Rhamnetin, a nutraceutical flavonoid arrests cell cycle progression of human ovarian cancer (SKOV3) cells by inhibiting the histone deacetylase 2 protein.

Overexpression of HDAC 2 promotes cell proliferation in ovarian cancer. HDAC 2 is involved in chromatin remodeling, transcriptional repression, and the formation of condensed chromatin structures. Targeting HDAC 2 presents a promising therapeutic approach for correcting cancer-associated epigenetic abnormalities. Consequently, HDAC 2 inhibitors have evolved as an attractive class of anti-cancer agents. This work intended to investigate the anti-cancer abilities and underlying molecular mechanisms of Rhamnetin in human epithelial ovarian carcinoma cells (SKOV3), which remain largely unexplored. We employed various in vitro methods, including MTT, apoptosis study, cell cycle analysis, fluorescence microscopy imaging, and in vitro enzymatic HDAC 2 protein inhibition, to examine the chemotherapeutic sensitivity of Rhamnetin in SKOV3 cells. Additionally, we conducted in silico studies using molecular docking, MD simulation, MM-GBSA, DFT, and pharmacokinetic analysis to investigate the binding interaction mechanism within Rhamnetin and HDAC 2, alongside the compound's prospective as a lead candidate. The in vitro assay confirmed the cytotoxic effects of Rhamnetin on SKOV3 cells, through its inhibition of HDAC 2 activity. Rhamnetin, a nutraceutical flavonoid, halted at the G1 phase of the cell cycle and triggered apoptosis in SKOV3 cells. Furthermore, computational studies provided additional evidence of its stable binding to the HDAC 2 protein's binding site cavity. Based on our findings, we conclude that Rhamnetin effectively promotes apoptosis and mitigates the proliferation of SKOV3 cells through HDAC 2 inhibition. These results highlight Rhamnetin as a potential lead compound, opening a new therapeutic strategy for human epithelial ovarian cancer.Communicated by Ramaswamy H. Sarma.

Screening of Phytocompounds for Identification of Prospective Histone Deacetylase 1 (HDAC1) Inhibitor: An In Silico Molecular Docking, Molecular Dynamics Simulation, and MM-GBSA Approach.

The upregulation of HDAC1 facilitate the induction of epigenetic repression of genes responsible for suppressing tumourigenesis, thereby triggering the development of cancer. HDAC1 inhibitors have thus emerged as possible therapeutic approaches against a variety of human malignancies, as they can inhibit the activity of certain HDACs, repair the overexpression of tumour suppressor genes, and induce cell differentiation, cell cycle arrest, and apoptosis. In this study, among 810 virtually screened compounds, Pinocembrin (PHUB000396) had a significant binding affinity (-7.99 kcal/mol). In molecular dynamics simulation (MD) studies for 200 ns time scale, the compound Pinocembrin effectively undergoes conformational optimization, thereby enabling its accommodation within the active site of the receptor. This outcome serves as a rational for the observed binding affinity. The optimal binding free energy calculations using the Molecular Mechanics Generalized Born Surface Area (MM-GBSA) (-35.86 ± 7.52 kcal/mol) showed the significant role of van der Waals forces and Coulomb interactions in the stability of the respective complex. The pharmacokinetic study showed its potential as a lead compound. The in-silico cytotoxicity prediction also confirmed its potential as an active anticancer phytocompound in lung and brain cancer. Therefore, it can be predicted that Pinocembrin could be a useful bioactive compound as an HDAC1 inhibitor and could be used in developing epigenetic therapy in cancer such as brain cancer and lung cancer to regulate gene expression.

Potent Bioactive Compounds From Seaweed Waste to Combat Cancer Through Bioinformatics Investigation.

The seaweed industries generate considerable amounts of waste that must be appropriately managed. This biomass from marine waste is a rich source of high-value bioactive compounds. Thus, this waste can be adequately utilized by recovering the compounds for therapeutic purposes. Histone deacetylases (HDACs) are key epigenetic regulators established as one of the most promising targets for cancer chemotherapy. In the present study, our objective is to find the HDAC 2 inhibitor. We performed top-down in silico methodologies to identify potential HDAC 2 inhibitors by screening compounds from edible seaweed waste. One hundred ninety-three (n = 193) compounds from edible seaweeds were initially screened and filtered with drug-likeness properties using SwissADME. After that, the filtered compounds were followed to further evaluate their binding potential with HDAC 2 protein by using Glide high throughput virtual screening (HTVS), standard precision (SP), extra precision (XP), and quantum polarized ligand docking (QPLD). One compound with higher negative binding energy was selected, and to validate the binding mode and stability of the complex, molecular dynamics (MD) simulations using Desmond were performed. The complex-binding free energy calculation was performed using molecular mechanics-generalized born surface area (MM-GBSA) calculation. Post-MD simulation analyses such as PCA, DCCM, and free energy landscape were also evaluated. The quantum mechanical and electronic properties of the potential bioactive compounds were assessed using the density functional theory (DFT) study. These findings support the use of marine resources like edible seaweed waste for cancer drug development by using its bioactive compounds. The obtained results encourage further in vitro and in vivo research. Our in silico findings show that the compound has a high binding affinity for the catalytic site of the HDAC 2 protein and has drug-likeness properties, and can be utilized in drug development against cancer.

