Molecular Targets Research Articles

A Detailed Examination of Retroperitoneal Undifferentiated Pleomorphic Sarcoma: A Case Report and Review of the Existing Literature.

This detailed review focuses on retroperitoneal undifferentiated pleomorphic sarcoma (UPS), a particularly aggressive soft-tissue sarcoma that poses unique diagnostic and therapeutic challenges due to its rarity and complex presentation. By documenting a new case of retroperitoneal UPS and conducting a comprehensive review of all known cases, this article aims to expand the existing body of knowledge on the epidemiology, molecular pathogenesis, and treatment strategies associated with this rare disease. The complexity of diagnosing UPS is emphasized given that it rarely occurs in the retroperitoneal space and its histological and molecular complexity often complicates its recognition. This review highlights the need for specialized diagnostic approaches, including advanced imaging techniques and histopathological studies, to accurately diagnose and stage the disease. In terms of treatment, this paper advocates a multidisciplinary approach that combines surgery, radiotherapy and chemotherapy and tailors it to individual patients to optimize treatment outcomes. This review highlights case studies that illustrate the effectiveness of surgical intervention in the treatment of these tumors and emphasize the importance of achieving clear surgical margins to prevent recurrence. Furthermore, this review discusses the potential of new molecular targets and the need for innovative therapies that could bring new hope to patients affected by this challenging sarcoma.

Drug Repurposing and Molecular Insights in the Fight Against Breast Cancer

Breast Cancer (BC) is a complex disease with high incidence in developed countries. According to the World Health Organization (WHO), it is accounted for 11.7% of all new cancer cases worldwide in 2020, with an estimated 2.3 million new diagnosis every year. A 2.5% annual reduction in the disease mortality could prevent 2.5 million deaths worldwide between 2020 and 2040. In the current work systematic review was conducted for drugs under clinical trials or approved for treatment of BC. It was observed that many drugs were repurposed for BC treatment over the course of time even though they were originally developed for some other disease. This is called as Drug Repurposing. It is an approach that has gained significant attention in recent years as a promising alternative to traditional drug discovery, which is often costly, time-consuming, and has a high failure rate. Thirteen drugs were observed to be repurposed for BC treatment and we dig deep into their molecular background and reasons for their efficacies in BC treatment. Molecular targets of these drugs in the human system were predicted and protein interaction networks were analysed to work out the genes responsible for their repurposed events. Few genes seen in the disease progression, were BRCA1, BRCA2, PALB-2, ATM, TP53, PTEN, and HER2/neu participate in various biological pathways, such as the PI3K/Akt/mTOR and ER pathways, and biological processes such as the tumor microenvironment, epithelial-mesenchymal transition, and DNA damage response pathways. Mutations or alterations in these genes or pathways can lead to the development and progression, and understanding their roles that can help in the development of new diagnostic and therapeutic strategies. This study offers an in-silico perspective and a powerful tool to find potentially effective drugs by analysing the molecular mechanisms and signalling pathways involved in the disease progression.

Transcriptomic Change in the Effects of Dichloroquinolinic Acid on the Development and Growth of Nicotiana tabacum

Dichloroquinolinic acid is a hormone-type herbicide widely used to control barnyard grass during crop cultivation. However, it can seriously inhibit the growth of susceptible crops, including tobacco, because it degrades slowly under field conditions. Additionally, the mechanism by which it damages crops is unclear. More specifically, the transcriptional changes in plants induced by dichloroquinolinic acid remain unknown. In this study, differentially expressed genes (DEGs) in tobacco treated with dichloroquinolinic acid (varying concentrations and durations) were analyzed and validated to explore the global transcriptome changes. The number of DEGs, which were determined according to the FPKM, varied from 758 to 21,340. The KEGG analysis revealed that many DEGs were involved in starch and sucrose metabolism, phenylpropanoid biosynthesis, photosynthesis, porphyrin and chlorophyll metabolism, and glutathione metabolism. Transcriptomic analyses indicated that dichloroquinolinic acid can inhibit tobacco growth by inhibiting photosynthesis and storage of energy. We discovered that the toxicity mechanism of the hormone herbicide dichloroquinolinic acid differs from that of high concentrations of IAA (Indoleacetic acid), despite studies confirming that the effects of hormone herbicides are consistent with the physiological disturbances and growth inhibition exhibited by plants in IAA overdose. Particularly, dichloroquinolinic acid suppresses photosynthesis while high concentration IAA stimulates nucleotide synthesis and photosynthesis. More importantly, we found by editing the IAA-responsive gene IAA16, tobacco could develop resistance to dichloroquinolinic acid. The results will help clarify plant responses to hormone-type herbicides at the transcriptional level, thereby providing insights into the diversity in the gene’s response to herbicides, the molecular targets of hormone-type herbicides, and the mechanism underlying the susceptibility of tobacco to dichloroquinolinic acid. Accordingly, this study may be helpful for future research to enhance crop resistance to herbicides residues.

