Author Correction: Aldo-keto reductase 1C2 (AKR1C2) as the second gene associated to non-syndromic primary lipedema: investigating activating mutation or overexpression as causative factors.

Correction to: Eur Rev Med Pharmacol Sci 2023; 27 (6 Suppl): 127-136-DOI: 10.26355/eurrev_202312_34697 After publication and following some post-publication concerns, the authors have applied the following corrections to the galley proof. -       The conflict of interest section has been amended as follows: J. Kaftalli and G. Marceddu are employees at MAGI EUREGIO. K. Donato is employee at MAGI EUREGIO and MAGISNAT. M. Bertelli is president of MAGI EUREGIO, MAGISNAT, and MAGI's LAB. G. Bonetti, K. Dhuli, A. Macchia, and P.E. Maltese are employees at MAGI's LAB. M. Bertelli, P.E. Maltese, K. Louise Herbst, Sa. Michelini, Se. Michelini, and P. Chiurazzi are patent inventors (US20220362260A1). M. Bertelli, P.E. Maltese, G. Marceddu are patent inventors (US20230173003A1). M. Bertelli, K. Dhuli and P.E. Maltese are patent inventors (WO2022079498A1). M. Bertelli, P.E. Maltese, Sa. Michelini, Se. Michelini, P. Chiurazzi, K. Louise Herbst, J. Kaftalli, K. Donato, and A. Bernini are patent applicants (Application Number 18/516,241). M. Bertelli, K. Donato, P. Chiurazzi, G. Marceddu, K. Dhuli, G. Bonetti and J. Kaftalli are patent applicants (Application Number: 18/466.879). M. Bertelli, G. Bonetti, G. Marceddu, K. Donato, K. Dhuli, J. Kaftalli, Sa. Michelini, and K. Louise Herbst are patent applicants (Application Number 63/495,155). The remaining authors have no conflict of interest to disclose. -       Figure 5 has been modified as follows to better distinguish outliers: -       The legend of Figure 5 has to be modified as follows: Relative expression of AKR1C1 and AKR1C3 in different groups (CTR = non affected controls, L = lipedema patients without overexpression of AKR1C2, L-over = Lipedema patients with overexpression of AKR1C2), showing that lipedema patients expressed AKR1C1 and AKR1C3 levels similar to the control group. Outliers are reported as black triangles. There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/34697.

AKR1C1 and hormone metabolism in lipedema pathogenesis: a computational biology approach.

OBJECTIVE: Lipedema is an autosomal dominant genetic disease that mainly affects women. It is characterized by excess deposition of subcutaneous adipose tissue, pain, and anxiety. The genetic and environmental etiology of lipedema is still largely unknown. Although considered a rare disease, this pathology has been suggested to be underdiagnosed or misdiagnosed as obesity or lymphedema. Steroid hormones seem to be involved in the pathogenesis of lipedema. Indeed, aldo-keto reductase family 1 member C1 (AKR1C1), a gene coding for a protein involved in steroid hormones metabolism, was the first proposed to be correlated with lipedema. PATIENTS AND METHODS: In this study, we employed a molecular dynamics approach to assess the pathogenicity of AKR1C1 genetic variants found in patients with lipedema. Moreover, we combined information theory and structural bioinformatics to identify AKR1C1 polymorphisms from the gnomAD database that could predispose to the development of lipedema. RESULTS: Three genetic variants in AKR1C1 found in patients with lipedema were disruptive to the protein's function. Furthermore, eight AKR1C1  variants found in the general population could predispose to the development of lipedema. CONCLUSIONS: The results of this study provide evidence that AKR1C1 may be a key gene in lipedema pathogenesis, and that common polymorphisms could predispose to lipedema development.

MAGI-Dock: a PyMOL companion to Autodock Vina.

