Structure-Based Virtual Screening Identifying Novel FOXM1 Inhibitors as the Lead Compounds for Glioblastoma.

BACKGROUND: Glioblastoma multiforme (GBM) is a highly heterogeneous brain tumor with limited treatment options and a poor prognosis. Cancer stem cells (CSCs) have emerged as a critical factor in GBM resistance and management, contributing to tumor growth, heterogeneity, and immunosuppression. The transcription factor FOXM1 has been identified as a key player in the progression, spread, and therapy resistance of various cancers, including GBM. OBJECTIVE: In this research, the objective was to perform structure-based in silico screening with the aim of identifying natural compounds proficient in targeting the DNA-binding domain (DBD) of the FOXM1 protein. METHODS: In this study, in silico tools were employed for screening a hundred naturally occurring compounds capable of targeting the FOXM1 protein. Through molecular docking analysis and pharmacokinetic profiling, five compounds were found to be promising candidates for extensive interaction with the FOXM1 protein. Further, these compounds were validated for the stability of the FOXM1-natural compound complex using molecular dynamics (MD) simulations. RESULTS: Four compounds, such as Withaferin A, Bryophyllin A, Silybin B, Sanguinarine and Troglitazone (control compound), emerged as promising candidates with substantial interactions with FOXM1, suggesting their potential as a protein inhibitor based on molecular docking investigations. After MD simulation analysis, the FOXM1- Bryophyllin A complex was found to maintain the highest stability, and the other three ligands had moderate but comparable binding affinities over a period of 100 ns. CONCLUSION: This study provides valuable insights into four promising FOXM1 inhibitors that have the ability to induce senescence in GBM stem cells. These findings contribute to the development of structure-based designing strategies for FOXM1 inhibitors and innovative therapeutic approaches for the treatment of Glioblastoma.

Lead phytochemicals and marine compounds against ceruloplasmin in cancer targeting.

In silico docking studies serve as a swift and efficient means to sift through a vast array of natural and synthetic small molecules, aiding in the identification of potential inhibitors for cancer biomarkers. One such biomarker, ceruloplasmin (CP), has been implicated in various tumor types due to its overexpression, earning it recognition as a marker of aggressive tumors. This study focused on pinpointing inhibitors for the CP -Myeloperoxidase (MPO) interaction site, a complex formation known to impede HOCl production, a crucial process for inducing apoptotic cell death in tumor cells. The initial phase of our investigation involved in silico docking studies, which screened a diverse library of phytochemicals and marine compounds. Through this process, we identified several promising drug candidates based on their binding affinities. Subsequently, these candidates underwent rigorous filtration based on Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties. Finally, we subjected the selected compounds to molecular dynamics (MDs) simulation to further assess their viability. Lycoperoside F, a steroidal alkaloid glycoside derived from tomatoes (Lycopersicon esculentum), stood out with notable interactions at the binding site. Another noteworthy compound was Xyloglucan (XG) oligosaccharides, predominantly found in the primary cell walls of higher plants. During the subsequent MDs simulations, these interactions were accompanied by highly stable root mean square deviation (RMSD) plots, signifying the consistency and robustness of the observed MDs behavior. XG oligosaccharides demonstrated the highest binding affinity with CP, reaffirming their potential as strong candidates. Additionally, Ardimerin digallate, known as a retroviral ribonuclease H inhibitor for HIV-1 and HIV-2, displayed favorable interactions at the MPO interaction site. Given that promising drug candidates must meet stringent criteria, including non-toxicity, effectiveness, specificity, stability and potency, these phytochemicals have the potential to progress to in vitro studies as CP inhibitors. Ultimately, this could contribute to the suppression of tumor growth, marking a significant step in cancer treatment research.Communicated by Ramaswamy H. Sarma.

Role of Oxidative Stress in Metabolic Reprogramming of Brain Cancer.

Brain cancer is known as one of the deadliest cancers globally. One of the causative factors is the imbalance between oxidative and antioxidant activities in the body, which is referred to as oxidative stress (OS). As part of regular metabolism, oxygen is reduced by electrons, resulting in the creation of numerous reactive oxygen species (ROS). Inflammation is intricately associated with the generation of OS, leading to the increased production and accumulation of reactive oxygen and nitrogen species (RONS). Glioma stands out as one of the most common malignant tumors affecting the central nervous system (CNS), characterized by changes in the redox balance. Brain cancer cells exhibit inherent resistance to most conventional treatments, primarily due to the distinctive tumor microenvironment. Oxidative stress (OS) plays a crucial role in the development of various brain-related malignancies, such as glioblastoma multiforme (GBM) and medulloblastoma, where OS significantly disrupts the normal homeostasis of the brain. In this review, we provide in-depth descriptions of prospective targets and therapeutics, along with an assessment of OS and its impact on brain cancer metabolism. We also discuss targeted therapies.

Multimodal Imaging of Pancreatic Cancer Microenvironment in Response to an Antiglycolytic Drug.