Phytochemical Characterization, Antioxidant, Anti-inflammatory, Anti-diabetic properties, Molecular Docking, Pharmacokinetic Profiling, and Network Pharmacology Analysis of the Major Phytoconstituents of Raw and Differently Dried Mangifera indica (Himsagar cultivar): an In Vitro and In Silico Investigations.

Mango (Himsagar cultivar) is a high moisture-bearing seasonal fruit and cultivated in a wide range of the world. Mango pulp is generally preserved by sun drying. In recent days, industries are using hot-air oven, freeze, and microwave drying for mango leather (dried mango pulp in the sheet like texture) processing. Here, all these four drying methods were studied to determine the effect of drying on mango leather processing. RP-HPLC and FTIR were studied for analysis of polyphenol profile and predominant functional groups in raw and processed samples. The phytochemical analysis and medicinal properties (antioxidant, anti-diabetic, and anti-inflammatory activity) of all five mango samples were studied. The bioinformatics approach was studied to evaluate the bioactive potential of the phytochemicals derived from the samples. Freeze-dried mango leather was found to be the highest in DPPH (74.23%) and Superoxide (66.04%) activity, though raw mango pulp was observed with the highest H2O2 activity (73.24%). Gallic acid was the predominant phenolic acid present in all five samples and it was maximum in the case of freeze-dried sample (2.76 ± 0.04 mg/100 g MD). On the other hand, quercetin was the predominant flavonoid, it was found maximum for freeze-dried sample (3.93 ± 0.21 mg/100 g MD).

Development of Polymer-Based Nanoformulations for Glioblastoma Brain Cancer Therapy and Diagnosis: An Update.

Brain cancers, mainly high-grade gliomas/glioblastoma, are characterized by uncontrolled proliferation and recurrence with an extremely poor prognosis. Despite various conventional treatment strategies, viz., resection, chemotherapy, and radiotherapy, the outcomes are still inefficient against glioblastoma. The blood-brain barrier is one of the major issues that affect the effective delivery of drugs to the brain for glioblastoma therapy. Various studies have been undergone in order to find novel therapeutic strategies for effective glioblastoma treatment. The advent of nanodiagnostics, i.e., imaging combined with therapies termed as nanotheranostics, can improve the therapeutic efficacy by determining the extent of tumour distribution prior to surgery as well as the response to a treatment regimen after surgery. Polymer nanoparticles gain tremendous attention due to their versatile nature for modification that allows precise targeting, diagnosis, and drug delivery to the brain with minimal adverse side effects. This review addresses the advancements of polymer nanoparticles in drug delivery, diagnosis, and therapy against brain cancer. The mechanisms of drug delivery to the brain of these systems and their future directions are also briefly discussed.

Green Synthesis of Gold Nanoparticles Using Plant Extracts as Beneficial Prospect for Cancer Theranostics.

Gold nanoparticles (AuNPs) have been widely explored and are well-known for their medical applications. Chemical and physical synthesis methods are a way to make AuNPs. In any case, the hunt for other more ecologically friendly and cost-effective large-scale technologies, such as environmentally friendly biological processes known as green synthesis, has been gaining interest by worldwide researchers. The international focus on green nanotechnology research has resulted in various nanomaterials being used in environmentally and physiologically acceptable applications. Several advantages over conventional physical and chemical synthesis (simple, one-step approach to synthesize, cost-effectiveness, energy efficiency, and biocompatibility) have drawn scientists' attention to exploring the green synthesis of AuNPs by exploiting plants' secondary metabolites. Biogenic approaches, mainly the plant-based synthesis of metal nanoparticles, have been chosen as the ideal strategy due to their environmental and in vivo safety, as well as their ease of synthesis. In this review, we reviewed the use of green synthesized AuNPs in the treatment of cancer by utilizing phytochemicals found in plant extracts. This article reviews plant-based methods for producing AuNPs, characterization methods of synthesized AuNPs, and discusses their physiochemical properties. This study also discusses recent breakthroughs and achievements in using green synthesized AuNPs in cancer treatment and different mechanisms of action, such as reactive oxygen species (ROS), mediated mitochondrial dysfunction and caspase activation, leading to apoptosis, etc., for their anticancer and cytotoxic effects. Understanding the mechanisms underlying AuNPs therapeutic efficacy will aid in developing personalized medicines and treatments for cancer as a potential cancer therapeutic strategy.

Green Synthesis of Silver Nanoparticles Using Diospyros malabarica Fruit Extract and Assessments of Their Antimicrobial, Anticancer and Catalytic Reduction of 4-Nitrophenol (4-NP).