Novel perspectives on autophagy-oxidative stress-inflammation axis in the orchestration of adipogenesis.

Adipose tissue, an indispensable organ, fulfils the pivotal role of energy storage and metabolism and is instrumental in maintaining the dynamic equilibrium of energy and health of the organism. Adipocyte hypertrophy and adipocyte hyperplasia (adipogenesis) are the two primary mechanisms of fat deposition. Mature adipocytes are obtained by differentiating mesenchymal stem cells into preadipocytes and redifferentiation. However, the mechanisms orchestrating adipogenesis remain unclear. Autophagy, an alternative cell death pathway that sustains intracellular energy homeostasis through the degradation of cellular components, is implicated in regulating adipogenesis. Furthermore, adipose tissue functions as an endocrine organ, producing various cytokines, and certain inflammatory factors, in turn, modulate autophagy and adipogenesis. Additionally, autophagy influences intracellular redox homeostasis by regulating reactive oxygen species, which play pivotal roles in adipogenesis. There is a growing interest in exploring the involvement of autophagy, inflammation, and oxidative stress in adipogenesis. The present manuscript reviews the impact of autophagy, oxidative stress, and inflammation on the regulation of adipogenesis and, for the first time, discusses their interactions during adipogenesis. An integrated analysis of the role of autophagy, inflammation and oxidative stress will contribute to elucidating the mechanisms of adipogenesis and expediting the exploration of molecular targets for treating obesity-related metabolic disorders.

Advances in relieving exercise fatigue for curcumin: Molecular targets, bioavailability, and potential mechanism.

Intense and prolonged physical activity can lead to a decrease in muscle capacity, making it difficult to maintain the desired exercise intensity and resulting in exercise fatigue. The long-term effects of exercise fatigue can be very damaging to the body, so it is an urgent problem to be addressed. The intervention of foodborne active substances will be an effective measure. There is growing evidence that the molecular structure and function of curcumin have a positive effect on relieving fatigue. In this review, we summarize curcumin's molecular structure, which enables it to bind to a wealth of molecular targets, regulate signaling pathways, and thus alleviate exercise fatigue through a variety of mechanisms, including reducing oxidative stress, inhibiting inflammation, reducing metabolite accumulation, and regulating energy metabolism. The effects of curcumin on fatigue-related markers were analyzed from the perspective of animal models and human models and based on the bidirectional interaction between curcumin and intestinal microbiota: Intestinal microbiota can transform curcumin, and curcumin regulates gut microbiota through metabolic pathways, providing a new perspective for alleviating fatigue. This review contributes to a more comprehensive understanding of the possible molecular mechanisms of curcumin in anti-fatigue and provides a new possibility for the development of functional foods in the future.

Role and Mechanism of Lactylation in Cancer

Post translational modifications (PTMs) can change the properties of a protein by covalent addition of functional groups to one or more amino acids, and influence almost all aspects of normal cell biology and pathogenesis. Lactylation is a novel identified PTM, and has been found in both histone and non-histone proteins. Since associated with the end product of glycolysis-- lactate, lactylation modification could provide a new perspective for understanding the relationship between metabolic reprogramming and epigenetic modifications. Accumulated evidences suggest that lactylation play important roles in tumor progression and links to poor prognosis in clinical studies. Histone lactylation can affect gene expression in tumor cells and immunological cells, further promoting tumor progression and immune suppression. Lactylation on non-histone proteins can also regulate tumor progression and drug resistance. In this review, we aimed to summarize the roles of lactylation in cancer progression, microenvironment interactions and immune suppression, try to identify new molecular targets for cancer therapy and provide a new direction for combined targeted therapy and immunotherapy. .

Antibody-drug conjugates in solid tumors: a new frontier.

