ISSN (Print): 1389-2037
ISSN (Online): 1875-5550
Volume 20, 12 Issues, 2019
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ISSN (Print): 1389-2037
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Ben M. Dunn Department of Biochemistry and Molecular Biology
University of Florida, College of Medicine,
P.O. Box 100245, Gainesville Florida, FL 32610-0245 USA
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Its my pleasure that I got to publish in your journal. Thank you for your supportive mail.
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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