Protocols for isolation and characterization of nanoparticle biomolecular corona complexes.

Engineered nanoparticles (NPs) pose a broad spectrum of interesting properties that make them useful for many applications. However, continuous exposure to NPs requires the need to deeply understand the outcomes when these NPs interact with different biological environments. After exposure within (to) these environments, the pristine surfaces of NPs strongly interact with the molecules from the surrounding medium, including metabolites, lipids, glycan, and proteins, forming the so-called protein corona (PC). It is well established that the NP-PC strongly influences the biological fate of various NPs types, including cellular uptake, toxicity, and biodistribution. Thus, for a proper assessment of potential hazards associated with engineered NPs, it is mandatory to study and evaluate the PC that forms around NPs. Herein, we describe protocols in detail for the isolation and characterization of NP-PC complexes and cover the following aspects: 1) isolation protocols for different nanomaterials in a range of exposing media, including magnetic isolation methods for superparamagnetic NPs, 2) NP physico-chemical characterization using advanced and standard techniques available in regular laboratories, and 3) NP- PC characterization of the protein and glycan components.

Revolutionizing treatment for topical fungal infections: evaluating penetration-enhancer-containing vesicles as a fluconazole delivery system: Ex-vivo and in-vivo dermal testing.

Fungal infections pose a significant challenge in numerous developing nations and worldwide, necessitating urgent solutions. Oral administration of antifungal medications often leads to severe adverse reactions. Hence, employing topical delivery systems is preferred to ensure efficient dermal delivery of antifungal agents while minimizing side effects. Furthermore, the incorporation of penetration enhancers into nanocarriers loaded with antifungal agents has demonstrated enhanced efficacy in combating mycotic infections. Consequently, ultra-deformable penetration enhancer-containing vesicles (PEVs) were developed to explore this promising approach. In this study, Labrasol® and Transcutol® were used as penetration enhancers in formulating ultra-deformable PEVs containing the antifungal agent Fluconazole (FCZ). The PEVs underwent comprehensive characterization, including measurements of particle size (PS), charge, and entrapment efficiency (EE%). The results revealed that the size of tested PEVs ranged from 100 to 762 nm. All particles exhibited a negative charge, with a minimum zeta potential (ZP) of -38.26 mV, and an intermediate entrapment efficiency (EE%) that reached approximately 40%w/w. Ex-vivo studies demonstrated the ability of PEVs to deliver FCZ to the dermis while minimizing transdermal delivery. The selected formula was tested in-vivo using candidiasis-induced rat model and showed a superiority in its antifungal effect against Candida Albicans compared to the drug control. Stability studies were executed for the selected formula, and revealed good stability shown by the insignificant change in the PS, ZP& EE% over a six-month period.

De Novo Rational Design of Peptide-Based Protein-Protein Inhibitors (Pep-PPIs) Approach by Mapping the Interaction Motifs of the PP Interface and Physicochemical Filtration: A Case on p25-Cdk5-Mediated Neurodegenerative Diseases.