Antibody-drug conjugates (ADCs) are designed to carry cytotoxic payloads and deliver them to specific molecular targets within tumor cells. Several ADCs are already approved with many more in development across several disease types. In this review, we will provide an overview of the ADCs currently approved and those under investigation in solid tumors. Currently there are dozens of ADCs under clinical study evaluation of a variety of solid tumors, and preliminary results are promising. Multiple ADCs have received regulatory approval in disease such as breast cancer, non-small cell lung cancer, and bladder cancer. While some are approved in biomarker selected settings with disease specific indication (e.g. breast cancer), others have been approved irrespective of biomarker expression (urothelial carcinoma) and pan-cancer indications in biomarker selected patients (HER2 3+ expression). Cytotoxic chemotherapy has been the mainstay of systemic treatment for patients with various solid tumors. ADCs offer the advantage of carrying the cytotoxic payload onto a specific molecular receptor, therapy inducing a more selective response. Optimizing selection of target antigen, payload delivery and investigating biomarkers of response will be crucial for further expanding the therapeutic benefit of ADCs across solid tumors.

Reviewing the Structure-Function Paradigm in Polyglutamine Disorders: A Synergistic Perspective on Theoretical and Experimental Approaches.

Polyglutamine (polyQ) disorders are a group of neurodegenerative diseases characterized by the excessive expansion of CAG (cytosine, adenine, guanine) repeats within host proteins. The quest to unravel the complex diseases mechanism has led researchers to adopt both theoretical and experimental methods, each offering unique insights into the underlying pathogenesis. This review emphasizes the significance of combining multiple approaches in the study of polyQ disorders, focusing on the structure-function correlations and the relevance of polyQ-related protein dynamics in neurodegeneration. By integrating computational/theoretical predictions with experimental observations, one can establish robust structure-function correlations, aiding in the identification of key molecular targets for therapeutic interventions. PolyQ proteins' dynamics, influenced by their length and interactions with other molecular partners, play a pivotal role in the polyQ-related pathogenic cascade. Moreover, conformational dynamics of polyQ proteins can trigger aggregation, leading to toxic assembles that hinder proper cellular homeostasis. Understanding these intricacies offers new avenues for therapeutic strategies by fine-tuning polyQ kinetics, in order to prevent and control disease progression. Last but not least, this review highlights the importance of integrating multidisciplinary efforts to advancing research in this field, bringing us closer to the ultimate goal of finding effective treatments against polyQ disorders.

Integrating network pharmacology and Mendelian randomization to explore potential targets of matrine against ovarian cancer.

Matrine has been reported inhibitory effects on ovarian cancer (OC) cell progression, development, and apoptosis. However, the molecular targets of matrine against OC and the underlying mechanisms of action remain elusive. This study endeavors to unveil the potential targets of matrine against OC and to explore the intricate relationships between these targets and the pathogenesis of OC. The effects of matrine on the OC cells (A2780 and AKOV3) viability, apoptosis, migration, and invasion was investigated through CCK-8, flow cytometry, wound healing, and Transwell analyses, respectively. Next, Matrine-related targets, OC-related genes, and ribonucleic acid (RNA) sequence data were harnessed from publicly available databases. Differentially expressed analyses, protein-protein interaction (PPI) network, and Venn diagram were involved to unravel the core targets of matrine against OC. Leveraging the GEPIA database, we further validated the expression levels of these core targets between OC cases and controls. Mendelian randomization (MR) study was implemented to delve into potential causal associations between core targets and OC. The AutoDock software was used for molecular docking, and its results were further validated using RT-qPCR in OC cell lines. Matrine reduced the cell viability, migration, invasion and increased the cell apoptosis of A2780 and AKOV3 cells (P< 0.01). A PPI network with 578 interactions among 105 candidate targets was developed. Finally, six core targets (TP53, CCND1, STAT3, LI1B, VEGFA, and CCL2) were derived, among which five core targets (TP53, CCND1, LI1B, VEGFA, and CCL2) differential expressed in OC and control samples were further picked for MR analysis. The results revealed that CCND1 and TP53 were risk factors for OC. Molecular docking analysis demonstrated that matrine had good potential to bind to TP53, CCND1, and IL1B. Moreover, matrine reduced the expression of CCND1 and IL1B while elevating P53 expression in OC cell lines. We identified six matrine-related targets against OC, offering novel insights into the molecular mechanisms underlying the therapeutic effects of matrine against OC. These findings provide valuable guidance for developing more efficient and targeted therapeutic approaches for treating OC.

