TGF-beta-activated kinase 1 (TAK1) is a critical regulator of inflammatory and oncogenic signaling pathways and represents a promising therapeutic target for diseases ranging from chronic inflammation to cancer. However, existing therapies targeting downstream mediators often face limitations such as drug resistance and inconsistent efficacy. Here, we report on drug repurposing to discover FDA-approved compounds that can suppress TAK1 activity. Molecular docking of 3500 drugs from the DrugBank database was performed, followed by drug profiling, biological activity analysis, and 500-nanosecond molecular dynamics (MD) simulations via a multi-step computational protocol. The systematic screening identified a few hits where two drugs, nilotinib and dabrafenib, showed appreciable binding affinity to the ATP-binding site of TAK1 and showed appropriate drug profiles. Stable interaction analyses indicated consistent engagement of catalytic residues and structural motifs essential for ATP binding and subsequent TAK1 function. MD simulations further indicated stable TAK1-ligand complexes for both nilotinib and dabrafenib, with persistent hydrogen-bonding interactions and maintenance of protein compactness throughout the simulations. These findings support the repositioning of nilotinib and dabrafenib as potential TAK1-targeting compounds toward therapeutic development against inflammation-driven pathologies and cancer. Experimentally validating these insights at the level of cells, tissues, organs, and body systems is necessary to translate computational insights into practical use for therapeutic development.
Bipolar disorder is a mental illness that causes people to have periods of mania and depression. The dopamine D2 receptor (D2DR), which modulates dopamine levels and is essential for the reward system, mood stabilization, and motivation, along with the serotonin 5-HT2A receptor (HT2AR), which significantly influences mood stability, cognitive function, and anxiety responses via serotonergic signaling, are crucial in bipolar disorder. It was studied the potential interactions of Allium sativum L. chemicals with the dopamine D2 receptor and serotonin 5-HT2A receptor by in silico approaches. This study suggests that the bioactive compounds found in A. sativum L. may exhibit binding affinity toward the dopamine D2 receptor. In contrast, considerably lower binding affinities were observed toward the serotonin 5-HT2A receptor. Their predicted binding characteristics toward the dopamine D2 receptor are reported for the first time. According to findings, especially N-trans-feruloyltramine possesses a structurally stable binding affinity for the dopamine D2 receptor and may represent a computationally prioritized ligand for future experimental investigation concentrating on dopaminergic signaling. Further experimental studies are required to validate these computational findings.
The isatin scaffold has emerged as a promising platform for the development of anticancer agents, as evidenced by several clinically relevant isatin-based compounds. In this study, 85 novel isatin derivatives were designed based on literature reports and evaluated using drug-likeness prediction, ADME profiling, molecular docking, and molecular dynamics simulations. The compounds were screened against VEGFR-2, EGFR, and caspase-6 to identify potential multi-target lead candidates. Based on their binding affinity and pharmacokinetic properties, 41 compounds were shortlisted for further evaluation. Among them, compound 4 exhibited the most favorable binding profile and stable interactions with the selected targets. These findings suggest that compound 4 represents a promising lead for further investigation. However, experimental studies, including enzyme inhibition, cell-based assays, and in vivo evaluation, are required to validate its therapeutic potential. Overall, this study highlights the usefulness of computational approaches in the discovery of novel isatin-based multi-target lead candidates for cancer therapy.
BACKGROUND:Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor, characterized by rapid progression, marked heterogeneity, and resistance to standard therapies. The complexity of its oncogenic networks necessitates multi-target therapeutic strategies. Panchagavya Ghrita (PG), a traditional Ayurvedic formulation containing diverse bioactive constituents with reported anti-inflammatory and antioxidant properties, has not been systematically explored for GBM. RESEARCH DESIGN AND METHODS:GC-MS identified PG compounds were evaluated for drug-likeness using SwissADME. Predicted targets were intersected with GBM-associated genes to identify common targets, which were subjected to functional enrichment and protein-protein interaction analyses. Key hub targets were prioritized, and molecular docking was performed using CB-Dock2. Expression patterns and prognostic relevance were assessed using GEPIA and the Human Protein Atlas. RESULTS:All evaluated compounds met drug-likeness criteria. Network analysis identified 10 hub targets enriched in GBM-relevant pathways, including PI3K-AKT, HIF-1, EGFR-related signaling, and apoptosis regulation. Docking analyses demonstrated favorable interactions between PG bioactives and multiple hub proteins. Expression analyses confirmed dysregulation of several hubs in GBM, with CASP3 showing significant survival association. CONCLUSIONS:This integrative in silico analysis suggests that PG contains multi-target bioactive molecules capable of modulating critical GBM-associated pathways, providing a rationale for further experimental validation.