Protein-protein interactions, or PPIs, are a part of every biological activity and have been linked to a number of diseases, including cancer, infectious diseases, and neurological disorders. As such, targeting PPIs is considered a strategic and vital approach in the development of new medications. Nonetheless, the wide and flat contact interface makes it difficult to find small-molecule PP inhibitors. An alternative strategy would be to use the PPI interaction motifs as building blocks for the design of peptide-based inhibitors. Herein, we designed 12-mer peptide inhibitors to target p25-inducing-cyclin-dependent kinase (Cdk5) hyperregulation, a PPI that has been shown to perpetuate neuroinflammation, which is one of the major causal implications of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and frontotemporal dementia. We generated a library of 5 062 500 peptide combination sequences (PCS) derived from the interaction motif of Cdk5/p25 PP interface. The 20 amino acids were differentiated into six groups, namely, hydrophobic (aliphatic), aromatic, basic, acidic, unique, and polar uncharged, on the basis of their physiochemical properties. To preserve the interaction motif necessary for ideal binding, de novo modeling of all possible peptide sequence substitutions was considered. A set of filters, backed by the Support Vector Machine (SVM) algorithm, was then used to create a shortlisted custom peptide library that met specific bioavailability, toxicity, and therapeutic relevance, leading to a refined library of 15 PCS. A greedy algorithm and coarse-grained force field were used to predict peptide structure and folding before subsequent modeling studies. Molecular docking was performed to estimate the relative binding affinities, and out of the top hits, Pep15 was subjected to molecular dynamics simulations and binding free-energy calculations in comparison to a known peptide inhibitor with experimental data (template peptide). Interestingly, the identified peptide through our protocol, Pep15, was found to show a significantly higher binding affinity than the reference template peptide (-48.10 ± 0.23 kcal/mol and -17.53 ± 0.27 kcal/mol, respectively). In comparison to the template peptide, Pep15 was found to possess a more compact and buried surface area, tighter binding landscape, and reduced conformational variability, leading to enhanced structural and kinetic stability of the Cdk5/p25 complex. Notably, both peptide inhibitors were found to have a minimal impact on the architectural integrity of the Cdk5/p25 secondary structure. Herein, we propose Pep15 as a novel and potentially disruptive peptide drug for Cdk5/p25-mediated neurodegenerative phenotypes that require further clinical investigation. The systematic protocol and findings of this report would serve as a valuable tool in the identification of critical PPI interface reactive residues, designing of analogs, and identification of more potent peptide-based PPI inhibitors.

Impact of smart technology use on sleep quality in individuals with autism spectrum disorder: a mixed-methods investigation.

Background: Sleep disturbances are common among individuals with autism spectrum disorder (ASD) and can have a negative impact on their daily functioning and core symptoms. As the use of smart technologies continues to rise, it is crucial to understand how these devices affect the sleep quality of individuals with ASD. Aim: The objective of this study was to examine the relationship between the use of smart technology and sleep quality in individuals with ASD. Methods: A mixed-methods approach was employed, combining both quantitative and qualitative data collection techniques. A sample of 83 individuals with ASD, aged between 8 and 25 years, assessed their sleep quality using the Pittsburgh Sleep Quality Index. Additionally, information regarding patterns of smart technology use and relevant covariates was collected. Correlation and regression analyses were conducted to analyze the data. Furthermore, semi-structured interviews were conducted with a subset of participants and their caregivers. Results: Significant positive correlations were found between poorer sleep quality scores and total screen time (r = 0.42, p < 0.001), pre-bedtime technology use (r = 0.51, p < 0.001), gaming (r = 0.32, p = 0.003), and social media use (r = 0.29, p = 0.008). Pre-bedtime technology use was a significant predictor of poorer sleep quality (ß = 0.32, p = 0.006), even after controlling for age, gender, and ASD severity. Conclusion: The findings of this study emphasize the significant associations between the use of smart technology, particularly before bedtime, and poorer sleep quality in individuals with ASD. These results underscore the importance of developing evidence-based interventions and guidelines to promote healthy sleep habits and mitigate the negative effects of technology exposure in this population.

Machine Learning in Enhancing Protein Binding Sites Predictions - What Has Changed Since Then?

Accurate identification of protein binding sites is pivotal for understanding molecular interactions and facilitating drug discovery efforts. However, the dynamic nature of proteinligand interactions presents a formidable challenge, necessitating innovative approaches to bridge the gap between theoretical predictions and experimental realities. This review explores the challenges and recent advancements in protein binding site prediction. Specifically, we highlight the integration of molecular dynamics simulations, machine learning, and deep learning techniques to capture the dynamic and complex nature of protein-ligand interactions. Additionally, we discuss the importance of integrating experimental data, such as structural information and biochemical assays, to enhance prediction accuracy and reliability. By navigating the intersection of classical and the onset of machine learning and deep learning approaches, we aim to provide insights into current state-of-the-art techniques and chart a course for future protein binding site prediction advancements. Ultimately, these efforts could unravel the mysteries of protein-ligand interactions and accelerate drug discovery endeavors.