Comparative genomics analysis to explore the biodiversity and mining novel target genes of Listeria monocytogenes strains from different regions.

As a common foodborne pathogen, infection with L. monocytogenes poses a significant threat to human life and health. The objective of this study was to employ comparative genomics to unveil the biodiversity and evolutionary characteristics of L. monocytogenes strains from different regions, screening for potential target genes and mining novel target genes, thus providing significant reference value for the specific molecular detection and therapeutic targets of L. monocytogenes strains. Pan-genomic analysis revealed that L. monocytogenes from different regions have open genomes, providing a solid genetic basis for adaptation to different environments. These strains contain numerous virulence genes that contribute to their high pathogenicity. They also exhibit relatively high resistance to phosphonic acid, glycopeptide, lincosamide, and peptide antibiotics. The results of mobile genetic elements indicate that, despite being located in different geographical locations, there is a certain degree of similarity in bacterial genome evolution and adaptation to specific environmental pressures. The potential target genes identified through pan-genomics are primarily associated with the fundamental life activities and infection invasion of L. monocytogenes, including known targets such as inlB, which can be utilized for molecular detection and therapeutic purposes. After screening a large number of potential target genes, we further screened them using hub gene selection methods to mining novel target genes. The present study employed eight different hub gene screening methods, ultimately identifying ten highly connected hub genes (bglF_1, davD, menE_1, tilS, dapX, iolC, gshAB, cysG, trpA, and hisC), which play crucial roles in the pathogenesis of L. monocytogenes. The results of pan-genomic analysis showed that L. monocytogenes from different regions exhibit high similarity in bacterial genome evolution. The PCR results demonstrated the excellent specificity of the bglF_1 and davD genes for L. monocytogenes. Therefore, the bglF_1 and davD genes hold promise as specific molecular detection and therapeutic targets for L. monocytogenes strains from different regions.

Next-generation risk assessment read-across case study: application of a 10-step framework to derive a safe concentration of daidzein in a body lotion.

Introduction: We performed an exposure-based Next Generation Risk Assessment case read-across study using New Approach Methodologies (NAMs) to determine the highest safe concentration of daidzein in a body lotion, based on its similarities with its structural analogue, genistein. Two assumptions were: (1) daidzein is a new chemical and its dietary intake omitted; (2) only in vitro data were used for daidzein, while in vitro and legacy in vivo data for genistein were considered. Methods: The 10-step tiered approach evaluating systemic toxicity included toxicokinetics NAMs: PBPK models and in vitro biokinetics measurements in cells used for toxicogenomics and toxicodynamic NAMs: pharmacology profiling (i.e., interaction with molecular targets), toxicogenomics and EATS assays (endocrine disruption endpoints). Whole body rat and human PBPK models were used to convert external doses of genistein to plasma concentrations and in vitro Points of Departure (PoD) to external doses. The PBPK human dermal module was refined using in vitro human skin metabolism and penetration data. Results: The most relevant endpoint for daidzein was from the ERα assay (Lowest Observed Effective Concentration was 100 ± 0.0nM), which was converted to an in vitro PoD of 33nM. After application of a safety factor of 3.3 for intra-individual variability, the safe concentration of daidzein was estimated to be 10nM. This was extrapolated to an external dose of 0.5μg/cm2 for a body lotion and face cream, equating to a concentration of 0.1%. Discussion: When in vitro PoD of 33nM for daidzein was converted to an external oral dose in rats, the value correlated with the in vivo NOAEL. This increased confidence that the rat oral PBPK model provided accurate estimates of internal and external exposure and that the in vitro PoD was relevant in the safety assessment of both chemicals. When plasma concentrations estimated from applications of 0.1% and 0.02% daidzein were used to calculate bioactivity exposure ratios, values were >1, indicating a good margin between exposure and concentrations causing adverse effects. In conclusion, this case study highlights the use of NAMs in a 10-step tiered workflow to conclude that the highest safe concentration of daidzein in a body lotion is 0.1%.

