In-silico study unveils potential phytocompounds in Andrographis paniculata against E6 protein of the high-risk HPV-16 subtype for cervical cancer therapy.

Despite therapeutic advancements, cervical cancer caused by high-risk subtypes of the human papillomavirus (HPV) remains a leading cause of cancer-related deaths among women worldwide. This study aimed to discover potential drug candidates from the Asian medicinal plant Andrographis paniculata, demonstrating efficacy against the E6 protein of high-risk HPV-16 subtype through an in-silico computational approach. The 3D structures of 32 compounds (selected from 42) derived from A. paniculata, exhibiting higher binding affinity, were obtained from the PubChem database. These structures underwent subsequent analysis and screening based on criteria including binding energy, molecular docking, drug likeness and toxicity prediction using computational techniques. Considering the spectrometry, pharmacokinetic properties, docking results, drug likeliness, and toxicological effects, five compounds-stigmasterol, 1H-Indole-3-carboxylic acid, 5-methoxy-, methyl ester (AP7), andrographolide, apigenin and wogonin-were selected as the potential inhibitors against the E6 protein of HPV-16. We also performed 200 ns molecular dynamics simulations of the compounds to analyze their stability and interactions as protein-ligand complexes using imiquimod (CID-57469) as a control. Screened compounds showed favorable characteristics, including stable root mean square deviation values, minimal root mean square fluctuations and consistent radius of gyration values. Intermolecular interactions, such as hydrogen bonds and hydrophobic contacts, were sustained throughout the simulations. The compounds displayed potential affinity, as indicated by negative binding free energy values. Overall, findings of this study suggest that the selected compounds have the potential to act as inhibitors against the E6 protein of HPV-16, offering promising prospects for the treatment and management of CC.

Transcriptomic analysis revealed potential regulatory biomarkers and repurposable drugs for breast cancer treatment.

Breast cancer (BC) is the most widespread cancer worldwide. Over 2 million new cases of BC were identified in 2020 alone. Despite previous studies, the lack of specific biomarkers and signaling pathways implicated in BC impedes the development of potential therapeutic strategies. We employed several RNAseq datasets to extract differentially expressed genes (DEGs) based on the intersection of all datasets, followed by protein-protein interaction network construction. Using the shared DEGs, we also identified significant gene ontology (GO) and KEGG pathways to understand the signaling pathways involved in BC development. A molecular docking simulation was performed to explore potential interactions between proteins and drugs. The intersection of the four datasets resulted in 146 DEGs common, including AURKB, PLK1, TTK, UBE2C, CDCA8, KIF15, and CDC45 that are significant hub-proteins associated with breastcancer development. These genes are crucial in complement activation, mitotic cytokinesis, aging, and cancer development. We identified key microRNAs (i.e., hsa-miR-16-5p, hsa-miR-1-3p, hsa-miR-147a, hsa-miR-195-5p, and hsa-miR-155-5p) that are associated with aggressive tumor behavior and poor clinical outcomes in BC. Notable transcription factors (TFs) were FOXC1, GATA2, FOXL1, ZNF24 and NR2F6. These biomarkers are involved in regulating cancer cell proliferation, invasion, and migration. Finally, molecular docking suggested Hesperidin, 2-amino-isoxazolopyridines, and NMS-P715 as potential lead compounds against BC progression. We believe that these findings will provide important insight into the BC progression as well as potential biomarkers and drug candidates for therapeutic development.

Unraveling the signaling mechanism behind astrocytoma and possible therapeutics strategies: A comprehensive review.

