piperazine derivatives and determined their antistaphylococcal, antimycobacterial, and antifungal activities [10]. Furthermore, testosterone has been associated with different cognitive functions in both adults and children. They brought evidence that aldosterone can act in the brain and produce anxiogenic and depressogenic effects and found a relationship between salivary aldosterone and anxiety.

Cardiovascular disease (CVD) is one of the leading cause of death worldwide, and is also the most common cause of death among men under the age of 65 years old in European and the second most common cause in women [1]. The prevalence of cardiovascular disease is increasing globally [2]. According to the World Health Organization, this condition is going to continue in the next few years. In 2012, it caused the death of 17.5 million people and it was predicted that the death toll would reach up to 22.2 million in 2030 (https://www.who.int/cardiovascular_diseases/about_cvd/en/). Natural products represent an important pool for the identification of novel drug leads [3]. The importance of natural products in treatment of CVD is very well known. In the last several decades, there are thousands of publications showing that natural products exhibit the promising effect to treat CVD. There is great interest in the discovery of molecules to treat CVD, including diabetic cardiomyopathy (DCM), atherosclerosis (AS), hypertensive, arrhythmia diseases and so on. Farnesoid X Receptor (FXR) [4], which is activated by primary bile acids (BAs) such as chenodeoxycholic acid, cholic acid and synthetic agonists [5], plays a critical role in regulating lipid and glucose metabolism, oxidative stress and inflammation [4]. BAs are the main active ingredients of many natural products and traditional medicines, especially bile or gallstones in animals, such as calculus bovis. Li C. et al. summarized the pathogenesis of DCM and the regulatory effect of BAs and FXR on DCM. They suggested that BA and FXR could be the novel targets for the treatment of DCM. RCT can remove excess cholesterol from macrophages and transport it to the liver for excretion, making this process vital to alleviate AS [6]. MicroRNAs (miRNAs) are small, noncoding RNAs that play critical roles in AS by regulating posttranscriptional gene expression [7]. Many natural compounds can exert anti-atherosclerotic effects by regulating different miRNAs that are implicated in RCT. Lian Z. et al. described the miRNAs involved in RCT and the potential uses of natural compounds to target RCT-related miRNAs to modulate AS. Hypertension is a disease with high incidence and high cardiovascular risk. Vitamin D receptor (VDR) is widely distributed in vascular endothelial cells, vascular smooth muscle cells [8] and cardiomyocytes [9]. Thus, the role of vitamin D and VDR in hypertension has received extensive attention. In recent years, both clinical trials and animal experiments have shown that vitamin D plays a regulatory role in decreasing blood pressure (BP) [10]. Lin L. et al reviewed the mechanisms of the vitamin D and VDR in regulating the BP and protecting against the target organ damage. They suggested that vitamin D supplementation therapy may be a new insight in the treatment of hypertension. Patients with ventricular arrhythmia can suffer from serious symptoms or degraded quality of life, potentially including sudden cardiac death [11]. It was indicated that allocryptopine, an isoquinoline alkaloid widely present in medicinal herbs, exhibits potential anti-arrhythmic actions in various animal models. Li J. et al. described the potential therapeutic benefit of allocryptopine in arrhythmia diseases. However, the clinical efficacy of allocryptopine is limited, and toxicological parameters and pharmacokinetics of allocryptopine is lacking in humans. Molecular docking and network pharmacology have been extensively used to search for potential active molecules in traditional medicine and explore their molecular mechanisms [12]. In this special issue, Zhang X. et al. reported that systems bioinformatic approach through molecular docking, network pharmacology and microarray data analysis could be used to determine the molecular mechanism underlying the effects of Rehmanniae Radix Praeparata on cardiovascular diseases. In this theme issue, we focus on the effect of different natural products on CVDs, including DCM, AS, hypertensive, arrhythmia diseases as well as others. We also aim to encourage investigators to publish reviews that summarize recent findings in both basic and clinical research in this field which will help to understand the cellular and molecular mechanism involved and to find new targets to treat CVD.