Unveiling therapeutic frontiers: DON/DRP-104 as innovative Plasma kallikrein inhibitors against carcinoma-associated hereditary angioedema shocks - a comprehensive molecular dynamics exploration.

Human plasma kallikrein (PKa) is a member of the serine protease family and serves as a key mediator of the kallikrein-kinin system (KKS), which is known for its regulatory roles in inflammation, vasodilation, blood pressure, and coagulation. Genetic dysregulation of KKS leads to Hereditary Angioedema (HAE), which is characterized by spontaneous, painful swelling in various body regions. Importantly, HAE frequently coexists with various cancers. Despite substantial efforts towards the development of PKa inhibitors for HAE, there remains a need for bifunctional agents addressing both anti-cancer and anti-HAE aspects, especially against carcinoma-associated comorbid HAE conditions. Consequently, we investigated the therapeutic potential of the anti-glutamine prodrug, isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate (DRP-104), and its active form, 6-Diazo-5-oxo-l-norleucine (DON), recognized for their anti-cancer properties, as novel PKa inhibitors. Utilizing structure-based in silico methods, we conducted a comparative analysis with berotralstat, a clinically approved HAE prophylactic, and sebetralstat, an investigational HAE therapeutic agent, in Phase 3 clinical trials. Inhibiting PKa with DON resulted in relatively heightened structural stability, rigidity, restricted protein folding, and solvent-accessible loop exposure, contributing to increased intra-atomic hydrogen bond formation. Conversely, PKa inhibition with DRP-104 induced restricted residue flexibility and significantly disrupted the critical SER195-HIS57 arrangement in the catalytic triad. Both DON and DRP-104, along with the reference drugs, induced strong cooperative intra-residue motion and bidirectional displacement in the PKa architecture. The results revealed favorable binding kinetics of DON/DRP-104, showing thermodynamic profiles that were either superior or comparable to those of the reference drugs. These findings support their consideration for clinical investigations into the management of carcinoma-associated HAE.

PCSK9 inhibitors as safer therapeutics for atherosclerotic cardiovascular disease (ASCVD): Pharmacophore design and molecular dynamics analysis.

Cardiovascular disorders are still challenging and are among the deadly diseases. As a major risk factor for atherosclerotic cardiovascular disease, dyslipidemia, and high low-density lipoprotein cholesterol in particular, can be prevented primary and secondary by lipid-lowering medications. Therefore, insights are still needed into designing new drugs with minimal side effects. Proprotein convertase subtilisin/kexin 9 (PCSK9) enzyme catalyses protein-protein interactions with low-density lipoprotein, making it a critical target for designing promising inhibitors compared to statins. Therefore, we screened for potential compounds using a redesigned PCSK9 conformational behaviour to search for a significantly extensive chemical library and investigated the inhibitory mechanisms of the final compounds using integrated computational methods, from ligand essential functional group screening to all-atoms MD simulations and MMGBSA-based binding free energy. The inhibitory mechanisms of the screened compounds compared with the standard inhibitor. K31 and K34 molecules showed stronger interactions for PCSK9, having binding energy (kcal/mol) of -33.39 and -63.51, respectively, against -27.97 of control. The final molecules showed suitable drug-likeness, non-mutagenesis, permeability, and high solubility values. The C-α atoms root mean square deviation and root mean square fluctuation of the bound-PCSK9 complexes showed stable and lower fluctuations compared to apo PCSK9. The findings present a model that unravels the mechanism by which the final molecules proposedly inhibit the PCSK9 function and could further improve the design of novel drugs against cardiovascular diseases.

Correction: Udosen et al. Meta-Analysis and Multivariate GWAS Analyses in 80,950 Individuals of African Ancestry Identify Novel Variants Associated with Blood Pressure Traits. Int. J. Mol. Sci. 2023, 24, 2164.

In the original publication [...].

