Nutrients that modulate gestational diabetes mellitus: A systematic review of cohort studies Jan 2019-Jan 2020.

BACKGROUND: The role of eating habits of pregnant women in the development and treatment of gestational diabetes mellitus (GDM) is well established. OBJECTIVES: To estimate the contribution of specific nutrients and dietary patterns in the development or privation of GDM in pregnant women. DATA SOURCES: A systematic review of cohort studies, published between January 2019 and January 2020, of English articles using PubMed, Scopus and Europe PMC databases. Search terms included diabetes, pregnancy, dietary, food, and nutrients. STUDY SELECTION: Only cohort studies about the association between eating habits before and during pregnancy and the risk of GDM in English were included. The studies used dietary patterns, specific nutrients or records of food intake of the participants using a questionnaire. DATA EXTRACTION: Two authors independently extracted data from articles-including dietary patterns, food intake, nutrients, number and demographic data of participants, data about pregnancies-using predefined criteria. RESULTS: In total, 28 cohort studies were organised to examine the correlation between dietary patterns and the prevention of GDM. Studies were conducted in 13 countries and included 3 058 242 participants. Of those, 13 (46%) studies focused on the consumption of vitamins, probiotics, micronutrients, folate, vegetables and fruits. Moreover, seven (25%) studies focused on what is considered to be "unhealthy" eating habits, including prudent and Western dietary patterns. The mediterranean pattern was used in three (11%) studies. CONCLUSIONS: Ongoing studies support advice to adhere to a healthy balanced diet, with the addition of folic acid and a multi-vitamin suitable for pregnancy. There is new evidence suggesting probiotics and cod-liver oil supplementation may improve glycaemic control and also the important consideration of the psychological influences of eating.

Genes' Interactions: A Major Contributor to the Malignant Transformation of Endometriosis.

The genetic and epigenetic factors that contribute to the malignant transformation of endometriosis are still under investigation. The objective of the present study was to investigate the genetic link between endometriosis and cancer by examining and correlating the latest clinical observations with biological experimental data. We collected updated evidence about the genetic relationship between endometriosis and cancers by conducting a comprehensive search of PubMed and Scopus databases, focusing on the papers published between January 2018 and January 2019. New insights into the mechanism of the malignant transformation of endometriosis have been published recently. The use of state-of-the-art techniques and methods, such as the genome-wide association study analysis and the weighted gene co-expression analysis, have significantly altered our understanding of the association between endometriosis and endometriosis-associated cancer development. Interestingly, the interactions formed between genes seem to play a pivotal role in the phenotypic expression of mutations. Therefore, the effect of single nucleotide polymorphisms and the function of the expression quantitative trait loci on genes' expression have been the subject of many recent works. In addition, it has been discovered that genes, the mutations of which have been related to the development of endometriosis, play a role as hub genes. This may lead to new areas of research for understanding the mechanism of malignant transformation of the disease. Significant steps forward have been made towards the identification of factors that control the malignant transformation of endometriosis. Still, due to rarity of the event, a better-organized scheme for sampling on a global level should be adopted.

Using physics-based pose predictions and free energy perturbation calculations to predict binding poses and relative binding affinities for FXR ligands in the D3R Grand Challenge 2.

Computer-aided drug design has become an integral part of drug discovery and development in the pharmaceutical and biotechnology industry, and is nowadays extensively used in the lead identification and lead optimization phases. The drug design data resource (D3R) organizes challenges against blinded experimental data to prospectively test computational methodologies as an opportunity for improved methods and algorithms to emerge. We participated in Grand Challenge 2 to predict the crystallographic poses of 36 Farnesoid X Receptor (FXR)-bound ligands and the relative binding affinities for two designated subsets of 18 and 15 FXR-bound ligands. Here, we present our methodology for pose and affinity predictions and its evaluation after the release of the experimental data. For predicting the crystallographic poses, we used docking and physics-based pose prediction methods guided by the binding poses of native ligands. For FXR ligands with known chemotypes in the PDB, we accurately predicted their binding modes, while for those with unknown chemotypes the predictions were more challenging. Our group ranked #1st (based on the median RMSD) out of 46 groups, which submitted complete entries for the binding pose prediction challenge. For the relative binding affinity prediction challenge, we performed free energy perturbation (FEP) calculations coupled with molecular dynamics (MD) simulations. FEP/MD calculations displayed a high success rate in identifying compounds with better or worse binding affinity than the reference (parent) compound. Our studies suggest that when ligands with chemical precedent are available in the literature, binding pose predictions using docking and physics-based methods are reliable; however, predictions are challenging for ligands with completely unknown chemotypes. We also show that FEP/MD calculations hold predictive value and can nowadays be used in a high throughput mode in a lead optimization project provided that crystal structures of sufficiently high quality are available.