Molecular docking simulation of small molecule drugs to macromolecules is valuable in structural biology and medicinal chemistry research. Its spread is supported by freely available software and databases. Like many resources in the free domain, docking software is command-line based, which comes to a limitation when defining the volume encompassing an active site, the so-called docking box. The box center and size, usually specified as cartesian coordinates, can be adjusted to correctly cover the active site only with a third-party molecular graphics program compatible with the docking input/output files, which reduces the choice to a few options. Moreover, the additional staff training may hamper the adoption of such software, e.g., in an enterprise environment. We exposed the functionality of Autodock and Autodock Vina into a graphical user interface extending upon that of PyMOL. Both the functionality of PyMOL and Autodock are merged, synergizing the capabilities of each program. To overcome such limitations, here we present MAGI-Dock. This graphical user interface combines the power of two of the most used free software for docking and graphics, Autodock Vina and PyMOL. MAGI-Dock is a free open-source software available under the GPL and can be downloaded from https://github.com/gjonwick/MAGI-Dock. The coupling of Autodock Vina with PyMOL through a graphical interface removes the molecular modeling limitations that come with Autodock. Therefore, MAGI-Dock could be conducive to lowering the learning curve for molecular docking simulation, with benefits for trainees in both academia and enterprise environments.

Aldo-keto reductase 1C2 (AKR1C2) as the second gene associated to non-syndromic primary lipedema: investigating activating mutation or overexpression as causative factors.

OBJECTIVE: Lipedema is a debilitating chronic condition predominantly affecting women, characterized by the abnormal accumulation of fat in a symmetrical, bilateral pattern in the extremities, often coinciding with hormonal imbalances. PATIENTS AND METHODS: Despite the conjectured role of sex hormones in its etiology, a definitive link has remained elusive. This study explores the case of a patient possessing a mutation deletion within the C-terminal region of Aldo-keto reductases Member C2 (AKR1C2), Ser320PheTer2, that could lead to heightened enzyme activity. A cohort of 19 additional lipedema patients and 2 additional affected family members14 were enrolled in this study. The two additional affected family members are relatives of the patient with the AKR1C1 L213Q variant, which is included in the 19 cohorts and described in literature. RESULTS: Our investigation revealed that AKR1C2 was overexpressed, as quantified by qPCR, in 5 out of 21 (24%) lipedema patients who did not possess mutations in the AKR1C2 gene. Collectively, these findings implicate AKR1C2 in the pathogenesis of lipedema, substantiating its causative role. CONCLUSIONS: This study demonstrates that the activating mutation in the enzyme or its overexpression is a causative factor in the development of lipedema. Further exploration and replication in diverse populations will bolster our understanding of this significant connection.

Omics sciences and precision medicine in lung cancer.

Abstract: Lung cancer is a complex disease, with a wide range of genetic alterations and clinical presentations. Understanding the natural and clinical history of the disease is crucial for developing effective diagnostic and treatment strategies. Omics approaches, such as genomics, transcriptomics, proteomics, and metabolomics, have emerged as powerful tools for understanding the molecular mechanisms underlying lung cancer and for identifying novel biomarkers and therapeutic targets. These approaches enable researchers to examine the entire genome, transcriptome, proteome, or metabolome of a cell or tissue, providing a comprehensive view of the biological processes involved in lung cancer development and progression. Targeted therapies that address specific genetic mutations and pathways hold promise for improving the diagnosis and treatment of this disease.

Omics sciences and precision medicine in sarcoma.

Background: Sarcomas are a relatively rare but diverse group of cancers that typically develop in the mesenchymal cells of bones and soft tissues. Occurring in more than 70 subtypes, sarcomas have broad histological presentations, posing significant challenges of prognosis and treatment. Modern multi-omics studies, which include genomics, proteomics, metabolomics, and micro-biomics, are vital to understand the underlying mechanisms of sarcoma development and progression, identify molecular biomarkers for early detection, develop personalized treatment plans, and discover drug resistance mechanisms in sarcomas to upsurge the survival rate. Aim: This study aims to highlight the genetic risk factors responsible for sarcoma-genesis, and to present a comprehensive review of multi-omics studies about sarcoma. Methods: Extensive literature research was undertaken using reliable and authentic medical journals, e-books, and online cancer research databases. Mendelian inheritance in man database (OMIM) was explored to study particular genes and their loci that are responsible to cause various sarcomas. Result: This in-depth research led to the finding out that omics studies provide a more comprehensive understanding of underlying molecular mechanisms of sarcomas. Through genomics, we can reveal genetic alterations that predispose to sarcoma, like mutation in TP53, NF1, and so on. Pharmacogenomics enable us to find molecular targets for specific drugs. Whereas, proteomic and metabolomic studies provide insights into the biological pathways involved in sarcoma development and progression. Conclusion: Future advancements in omics sciences for sarcoma are on the cutting-edge of defining precision treatment plans and improved resilience of sarcoma patients.