Novel green-based polyglycerol polymeric nanoparticles loaded with ferulic acid: A promising approach for hepatoprotection.

In the pursuit of eco-friendly and sustainable materials, polyglycerol diacid polymers hold immense promise for drug delivery compared to those derived from fossil fuels. Harnessing this potential, we aimed to prepare nanoparticles (NPs) derived from sustainable polymers, loaded with ferulic acid (FA), a natural polyphenolic compound known for its shielding effect against liver-damaging agents, including carbon tetrachloride (CCl4). Glycerol was esterified with renewable monomers, such as succinic acid, adipic acid, and/or FA, resulting in the creation of a novel class of polyglycerol diacid polymers. Characterization via Fourier-transform infrared spectroscopy and nuclear magnetic resonance confirmed the successful synthesis of these polymers with <7 % residual monomers. FA-loaded NPs were fabricated using the newly synthesized polymers. To further augment their potential, the NPs were coated with chitosan. The chitosan-coated NPs boasted an optimal PS of 290 ± 5.03 nm, showing superior physical stability, and a commendable EE% of 58.79 ± 0.43%w/v. The cytotoxicity was examined on fibroblast cells using the SRB assay. In-vivo experiments employing a CCl4-induced liver injury model yielded compelling evidence of the heightened hepatoprotective effects conferred by chitosan-coated particles. This demonstrates the benefits of incorporating sustainable polymers into innovative composites for efficient drug delivery, indicating their potential for creating versatile platforms for various therapeutic applications.

DON/DRP-104 as potent serine protease inhibitors implicated in SARS-CoV-2 infection: Comparative binding modes with human TMPRSS2 and novel therapeutic approach.

Human transmembrane serine protease 2 (TMPRSS2) is an important member of the type 2 transmembrane serine protease (TTSP) family with significant therapeutic markings. The search for potent TMPRSS2 inhibitors against severe acute respiratory syndrome coronavirus 2 infection with favorable tissue specificity and off-site toxicity profiles remains limited. Therefore, probing the anti-TMPRSS2 potential of enhanced drug delivery systems, such as nanotechnology and prodrug systems, has become compelling. We report the first in silico study of TMPRSS2 against a prodrug, [isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate] also known as DRP-104 synthesized from 6-Diazo-5-oxo-l-norleucine (DON). We performed comparative studies on DON and DRP-104 against a clinically potent TMPRSS2 inhibitor, nafamostat, and a standard serine protease inhibitor, 4-(2-Aminoethyl) benzenesulfonyl fluoride (AEBSF) against TMPRSS2 and found improved TMPRSS2 inhibition through synergistic binding of the S1/S1' subdomains. Both DON and DRP-104 had better thermodynamic profiles than AEBSF and nafamostat. DON was found to confer structural stability with strong positive correlated inter-residue motions, whereas DRP-104 was found to confer kinetic stability with restricted residue displacements and reduced loop flexibility. Interestingly, the Scavenger Receptor Cysteine-Rich (SRCR) domain of TMPRSS2 may be involved in its inhibition mechanics. Two previously unidentified loops, designated X (270-275) and Y (293-296) underwent minimal and major structural transitions, respectively. In addition, residues 273-277 consistently transitioned to a turn conformation in all ligated systems, whereas unique transitions were identified for other transitioning residue groups in each TMPRSS2-inhibitor complex. Intriguingly, while both DON and DRP-104 showed similar loop transition patterns, DRP-104 preserved loop structural integrity. As evident from our systematic comparative study using experimentally/clinically validated inhibitors, DRP-104 may serve as a potent and novel TMPRSS2 inhibitor and warrants further clinical investigation.

New strategies for sterilization and preservation of fresh fish skin grafts.

