ISSN (Print): 1389-2010
ISSN (Online): 1873-4316
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ISSN (Print): 1389-2010
ISSN (Online): 1873-4316
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Davide Prosperi Department of Biotechnology and Bioscience University of Milan Bicocca Milano Italy
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Special Issue Submission
"Current Pharmaceutical Biotechnology presents the latest developments in the area of biotechnology. This is strongly recommended."
PREECLAMPSIA - AETIOPATHOGENESIS AND CLINICAL MANAGEMENT
Guest Editor(s): Marzena Laskowska
Tentative Publication Date: March, 2018
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DIAGNOSTIC AND PROGNOSTIC INSIGHTS OF BIOMARKERS IN CARDIOVASCULAR DISEASES
Guest Editor(s): Michael Behnes, Ibrahim Akin
It was a great experience for me working with Bentham Science Publishers because of the following reasons:
-High quality services
-Great and kind cooperation and collaboration
Dr. Helmy Selman(The CIVF Center Doha Center Clinic Hospital Doha, Qatar)
Has contributed: Ovarian Stimulation Protocol in IVF: An Up-to-Date Review of the Literature
In the second last decade of the last century circulating extracellular RNA (exRNA)-
proteolipid complexes have been identified in cancer patients. It has been hypothesized that
they mediate host-tumor interactions and specific exRNAs have been shown to be useful
tumor markers. Meanwhile, extracellular nucleic acids were demonstrated to trigger
inflammation and accordingly to promote inflammatory diseases such as cancer, rheumatoid
arthritis, and atherosclerosis. Moreover, exRNA has been identified as “natural foreign
surface” initiating blood coagulation and hence thrombus formation, and to trigger edema
formation. Neutrophil extracellular traps (NETs), which were initially thought to have
beneficial functions by trapping bacteria and limit their dissemination, are now known to
trigger pathological situations. In a model of experimental heart transplantation promoting
exRNA degradation has not been only demonstrated to be safe but to counteract graft
rejection. Accordingly, extracellular nucleic acids present promising new drug targets for
treatment of a multitude of burdening diseases. The purpose of this issue is to summarize the
functions of extracellular nucleic acids in chronic and acute diseases disclosing them as
specific drug targets. Moreover, the nature of pharmaceutical drugs required for treating acute
diseases on the one hand, and more chronic diseases on the other hand will be outlined.
Food Science is a modern, multidimensional, rapidly developing scientific field which is continuously and drastically promoting
significant and innovative scientific advances that strongly reinforce human public health and quality of life. In the last
few decades, there is plenty of substantial evidence that several bioactive food components may exert beneficial effects against
diverse chronic diseases by preventive and/or therapeutic mechanisms of action [1-3]. Notably, it should be noted that more
than 60% of the currently available drugs in medicine have been directly or indirectly derived by naturally occurring sources
such as foods, plants and herbs [1-3]. In this aspect, Food Science cooperatively utilizes modern methodological techniques and
cutting edge technologies based on diverse basic sciences such as molecular biology, biotechnology, biochemistry, physiology
and epidemiology. In view of the above considerations, the purpose of this special issue is to highlight recent advances in the
multidimensional field of Food Science that collectively promote human public health and quality of life.
Medicinal Chemistry and Drug Design scientific domains have been currently focused on drug-like compounds of natural
origin, e.g. naturally-derived molecules from foods, plants and herbs that are used as lead compounds for discovering novel,
more effective drug candidates with less adverse effects in order to be introduced in the clinical practice. In this aspect, at the
first part of this special issue, Pontiki et al. present in depth, from a medicinal chemistry and pharmacological point of view, the
multiple biological activities of cinnamate hybrids analogues, such as anti-Alzheimer, anticancer, cardioprotective, antiviral and
antimalarial activities . In a second review article, Mantzorou and Giaginis critically analyze, at a clinical level, the currently
existing clinical trials that have evaluated the efficacy of supplementing cranberry products against urinary tract infections in
different human subpopulations . The authors conclude that cranberry supplementation can safely be suggested as complementary
therapy in women with recurrent urinary tract infections, whereas no conclusive and precise results have currently
been obtained concerning other human subpopulations, especially in human populations at increased risk for contracting urinary
tract infections .