Inflammation plays a key role in tissue and organ injury, as well as subsequent repair and regeneration. Inflammation is a double-edge sword for injury and repair. Proper inflammation is an essential process for cytokines and chemokines secretion, which are responsible for anti-infection and activation of adaptive immune system. However, persistent chronic inflammation will trigger fibrosis. In this process, numerous tissue cells, immune cells and proteins are connected. In this issue, we invited some leading scholars and physicians to review and discuss recent advance and new aspects of inflammation in different tissues and organs injury, repair and regeneration, such as kidney, liver and brain. These reviews will cover basic and clinical research. I believe this issue will provide new insights and inspirations for readers in their research field. Acute kidney injury (AKI) affects approximately 13.3 million individuals and contributes to about 1.7 million deaths globally per year. As estimated 85% of those affected live in the developing world. Nowadays, AKI is believed to be an overreacted immune response-related disease. Both innate and adaptive immune systems are of importance in the pathophysiological process. Dr. Zheng introduced important immune cells in the pathogenesis and repair of ischemic AKI and emphasized treatments potentially targeting them [1]. This review is very helpful for understanding the role of immune system during AKI in a bird’s eye view. Next, Dr. Liu focused on a specific protein named transient receptor potential melastatin 7 (TRPM7). Dr. Liu et al. found that TRMP7, an ion channel and kinase, is a potential biomarker for ischemia reperfusion-induced AKI in their previous study [2]. Therefore, here they reviewed the mechanism of TRPM7 involved in the pathophysiology of IRI, including inflammatory response, apoptosis and necroptosis, renal microvasculature, as well as maladaptive fibrogenesis leading to chronic kidney disease. The second disease included in this issue is hemodynamic-induced intracranial aneurysm. Indeed, the dysfunction of endothelial cells, smooth muscle cells, macrophages and lymphocytes, as well as their secreted cytokines, collectively contribute to the formation, growth and rupture of intracranial aneurysm. In other words, inflammation is indispensable in intracranial aneurysm. Dr. Tang summarised and discussed the mechanisms of various inflammatory cells and cytokines in intracranial aneurysm [3]. The first cognition of inflammation for physicians is infection. Sepsis is a severe systemic inflammatory response syndrome (SIRS). In the review entitled with “The Immune System Regulation in Sepsis: from Innate to Adaptive”, Miss Qiu and Prof. Luo [4] summarized many innate and adaptive immune cells during sepsis development. They also discussed the network regulation among these various immune cells. This review will help us understand the role of immune system in sepsis. Besides sepsis, we also present a chronic inflammation condition-related disease. Dr. Tseng and Prof. Wu [5] introduced chronic liver inflammation and fibrosis with a fashion view, autophagy. In this review, they provide a concise overview of the role of autophagy in regulating hepatic metabolism in healthy conditions and various chronic liver diseases. I recommend that any scientist who investigates liver fibrosis should read this review. The other three reviews “Potential Roles of Siglecs in the Regulation of Inflammatory and Immune Response” by Dr. Cai [6], “Wnt Signaling in Inflammation in Tissue Repair and Regeneration” by Dr. Zhou [7] and “Crosstalk between the CX3CL1/CX3CR1 Axis and Inflammatory Signaling Pathways in Tissue Injury” by Miss Ou [8] discussed some key pathways and proteins in inflammation during tissue injury and repair. I think these are favorable for readers who are interested in these research fields. I believe all the reviews in this issue will attract your attention and give you some inspiration for further research in inflammation in a broader disease spectrum.