Voltage-gated sodium channels (VGSCs; Nav1.1-Nav1.9) are necessary for the initiation and propagation of action potentials in neurons, cardiac muscle and skeletal muscle. Because of their functional importance, VGSCs have become promising candidates for drug development in the brain, heart, and pain. The aim of this review is to highlight the structure, physiological role and pathological involvement of VGSCs in several different diseases, such as epilepsy, arrhythmias, chronic pain and cancer. Clinically established VGSC-targeting drugs are discussed, as well as recent evidence that shows an involvement of VGSCs in tumor progression and metastasis. Lack of selectivity, blood-brain barrier penetration, and regulatory complexities are among the challenges faced by VGSC-targeted therapy, as discussed in the review. Other challenges with VGSC-targeted therapy, such as high isoform homology, limited selectivity, blood-brain barrier penetration, and regulatory complexities, are also discussed in the review. In addition, new isoform-specific modulation strategies, innovative drug delivery devices, and new therapeutic approaches are highlighted. In summary, VGSCs are interesting but complex therapeutic targets, and future progress in selective targeting and drug delivery will likely increase their potential use across a variety of neurological, cardiovascular, and oncological disorders.
Non-small cell lung cancer (NSCLC) is responsible for about 85% of all lung cancers and is a major contributor to cancer deaths worldwide. Angiogenesis, mainly mediated by vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), is a key factor involved in the progression and metastasis of NSCLCs and the development of drug resistance. Anti-angiogenic therapy, for instance, with monoclonal antibodies like bevacizumab and ramucirumab, as well as multi-targeted tyrosine kinase inhibitors (TKIs) like nintedanib and anlotinib has been shown to improve the management of NSCLC. Despite the improvement in the management, patients develop resistance through mechanisms such as hypoxia signaling, alternative angiogenic factor activation, vascular structure remodeling, and a suppressive tumor microenvironment (TME). Recent studies have revealed the use of a combination of anti-angiogenic therapy and immune checkpoint blockade to normalize the tumor vasculature, thus enhancing treatment efficacy. Angiogenesis-associated biomarkers, despite extensive research, have not been seen to have a clinical impact in the management and treatment of NSCLC because of the heterogeneous characteristics and the dynamic regulation of the cascade. This review summarizes current VEGF/VEGFR-targeted therapies in NSCLC, mechanisms of resistance, and future directions toward biomarker-guided therapeutic optimization.
The regulation of beta-adrenergic receptors (β-ARs) is crucial for maintaining pancreatic function and metabolic balance. However, the rising incidence of metabolic syndrome (MetS) highlights the need to understand how a high-fat simple carbohydrate (HFSC) diet affects β-AR signaling in the pancreas. Despite its potential significance, this aspect remains underexplored. We hypothesized that MetS-induced alterations in β-AR subtypes may disrupt regulatory mechanisms, potentially affecting adenylate cyclase coupling. This study investigated the impact of an HFSC diet on β-AR subtype expression and downstream signaling in pancreatic islets. MetS was induced in C57BL/6J mice through a 150-day HFSC diet. Metabolic changes were assessed through anthropometric parameters, blood glucose levels, lipid profiles, and pancreatic islet morphology. β-AR subtype expression (Adrb1/ADRB1, Adrb2/ADRB2, Adrb3/ADRB3), cAMP levels, and receptor localization were evaluated using quantitative real-time PCR (qRT-PCR), Western blotting, and immunofluorescence. The HFSC diet led to metabolic disturbances and pancreatic inflammation. Adrb1 mRNA expression was elevated (p < 0.001), but β1-AR localization did not show a corresponding increase. Both β2-AR transcription and translation were downregulated (p < 0.001). Although β3-AR protein levels were markedly increased (p < 0.001), cAMP levels were significantly reduced (p < 0.01). These findings indicate significant β-AR dysregulation under metabolic stress. Altered β1-AR and β2-AR expression, along with increased but functionally insufficient β3-AR signaling, suggest impaired adrenergic regulation in pancreatic islets during MetS. This study contributes to understanding MetS pathophysiology and highlights the relevance of β-AR signaling as a potential therapeutic target.