Medical and Molecular Biology scientific domains have also been focused on natural-derived drugs that are currently used
in the clinical practice, as well as natural-derived drug-like compounds, evaluating their biological activity against several
chronic diseases. In this aspect, Kontos et al. assessed the molecular effects of treatment of human colorectal cancer cells with
doxorubicin, a 14-OH derivative of the natural product daunorubicin, and common chemotherapeutic drugs . They found
significant alterations in the expression levels of BCL2 family genes favoring apoptosis and/or particular proapoptotic transcripts
. In another study, Mavrogiannis et al. investigated the effects of vinca alkaloids (vincristine, vinblastine, and vinorelbine)
on miRNA expression of breast cancer cells . This study supports substantial evidence for the possible involvement
of miR-222-3p in breast cancer cell apoptosis, triggered by vincristine, vinblastine, and vinorelbine . Moreover,
Kalantzis et al. evaluated the effect of chemotherapeutic agents, Docetaxel and Mitoxantrone, on the expression of human LDopa
decarboxylase in human prostate and breast cancer cell lines . L-Dopa decarboxylase has been implicated in the pathophysiological
mechanisms of several human cancers. Interestingly, Docetaxel is a semi-synthetic analogue of Paclitaxel, an
extract from the bark of the rare Pacific yew tree Taxus brevifolia, and Mitoxantrone is an anthraquinone derivative bearing
polyamine side chains that can be considered as a partial analog of anthracyclines which are extracted from Streptomyces bacterium.
This study supports substantial evidence for the possible involvement of L-Dopa decarboxylase expression in Docetaxel
and Mitoxantrone induced cytotoxicity and apoptosis . In conclusion, all the above studies cooperatively reinforce the multidimensional
advancements of Food Science that significantly promote human public health and quality of life.
Preeclampsia, a unique human pregnancy disorder, is a major cause of maternal and fetal mortality and
morbidity worldwide. It remains amongst the biggest challenges in obstetrics, but its precise
aetiopathogenesis is still unclear.
Although the main symptom is hypertension, preeclamptic woman manifests the change in many
organs. PE is characterized by an increased vascular resistance, increased activation of the coagulation
system, and reduction of intravascular volume, injury of vascular endothelium, leading to a reduced
perfusion of all maternal organs, including the uterus, kidney, brain and placenta. Severe cases may
include eclamptic seizures, placental abruption, premature labour, intracranial haemorrhage, DIC,
HELLP syndrome, renal and hepatic failure. Severe preeclampsia is always a life threatening human
pregnancy complication. Preeclampsia affects not only the mother but also fetus. IUGR affects
approximately 13 to 60% of infants born from preeclamptic pregnancies.
Currently, no definitive treatment or effective prophylaxis for preeclampsia are available. Delivery still
remains the only curative treatment in cases of severe preeclampsia, but is not always advantageous for
the fetus. The decision is always very difficult because preterm birth may result in many health
consequences for the child.
The aim of this special issue is exploration of aetiopathogenesis of preeclampsia as well as best practices
update and current clinical management of severe preeclampsia, eclampsia and HELLP syndrome.
The understanding the etiological determinants of preeclampsia may lead to new therapeutic
approaches and is essential for effective therapies and lowering maternal and fetal mortality and
morbidity related to these serious pregnancy complications.
Along with the increasing prevalence of cardiovascular and immunological disorders, in a continuously-
ageing population, our understanding of the precise mechanisms that regulate cellular complex
biochemical environments is increasing. Cellular networks, pathways and biochemical codes are being
deciphered, shedding lights on novel therapeutic routes. In this context, inflammation and dysregulated
immune system represent a true cellular model that links the pathophysiology of cardiovascular disease
and the fine tuning of all the mechanisms that orchestrate the cellular systems. This Special Issue is
composed of important contributions on the topic.