Omics sciences and precision medicine in prostate cancer.

Abstract: In the last decade, Prostate Cancer (PCa) has emerged as the second most prevalent and serious medical condition, and is considered one of the leading factors contributing to global mortality rates. Several factors (genetic as well as environmental) contribute to its development and seriousness. Since the disease is usually asymptomatic at early stages, it is typically misdiagnosed or over-diagnosed by the diagnostic procedures currently in use, leading to improper treatment. Effective biomarkers and diagnostic techniques are desperately needed in clinical settings for better management of PCa patients. Studies integrating omics sciences have shown that the accuracy and dependability of diagnostic and prognostic evaluations have increased because of the use of omics data; also, the treatment plans using omics can be facilitated by personalized medicine. The present review emphasizes innovative multi-omics methodologies, encompassing proteomics, genomics, microbiomics, metabolomics, and transcriptomics, with the aim of comprehending the molecular alterations that trigger and contribute to PCa. The review shows how early genomic and transcriptomic research has made it possible to identify PCa-related genes that are controlled by tumor-relevant signaling pathways. Proteomic and metabolomic analyses have recently been integrated, advancing our understanding of the complex mechanisms at play, the multiple levels of regulation, and how they interact. By applying the omics approach, new vulnerabilities may be discovered, and customized treatments with improved efficacy will soon be accessible.

Omics sciences and precision medicine in glioblastoma.

Abstract: Glioblastoma is a highly aggressive and malignant type of brain cancer with a poor prognosis, despite current treatment options of surgery, radiation therapy, and chemotherapy. These treatments have limitations due to the aggressive nature of the cancer and the difficulty in completely removing the tumor without damaging healthy brain tissue. Personalized medicine, using genomic profiling to tailor treatment to the patient's specific tumor, and immunotherapy have shown promise in clinical trials. The blood-brain barrier also poses a challenge in delivering treatments to the brain, and researchers are exploring various approaches to bypass it. More effective, personalized treatment approaches are needed to improve outcomes for glioblastoma patients. This tumor is studied using genomics, transcriptomics, and proteomics techniques, to better understand its underlying molecular mechanisms. Recent studies have used these techniques to identify potential therapeutic targets, molecular subtypes, and heterogeneity of tumor cells. Advancements in omics sciences have improved our understanding of glioblastoma biology, and precision medicine approaches have impli-cations for more accurate diagnoses, improved treatment outcomes, and personalized preventive care. Precision medicine can match patients with drugs that target specific genetic mutations, improve clinical trials, and identify individuals at higher risk for certain diseases. Precision medicine, which involves customizing medical treatment based on an individual's genetic makeup, lifestyle, and environmental factors, has shown promise in improving treatment outcomes for glioblastoma patients. Identifying biomarkers is essential for patient stratification and treatment selection in precision medicine approaches for glioblastoma, and several biomarkers have shown promise in predicting patient response to treatment. Targeted therapies are a key component of precision medicine approaches in glioblastoma, but there is still a need to improve their effectiveness. Technical challenges, such as sample quality and availability, and challenges in analyzing and interpreting large amounts of data remain significant obstacles in omics sciences and precision medicine for glioblastoma. The clinical implementation of precision medicine in glioblastoma treatment faces challenges related to patient selection, drug development, and clinical trial design, as well as ethical and legal considerations related to patient privacy, informed consent, and access to expensive treatments.

Omics sciences and precision medicine in colon cancer.