Exploring the Use of Natural Ingredients for the Protection of Textured Hair from Ultraviolet Radiation: An In Vitro Study

Human hair is characterized by significant diversity, which is dictated by the individual genetic makeup. It is estimated that up to 70% of the world’s population has textured hair, with a significant proportion also living in areas with high exposure to ultraviolet radiation (UVR). This highlights the unique requirements for textured hair care products that can protect hair shafts from the harmful effects of the environment whilst enhancing the natural features of the fibre. In this study, we investigated the UV-protective effects of hair conditioner formulated from active ingredients, mangiferin, ferulic acid and naringin. The analysis of UV-irradiated straight and textured hair was performed by measurements of hair thickness and darkness, the uptake of the fluorescent dye, spectral absorbance of keratin extracts, ATR-FTIR and SEM. We found that textured hair was more sensitive to UVR-induced changes than straight hair, with the primary molecular targets represented by chemical groups in keratins. Pre-treatment of the hair with conditioner had protective effects against structural damage and oxidative stress caused by UVR. These data indicate the importance of the personalized approach to hair research and the formulation of hair care products tailored to the individual demands of textured hair types.

2-Styryl-quinoline-4-carboxylic acids: Synthesis, characterization, and investigation of their optical properties and antimicrobial activity

Styrylquinoline-based fluorophores 1–10 were synthesized via Knoevenagel and Pfitzinger reactions. The molecules were fully characterized and studied for the impact of their substitution patterns (A-D) on their optical and bioactivity properties. With exception of nitro substituted compounds 9-D and 10-D, all compounds were fluorescent in solution with a significant solvatochromic behavior measured in toluene, dioxane, tetrahydrofurane, ethyl acetate, dichloromethane, dimethylformamide, dimethylsulfoxide, acetonitrile, isopropanol, and methanol. The maximum wavelength of their emission ranged from 408 to 539 nm. Additionally, there was a significant variation in the photoluminescence (PL) quantum yield concerning different solvent polarities. The PL quantum yields ranged from small values, such as 1.7 % in methanol for compound 1-A, to good PL quantum yields, such as 44.4 % in dioxane for 7-C. For comparison, the quantum yield of 7-C in methanol was 3.3 %, a total range variation of 41.1 %. 4-B and 5-B with O-acetyl groups at ortho and at para position to the CC double bond, respectively, presented an interesting acidochromism with a redshift of about 102 nm in their emission bands along with a visible emitted color change from blue to green. In addition, the antimicrobial activity for all compounds and the theoretical mechanism of action of the more significant bioactive compounds were investigated. In inverse virtual screening studies, the enzymes Dehydrosqualene synthase and Squalene synthase were indicated as putative biological targets for 3-B and 4-B. Molecular docking indicated the amino acid residues critical for interaction in bacteria and fungi.

Understanding epileptogenesis from molecules to network alteration.

Epilepsy is characterized by recurrent seizures. Following an initial insult, a latent period precedes the onset of spontaneous seizures, a process referred to as epileptogenesis. This period plays a critical role in halting the progression toward epilepsy before the onset of abnormal molecular and network alterations. In this study, the fundamental concepts of epileptogenesis as well as the associated molecular and cellular targets are reviewed.

Molecular mechanisms, targets and clinical potential of berberine in regulating metabolism: a review focussing on databases and molecular docking studies.

Background: Metabolic imbalance is the common basis of many diseases. As natural isoquinoline alkaloid, berberine (BBR) has shown great promise in regulating glucose and lipids metabolism and treating metabolic disorders. However, the related mechanism still lacks systematic research. Aim: To discuss the role of BBR in the whole body's systemic metabolic regulation and further explore its therapeutic potential and targets. Method: Based on animal and cell experiments, the mechanism of BBR regulating systemic metabolic processes is reviewed. Potential metabolism-related targets were summarized using Therapeutic Target Database (TTD), DrugBank, GeneCards, and cutting-edge literature. Molecular modeling was applied to explore BBR binding to the potential targets. Results: BBR regulates the whole-body metabolic response including digestive, circulatory, immune, endocrine, and motor systems through adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR), sirtuin (SIRT)1/forkhead box O (FOXO)1/sterol regulatory element-binding protein (SREBP)2, nuclear factor erythroid 2-related factor (Nrf) 2/heme oxygenase (HO)-1, and other signaling pathways. Through these reactions, BBR exerts hypoglycemic, lipid-regulating, anti-inflammatory, anti-oxidation, and immune regulation. Molecular docking results showed that BBR could regulate metabolism targeting FOXO3, Nrf2, NAD(P)H quinone oxidoreductase 1 (NQO1), glutathione peroxidase (Gpx) 4 and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA). Evaluating the target clinical effects, we found that BBR has the therapeutic potential of anti-aging, anti-cancer, relieving kidney disease, regulating the nervous system, and alleviating other chronic diseases. Conclusion: This review elucidates the interaction between potential targets and small molecular metabolites by exploring the mechanism of BBR regulating metabolism. That will help pharmacologists to identify new promising metabolites interacting with these targets.

