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Volume 21, 12 Issues, 2020
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28 Articles Ahead of Print are available electronically
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 . Reviewed how
melatonin modulates lactation by regulating prolactin secretion via tuberoinfundibular dopaminergic neurons in Hypothalamus-
Pituitary system. Shan et al.  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 . Xie et al.  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  and only ileum of growing pig model .
The emergence of the gut microbiota as a key regulator of health and disease further complicates the function of the protein
. 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 . Peng et al.  summarized the regulation of probiotics on metabolism of
dietary protein in intestine. Peng et al.  also reviewed the effect of Escherichia Coli infection on metabolism of dietary protein
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 . 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 . Moreover, a range of active metabolites of tryptophan is generated involving
in immune response . Serotonin can be regulated by toll-like receptors (TLRs) to connect gut-brain axis .
Kynurenine serves as the ligand for aryl hydrocarbon receptor (AhR), which exert bidirectional functions in the crosstalk
among tryptophan, microbiota, and the immune system . AhR can also be regulated by cytochrome P450 1 enzymes via a
feedback loop . Furthermore, CARD9 was reported to impact colitis by altering gut microbiota metabolism of tryptophan
into AhR ligands . Jia et al.  summarized the effects of medium-chain fatty acids in intestinal health of monogastric
animals. Sun et al.  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 . 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 . 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) . TMAO is predictive of cardiovascular events in various populations and has been implicated in the development
of fatty liver disease , which is expected to be a therapy target. Zheng et al.  revealed the role of BCL-2 family
proteins in apoptosis and its regulation by nutrients. Zhang et al.  concluded the fermentation and metabolism of dietary
protein by intestinal microorganisms.
Nie et al.  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 , 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
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
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 .
The contribution by Reynoird’s group provides a comprehensive overview of the lysine methyltransferases (KMTs) signalling
in non-histone proteins . 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 
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 . 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 .
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 .
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 . 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 .
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 .
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 . 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 . 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 .
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 .
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 . 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 .
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 . 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 . 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 .
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 . 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 .
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. . 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 ; while García-Carnero
et al. describe the relevance of these polysaccharides and proteins during recognition by the host immunity . 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 . 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 . 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 . 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 .
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 . 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 .
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 . 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 .
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 . 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 .
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 . 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 . Secondly, storage mite,
Blomia tropicalis, is a major source of dust allergens in subtropical and tropical regions . Among the common household
pests, the cockroach is a potent producer of inhalant insect allergens . Other domiciliary insects such as ant, mosquito, mayfly,
housefly, silkworm moth, silverfish and termite have been documented as the source of indoor allergens .
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
. 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 . 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
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 . 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 . 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  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 . 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 . 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 . This is a prerequisite for developing either inhibitors or promoters of amyloidforming
processes. Menyhárd et al. describe structure and size selection of serine oligopeptidases . 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 . 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 . The group of Professor Jampilek prepared ten new 1-(4-nitrophenyl)piperazine derivatives
and determined their antistaphylococcal, antimycobacterial, and antifungal activities . 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 . The prevalence of
cardiovascular disease is increasing globally . 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 . 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) , which is activated by primary bile acids (BAs) such as chenodeoxycholic acid, cholic acid
and synthetic agonists , plays a critical role in regulating lipid and glucose metabolism, oxidative stress and inflammation
. 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 . MicroRNAs (miRNAs) are small, noncoding RNAs that play critical roles in AS by regulating posttranscriptional
gene expression . 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  and cardiomyocytes . 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) . 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 . 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 . 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 . 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 . 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
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  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  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
, “Wnt Signaling in Inflammation in Tissue Repair and Regeneration” by Dr. Zhou  and “Crosstalk between the
CX3CL1/CX3CR1 Axis and Inflammatory Signaling Pathways in Tissue Injury” by Miss Ou  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
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 . Autophagy has been reported critical in a
variety of cell differentiation processes . 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 . 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
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 . 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 . 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 . 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 . 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) . 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 . 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 .
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 .
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 . 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 . 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 . Santarelli and Cabanne describe application of mixed-mode chromatography for antibody purification and its selectivity
, followed by Cabanne and Santarelli who describe the development of a high-throughput screening to fully utilize mixed-mode
chromatography technique . Arakawa et al.  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 . Hirano et al. describe the mechanism by which arginine exerts its effects on disrupting interactions between
proteins and mixed-mode ligands . 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 . 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 . 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 .
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
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
β Signaling pathways that contribute effect of TGF-β family of peptides during development or
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
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
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
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
Alexiou et al. contributed an article describing significant correlations between proteins linked to Autism Spectrum Disorders and Alzheimer’s
Khan et al. contributed an article describing the impact of hydroxyl radical modified-human serum albumin autoantigens in Systemic
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  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.  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.
, 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. .
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.  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  and Scicchitano & Sica , respectively.
The last contribution discusses the importance of the assessment of sarcopenia in the clinical management of patients with advanced
liver disease . 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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