Lipid metabolism and glycolysis play crucial roles in the progression and metastasis of cancer, and the use of 3-bromopyruvate (3-BP) as an antiglycolytic agent has shown promise in killing pancreatic cancer cells. However, developing an effective strategy to avoid chemoresistance requires the ability to probe the interaction of cancer drugs with complex tumor-associated microenvironments (TAMs). Unfortunately, no robust and multiplexed molecular imaging technology is currently available to analyze TAMs. In this study, the simultaneous profiling of three protein biomarkers using SERS nanotags and antibody-functionalized nanoparticles in a syngeneic mouse model of pancreatic cancer (PC) is demonstrated. This allows for comprehensive information about biomarkers and TAM alterations before and after treatment. These multimodal imaging techniques include surface-enhanced Raman spectroscopy (SERS), immunohistochemistry (IHC), polarized light microscopy, second harmonic generation (SHG) microscopy, fluorescence lifetime imaging microscopy (FLIM), and untargeted liquid chromatography and mass spectrometry (LC-MS) analysis. The study reveals the efficacy of 3-BP in treating pancreatic cancer and identifies drug treatment-induced lipid species remodeling and associated pathways through bioinformatics analysis.

Expression analysis and regulation of GLI and its correlation with stemness and metabolic alteration in human brain tumor.

GLI gene-mediated hedgehog (Hh) signaling pathway plays a substantial role in brain cancer development and growth including glioblastoma multiforme (GBM), lower-grade glioma (LGG), and medulloblastoma (MB). GLI2 and GLI3 gene expression levels are extremely enhanced in these cancers with poor patient survival. Moreover, GLI genes are correlated with stemness-related factors SOX2, SOX9, POU5F1, and NANOG that work as the driving factors for brain cancer stem cells (CSCs) progression. It's critical to find new ways to combat this deadly malignancy and CSCs. Using in silico approaches, our study explored the role of GLI genes (GLI1, GLI2, and GLI3), the primary transcription factors of the sonic hedgehog (SHH) signaling pathway, in GBM, LGG, MB, and glioblastoma stem-like cells (GSCs). Additionally, we found strong association of angiogenic-related gene VEGFA, metabolic genes ENO1, ENO2, and pluripotency-related genes SOX2, SOX9, NANOG, POU5F1 with GLI genes, suggesting their role in brain tumor initiation and progression. We also studied their transcriptional network and functional category enrichment analysis about brain tumor development to find a better therapeutic strategy against brain cancer and their stem cells. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03419-5.

Neuropharmacological interventions of quercetin and its derivatives in neurological and psychological disorders.

Quercetin is a naturally occurring bioactive flavonoid abundant in many plants and fruits. Quercetin and its derivatives have shown an array of pharmacological activities in preclinical tests against various illnesses and ailments. Owing to its protective role against oxidative stress and neuroinflammation, quercetin is a possible therapeutic choice for the treatment of neurological disorders. Quercetin and its derivatives can modulate a variety of signal transductions, including neuroreceptor, neuroinflammatory receptor, and redox signaling events. The research on quercetin and its derivatives in neurology-related illnesses mainly focused on the targets, such as redox stress, neuroinflammation, and signaling pathways; however, the function of quercetin and its derivatives on specific molecular targets, such as nuclear receptors and proinflammatory mediators are yet to be explored. Findings showed that various molecular targets of quercetin and its derivatives have therapeutic potential against psychological and neurodegenerative disorders.

Molecular mechanism(s) of regulations of cancer stem cell in brain cancer propagation.

Brain tumors are most often diagnosed with solid neoplasms and are the primary reason for cancer-related deaths in both children and adults worldwide. With recent developments in the progression of novel targeted chemotherapies, the prognosis of malignant glioma remains dismal. However, the high recurrence rate and high mortality rate remain unresolved and are closely linked to the biological features of cancer stem cells (CSCs). Research on tumor biology has reached a new age with more understanding of CSC features. CSCs, a subpopulation of whole tumor cells, are now regarded as candidate therapeutic targets. Therefore, in the diagnosis and treatment of tumors, recognizing the biological properties of CSCs is of considerable significance. Here, we have discussed the concept of CSCs and their significant role in brain cancer growth and propagation. We have also discussed personalized therapeutic development and immunotherapies for brain cancer by specifically targeting CSCs.

Exploring state-of-the-art advances in targeted nanomedicines for managing acute and chronic inflammatory lung diseases.

Diagnosis and treatment of lung diseases pose serious challenges. Currently, diagnostic as well as therapeutic methods show poor efficacy toward drug-resistant bacterial infections, while chemotherapy causes toxicity and nonspecific delivery of drugs. Advanced treatment methods that cure lung-related diseases, by enabling drug bioavailability via nasal passages during mucosal formation, which interferes with drug penetration to targeted sites, are in demand. Nanotechnology confers several advantages. Currently, different nanoparticles, or their combinations, are being used to enhance targeted drug delivery. Nanomedicine, a combination of nanoparticles and therapeutic agents, that delivers drugs to targeted sites increases the bioavailability of drugs at these sites. Thus, nanotechnology is superior to conventional chemotherapeutic strategies. Here, the authors review the latest advancements in nanomedicine-based drug-delivery methods for managing acute and chronic inflammatory lung diseases.

Pharmacophore modeling coupled with scaffold hopping to identify novel and potent ribosomal S6 kinase (RSK2) protein antagonists as anti-cancer agents.

Communicated by Ramaswamy H. Sarma.