Tissue differentiation is a complex physiological process accompanied with cellular proliferation and differentiation, which may be regulated by the nutrition status, genes, secreted signaling proteins and related signaling pathways. The growth and development of different tissues such as adipose, muscle, blood, immune, and intestine are critical in different physiological phases, especially weaning. Gu et al. concluded that isoleucine played an important role for maintaining immune function. Wang et al. summarized that the role of the tight junction proteins in the weaned piglet. Accumulated research has indicated that nutrients are key regulators in tissue differentiation. Dietary nutrients are delivered to blood or target organs such as brain, liver, muscle and adipose tissues, and serve as energy source for life activities, or substrates for biologically synthetic molecules via metabolic conversion of nutrients [1]. Autophagy has been reported critical in a variety of cell differentiation processes [2]. In response to nutrients starvation, autophagy can be activated to promote cell survival [3, 4]. Nie et al. reviewed the nutrients which mediate bioavailability and turnover of proteins in mammals, and Ding et al. concluded that the microRNA determines the fate of intestinal epithelial cell differentiation and regulates intestinal diseases. Protein serves as a nutrient supply or signaling molecular functions in the process of tissue differentiation via various signal pathways [5]. Wu et al. concluded epigenetic mechanisms of maternal dietary protein and amino acids affect growth and development of offspring. Che et al. summarized the effects of dietary L-arginine supplementation from conception to post-weaning in piglets. Wu et al. summarized the roles of neuropeptide Y and peptide YY in the adipose tissue and obesity via gut-brain axis. In addition, as the metabolite of protein, some amino acids have been demonstrated to play important functions during this process of tissue differentiation. It is well known that mammalian target protein (mTOR), the main mediator of cellular nutrient sensing, plays a vital regulatory role in the process of cell growth, such as protein synthesis [6]. mTORC1 is a highly conserved protein kinase complex in eukaryotic cells and regulates cell growth, development and autophagy by sensing and integrating external information, such as growth factor, energy status and nutritional level. mTORC1-mediated NRBF2 phosphorylation functions as a switch for autophagy [2]. Moreover, proteins such as Ras, PI3K, Akt, JAK, and STAT are all involved in cell proliferation, differentiation and autophagy, acting as various kinase and transcription factors. Ma F. et al. summarized the bioactive proteins and their physiological functions in milk. Chen J. et al. described the functions of fatty acids with different chain lengths on the intestinal health in pigs. Different tissues during weaning, such as adipose tissue, small intestine, skin, breast and brain need to be constantly updated, which depended on the proliferation and differentiation of stem cells. Ma W. et al. reviewed tissue differentiation and its regulatory mechanisms by master proteins of nervous system during weaning. Chen X. et al. reviewed differentiation and proliferation of intestinal stem cells and its underlying regulated mechanisms during weaning. Kindlin-2 signaling axis has been reported to take part in the differentiation of mesenchymal stem cell (MSC) that are important candidates for therapeutic applications duo to their critical roles in tissue development and regeneration [1]. Dong et al. summarized the mechanisms of adipose differentiation and apoptosis of breast cells after weaning. Zhang et al. reviewed the tissue differentiation of brain using the weaning mouse model. Microbiota and their metabolites can accelerate the stem cell differentiation in pre-weanling phase; for example, microbial components such as Lactobacillus modulate the proliferation and differentiation of intestinal stem cells (ISCs) via activation of the STAT3 signaling pathway induced IL-22 secretion in lamina propria lymphocytes [7]. The short-chain fatty acids (SCFA), such as acetic acid, propionic acid and butyric acid, which are produced by fermentation of gut microbiota, have shown their function in adipocyte differentiation through modulating the expression of enzymes involved in fatty acid metabolism, such as lipoprotein lipase (LPL), adipocyte fatty acid binding protein 4 (FABP4), fatty acid transporter protein 4 (FATP4), and fatty acid synthase (FAS) [8]. Tao et al. revealed that intrauterine growth restriction alters the genome-wide DNA methylation profiles in small intestine, liver and longissimus dorsi muscle of newborn piglets. In this theme issue, we focus on the tissue growth-differentiation and its regulatory mechanisms, as well as the functional proteins involved in these processes and their interaction with microbiota and their metabolites. In addition, the influence of nutrients or bioactive molecules on tissue growth-differentiation will be discussed.

Proteins and Peptides from Traditional Chinese Medicine (TCM)