The introduction of fish skin as a biological dressing for treating burns and wounds holds great promise, offering an alternative to existing management strategies. However, the risk of disease transmission is a significant concern. Therefore, this study aimed to examine how established sterilization and preservation procedures affected fish skin grafts' microbiological and histological properties for long-term usage. Lyophilization of the fish skin graft followed by rehydration in normal saline for 15 min did not change the collagen content. Furthermore, gamma irradiation of the lyophilized fish skin graft at different lengths 5, 10, and 25 KGy showed a significant reduction in microbial growth (aerobic bacteria, aerobic yeasts, and fungi) at 15- and 30 days after the irradiation. However, exposure to 10 KGy was found to be the most effective intensity among the different gamma irradiation lengths since it preserved the collagen fiber content and intensity in the lyophilized fish skin grafts at 15- and 30 days after the irradiation. These findings provide efficient preservation and sterilization methods for long-term usage of the fresh Tilapia skin grafts used for biological dressings.

Development of a fast and simple method for the isolation of superparamagnetic iron oxide nanoparticles protein corona from protein-rich matrices.

The adsorption of proteins onto the surface of nanoparticle (NP) leads to the formation of the so-called "protein corona" as consisting both loosely and tightly bound proteins. It is well established that the biological identity of NPs that may be acquired after exposure to a biological matrix is mostly provided by the components of the hard corona as the pristine surface is generally less accessible for binding. For that reason, the isolation and the characterisation of the NP-corona complexes and identification of the associated biomolecules can help in understanding its biological behaviour. Established methods for the isolation of the NP-HC complexes are time-demanding and can lead to different results based on the isolation method applied. Herein, we have developed a fast and simple method using ferromagnetic beads isolated from commercial MACS column and used for the isolation of superparamagnetic NP following exposure to different types of biological milieu. We first demonstrated the ability to easily isolate superparamagnetic iron oxide NPs (IONPs) from different concentrations of human blood plasma, and also tested the method on the corona isolation using more complex biological matrices, such as culture medium containing pulmonary mucus where the ordinary corona methods cannot be applied. Our developed method showed less than 20% difference in plasma corona composition when compared with centrifugation. It also showed effective isolation of NP-HC complexes from mucus-containing culture media upon comparing with centrifugation and MACS columns, which failed to wash out the unbound proteins. Our study was supported with a full characterisation profile including dynamic light scattering, nanoparticle tracking analysis, analytical disk centrifuge, and zeta potentials. The biomolecules/ proteins composing the HC were separated by vertical gel electrophoresis and subsequently analysed by liquid chromatography-tandem mass spectrometry. In addition to our achievements in comparing different isolation methods to separate IONPs with corona from human plasma, this is the first study that provides a complete characterisation profile of particle protein corona after exposure in vitro to pulmonary mucus-containing culture media.

The use of a complex tetra-culture alveolar model to study the biological effects induced by gold nanoparticles with different physicochemical properties.

A substantial increase in engineered nanoparticles in consumer products has been observed, heightening human and environmental exposure. Inhalation represents the primary route of human exposure, necessitating a focus on lung toxicity studies. However, to avoid ethical concerns the use of in vitro models is an efficient alternative to in vivo models. This study utilized an in vitro human alveolar barrier model at air-liquid-interface with four cell lines, for evaluating the biological effects of different gold nanoparticles. Exposure to PEGylated gold nanospheres, nanorods, and nanostars did not significantly impact viability after 24 h, yet all AuNPs induced cytotoxicity in the form of membrane integrity impairment. Gold quantification revealed cellular uptake and transport. Transcriptomic analysis identified gene expression changes, particularly related to the enhancement of immune cells. Despite limited impact, distinct effects were observed, emphasizing the influence of nanoparticles physicochemical parameters while demonstrating the model's efficacy in investigating particle biological effects.

Multi-cavity molecular descriptor interconnections: Enhanced protocol for prediction of serum albumin drug binding.