BACKGROUND:Urotensin-II (U-II) is a potent vasoconstrictor acting via UT receptors. Endothelial buffering normally restrains U-II signaling, but this protection is diminished in diabetes mellitus, contributing to vascular dysfunction. Selective UT antagonists such as Urantide (peptidic) and Palosuran (non-peptidic) are promising, yet direct comparisons under diabetic conditions remain limited. OBJECTIVE:To assess the effects of Urantide and Palosuran on U-II-induced vasoconstriction in aortae from non-diabetic and diabetic rats with intact and denuded endothelium. METHODS:Thoracic aortic rings were mounted for isometric recording. Concentration-response curves to U-II (10-11-10-8 M) were generated in the presence or absence of Urantide or Palosuran (1 µM). RESULTS:Endothelial loss nearly doubled U-II contractions in non-diabetic aorta and unmasked hyperreactivity in diabetic vessels. Urantide abolished efficacy, while Palosuran attenuated both efficacy and potency, with pronounced inhibition in diabetic denuded rings. CONCLUSION:UT antagonism effectively suppresses U-II reactivity through distinct pharmacological profiles, highlighting therapeutic potential in diabetic vasculopathy.
BACKGROUND:Poly (ADP-ribose) polymerase 1 (PARP1) is a critical enzyme involved in DNA repair mechanisms, making it a promising target for anticancer drug development. Triazole derivatives have shown potential as PARP1 inhibitors, but systematic evaluation of a large library remains limited. OBJECTIVE:To perform comprehensive in silico screening and molecular dynamics simulations of 180 triazole derivatives to identify potent PARP1 inhibitors and evaluate their binding stability and interaction profiles. METHODS:A library of 180 triazole derivatives was subjected to molecular docking against the active site of PARP1 using [Schrodinger suite 2024-4]. Top-ranking compounds based on binding affinity were selected for further molecular dynamics (MD) simulations using to assess the stability of the ligand-protein complexes over a 100 ns simulation period. Binding free energies were calculated using MM-GBSA approaches. Key protein-ligand interactions were analyzed to elucidate binding mechanisms. RESULTS:Docking results identified 10 triazole derivatives with superior binding affinities -9.4 to -5.5 kcal/mol compared to reference inhibitors. MD simulations confirmed stable binding conformations with root mean square deviation (RMSD) fluctuations within acceptable limits. Interaction analysis highlighted crucial hydrogen bonds and hydrophobic contacts with catalytic residues of PARP1. CONCLUSION:The integrated in silico screening and molecular dynamics simulation approach successfully identified promising triazole derivatives as potential PARP1 inhibitors. These findings provide valuable insights for the rational design and optimization of novel anticancer agents targeting PARP1.