The first manuscript addresses an important immunological disease, such as Common variable immunodeficiency
(CVID), the most frequent symptomatic antibody deficiency in adults, in which the
humoral immune impairment exposes patients to a wide spectrum of clinical manifestation, including recurrent infections. Interestingly,
patients with CVID can present with inflammatory, autoimmune disease, hematologic disease and cancers. Varricchi
and collaborators  present interesting results from 58 patients diagnosed with CVID and treated with regular immunoglobulin
replacement therapy who underwent gastrointestinal endoscopic examination for the evaluation of gastroduodenal
manifestations of their CVID. Histopathologic findings revealed a high prevalence of chronic inflammatory gastrointestinal
disorders (chronic gastritis, chronic duodenitis, increasing intraepitelial lymphocytes, and the absence of plasma cells) that are
not responsive to the immunoglobulin replacement therapy. This observation points out that in CVID patients there is a more
complex immune dysregulation rather than a true humoral immunity deficiency. Indeed, these patients could represent a real in
vivo model to deeply study immune system activation, autoimmunity and inflammation. In this context, in the second article, dr
Pecoraro and colleagues  explored the ability of a simple screening test, the Calculated Gobulin (CG), to be effective in the
early detection of antibody deficiency, in order to reduce diagnostic delays as well as the healthcare costs of specific immunoglobulin
dosage. The CG derives from the difference between total protein and albumin, and a ROC curve analysis-derived cutoff
of 19 g/l was able to detected patients with IgG lower than 600 mg/dl with a sensitivity of 70% and a specificity of 75%.
Inflammation plays a major role also in the manuscript authored by Pasqua and coworkers , that addresses mechanisms
of hypertension, the most prevalent cardiovascular disorder. Here, the authors describe in details the role of NLRP (nucleotide
binding oligomerization domain Leucine-rich repeat) in the pathophysiology of arterial hypertension. NLRPs are members of
pattern recognition receptors (PRR) that have the ability to activate immune cells detecting PAMPs (pattern associated molecular
patterns) and DAMPs (damage associated molecular patterns). In the context of the danger-model of hypertension, priming
hypertensive stimuli could promote the activation of the NLRP3-inflammosome that maintains a low-grade of sterile inflammation
in a vicious circle that sustains hypertension itself, thus leading to organ damages.
Despite the role of Chemokines in inflammation has been extensively underscored, Sara Paccosi and Astrid Parenti  dissect
the role of chemokine pathways in modulating vascular growth mechanisms. In particular, the family of CC-Chemokines
directly interacts with vascular cells, endothelial cells, vascular smooth muscular cells (VSMC), fibroblasts, platelets, erythrocytes,
and glomerular renal cells in a leukocyte independent-way, being involved in compensatory vascular remodeling such as
angiogenesis, atherosclerosis, arteriogenesis. For example, the CCL-2/CCR2 axis plays an important role in restenosis and
plaque formation, with a direct effect on VSMC proliferation. The authors focused on Atypical Chemokine Receptors Families
(ACKRs), chemokine receptors that were found to have an important scavenger function in regulating chemokine trafficking,
and could be considered an interesting potential therapeutic target.
Finally, two complementary and extensive reviews point out the crucial role of the endothelial progenitor cells (EPCs), a
subunit of mononuclear cells (MNCs), in the angiogenesis and remodeling processes, with a special focus as potential therapeutic
targets. Guerra and collaborators  investigate the precise role of the circulating EPCs in the remodeling mechanism involved
in pulmonary vascular diseases. Pulmonary arterial hypertension (PAH) is characterized by circulating progenitor recruitment,
enhanced angiogenesis and endothelial cell dysfunction that lead to increasing vascular resistances. Manipulating the
VEGF (vascular endotelial grow factor) signaling pathway to stimulate endothelial vascular growth seems to be a promising venate the angiogenic activity. The exhaustive review of Moccia and coworkers  illustrates how the Ca2+ toolkit, the “signalosome”
that regulates the intracellular Ca2+ concentration, drives proliferation, tube formation and neovessel formation, in
the ECFCs cells, a subset of EPCs that possesses high intrinsic clonal potential. All the signaling components (channels, transporters,
pumps and receptors) of the Ca2+toolkit can be tuned and genetically manipulated to improve the vascular regenerative
potential. This systematic review offers a complete survey of the signaling cascade that from VEGF and Stromal cell-derived
factor-1a (SDF-1a) leads to oscillation of intracellular Ca2+ concentrations in peripheral blood and umbilical cord blood-derived
ECFCs, triggering store operated Ca2+entry (SOCE). Arachidonic-acid and nicotine acid adenine dinucleotide phosphate
(NAAP) could stimulate Ca2+ release from the endolysosomal compartment and activate ECFC proliferation, supported by TRP
In conclusion, all the manuscripts of this Special Issue offer different views of the complex mechanisms that regulate inflammation
and cardiovascular diseases, from basic science to clinical works, focusing on the special approach that regenerative
medicine and genetic manipulation have opened. These observations should open new routes in the knowledge of different
conditions and new promising therapeutic targets.