The role of human serum albumin (HSA) in the transport of molecules predicates its involvement in the determination of drug distribution and metabolism. Optimization of ADME properties are analogous to HSA binding thus this is imperative to the drug discovery process. Currently, various in silico predictive tools exist to complement the drug discovery process, however, the prediction of possible ligand-binding sites on HSA has posed several challenges. Herein, we present a strong and deeper-than-surface case for the prediction of HSA-ligand binding sites using multi-cavity molecular descriptors by exploiting all experimentally available and crystallized HSA-bound drugs. Unlike previously proposed models found in literature, we established an in-depth correlation between the physicochemical properties of available crystallized HSA-bound drugs and different HSA binding site characteristics to precisely predict the binding sites of investigational molecules. Molecular descriptors such as the number of hydrogen bond donors (nHD), number of heteroatoms (nHet), topological polar surface area (TPSA), molecular weight (MW), and distribution coefficient (LogD) were correlated against HSA binding site characteristics, including hydrophobicity, hydrophilicity, enclosure, exposure, contact, site volume, and donor/acceptor ratio. Molecular descriptors nHD, TPSA, LogD, nHet, and MW were found to possess the most inherent capacities providing baseline information for the prediction of serum albumin binding site. We believe that these associations may form the bedrock for establishing a solid correlation between the physicochemical properties and Albumin binding site architecture. Information presented in this report would serve as critical in provisions of rational drug designing as well as drug delivery, bioavailability, and pharmacokinetics.

Exploring the potential of biologically active phenolic acids from marine natural products as anticancer agents targeting the epidermal growth factor receptor.

The epidermal growth factor receptor (EGFR) dimerizes upon ligand bindings to the extracellular domain that initiates the downstream signaling cascades and activates intracellular kinase domain. Thus, activation of autophosphorylation through kinase domain results in metastasis, cell proliferation, and angiogenesis. The main objective of this research is to discover more promising anti-cancer lead compound against EGRF from the phenolic acids of marine natural products using in-silico approaches. Phenolic compounds reported from marine sources are reviewed from previous literatures. Furthermore, molecular docking was carried out using the online tool CB-Dock. The molecules with good docking and binding energies scores were subjected to ADME, toxicity and drug-likeness analysis. Subsequently, molecules from the docking experiments were also evaluated using the acute toxicity and MD simulation studies. Fourteen phenolic compounds from the reported literatures were reviewed based on the findings, isolation, characterized and applications. Molecular docking studies proved that the phenolic acids have good binding fitting by forming hydrogen bonds with amino acid residues at the binding site of EGFR. Chlorogenic acid, Chicoric acid and Rosmarinic acid showed the best binding energies score and forming hydrogen bonds with amino acid residues compare to the reference drug Erlotinib. Among these compounds, Rosmarinic acid showed the good pharmacokinetics profiles as well as acute toxicity profile. The MD simulation study further revealed that the lead complex is stable and could be future drug to treat the cancer disease. Furthermore, in a wet lab environment, both in-vitro and in-vivo testing will be employed to validate the existing computational results.Communicated by Ramaswamy H. Sarma.

In-vitro Antimicrobial Study of Non/irradiated Ylang-ylang Essential Oil Against Multi Drug Resistant Pathogens with Reference to Microscopic Morphological Alterations.

Essential oils have proven to possess great potential in the field of biomedicine due to their ability to effectively eradicate a diverse range of pathogenic microbes. In this study, the antimicrobial activity of ylang-ylang essential oil (YY-EO) was screened against twelve multidrug-resistant pathogens. The YY-EO was effective up to 536 µg/ml, with the highest inhibition zone in case of S. aureus MMCC21 and Escherichia coli MMCC24. The least effect on both Bacillus cereus MMCC11 and Klebsiella pneumonia MMCC16. The major components of the essential oil were identified using GC-MS analysis. Different gamma irradiation doses against the YY-EO were evaluated as a tool of natural decontamination. Moreover, the antimicrobial assay after irradiation proved no significant changes regarding the antimicrobial activity before and after irradiation of EO at the applied dose. The minimum inhibitory concentration (MIC) for the EO against the tested pathogens was detected. The possible morphological changes in some of the bacterial and yeast cells at the recognized MIC and 2MIC were detected using the scanning electron microscope (SEM). Results revealed a notable change in terms of both the microbial cell population and the morphology of the tested bacterial and yeast cells. The cytotoxicity of ylang-ylang EO was evaluated against normal skin tissue culture and showed a potential cytotoxic effect at concentrated doses. These results refer to the importance of YY-EO as a natural antimicrobial agent and the possible application of YY-EO as a surface decontaminant, but they also draw attention to the importance of the EO concentration used in different applications to avoid possible toxic effects. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-023-01122-4.