The green synthesis of silver nanoparticles (AgNPs) has currently been gaining wide applications in the medical field of nanomedicine. Green synthesis is one of the most effective procedures for the production of AgNPs. The Diospyros malabarica tree grown throughout India has been reported to have antioxidant and various therapeutic applications. In the context of this, we have investigated the fruit of Diospyros malabarica for the potential of forming AgNPs and analyzed its antibacterial and anticancer activity. We have developed a rapid, single-step, cost-effective and eco-friendly method for the synthesis of AgNPs using Diospyros malabarica aqueous fruit extract at room temperature. The AgNPs began to form just after the reaction was initiated. The formation and characterization of AgNPs were confirmed by UV-Vis spectrophotometry, XRD, FTIR, DLS, Zeta potential, FESEM, EDX, TEM and photoluminescence (PL) methods. The average size of AgNPs, in accordance with TEM results, was found to be 17.4 nm. The antibacterial activity of the silver nanoparticles against pathogenic microorganism strains of Staphylococcus aureus and Escherichia coli was confirmed by the well diffusion method and was found to inhibit the growth of the bacteria with an average zone of inhibition size of (8.4 ± 0.3 mm and 12.1 ± 0.5 mm) and (6.1 ± 0.7 mm and 13.1 ± 0.5 mm) at 500 and 1000 µg/mL concentrations of AgNPs, respectively. The anticancer effect of the AgNPs was confirmed by MTT assay using the U87-MG (human primary glioblastoma) cell line. The IC50 value was found to be 58.63 ± 5.74 µg/mL. The results showed that green synthesized AgNPs exhibited significant antimicrobial and anticancer potency. In addition, nitrophenols, which are regarded as priority pollutants by the United States Environmental Protection Agency (USEPA), can also be catalytically reduced to less toxic aminophenols by utilizing synthesized AgNPs. As a model reaction, AgNPs are employed as a catalyst in the reduction of 4-nitrophenol to 4-aminophenol, which is an intermediate for numerous analgesics and antipyretic drugs. Thus, the study is expected to help immensely in the pharmaceutical industries in developing antimicrobial drugs and/or as an anticancer drug, as well as in the cosmetic and food industries.

Macrolactin A as a Novel Inhibitory Agent for SARS-CoV-2 Mpro: Bioinformatics Approach.

COVID-19 is a disease that puts most of the world on lockdown and the search for therapeutic drugs is still ongoing. Therefore, this study used in silico screening to identify natural bioactive compounds from fruits, herbaceous plants, and marine invertebrates that are able to inhibit protease activity in SARS-CoV-2 (PDB: 6LU7). We have used extensive screening strategies such as drug likeliness, antiviral activity value prediction, molecular docking, ADME, molecular dynamics (MD) simulation, and MM/GBSA. A total of 17 compounds were shortlisted using Lipinski's rule in which 5 compounds showed significant predicted antiviral activity values. Among these 5, only 2 compounds, Macrolactin A and Stachyflin, showed good binding energy of -9.22 and -8.00 kcal/mol, respectively, within the binding pocket of the Mpro catalytic residues (HIS 41 and CYS 145). These two compounds were further analyzed to determine their ADME properties. The ADME evaluation of these 2 compounds suggested that they could be effective in developing therapeutic drugs to be used in clinical trials. MD simulations showed that protein-ligand complexes of Macrolactin A and Stachyflin with the target receptor (6LU7) were stable for 100 nanoseconds. The MM/GBSA calculations of Mpro-Macrolactin A complex indicated higher binding free energy (-42.58 ± 6.35 kcal/mol). Dynamic cross-correlation matrix (DCCM) and principal component analysis (PCA) on the residual movement in the MD trajectories further confirmed the stability of Macrolactin A bound state with 6LU7. In conclusion, this study showed that marine natural compound Macrolactin A could be an effective therapeutic inhibitor against SARS-CoV-2 protease (6LU7). Additional in vitro and in vivo validations are strongly needed to determine the efficacy and therapeutic dose of Macrolactin A in biological systems.

Synthesis and Characterization of Diosgenin Encapsulated Poly-ε-Caprolactone-Pluronic Nanoparticles and Its Effect on Brain Cancer Cells.

Diosgenin encapsulated PCL-Pluronic nanoparticles (PCL-F68-D-NPs) were developed using the nanoprecipitation method to improve performance in brain cancer (glioblastoma) therapy. The nanoparticles were characterized by dynamic light scattering (DLS)/Zeta potential, Fourier-transform infrared (FTIR) spectra, X-ray diffraction (XRD), Field Emission Scanning Electron Microscopy (FESEM), and Transmission electron microscopy (TEM). The encapsulation efficiency, loading efficiency, and yield were calculated. The in vitro release rate was determined, and the kinetic model of diosgenin release was plotted and ascertained. The cytotoxicity was checked by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide)assay against U87-MG cells (glioblastoma cell lines). The obtained nanoparticles demonstrated good size distribution, stability, morphology, chemical, and mechanical properties. The nanoparticles also possessed high encapsulation efficiency, loading efficiency, and yield. The release rate of Diosgenin was shown in a sustained manner. The in vitro cytotoxicity of PCL-F68-D-NPs showed higher toxicity against U87-MG cells than free Diosgenin.