MDB-66. HIGH-THROUGHPUT SMALL MOLECULE DRUG SCREENING, TRANSCRIPTOMICS AND INTEGRATIVE AI IDENTIFY TARGETABLE MYC-DEPENDENT THERAPEUTIC VULNERABILITIES IN HIGH-RISK MEDULLOBLASTOMA

Abstract INTRODUCTION MYC-amplified Group 3 medulloblastomas (MBGroup3-MYC) do not respond to conventional up-front therapies and are almost universally fatal (&amp;lt;5% survival). MYC is not directly targetable. Thus, the systematic development of therapies which target complementary MYC-dependencies offers clear potential to rationally re-design effective therapeutic strategies. METHODS Isogenic cell-based models with regulable shRNA MYC-knockdown were developed in three independent MYC-amplified backgrounds (D283Med; D425Med; HD-MB03). These were utilised to i) define the MYC-dependent transcriptome/proteome in MBGroup3, through analysis in conjunction with our primary tumour cohort, and ii) as the basis of an automated MYC-dependent high-throughput drug screen (HTS; &amp;gt;500 clinically-actionable compounds). Bespoke integrative AI tools and bioinformatic analysis, and subsequent siRNA/pharmacodynamic validation, identified and validated candidate MYC-dependent therapeutic vulnerabilities. Prioritised drugs were advanced to pre-clinical trials across two in vivo MBGroup3 models (GTML/Trp53KI/KI (GEMM; MYCN-driven) and GMYC (GEMM-derived allografts; MYC-driven)) to evaluate candidate efficacy and toxicity. RESULTS shRNA-mediated MYC knockdown could be maintained for 28 days without escape in all models and, as anticipated, was associated with cell cycle abrogation and elevated caspase-3/-7 activity. HTS across all models revealed that MYC expression confers differential dependencies to small molecule inhibitors, with 82 compounds spanning 11 major drug classes demonstrating MYC-dependent activity. AI-based integration of HTS data with model and primary patient MYC-dependent transcriptome data shortlisted multiple druggable molecular targets which, in turn, were independently validated. To date, we have progressed alisertib (AURKAi), volasertib (PLK1i) and prexasertib (CHK1i) to in vivo pre-clinical trials. Promisingly, both alisertib and prexasertib demonstrated efficacy within MBGroup3-MYC models. CONCLUSIONS Integrated human tumour and model-based screening approaches have enabled identification and validation of critical MYC co-dependencies, targetable using established small-molecules, to inhibit MBGroup3 tumour growth. Their further evaluation, including integration into established and/or rationally-designed combinations, will be essential next steps in their (pre-)clinical development.

Pharmacological potential of 3,5-dimethyl-4-(3-(5-nitrofuran-2-yl)allylidenamino)-1-alkyl-1,2,4-triazolium bromides