Small Peptides Able to Suppress Prostaglandin E2 Generation in Renal Mesangial Cells.

Peptide drug discovery may play a key role in the identification of novel medicinal agents. Here, we present the development of novel small peptides able to suppress the production of PGE2 in mesangial cells. The new compounds were generated by structural alterations applied on GK115, a novel inhibitor of secreted phospholipase A2, which has been previously shown to reduce PGE2 synthesis in rat renal mesangial cells. Among the synthesized compounds, the tripeptide derivative 11 exhibited a nice dose-dependent suppression of PGE2 production, similar to that observed for GK115.

Development of a potent 2-oxoamide inhibitor of secreted phospholipase A2 guided by molecular docking calculations and molecular dynamics simulations.

Inhibition of group IIA secreted phospholipase A2 (GIIA sPLA2) has been an important objective for medicinal chemists. We have previously shown that inhibitors incorporating the 2-oxoamide functionality may inhibit human and mouse GIIA sPLA2s. Herein, the development of new potent inhibitors by molecular docking calculations using the structure of the known inhibitor 7 as scaffold, are described. Synthesis and biological evaluation of the new compounds revealed that the long chain 2-oxoamide based on (S)-valine GK241 led to improved activity (IC50=143 nM and 68 nM against human and mouse GIIA sPLA2, respectively). In addition, molecular dynamics simulations were employed to shed light on GK241 potent and selective inhibitory activity.

Inhibitors of secreted phospholipase A2 suppress the release of PGE2 in renal mesangial cells.

The upregulation of PGE2 by mesangial cells has been observed under chronic inflammation condition. In the present work, renal mesangial cells were stimulated to trigger a huge increase of PGE2 synthesis and were treated in the absence or presence of known PLA2 inhibitors. A variety of synthetic inhibitors, mainly developed in our labs, which are known to selectively inhibit each of GIVA cPLA2, GVIA iPLA2, and GIIA/GV sPLA2, were used as tools in this study. Synthetic sPLA2 inhibitors, such as GK115 (an amide derivative based on the non-natural amino acid (R)-γ-norleucine) as well as GK126 and GK241 (2-oxoamides based on the natural (S)-α-amino acid leucine and valine, respectively) presented an interesting effect on the suppression of PGE2 formation.

Molecular interactions of antibodies with PD-1/PD-L1 proteins.

Aim: To compare the protein-protein interactions of antibodies targeting PD-1 and its ligand (PD-L1) with their targets in an attempt to explain the antibodies' binding affinity. Materials & methods: The structural features of complexes between pembrolizumab, nivolumab, durvalumab, atezolizumab, avelumab and PD-1/PD-L1 are described, with the use of software and based on crystallographic data. Results: Pembrolizumab has more structural features, including the number and type of the bonds and total binding surface area, which could rationalize its different clinical behavior compared with nivolumab. Similarly, protein-protein interactions with PD-L1 differ among durvalumab, atezolizumab and avelumab. Conclusion: Differential protein-protein interactions between antibodies and PD-1/PD-L1 may indicate differential clinical activity; however, further research is needed to provide evidence.

This study looked at different immunotherapy drugs used to treat cancer. These drugs bind to two different proteins, called PD-1 and PD-L1, that are part of our immune system. These proteins usually act as brakes in our immune system. The drugs block the brakes, which boosts the immune system and improves the immune defense against cancer. Using computer images, the authors compared how each drug binds to PD-1/PD-L1. The results showed that these drugs bind to PD-1 and PD-L1 with different chemical bonds. These bonds can be smaller or larger depending on the drug. The drugs' different chemical bonds with PD-1/PD-L1 might show that they do not act exactly the same when they are given to patients. However, further studies are needed for more information.

The discovery and development of transmembrane serine protease 2 (TMPRSS2) inhibitors as candidate drugs for the treatment of COVID-19.

INTRODUCTION: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused the devastating pandemic named coronavirus disease 2019 (COVID-19). Unfortunately, the discovery of antiviral agents to combat COVID-19 is still an unmet need. Transmembrane serine protease 2 (TMPRSS2) is an important mediator in viral infection and thus, TMPRRS2 inhibitors may be attractive agents for COVID-19 treatment. AREAS COVERED: This review article discusses the role of TMPRSS2 in SARS-CoV-2 cell entry and summarizes the inhibitors of TMPRSS2 and their potential anti-SARS activity. Two known TMPRSS2 inhibitors, namely camostat and nafamostat, approved drugs for the treatment of pancreatitis, are under clinical trials as potential drugs against COVID-19. EXPERT OPINION: Due to the lack of the crystal structure of TMPRSS2, homology models have been developed to study the interactions of known inhibitors, including repurposed drugs, with the enzyme. However, novel TMPRSS2 inhibitors have been identified through high-throughput screening, and appropriate assays studying their in vitro activity have been set up. The discovery of TMPRSS2's crystal structure will facilitate the rational design of novel inhibitors and in vivo studies and clinical trials will give a clear answer if TMPRSS2 inhibitors could be a new weapon against COVID-19.