Bilaterality of varicocele: The overlooked culprit in male infertility. Case series study.

OBJECTIVES: Varicocele is the most common correctable cause of male infertility that always has been a debatable subject as regards how it affects fertility and the best way to treat it. Proper assessment of the disease bilaterality is crucial not to miss one side and not to jeopardize treatment outcome. This study aimed to objectively assess varicocele bilaterality in infertile men aiming to improve treatment outcome in this cohort of patients. METHODS: This prospective study was conducted between January 2019 and January 2022 including infertile males with varicoceles. Assessment of missed concomitant contralateral varicocele done pre-operatively by Color Doppler Ultrasound and intraoperatively by intraoperative Doppler device and measurement of maximal vein diameter of contralateral side. RESULTS: A total of 329 cases completed the study. A hundred cases (30.4%) were initially referred as unilateral varicoceles and 229 (69.6%) as bilateral varicoceles. After reassessment of the study population, bilaterality of varicocele was found to be as high as 98.5% (324/329). Repeat CDUS strongly correlated with the intraoperative measured varicocele diameter (r = 0.9, p < 0.001). Moreover, sperm parameters showed significant improvement 3 and 6 months post varicocelectomy. Normal pregnancy after 1 year of surgery occurred in 118 cases (35.9%). CONCLUSIONS: Varicocele bilaterality in infertile men is underreported. Thorough assessment by expert radiologists and andrologists is of paramount importance not to miss significant pathology or hazard treatment outcome.

Selected phytochemicals of Momordica charantia L. as potential anti-DENV-2 through the docking, DFT and molecular dynamic simulation.

Dengue fever is now one of the major global health concerns particularly for tropical and sub-tropical countries. However, there has been no FDA approved medication to treat dengue fever. Researchers are looking into DENV NS5 RdRp protease as a potential therapeutic target for discovering effective anti-dengue agents. The aim of this study to discover dengue virus inhibitor from a set of five compounds from Momordica charantia L. using a series of in-silico approaches. The compounds were docked into the active area of the DENV-2 NS5 RdRp protease to obtain the hit compounds. The successful compounds underwent additional testing for a study on drug-likeness similarity. Our study obtained Momordicoside-I as a lead compound which was further exposed to the Cytochrome P450 (CYP450) toxicity analysis to determine the toxicity based on docking scores and drug-likeness studies. Moreover, DFT studies were carried out to calculate the thermodynamic, molecular orbital and electrostatic potential properties for the lead compound. Moreover, the lead compound was next subjected to molecular dynamic simulation for 200 ns in order to confirm the stability of the docked complex and the binding posture discovered during docking experiment. Overall, the lead compound has demonstrated good medication like qualities, non-toxicity, and significant binding affinity towards the DENV-2 RdRp enzyme.Communicated by Ramaswamy H. Sarma.

Inherent efficacies of pyrazole-based derivatives for cancer therapy: the interface between experiment and in silico.

There has been an increasing trend in the design of novel pyrazole derivatives for desired biological applications. For a cost-effective strategy, scientists have implemented various computational drug design tools to go hand in hand with experiments for the design and discovery of potentially effective pyrazole-based therapeutics. This review highlights the milestones of pyrazole-containing inhibitors and the use of molecular modeling techniques in conjunction with experimental studies to provide a view of the binding mechanism of these compounds. The review focuses on the established targets that play a key role in cancer therapy, including proteins involved in tubulin polymerization, carbonic anhydrase and tyrosine kinase. Overall, using both experimental and computational methods in drug design represents a promising approach to cancer therapy.