Dietary protein is of vital importance in mammals, which can serve as building blocks for tissue, fuels for small intestinal mucosa and precursors of numerous essential substances such as enzymes, hormones and antibodies. The digestion of dietary protein in mammals is mainly carried out in the stomach and small intestine. In mammals, protein is broken down into amino acids (AAs), and then sent to the body through blood circulation. AAs that reach liver contribute to liver proteins and plasma proteins, and the rest go through the systemic circulation from liver to other tissue cells for tissue proteins, and promote body tissue update, growth and the formation of animal products [1]. Lv et al. reported the regulatory role of dietary protein on bone metabolism via GH/IGF axis. AAs can also compound antibodies, enzymes, nitrogen hormones and convert to nucleotides, choline and other active substances. The escaped AAs will enter the large intestine for further fermentation by the vast gut microbiota and generates short chain fatty acids or amines. He et al. revealed the gut mucus-microbial interplay under stress. Wang et al. reviewed the protein utilization by probiotics in gastrointestinal tract. These metabolites elicit a wide range of biological functions via different receptors and mechanisms [2]. Bioavailability of protein in mammals is affected by many factors. Different kinds of animals have varied digestion and absorption mode for the same dietary protein for their different physiological features of digestive system. The AA composition of the protein is closely related to the nutritional value of the protein. It is necessary to consider AA imbalance and antagonism in order to ensure that the animals achieve the maximum deposition rate of dietary protein. Kim et al. reported the significance of AAs supplementation on protein-restricted diets in pigs. Zhao et al. proposed some nutritional approaches to improve the feed protein utilization in cattle. The composition of diets such as protein and fiber level also matters. With the increase of fiber level, the rate of protein emptying in the digestive tract also increases, which reduces the enzyme action time and the absorption by the intestinal tract [3]. There is increasing evidence that microbial ecosystem of the gastrointestinal tract is largely influenced by dietary factors. Ingested nutrients can be digested and bio-conversed in the digestive tract by host and intestinal microbiota. Both level and source of proteins modulate intestinal micobiota composition and function [4]. Hao et al. summarized the physiological functions of lactoferrin. Different dietary protein level alters the composition of gut microbiota and intestinal barrier function in adult pig model [5]. Highly digestible protein sources can be digested by enzymes in the proximal intestine, resulting in less possibility for microbial fermentation [6, 7]. In addition, proteins from different sources in diet have specific AA composition, which can induce the transcription level of genes such as Cationic amino acid transporters (CAT1) and Excitatory amino acid carrier (EAAC1), which plays a role in AA transporter in gut. Intestinal microbiota composition and function are affected in this process by the alteration of AA balance [8, 9], and Zhao et al. reviewed the role of dietary protein on gut microbiota composition and function. When these AA materials are transported to the liver, the hepatocytes play important metabolic and detoxifying roles. Che et al. concluded the Xenosensors act in chemical detoxification metabolism. In this theme issue, we focus on the bioavailability and turnover of dietary protein in mammals, as well as their interactions with microbiota, which will shed light on highlighting their mechanisms of physiological functions in mammals.

Mixed-mode (multimodal) chromatography now occupies an important place in biopharmaceutical purification. It adds a new dimension to such conventional chromatographies as ion-exchange, hydrophobic interaction, reverse-phase and size-exclusion. Mixed-mode chromatography resins are composed of multiple functional groups that help protein binding and elution. These groups on resins confer hydrophobic, aromatic, electrostatic and hydrogen-bonding interactions. Earlier version of mixed-mode resins was composed of aliphatic hydrophobic groups and used extensively for extraction and purification of small organic compounds, but is not useful for proteins, as the protein binding is too strong to elute without application of organic solvents. Namely, such aliphatic mixed-mode resins are essentially identical to the operational procedure of reverse-phase chromatography. Later version of mixed-mode resin is composed of aromatic and charged groups, which make protein binding salt-tolerant: namely, protein binding occurs in the presence of salt. Such multiple binding mechanisms of mixed-mode chromatography offer various advantages, which are a topic of this special issue. Halan et al. provide an overview of various mixed-mode ligands and their application for separation of peptides, proteins, nucleic acids and small molecules [1]. Santarelli and Cabanne describe application of mixed-mode chromatography for antibody purification and its selectivity [2], followed by Cabanne and Santarelli who describe the development of a high-throughput screening to fully utilize mixed-mode chromatography technique [3]. Arakawa et al. [4] describe solvents to selectively elute the bound proteins during MEP chromatography, as an alternative to the conventional low pH elution. Solvents, or elution modifiers, play a critical role in separation and recovery during mixedmode chromatography. Arakawa and Kita describe fundamental mechanism of the effects of solvents on macromolecular interactions based on protein-solvent interaction analysis. Among the elution modifiers used, arginine has been extensively used for washing and elution in mixed-mode chromatography [5]. Hirano et al. describe the mechanism by which arginine exerts its effects on disrupting interactions between proteins and mixed-mode ligands [6]. Nucleic acids also have both electrostatic and hydrophobic properties and hence are potential candidates for purification by mixed-mode chromatography, in particular due to their different conformational states. Matos and Bülow compare mixed-mode chromatography with ion-exchange or hydrophobic interaction chromatography for nucleic acid purification [7]. In two papers Arakawa et al. and Arakawa demonstrate the usefulness of mixed-mode chromatography in separation of protein isoforms [8, 9]. He et al. report use of mixed-mode chromatography in removal of contaminants, which have similar properties to the target antibody, IgM [10]. Yoshimoto et al. report the selectivity of hydroxyapatite chromatography utilizing its electrostatic and metal affinity properties. I believe that these papers provide readers comprehensive views of mixed-mode chromatography [11]. I wish to thank the staff of Current Peptide and Protein Science for their assistance in developing this Hot Topics issue and Professor Ben Dunn, Editor-in-Chief of CPPS, for his encouragement.