The mechanism of RNA interference (RNAi) mediated by small non-coding RNAs (ncRNAs) was
discovered only two decades ago, and research into this field has already achieved therapeutical results
by the development of a small interfering RNA (siRNA)-based drug for the treatment of the Hereditary
Transthyretin Amyloidosis, an autosomal dominant disease . Moreover, microRNAs (miRNAs)
known to trigger the RNAi pathway in human cells have also shown to be useful biomarkers for disease
diagnosis and therapy response [2-4]. Nowadays, ncRNAs are recognized to be important
transcriptional modulators not only capable of suppressing but also of promoting gene expression. This
mechanism, referred to as RNA-mediated gene activation (RNAa), is triggered by small activating
RNA (saRNA) molecules that bind to complementary gene sequences and activate transcription [5-9].
Recent research into RNAa has started to unravel the underlying basis linked to saRNA-based activation
phenomena and enabled the design of saRNAs with ability to regulate the expression of target genes in different cells types
[10-13], even being in the process of developing a RNAa therapy against hepatocellular carcinoma [14,15]. Similarly to siRNAs,
short activating RNAs might be used as therapeutic agents for treatment of different diseases, associated in this last case
with the occurrence of loss of function mutations and/or haploinsufficiencies [8,16]. In the near future, it is expected that versatile
delivery systems consisting of siRNA/saRNA-based drugs enable the setup of personalized therapeutic treatments and targeted
molecular therapies, thereby opening exciting new possibilities in clinical medicine and pharmaceutical biotechnology.
In this thematic issue, Drs. Yoon and Rossi  provided a comprehensive overview about the RNAa mechanism, methodologies/
insights for the design and delivery of saRNAs, intracellular functioning and chemical modifications to increase the
oligonucleotide's resistance to nuclease degradation. This work is an analytical overview that focuses on the potential that
RNAa have for the development of therapeutic strategies. Moreover, canonical and non-canonical mechanisms involving
saRNA-mediated gene activation phenomena are also illustrated here.
In the next article, Setten et al.  described the progress of MTL-CEBPA (MiNA Therapeutics, UK), the first saRNAtargeting
drug currently tested in clinical trials (Phase I). Remarkably, this oligonucleotide can be used to induce targeted expression
of the CCAAT/enhancer-binding protein alpha (CEBPα) gene, a known tumor suppressor capable of modulating transcriptional
activity in hepatic cells . In this work, the authors considered the reasons for which MTL-CEBPA represents a
promising saRNA drug against hepatocellular carcinoma, thereby opening the door to the development of new therapeutic
agents in the treatment of patients with cancer and other diseases.
Finally, Drs. Li and Hu  reviewed the state of the research in the RNAa field and underlie the potential of saRNAs to act
as gene modulators, with special emphasis on their use in the treatment of kidney diseases. In this article, the authors associated
short ncRNA-mediated gene regulation pathways (i.e., RNAi and RNAa), and discussed how research into RNAi might be useful
for understanding the molecular mechanisms underlying the endogenous RNAa phenomena.
We here introduce the second part of a thematic issue devoted to the analytical advances in clinical and forensic toxicology,
with a particular focus on the determination of new psychoactive substances and eventual metabolites in conventional and nonconventional
biological matrices .
This second part opens with a review which explores the close connections between clinical and forensic toxicology in
overlapping areas of interest, such as prenatal exposure to drugs or fetal alcohol syndrome, doping control, sudden cardiac
death, determination of brain death, sudden infant death syndrome, Munchausen syndrome by proxy, drug-facilitated crimes
and intoxications by new psychoactive substances. Some of these topics are initially treated in hospital emergency departments,
involving clinical laboratories and sometimes lately derived to forensic laboratories. Conversely, cases with initial medicallegal
implications and fatalities are directly handled by forensic toxicology, but may trigger further studies in the clinical setting.
Thus, increasing relationships are improving the growth, reliability and robustness of both kind of laboratories, respecting
in both cases most recent updated and standard practices for the development and validation of the analytical methods [2-4].
The first example of the bridges between clinical and forensic toxicology laboratories is given by the case report described
by Jarque et al. concerning a case report of prenatal methamphetamine exposure with toxicological analytical confirmation in
maternal and biological matrices. The toxicological findings prompted the removal of guardianship to the parents and authorized
a temporary foster care. In addition, authors reviewed the updated literature regarding this new outbreak of methamphetamine
abuse with several consequences in young male and male adults .