Inflammatory Mediators and Pain in Endometriosis: A Systematic Review.

BACKGROUND: pain is one of the main symptoms of endometriosis and it has a deleterious effect on a patients' personal and social life. To date, the clinical management of pain includes prolonged medication use and, in some cases, surgery, both of which are disruptive events for patients. Hence, there is an urgency for the development of a sufficient non-invasive medical treatment. Inflammation is one of the causative factors of pain in endometriosis. It is well established that inflammatory mediators promote angiogenesis and interact with the sensory neurons inducing the pain signal; the threshold of pain varies and it depends on the state and location of the disease. The inhibition of inflammatory mediators' synthesis might offer a novel and effective treatment of the pain that is caused by inflammation in endometriosis. OBJECTIVES: patients with endometriosis experience chronic pelvic pain, which is moderate to severe in terms of intensity. The objective of this systematic review is to highlight the inflammatory mediators that contribute to the induction of pain in endometriosis and present their biological mechanism of action. In addition, the authors aim to identify new targets for the development of novel treatments for chronic pelvic pain in patients with endometriosis. DATA SOURCES: three databases (PubMed, Scopus, and Europe PMC) were searched in order to retrieve articles with the keywords 'inflammation, pain, and endometriosis' between the review period of 1 January 2016 to 31 December 2020. This review has been registered with PROSPERO (registry number: CRD42020171018). Eligibility Criteria: only original articles that presented the regulation of inflammatory mediators and related biological molecules in endometriosis and their contribution in the stimulation of pain signal were included. DATA EXTRACTION: two authors independently extracted data from articles, using predefined criteria. RESULTS: the database search yielded 1871 articles, which were narrowed down to 56 relevant articles of interest according to the eligibility criteria. CONCLUSIONS: inflammatory factors that promote angiogenesis and neuroangiogenesis are promising targets for the treatment of inflammatory pain in endometriosis. Specifically, CXC chemokine family, chemokine fractalkine, and PGE2 have an active role in the induction of pain. Additionally, IL-1ß appears to be the primary interleukin (IL), which stimulates the majority of the inflammatory factors that contribute to neuroangiogenesis along with IL-6. Finally, the role of Ninj1 and BDNF proteins needs further investigation.

Hydration thermodynamics of cytosolic phospholipase A2 GIVA predict its membrane-associated parts and its highly hydrated binding site.

During biological events, the water molecules associated with the protein are re-oriented to adapt to the new conditions, inducing changes in the system's free energy. The characterization of water structure and thermodynamics may facilitate the prediction of certain biological events, such as the binding of a ligand and the membrane-associated parts of a protein. In this computational study, we calculated the hydration thermodynamics of cytosolic phospholipase A2 group IV (GIVA cPLA2) to study the hydration properties of the protein's surface and binding pocket. Hydrophobicity scales and the Grid Inhomogeneous Solvation Theory (GIST) tool were employed for the calculations. The hydrophobic areas of the protein's surface were predicted more accurately with the GIST method rather than with the hydrophobicity scales. Based on this, a model of the protein-membrane complex was constructed. In addition, the calculation revealed the highly hydrated binding pocket that further contribute to our understanding of the ligands' binding. Communicated by Ramaswamy H. Sarma.

The design and discovery of phospholipase A2 inhibitors for the treatment of inflammatory diseases.

AREAS COVERED: This review article summarizes the most important synthetic PLA2 inhibitors developed to target each one of the four major types of human PLA2 (cytosolic cPLA2, calcium-independent iPLA2, secreted sPLA2, and lipoprotein-associated Lp-PLA2), discussing their in vitro and in vivo activities as well as their recent applications and therapeutic properties. Recent findings on the role of PLA2 in the pathobiology of COVID-19 are also discussed. EXPERT OPINION: Although a number of PLA2 inhibitors have entered clinical trials, none has reached the market yet. Lipoprotein-associated PLA2 is now considered a biomarker of vascular inflammation rather than a therapeutic target for inhibitors like darapladib. Inhibitors of cytosolic PLA2 may find topical applications for diseases like atopic dermatitis and psoriasis. Inhibitors of secreted PLA2, varespladib and varespladib methyl, are under investigation for repositioning in snakebite envenoming. A deeper understanding of PLA2 enzymes is needed for the development of novel selective inhibitors. Lipidomic technologies combined with medicinal chemistry approaches may be useful tools toward this goal.

Novel Aryl-Substituted Pyrimidones as Inhibitors of 3-Mercaptopyruvate Sulfurtransferase with Antiproliferative Efficacy in Colon Cancer.

The enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is one of the more recently identified mammalian sources of H2S. A recent study identified several novel 3-MST inhibitors with micromolar potency. Among those, (2-[(4-hydroxy-6-methylpyrimidin-2-yl)sulfanyl]-1-(naphthalen-1-yl)ethan-1-one) or HMPSNE was found to be the most potent and selective. We now took the central core of this compound and modified the pyrimidone and the arylketone sides independently. A 63-compound library was synthesized; compounds were tested for H2S generation from recombinant 3-MST in vitro. Active compounds were subsequently tested to elucidate their potency and selectivity. Computer modeling studies have delineated some of the key structural features necessary for binding to the 3-MST's active site. Six novel 3-MST inhibitors were tested in cell-based assays: they exerted inhibitory effects in murine MC38 and CT26 colon cancer cell proliferation; the antiproliferative effect of the compound with the highest potency and best cell-based activity (1b) was also confirmed on the growth of MC38 tumors in mice.

α-Ketoheterocycles Able to Inhibit the Generation of Prostaglandin E2 (PGE2) in Rat Mesangial Cells.

Prostaglandin E2 (PGE2) is a key mediator of inflammation, and consequently huge efforts have been devoted to the development of novel agents able to regulate its formation. In this work, we present the synthesis of various α-ketoheterocycles and a study of their ability to inhibit the formation of PGE2 at a cellular level. A series of α-ketobenzothiazoles, α-ketobenzoxazoles, α-ketobenzimidazoles, and α-keto-1,2,4-oxadiazoles were synthesized and chemically characterized. Evaluation of their ability to suppress the generation of PGE2 in interleukin-1ß plus forskolin-stimulated mesangial cells led to the identification of one α-ketobenzothiazole (GK181) and one α-ketobenzoxazole (GK491), which are able to suppress the PGE2 generation at a nanomolar level.

Natural products: Potential lead compounds for the treatment of endometriosis.

OBJECTIVE: Medical plants have been used for centuries for the treatment of various disorders in humans and animals. The therapeutic properties of herbs and plants have been documented for years, giving rise to ethnobotany, and have been a source for the development of novel drugs. Natural products usually have more than one pharmaceutical effects, due to the fact that they interact with more than one biological targets. This property could be used for the efficient treatment of diseases with multiple putative physiopathologic mechanisms, such as endometriosis. STUDY DESIGN: In the current study, we search the literature to find recent progress in the identification of compounds, which derived from plants and herbs and have therapeutic properties against endometriosis and its symptoms. The Scopus and PubMed databases were used to search for original articles, published between January 2018 and July 2019. The words "endometriosis", "pain", "treatment", "medication" were used for the query. RESULTS AND CONCLUSION: 14 compounds derived from plants and herbs have demonstrated pharmaceutical activity in experiments, including animal models and human endometriotic samples. The experimental data evidence the therapeutic effect of several natural products against endometriosis. Given that most of them are already well known for their pharmaceutical properties, these compounds should be used as leads for the development of novel drugs for the treatment of endometriosis.

Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2.

Phospholipase A2 (PLA2) enzymes are involved in various inflammatory pathological conditions including arthritis, cardiovascular and autoimmune diseases. The regulation of their catalytic activity is of high importance and a great effort has been devoted in developing synthetic inhibitors. We summarize the most important small-molecule synthetic PLA2 inhibitors developed to target each one of the four major types of human PLA2 (cytosolic cPLA2, calcium-independent iPLA2, secreted sPLA2, and lipoprotein-associated LpPLA2). We discuss recent applications of inhibitors to understand the role of each PLA2 type and their therapeutic potential. Potent and selective PLA2 inhibitors have been developed. Although some of them have been evaluated in clinical trials, none reached the market yet. Apart from their importance as potential medicinal agents, PLA2 inhibitors are excellent tools to unveil the role that each PLA2 type plays in cells and in vivo. Modern medicinal chemistry approaches are expected to generate improved PLA2 inhibitors as new agents to treat inflammatory diseases.

A facile consensus ranking approach enhances virtual screening robustness and identifies a cell-active DYRK1α inhibitor.

BACKGROUND: Virtual screening is vital for contemporary drug discovery but striking performance fluctuations are commonly encountered, thus hampering error-free use. Results and Methodology: A conceptual framework is suggested for combining screening algorithms characterized by orthogonality (docking-scoring calculations, 3D shape similarity, 2D fingerprint similarity) into a simple, efficient and expansible python-based consensus ranking scheme. An original experimental dataset is created for comparing individual screening methods versus the novel approach. Its utilization leads to identification and phosphoproteomic evaluation of a cell-active DYRK1α inhibitor. CONCLUSION: Consensus ranking considerably stabilizes screening performance at reasonable computational cost, whereas individual screens are heavily dependent on calculation settings. Results indicate that the novel approach, currently available as a free online tool, is highly suitable for prospective screening by nonexperts.