The discovery of new 1,2,4-triazole derivatives offers significant potential for the development of innovative medications. Researchers often favor derivatives of this heterocyclic system due to their ability to create chemical structures with desired pharmacokinetic and pharmacodynamic properties, allowing for targeted effects on specific biological targets. Importantly, biologically active compounds containing triazole have demonstrated relatively low toxicity and minimal risks of mutagenicity. The synergistic combination of these characteristics provides favorable conditions for the development of complex therapeutic effects, ultimately leading to the creation of novel biologically active substances and offering new avenues for the effective treatment of various diseases. Indeed, the utilization of a diverse array of chemical transformations and functionalizations is crucial for obtaining bioactive molecules with desired properties. In this context, 1,2,4-triazole and its derivatives offer a platform for executing a comprehensive range of chemical transformations, thereby enabling the development of compounds with enhanced pharmacokinetic and pharmacodynamic parameters. The aim of the study was to preliminarily assess the possibility of creating a biologically active substance based on 3,5-dimethyl-4-(3-(5-nitrofuran-2-yl)allylidenamino)-1-R-1,2,4-triazole halides. Materials and methods. In silico analysis was used to assess the safety and potential toxicity of the presented compounds, which was implemented using the T.E.S.T. software developed by the US Environmental Protection Agency. SwissADME is an online resource as an effective tool for studying the physicochemical properties and pharmacokinetic parameters of the compounds proposed for study. A molecular docking method that uses a variety of computational algorithms to predict and analyze interactions, including determining the presence of possible binding sites, estimating binding energies, and the spatial arrangement of molecules. The ligand models were created using MarvinSketch 6.3.0, Hyper Chem 8, and AutoDockTools-1.5.6. Discovery Studio 4.0 and AutoDockTools-1.5.6 have been used to prepare the enzymes for analysis. For direct molecular docking, Vina software has been used, which allows predicting and evaluating the interaction between the ligand molecule and the three-dimensional structure of the target protein, taking into account their energy and spatial compatibility. Results. A virtual set of 3,5-dimethyl-4-(3-(5-nitrofuran-2-yl)allylidenamino)-1-alkyl-1,2,4-triazolium bromides was prescreened, which are potential candidates for the further synthesis of biologically active compounds. The general level of toxicity and harmlessness was determined at the predictive level. The key physicochemical characteristics of the molecules have been determined and the general pharmacokinetic parameters have been identified, which allows for a better understanding of their interaction and behavior in the body. The active sites of the model enzymes were analyzed using Vina software, which contributes to a deeper understanding of the interaction of enzymes with their substrates. According to the results of the study, an increased probability of the formation of anti-inflammatory and anticancer properties occurs in 1-alkyl derivatives of 3,5-dimethyl-4-(3-((5-nitrofuran-2-yl)allylidenamino)-1,2,4-triazolium halides with an odd number of Сarbon atoms. Instead, the highest affinity for lanosterol 14α-demethylase has been demonstrated in the studied derivatives with octyl and nonyl substituents, which shows a certain probability of antifungal activity. Conclusions. The prognosis for the creation of a biologically active substance using 1-alkyl derivatives of 3,5-dimethyl-4-(3-(5-nitrofuran-2-yl)allylidenamino)-1,2,4-triazolium halides is quite favorable.

Pharmacological potential of 3,5-dimethyl-4-(3-(5-nitrofuran-2-yl)allylidenamino)-1-alkyl-1,2,4-triazolium bromides

The discovery of new 1,2,4-triazole derivatives offers significant potential for the development of innovative medications. Researchers often favor derivatives of this heterocyclic system due to their ability to create chemical structures with desired pharmacokinetic and pharmacodynamic properties, allowing for targeted effects on specific biological targets. Importantly, biologically active compounds containing triazole have demonstrated relatively low toxicity and minimal risks of mutagenicity. The synergistic combination of these characteristics provides favorable conditions for the development of complex therapeutic effects, ultimately leading to the creation of novel biologically active substances and offering new avenues for the effective treatment of various diseases. Indeed, the utilization of a diverse array of chemical transformations and functionalizations is crucial for obtaining bioactive molecules with desired properties. In this context, 1,2,4-triazole and its derivatives offer a platform for executing a comprehensive range of chemical transformations, thereby enabling the development of compounds with enhanced pharmacokinetic and pharmacodynamic parameters. The aim of the study was to preliminarily assess the possibility of creating a biologically active substance based on 3,5-dimethyl-4-(3-(5-nitrofuran-2-yl)allylidenamino)-1-R-1,2,4-triazole halides. Materials and methods. In silico analysis was used to assess the safety and potential toxicity of the presented compounds, which was implemented using the T.E.S.T. software developed by the US Environmental Protection Agency. SwissADME is an online resource as an effective tool for studying the physicochemical properties and pharmacokinetic parameters of the compounds proposed for study. A molecular docking method that uses a variety of computational algorithms to predict and analyze interactions, including determining the presence of possible binding sites, estimating binding energies, and the spatial arrangement of molecules. The ligand models were created using MarvinSketch 6.3.0, Hyper Chem 8, and AutoDockTools-1.5.6. Discovery Studio 4.0 and AutoDockTools-1.5.6 have been used to prepare the enzymes for analysis. For direct molecular docking, Vina software has been used, which allows predicting and evaluating the interaction between the ligand molecule and the three-dimensional structure of the target protein, taking into account their energy and spatial compatibility. Results. A virtual set of 3,5-dimethyl-4-(3-(5-nitrofuran-2-yl)allylidenamino)-1-alkyl-1,2,4-triazolium bromides was prescreened, which are potential candidates for the further synthesis of biologically active compounds. The general level of toxicity and harmlessness was determined at the predictive level. The key physicochemical characteristics of the molecules have been determined and the general pharmacokinetic parameters have been identified, which allows for a better understanding of their interaction and behavior in the body. The active sites of the model enzymes were analyzed using Vina software, which contributes to a deeper understanding of the interaction of enzymes with their substrates. According to the results of the study, an increased probability of the formation of anti-inflammatory and anticancer properties occurs in 1-alkyl derivatives of 3,5-dimethyl-4-(3-((5-nitrofuran-2-yl)allylidenamino)-1,2,4-triazolium halides with an odd number of Сarbon atoms. Instead, the highest affinity for lanosterol 14α-demethylase has been demonstrated in the studied derivatives with octyl and nonyl substituents, which shows a certain probability of antifungal activity. Conclusions. The prognosis for the creation of a biologically active substance using 1-alkyl derivatives of 3,5-dimethyl-4-(3-(5-nitrofuran-2-yl)allylidenamino)-1,2,4-triazolium halides is quite favorable.