Transforming Growth Factor beta (TGF-β) family of peptides is compose by the subfamilies of TGF-β, BMP and Activins. This broad and versatile family of peptide has several physiological and pathological functions in many tissues. The importance of these functions has been demonstrated in a wide variety of processes, including development, differentiation, angiogenesis, apoptosis and survival. Moreover a dysregulated expression or aberrant signaling associated to peptides of (TGF-β) family can contribute to the development and progression of multiple human pathophysiological processes such as diabetes, cancer, and cardiovascular, skeletal muscle and renal disease. These pathological status can be potentiated by aging which is highly relevant considering that the population affected by chronic disease and aging is increasing in the last decades. We encourage investigators to contribute reviews articles that summarize recent findings in both basic and clinical research in the field of the role of TGF-β family of peptides in both physiological and pathological status that will help to discuss current outcome and to understand the cellular and molecular mechanism involved. The potential topics include, but are not limited to: β New mechanisms involved on the deleterious effect of TGF-β family of peptides in aging and chronic diseases. β Recent advances on cellular and molecular aspects of mechanism, therapy or prevention of diseases in which TGF-β family is involved and potentially can be a target for interventions. β Studies directed to find and develop new drugs anti- TGF-β family for prevention of pathological status. β Signaling pathways that contribute effect of TGF-β family of peptides during development or healthy status.

Protein and peptide based therapy of various human diseases has been the backbone of healthy society. Over the years, this approach has yielded rich dividends in terms of scientific achievements and medical accomplishments. This hot topic issue covers new emerging trends in protein and peptide based therapeutic approaches. The part-II of this issue has incorporated the review articles covering new dimensions of protein and peptide based vaccine development with articles exploring new dimensions of chemotherapeutic drugs and plasma proteins, protein-protein interaction in various diseases, immunogenicity in protein and peptide based therapeutics, and polymer based protein therapeutics, urotensin based pathophysiological regulation of various disorders. These articles provide a detailed account of the usage and applications of the above-mentioned approaches in therapeutics of various human diseases. Zia et al. contributed an article describing a detailed view of the interaction of a number of clinically important therapeutic drugs currently in use that show covalent or non-covalent interaction with serum proteins. Rabbani et al. contributed an article describing the role of protein-protein interactions in various diseases and their prediction techniques. Fernández et al. contributed an article describing the overview of immunogenicity in protein and peptide based-therapeutics. Bhawani et al. contributed an article describing the challenges in formulation of therapeutic proteins, synthetic routes of conjugates, smart polymer–proteins conjugates and some advantages/disadvantages of polymers as a carrier system of proteins. These review articles would expectedly make a wonderful read for the researchers and clinicians working for the quest of protein and peptide based therapeutics. I, as Guest Editor, would like to express my heartfelt gratitude to the many authors who contributed to this special issue, reporting investigations on various aspects concerning New Emerging Trends in Protein and Peptide Based Therapeutic Approaches–Part II.