Diabetic neuropathy (DN), a prevalent and disabling complication of diabetes mellitus is characterized by chronic pain, sensory loss, and motor impairment arising from multifaceted metabolic, inflammatory, and oxidative mechanisms triggered by chronic hyperglycemia. Among the metabolic contributors, polyol pathway, AGE, PKC pathway, and hexosamine biosynthetic pathway are key players. These are closely intertwined with inflammatory mediators and pathways, including NF-κB, MAPK, the NLRP3 inflammasome, cytokine/chemokine signaling, and emerging inflammatory circuits. Mitochondrial dysfunction and oxidative stress, exacerbated by the impairment of AMPK/SIRT/PGC-1α and Nrf2 signaling, contribute to cellular damage and bioenergetic failure. Additionally, disruptions in insulin signaling, specifically involving Akt and RAC1 pathways, worsen neuronal survival, cytoskeletal function, and glucose metabolism. The interplay between these pathways establishes a self-propagating cycle of metabolic stress, inflammation, and neurodegeneration. Recent research has focused on targeting these specific mechanisms, including aldose reductase inhibitors, RAGE antagonists, PKC inhibitors, AMPK activators, and Nrf2 inducers. While many have shown promise in preclinical models, clinical translation remains limited. Understanding the intricate crosstalk between these pathways is essential for developing more effective, multi-targeted interventions aimed at halting or reversing the progression of DN. This review explores the multifaceted pathways underlying DN, including metabolic, inflammatory, mitochondrial dysfunction, and insulin signaling pathways. It highlights the intricate interlinks between these mechanisms and discusses recent advancements in targeted therapeutic approaches.
Epidermal growth factor receptor (EGFR) is a transmembrane protein belonging to the receptor tyrosine kinase (RTK) superfamily, reported as a promising anticancer target in treating diverse malignancies. Previous studies on microarray gene expression and methylation status in cell and animal models revealed the differential expression of EGFR at the early stages of cellular transformation. Additionally, an unpublished study of methylation analysis of EGFR gene promoters conducted in human cancer-related samples showed a several-fold increase in EGFR gene expression, suggesting epigenetic upregulation in tumors. Considering these findings, in the present study, we selected inactive (DFGout) (D: aspartic acid, F: phenylalanine, G: glycine) and active (DFGin) confirmations of EGFR to identify novel lead molecules against aberrant EGFR activity in cancer. Extra precision (XP) docking, molecular mechanics/generalized born surface area (MM/GBSA), molecular dynamics (MD) simulations, and ADME/T were performed, and the results showed that the lead 1 molecule of each target exhibited a better binding affinity and favorable stability than the existing ligands.
Myocardial infarction (MI) is caused by blocked blood flow that leads to tissue damage and impaired cardiac function. This study explored the function and mechanism of Killer Cell Lectin-Like Receptor B1 (KLRB1) in MI, and examined how n6-methyladenosine (m6A) modification regulates its function. The expressions of KLRB1 in MI cell model was evaluated using qRT-PCR and western blotting. The effect of KLRB1 on MI injury was assessed in both cell and animal models. In cell model, cell viability, apoptosis, and inflammation were evaluated using CCK-8, flow cytometry, and enzyme-linked immunosorbent assay (ELISA). In animal model, cardiac function, infract area, structure, apoptosis, injury marker, and inflammation were examined through echocardiography, 2,3,5-Triphenyltetrazolium chloride (TTC) staining, hematoxylin and eosin (H&E) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and ELISA. The relationship between KLRB1 and ZC3H13 was explored using qRT-PCR, western blotting, and methylated RNA immunoprecipitation (MeRIP) assay. KLRB1 showed substantial downregulation in MI. KLRB1 was downregulated in MI, and its overexpression enhanced cell viability, reduced apoptosis and inflammation, and improved infarct size and tissue structure in vivo. ZC3H13 was downregulated in MI. ZC3H13 was downregulated in the MI, and its overexpression increased KLRB1 mRNA and protein levels via regulating KLRB1 m6A modification. In conclusion, these findings suggest that KLRB1 alleviates the MI injury, and ZC3H13 induces the upregulation of KLRB1 through m6A modification. These results may provide insight into the ZC3H13/KLRB1 axis as a potential therapeutic avenue for reducing myocardial injury and improving cardiac outcomes after MI.