Abstract: Colon cancer presents a complex pathophysiological landscape, which poses a significant challenge to the precise prediction of patient prognosis and treatment response. However, the emergence of omics sciences such as genomics, transcriptomics, proteomics, and metabolomics has provided powerful tools to identify molecular alterations and pathways involved in colon cancer development and progression. To address the lack of literature exploring the intersection of omics sciences, precision medicine, and colon cancer, we conducted a comprehensive search in ScienceDirect and PubMed databases. We included systematic reviews, reviews, case studies, clinical studies, and randomized controlled trials that were published between 2015-2023. To refine our search, we excluded abstracts and non-English studies. This review provides a comprehensive summary of the current understanding of the latest developments in precision medicine and omics sciences in the context of colon cancer. Studies have identified molecular subtypes of colon cancer based on genomic and transcrip-tomic profiles, which have implications for prognosis and treatment selection. Furthermore, precision medicine (which involves tailoring treatments, based on the unique molecular characteristics of each patient's tumor) has shown promise in improving outcomes for colon cancer patients. Omics sciences and precision medicine hold great promise for identifying new therapeutic targets and developing more effective treatments for colon cancer. Although not strictly designed as a systematic review, this review provides a readily accessible and up-to-date summary of the latest developments in the field, highlighting the challenges and opportunities for future research.

Omics sciences and precision medicine in breast and ovarian cancer.

Background: Human breast carcinoma is a complex disease, affecting 1 in 8 women worldwide. The seriousness of the disease increases when the definite cause of the disease remains obscure, thus making prognosis challenging. Researchers are emphasizing on adapting more advanced and targeted therapeutic approaches to address the multifaceted impacts of the disease. Hence, modern multi-omics systems have gained popularity among clinicians, as they offer insights into the genomic, pharmacogenomic, metabolomic, and microbiomic factors, thus allowing researchers to develop targeted and personalized approaches for breast cancer prevention and early detection, and eventually improving patient outcomes. Aim: The primary focus of this study is to elucidate, through the integration of multi-omics research findings, the inherent molecular origins of diverse subtypes of breast cancer and to evaluate the effectiveness of these findings in reducing breast cancer-related mortalities. Methods: Thorough investigation was conducted by reviewing reputable and authoritative medical journals, e-books, and online databases dedicated to cancer research. The Mendelian inheritance in man database (OMIM) was used to scrutinize specific genes and their respective loci associated with the development of different types of breast cancer. Results: Our present research revealed the holistic picture of sundry molecular, genomic, pharmacogenomic, metabolomic, and microbiomic features of breast cancer. Such findings, like genetic alterations in highly penetrant genes, plus metabolomic and microbiomic signatures of breast cancer, unveil valuable insights and show great potential for multi-omics research in breast oncology. Conclusion: Further research in omics sciences pertaining to breast cancer are at the forefront of shaping precise treatment and bolstering patient survival.

Genetics of fat deposition.

Adipose tissue distribution usually varies among men and women. In men, adipose tissue is known to accumulate in the abdominal region surrounding the visceral organs (android fat distribution) whereas, in women, the accumulation of adipose tissue generally occurs in the gluteal-femoral regions (gynoid fat distribution). In some cases, however, android distribution can be found in women and gynoid distribution can be found in men. The regulation of adipose tissue accumulation involves interaction of a variety of genetic and environmental factors. This review examines genetic factors that cause differential distribution of adipose tissue in different depots of the body, between men and women and between different ethnicities. Genome-wide association studies can be used to identify genetic associations with the distribution and accumulation of adipose tissue. Insight into adipose tissue accumulation and distribution mechanisms could lead to development of personalized interventions for people who develop increased fat mass.

Steroid-converting enzymes in human adipose tissues and fat deposition with a focus on AKR1C enzymes.