Protein and peptide based therapy of various human diseases has been the backbone of healthy society. Over the years, this approach has yielded rich dividends in terms of scientific achievements and medical accomplishments. This hot topic issue covers new emerging trends in protein and peptide based therapeutic approaches. The part-I of this issue has incorporated the review articles covering latest updates on the therapeutic role of proteins and peptides in various human diseases like breast cancer, neurodegenerative disorders like Autism Spectrum Disorders and Alzheimer’s disease, systemic lupus erythematosus, leprosy, and obesity. One review article explores urotensin based pathophysiological regulation of various disorders. These articles effectively update the latest findings on the role of protein and peptide based therapeutic approaches for these major human diseases. Rizvi et al. contributed an article describing therapeutic targeting of amyloid precursor protein and its processing enzymes for breast cancer treatment. Alexiou et al. contributed an article describing several pieces of evidence associated with the correlations of misfolding proteins and neurodegenerative diseases, and presented computational analysis of the various essential proteins. Fatima et al. contributed an article describing emerging targets and latest proteomics based therapeutic approaches in neurodegenerative diseases. Alexiou et al. contributed an article describing significant correlations between proteins linked to Autism Spectrum Disorders and Alzheimer’s disease. Khan et al. contributed an article describing the impact of hydroxyl radical modified-human serum albumin autoantigens in Systemic Lupus Erythematosus. Tarique et al. contributed an article describing the role of various subtypes of T-cell and their cytokines in the pathogenesis of leprosy. Guilherme et al. contributed an article focusing on the genes that confer susceptibility with a perspective on vaccine development to prevent the rheumatic heart disease. Queen et al. contributed an article describing the role and mechanism of carbonic anhydrase V in obesity and its therapeutic implications. Svistunov et al. contributed an article describing the targets at Urotensin system for pharmacological intervention of a number of pathological statuses and diseases. These review articles would expectedly make a wonderful read for the researchers and clinicians working for the quest of protein and peptide based therapeutics. I, as Guest Editor, would like to express my heartfelt gratitude to the many authors who contributed to this special issue, reporting investigations on various aspects concerning New Emerging Trends in Protein and Peptide Based Therapeutic Approaches– Part I.

Sarcopenia, the age-related loss of muscle mass and strength/function, is increasingly recognized as a major issue in geriatric medicine. It is noteworthy that the study of this condition has recently extended beyond the boundaries of geriatrics, highlighting the relevance of muscle physiology to the overall health status. Indeed, the assessment of sarcopenia is increasingly invoked as an important tool for the risk stratification of patients suffering from a variety of medical conditions, such as liver disease, cancer, cardiovascular disease, chronic kidney failure, among others. The wide range of negative health-related events to which sarcopenia contributes has instigated intensive research efforts in the attempt to decipher its complex pathophysiology and develop effective treatments. This mini thematic issue has been conceived as a fairly comprehensive overview of the state of art on sarcopenia, including operational definition, pathogenic processes, candidate biomarkers, and potential therapeutic interventions [1-6]. The contribution by Ponziani & Gasbarrini [7] on the relevance of sarcopenia in advanced liver disease has been included to acknowledge the growing interest in muscle decline outside the original field of geriatric medicine. The opening article by Landi et al. [1] provides an overview on current definitions, diagnosis, and treatment of sarcopenia. Special emphasis is placed on the ongoing debate regarding the need of adopting an univocal definition of sarcopenia as an essential requisite to promote its clinical implementation and the development of new treatments. As pointed out by Calvani et al. [2], the lack of a unique definition of sarcopenia impacts the identification of meaningful biomarkers for the condition. Such a task is also challenged by the multifaceted and only partly understood pathophysiology of sarcopenia. The complexity of muscle aging is epitomized by the controversial role played by oxidative stress in this process, as discussed by Fougère et al. [3]. While the free radical theory of aging provides a strong rationale for the use of antioxidants as a countermeasure for sarcopenia, the evidence of benefits is still inconclusive. On the other hand, the review by Anton et al. [4] reports on the efficacy of multimodal interventions combining exercise and specific nutritional supplementation regimens at improving muscle mass and strength in old age. β-hydroxy-β-methylbutyrate, a metabolite of leucine, and taurine, a pleiotropic amino acid, are two promising nutritional agents against age-related muscle loss, as reviewed by Cruz-Jentoft [5] and Scicchitano & Sica [6], respectively. The last contribution discusses the importance of the assessment of sarcopenia in the clinical management of patients with advanced liver disease [7]. The authors also illustrate similarities and differences in the pathogenesis of sarcopenia of aging and liver disease-associated muscle wasting. As the guest editors, we wish that the collection of articles chosen for this mini thematic issue will stimulate the interest not only of those working in the field, but also of scientists from other biomedical disciplines. Finally, we would like to sincerely thank all of the authors and referees who have contributed to this issue.

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