Ubiquitin-specific peptidase 22 (USP22) has emerged as a promising target in cancer research because of its pivotal role in tumor progression, metastasis, and therapy resistance. USP22 is frequently overexpressed in multiple malignancies and facilitates essential cellular processes, including DNA repair, cell cycle regulation, and cancer stem cell (CSC) maintenance. The strength of these attributes makes it an attractive candidate for therapeutic intervention. Despite the advances in conventional cancer treatment, recurrent and resistant USP22-overexpressing tumors demand novel treatment strategies. Drug repurposing is a cost-effective and efficient approach to overcome this challenge by taking advantage of FDA-approved drugs, wherein the safety profiles of used drugs are known for different therapeutic uses. To identify potential repurposed USP22 inhibitors, this study used an integrated computational workflow consisting of molecular docking and molecular dynamics (MD) simulations. The virtual screening of FDA-approved compounds from DrugBank revealed that Ergotamine showed high binding affinities and specific interactions with the USP22 binding pocket. Pharmacokinetic evaluations demonstrate that Ergotamine has an appropriate drug profile and biological activities in anticancer interventions. The stability and conformational dynamics of the USP22-Ergotamine complex were investigated by all-atom MD simulations for 300 ns. The robustness of these interactions was verified in these simulations and MM/PBSA, and insights into the molecular mechanisms that underlie their ability to inhibit USP22 were provided. Our findings reveal a potentially promising role for Ergotamine as a repurposed USP22 inhibitor that would be worthwhile to validate experimentally for therapeutic development against cancer.
G protein-coupled receptors (GPCRs) are a large and diverse superfamily of membrane proteins that mediate cellular responses to a wide range of stimuli, making them critical players in a variety of physiological and pathological processes. Despite their recognized therapeutic potential, many GPCRs are still considered orphans, their ligands and biological functions remaining unknown. Among these, GPR75 has garnered increasing attention due to its high expression in the brain and retina and its proposed roles in cardiovascular function, metabolism, and cancer. Recent studies have suggested several potential endogenous ligands for GPR75, including 20-HETE and RANTES/CCL5, but their status as true receptor agonists remains controversial. Here, we summarize the current state of knowledge regarding GPR75, from its discovery and evolutionary context to its expression profile, putative ligands, and emerging physiological functions. Understanding the role of GPR75 may offer new therapeutic avenues for neurological disorders, metabolic diseases, and cancer.
BACKGROUND:Anxiety disorders (ADs) and thyroid tumors (TTs) are prevalent and frequently co-occur. Previous studies suggest that the N-methyl-d-aspartate receptor (NMDAR) may play a role in their co-occurrence, but the understanding of their relationship is not comprehensive. The aim of this study was to investigate the role of NMDAR in the progression of animal models of AD with TT. METHODS:We developed an animal model of AD with TT in Balb/c mice using chronic unpredictable mild stress (CUMS) combined with subcutaneous IHH4 cell xenotransplantation. Mice were treated with d-serine and MK-801 to assess behavioral changes and tumor growth. The expression of NMDAR subunits in the thyroid and transplanted TT tissues was also analyzed. RESULTS:The combination of CUMS and IHH4 cell xenotransplantation helped successfully create an AD with TT model, which exhibited stable anxiety-like behavior, a high tumor formation rate, and ease of implementation. d-Serine alleviated anxiety behaviors but increased NR2A subunit activity in both thyroid and TT tissues, disrupted the normal structure of the thyroid, and accelerated TT growth. In contrast, MK-801 had the opposite effect. CONCLUSIONS:NMDAR, particularly the NR2A subunit, plays a crucial role in TT progression associated with AD. In the clinical drug selection for the patients with ADs with concomitant TT, special attention should be paid to the two-sidedness of drugs. The CUMS and IHH4 xenotransplantation model is an effective tool for studying AD with TT.