Adipocytes express various enzymes, such as aldo-keto reductases (AKR1C), 11ß-hydroxysteroid dehydrogenase (11ß-HSD), aromatase, 5α-reductases, 3ß-HSD, and 17ß-HSDs involved in steroid hormone metabolism in adipose tissues. Increased activity of AKR1C enzymes and their expression in mature adipocytes might indicate the association of these enzymes with subcutaneous adipose tissue deposition. The inactivation of androgens by AKR1C enzymes increases adipogenesis and fat mass, particularly subcutaneous fat. AKR1C also causes reduction of estrone, a weak estrogen, to produce 17ß-estradiol, a potent estrogen and, in addition, it plays a role in progesterone metabolism. Functional impairments of adipose tissue and imbalance of steroid biosynthesis could lead to metabolic disturbances. In this review, we will focus on the enzymes involved in steroid metabolism and fat tissue deposition.

Adenosine kinase gene expression in human colorectal cancer.

Real-time reverse transcription polymerase chain reaction (qRT-PCR) was used to evaluate gene expression of adenosine kinase, a key enzyme in adenosine metabolism, in human intestinal biopsy specimens of 10 colorectal cancer patients. Quantitative mRNA expression levels were normalized against the reference gene beta-actin. The results showed that adenosine kinase gene expression was significantly higher in cancer than in normal-appearing tissue, in line with our previous measurements of adenosine kinase enzyme activities in colorectal tumor samples.

Circulating gastrin and ghrelin levels in patients with colorectal cancer: correlation with tumour stage, Helicobacter pylori infection and BMI.

Many studies have pointed out a possible role of gut peptides, including gastrin and ghrelin, in the pathogenesis and natural history of gastrointestinal malignancies, one of the most common death cause in the Western world. The objective of this work is to check gastrin and ghrelin serum levels in patients with colorectal cancer according to tumour's location, stage, Helicobacter pylori infection and BMI, in order to understand the two peptides' behaviour through the tumour's natural history and evaluate their assay's use in research and clinical practice. Twenty-nine subjects affected by colorectal cancer and 50 healthy controls were studied. Circulating gastrin and ghrelin levels and H. pylori serum antibodies were assessed by radioimmunologic assay and ELISA method. Gastrin and ghrelin serum levels were respectively slightly higher and significantly lower in colon cancer patients than in controls. Gastrin levels were higher in patients carrying left colon cancer and H. pylori infection while ghrelin levels were lower in both these groups. Both hormones' serum levels decreased from tumour earlier to later stages. Significant differences persisted in the correlation between BMI and ghrelin levels in controls but not in patients. Additional studies are necessary to ascertain the significance of gastrin and ghrelin opposite behaviour in colon cancer probably linked with interferences in endocrine pathways involving other gut peptides in this compromised condition.

Metabolism of adenosine in human colorectal tumour.

The aim of this work is to analyse the activities of the enzymes metabolising adenosine in fragments of neoplastic and normal-appearing mucosa, surrounding the tumour in 20 patients affected by colorectal cancer. The results show that the activities of the enzymes are markedly higher in tumour in comparison to normal mucosa to coope with the accelerated purine metabolism in cancerous tissues.

On the dynamics of water molecules at the protein solute interfaces.

Proteins, with the large variety of chemical groups they present at their molecular surface, are a class of molecules which can be very informative on most of the possible solute-solvent interactions. Hen egg white lysozyme has been used as a probe to investigate the complex solvent dynamics occurring at the protein surface, by analysing the results obtained from Nuclear Magnetic Resonance, X-ray diffractometry and Molecular Dynamics simulations. A consistent overall picture for the dynamics of water molecules close to the protein is obtained, suggesting that a rapid exchange occurs, in a picosecond timescale, among all the possible hydration surface sites both in solution and the solid state, excluding the possibility that solvent molecules can form liquid-crystal-like supramolecular adducts, which have been proposed as a molecular basis of 'memory of water'.

Enzyme activities controlling adenosine levels in normal and neoplastic tissues.