Flavonoid-quinoxaline Hybrid Compounds as Cathepsin Inhibitors Against Fascioliasis.

Fasciola hepatica is a parasitic trematode that infects livestock animals and humans, causing significant health and economic burdens worldwide. The extensive use of anthelmintic drugs has led to the emergence of resistant parasite strains, posing a threat to treatment success. The complex life cycle of the liver fluke, coupled with limited funding and research interest, have hindered progress in drug discovery. Our group has been working in drug development against this parasite using cathepsin proteases as molecular targets, finding promising compound candidates with in vitro and in vivo efficacy. Here, we evaluated hybrid molecules that combine two chemotypes, chalcones and quinoxaline 1,4-di- N-oxides, previously found to inhibit F. hepatica cathepsin Ls and tested their in vitro activity with the isolated targets and the parasites in culture. These molecules proved to be good cathepsin inhibitors and to kill the juvenile parasites at micromolar concentrations. Also, we performed molecular docking studies to analyze the compounds-cathepsins interface, finding that the best inhibitors interact at the active site cleft and contact the catalytic dyad and residues belonging to the substrate binding pockets. We conclude that the hybrid compounds constitute promising scaffolds for the further development of new fasciolicidal compounds.

Genetically predicted 91 circulating inflammatory proteins in relation to risk of urological malignancies: a Mendelian randomization study.

Urological malignancies, including kidney, bladder, and prostate cancer, are major health concerns worldwide. Inflammation has been implicated in the pathogenesis of these cancers, and circulating inflammatory proteins may play a role in their development. However, the causal relationship between specific plasma proteins and urological malignancies remains unclear. We performed a two-sample Mendelian randomization (MR) analysis using summary statistics from genome-wide association studies (GWAS). Instrumental variables representing genetic variants associated with circulating inflammatory proteins were used to infer causality on the risk of kidney, bladder, and prostate cancer. Four MR methods were utilized to provide robust effect estimates. Our analysis identified several plasma proteins associated with a lower risk of kidney and bladder cancer, including Eukaryotic translation initiation factor 4E-binding protein 1, Caspase 8, Natural killer cell receptor 2B4, and Tumor necrosis factor ligand superfamily member 12. However, after adjusting for multiple testing, these associations did not remain statistically significant. For prostate cancer, CUB domain-containing protein 1 and Interleukin-10 receptor subunit beta were found to be protective, while Glial cell line-derived neurotrophic factor and SIR2-like protein 2 were identified as risk factors. After FDR adjustment, none of the inflammatory proteins were found to be significantly associated with a lower risk of prostate cancer. Our findings suggest that certain plasma proteins may be involved in the development of urological malignancies. Mendelian randomization provides a useful framework for investigating causal relationships between inflammatory proteins and urological cancers, offering potential insights into their underlying biology and therapeutic targets.