Zolpidem, or commercially known as Ambien or Stilnox, is a sedative-hypnotic agent, which is usually prescribed to manage sleeping difficulties in individuals with insomnia. The site of its sedative-hypnotic action is the γ-aminobutyric acid type A receptor, which it shares with benzodiazepines. However, this substance has been consistently associated to awaken patients with brain injuries such as trauma, stroke, disorders of consciousness and has also been expanded to the recovery of brain function in the event of hypoxic damage, cerebrovascular ischemic injury, infection of the central nervous system, toxins and poisoning, degenerative diseases, tumors, and congenital disorders. Aside from that, the effect has been observed in a wide spectrum of neurological diseases, from movement disorders such as Parkinson's disease and dystonia to neurological deficits and anaphylactic hypoxia. The wide spectrum of injuries and disorders reported poses a challenge in investigating the exact mechanisms of action underlying the awakening effect. Therefore, the main question is how it is possible for a substance originally intended as a sedative-hypnotic agent to induce an awakening effect? In this review, we discuss the synergetic roles of GABAA receptors, which are the target receptor for zolpidem, along with neuronal cation-Cl- co-transporters KCC2/NKCC1 in regulating the inhibitory nature of the GABAergic transmission in brain injury, which might explain the awakening effect of zolpidem in brain injuries.
Preeclampsia (PE) is characterized by systemic endothelial dysfunction and remains a significant clinical challenge. Activation of NLRP3 inflammasome, reactive oxygen species (ROS) production, and pyroptosis and autophagy are important mechanisms in this condition. To evaluate the NLRP3 inhibitors effects: glibenclamide (GB) and MCC950, on markers of inflammation, endothelial dysfunction, cell death, and oxidative stress in an in vitro model of PE. Plasma from pregnant women with PE and normotensive pregnant women (NT) was used to investigate its impact on NLRP3 inflammasome activation (NLRP3, TLR4, MyD88, and caspase-1) in endothelial cells (ECs), analyzed by Western Blotting; effects of pharmacological inhibition on the function of ECs was assessed by the evaluation of permeability (VE-cadherin) and markers of endothelial dysfunction by flow cytometry (Flt-1, VEGFR2, E-selectin, VCAM-1, and ICAM-1), as well as cytotoxicity measured by lactate dehydrogenase (LDH), oxidative stress (ROS, nitric oxide - NO and antioxidant capacity), autophagy, and pyroptosis (interleukin IL-1β and high-mobility group box one - HMGB1). Both GB and MCC950 reduced NLRP3 inflammasome activation and its related effects in ECs exposed to PE plasma, including lowered IL-1β, caspase-1, modulated adhesion molecules expression, as well as decreased ROS and cytotoxicity. GB increased NO and restored VE-cadherin expression, while MCC950 enhanced antioxidant capacity. GB also induced autophagy, unlike MCC950. The NLRP3 inhibitors showed the potential to mitigate endothelial dysfunction, oxidative stress, and inflammation, suggesting both compounds hold potential therapeutic value for PE through distinct mechanisms.
G protein-coupled receptor 4 (GPR4) is a dual ligand receptor that can be activated by both protons and lysophosphatidylcholine (LPC), which is a bioactive phospholipid. It plays a pivotal role in numerous physiological and pathological processes and is regulated by these two ligands through distinct mechanisms. Recently, there has been growing interest in the role of GPR4 in diseases characterized by an acidic microenvironment. This review aims to explore the specific signaling pathways through which protons and LPC regulate GPR4 in the inflammatory microenvironment and to clarify the distinct roles of these ligands in various diseases, including inflammation, atherosclerosis, and cancer. Additionally, the potential benefits and challenges of targeting GPR4 as a therapeutic strategy for these diseases are analyzed.
Breast cancer is one of the leading cancer types in terms of morbidity and mortality worldwide. Although developing technology, early diagnosis and treatment opportunities provide positive contributions to the treatment of breast cancer, research on new drugs that are less toxic to healthy cells, safer and more effective for cancer cells, increasing the quality of life of the patient is still ongoing. Coumarin and its derivatives have been shown great interest to develop safer and more effective anticancer drugs. Therefore, we investigated the anticancer activity of novel coumarin-3-carboxamide derivative 3i in MDA-MB-231 cells. We found that coumarin-3-carboxamide derivative 3i inhibited cell proliferation, colony formation and migration. However, coumarin-3-carboxamide derivative 3i did not induce apoptosis and autophagy. Consequently, our findings suggest for the first time that novel coumarin-3-carboxamide 3i has anticancer activity and may be an important drug candidate for the treatment of triple-negative breast cancer. Further investigations are required to elucidate its impact on breast cancer.