Adenosine is known to be associated with effects such as inhibition of immune response, coronary vasodilation, stimulation of angiogenesis, and inhibition of inflammatory reactions. Some authors suggest that adenosine may also have similar functions in tumor tissues. Tissue levels of adenosine are under close regulation by different enzymes acting at different levels. Adenosine is produced from AMP by the action of 5'-nucleotidase (5'-NT) and is converted back into AMP by adenosine kinase (AK) or into inosine by adenosine deaminase (ADA). Inosine is converted into purine catabolites by purine nucleoside phosphorylase (PNP), whereas AMP is converted into ADP and ATP by adenylate kinase (MK). The aim of this study was to analyze the activities of the above enzymes in fragments of neoplastic and apparently normal mucosa, obtained less than 5 cm and at least 10 cm from tumors, in 40 patients with colorectal cancer. The results showed much higher activities of ADA, AK, 5'-NT, and PNP in tumor tissue than in neighboring mucosa (p > 0.01 for ADA, AK, and PNP; p > 0.05 for 5'-NT), suggesting that the activities of purine metabolizing enzymes increase to cope with accelerated purine metabolism in cancerous tissue. The simultaneous increase in ADA and 5'-NT activities might be a physiological attempt by cancer cells to provide more substrate to accelerate salvage pathway activity.

NMR studies of protein surface accessibility.

Characterization of protein surface accessibility represents a new frontier of structural biology. A surface accessibility investigation for two structurally well-defined proteins, tendamistat and bovine pancreatic trypsin inhibitor, is performed here by a combined analysis of water-protein Overhauser effects and paramagnetic perturbation profiles induced by the soluble spin-label 4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl on NMR spectra. This approach seems to be reliable not only for distinguishing between buried and exposed residues but also for finding molecular locations where a network of more ordered waters covers the protein surface. From the presented set of data, an overall picture of the surface accessibility of the two proteins can be inferred. Detailed knowledge of protein accessibility can form the basis for successful design of mutants with increased activity and/or greater specificity.

Mimicking the nicotinic receptor binding site by a single chain Fv selected by competitive panning from a synthetic phage library.

We have developed a novel competitive method to select from a phage display library a single chain Fv which is able to mimic the alpha-bungarotoxin binding site of the muscle nicotinic receptor. The single chain Fv was selected from a large synthetic library using alpha-bungarotoxin-coated magnetic beads. Toxin-bound phages were then eluted by competition with affinity purified nicotinic receptor. Recognition of the toxin by the anti-alpha-bungarotoxin single chain Fv was very similar to that of the receptor, such as indicated by the epitope mapping of alpha-bungarotoxin through overlapping synthetic peptides. Moreover, several positively charged residues located in the toxin second loop and in the C-terminal region were found to be critical, to a similar extent, for toxin recognition by the single chain Fv and the receptor. However, although the anti-alpha-bungarotoxin single chain Fv seems to mimic the toxin binding site of the nicotinic receptor, it does not bind other nicotinic agonists or antagonists. Our results suggest that competitive selection of anti-ligand antibody phages can allow the production of receptor-mimicking molecules directly and exclusively targeted at one specific ligand. Since physiologically and pharmacologically different ligands can produce opposite effects on receptor functions, such selective ligand decoys can have important therapeutic applications.

Probing the surface of a sweet protein: NMR study of MNEI with a paramagnetic probe.

The design of safe sweeteners is very important for people who are affected by diabetes, hyperlipemia, and caries and other diseases that are linked to the consumption of sugars. Sweet proteins, which are found in several tropical plants, are many times sweeter than sucrose on a molar basis. A good understanding of their structure-function relationship can complement traditional SAR studies on small molecular weight sweeteners and thus help in the design of safe sweeteners. However, there is virtually no sequence homology and very little structural similarity among known sweet proteins. Studies on mutants of monellin, the best characterized of sweet proteins, proved not decisive in the localization of the main interaction points of monellin with its receptor. Accordingly, we resorted to an unbiased approach to restrict the search of likely areas of interaction on the surface of a typical sweet protein. It has been recently shown that an accurate survey of the surface of proteins by appropriate paramagnetic probes may locate interaction points on protein surface. Here we report the survey of the surface of MNEI, a single chain monellin, by means of a paramagnetic probe, and a direct assessment of bound water based on an application of ePHOGSY, an NMR experiment that is ideally suited to detect interactions of small ligands to a protein. Detailed surface mapping reveals the presence, on the surface of MNEI, of interaction points that include residues previously predicted by ELISA tests and by mutagenesis.