Not only a case report was presented concerning prenatal exposure to a psychotropic drug, but also an epidemiological
study on gestational consumption and consequent prenatal exposure to drugs of abuse and psychoactive prescription drugs in
513 mother-newborn dyads from Sant Joan de Déu Barcelona Hospital analysing maternal hair and neonatal meconium by
validated chromatographic mass spectrometric methodologies.
An amount of 1.2% gestational drugs of abuse consumption was objectively assessed in maternal hair and 0.4% prenatal
exposure measured in meconium while gestational consumption of psychoactive prescription drugs was 1.7% as measured maternal
hair and prenatal exposure 1.2% in meconium .
Another interesting issue in clinical and forensic toxicology is that of ethyl glucuronide in hair (hEtG) used as a biomarker
in the diagnosis of chronic excessive alcohol consumption. Since some cosmetic treatments may influence the hEtG concentration
leading to false positive results, the effect of alcohol-based perfumes was studied in four different subjects. The liquid
chromatographic mass spectrometric analysis showed in all the cases that prolonged exposition of hair to alcohol-based perfumes
may increase hEtG levels, resulting in false positive results .
Analytical advances were also reported in a remarkable study concerning a striking problem in doping control: the detection
of autologous blood transfusion. The article of Donati et al. reported the results of an investigation aimed to pre-select potential
biomarkers of blood aging and storage that can be measured to identify the presence in the sample of re-infused blood. The parameters
more strongly affected by the ex vivo storage of whole blood resulted to be erythrocytes size and density, annexin V
and microparticles, appearing as a very encouraging suggestion towards the development of a direct method for detecting
autologous blood transfusion in sport doping .
With respect to the determination of new psychoactive substances and eventual metabolites in conventional and nonconventional
biological matrices, an essential contribution has been that of Guillou et al. from the Joint Research Centre of
European Commission in charge of providing its scientific support to the EU Customs laboratories and more in general to the
European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) to facilitate the rapid identification and characterisation
of new psychoactive substances in suspected seized samples.
In the presented report the research group described and discussed the implementation of the workflow mechanism, regarding
the harmonisation of procedures to facilitate the monitoring, communication and management of analytical data obtained by
extensive analysis of unknown seized material with some recent real examples. The rapid dissemination of the obtained information
is at the moment an essential tool for control authorities to facilitate the protection against the health risks posed by potential
harmful psychotropic substances .
On the same line of the previous report has been that of the analytical approaches reviewed by Gerace et al. to disclose the
presence of new synthetic opioids in fatal intoxications . Due to the high potency and the low doses required to produce
desired effects, the risk of overdose for these compounds including severe health implications, is quite high. For this reason, the
detection of these compounds in biological samples is crucial in order to get a better understanding of their concentration and
distribution in body fluids.
A specific example of analytical approach to detect a new synthetic opioid as a cause of an intoxication is that of Vogliardi
et al. using liquid chromatography-high resolution mass spectrometry (LC-HRMS) in a case involving U-47700, a synthetic hair and a white powder found at consumer home were analysed by LC-HRMS, which allowed to reveal the presence of
U-47700 and its phase I and phase II metabolites in blood, urine and pubic hair and also cocaine, benzoylecgonine, norcocaine,
mephedrone, ketamine, norketamine, 3,4-methylenedioxymethamphetamine, tetrahydrocannabinol and cannabinol only in pubic
hair . Conclusion. The toxicological findings confirmed the use of U-47700 in the intoxicated patient and also revealed a
history of a poly-drug use. The use of LC-HRMS allowed the easy identification of the NPS and its metabolites in fluids and
The thematic issue closes with a noteworthy investigation on the metabolites of synthetic cannabinoids most recently used
and encountered in clinical/forensic caseworks . This is the last of a series of studies leadered by Prof Auwarter [13-15],
which provided useful information on what to look for in biological fluids of suspected intoxications by risky synthetic cannabinoids
and analytical methods to better recognize the causing substances.
We wish to thank all the authors who have contributed with valuable manuscripts to this Thematic Issue, the Reviewers who
carried out an excellent job in guarantying the highest standard of quality for each manuscript, the Editorial Manager (Ms. Sumaiya
Azhar) of the Journal for the continuous support and expertise and finally a special thanks to Prof. Davide Prosperi, Editor
in Chief of Current Pharmaceutical Biotechnology, who allowed us to guest edit this thematic issue.
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