BACKGROUND: A form of cancer called astrocytoma can develop in the brain or spinal cord and sometimes causes death. A detailed overview of the precise signaling cascade underlying astrocytoma formation has not yet been revealed, although various factors have been investigated. Therefore, our objective was to unravel and summarize our current understanding of molecular genetics and associated signaling pathways with some possible therapeutic strategies for astrocytoma. RECENT FINDINGS: In general, four different forms of astrocytoma have been identified in individuals, including circumscribed, diffuse, anaplastic, and multiforme glioblastoma, according to a recent literature review. All types of astrocytoma have a direct connection with some oncogenic signaling cascade. Common signaling is MAPK cascade, including Ras-Raf-ERK, up-regulated with activating EGFR/AKT/PTEN/mTOR and PDGFR. Recent breakthrough studies found that BRAF mutations, including KIAA1549: BRAF and BRAF V600E are responsible for astrocytoma progression. Additionally, cancer progression is influenced by mutations in some tumor suppressor genes, such as the Tp53/ATRX and MGMT mutant. As synthetic medications must cross the blood-brain barrier (BBB), modulating signal systems such as miRNA is the primary option for treating patients with astrocytoma. However, available surgery, radiation therapy, and experimental therapies such as adjuvant therapy, anti-angiogenic therapy, and EGFR-targeting antibody drug are the usual treatment for most types of astrocytoma. Similar to conventional anticancer medications, some phytochemicals slow tumor growth by simultaneously controlling several cellular proteins, including those involved in cell cycle regulation, apoptosis, metastatic spread, tyrosine kinase, growth factor receptor, and antioxidant-related proteins. CONCLUSION: In conclusion, cellular and molecular signaling is directly associated with the development of astrocytoma, and a combination of conventional and alternative therapies can improve the malignancy of cancer patients.

Exploring the anti-cancer potential of dietary phytochemicals for the patients with breast cancer: A comprehensive review.

BACKGROUND: The most common and deadly cancer in female is breast cancer (BC) and new incidence and deaths related to this cancer are rising. AIMS: Several issues, that is, high cost, toxicity, allergic reactions, less efficacy, multidrug resistance, and the economic cost of conventional anti-cancer therapies, has prompted scientists to discover innovative approaches and new chemo-preventive agents. MATERIALS: Numerous studies are being conducted on plant-based and dietary phytochemicals to discover new-fangled and more advanced therapeutic approaches for BC management. RESULT: We have identified that natural compounds modulated many molecular mechanisms and cellular phenomena, including apoptosis, cell cycle progression, cell proliferation, angiogenesis and metastasis, up-regulation of tumor-suppressive genes, and down-regulation of oncogenes, modulation of hypoxia, mammosphere formation, onco-inflammation, enzymatic regulation, and epigenetic modifications in BC. We found that a number of signaling networks and their components such as PI3K/Akt/mTOR, MMP-2 and 9, Wnt/-catenin, PARP, MAPK, NF-κB, Caspase-3/8/9, Bax, Bcl2, Smad4, Notch1, STAT3, Nrf2, and ROS signaling can be regulated in cancer cells by phytochemicals. They induce up-regulation of tumor inhibitor microRNAs, which have been highlighted as a key player for ani-BC treatments followed by phytochemical supplementation. CONCLUSION: Therefore, this collection offers a sound foundation for further investigation into phytochemicals as a potential route for the development of anti-cancer drugs in treating patients with BC.

Drug Repurposing and Systems Biology approaches of Enzastaurin can target potential biomarkers and critical pathways in Colorectal Cancer.

Colorectal cancer (CRC) is a severe health concern that results from a cocktail of genetic, epigenetic, and environmental abnormalities. Because it is the second most lethal malignancy in the world and the third-most common malignant tumor, but the treatment is unavailable. The goal of the current study was to use bioinformatics and systems biology techniques to determine the pharmacological mechanism underlying putative important genes and linked pathways in early-onset CRC. Computer-aided methods were used to uncover similar biological targets and signaling pathways associated with CRC, along with bioinformatics and network pharmacology techniques to assess the effects of enzastaurin on CRC. The KEGG and gene ontology (GO) pathway analysis revealed several significant pathways including in positive regulation of protein phosphorylation, negative regulation of the apoptotic process, nucleus, nucleoplasm, protein tyrosine kinase activity, PI3K-Akt signaling pathway, pathways in cancer, focal adhesion, HIF-1 signaling pathway, and Rap1 signaling pathway. Later, the hub protein module identified from the protein-protein interactions (PPIs) network, molecular docking and molecular dynamics simulation represented that enzastaurin showed strong binding interaction with two hub proteins including CASP3 (-8.6 kcal/mol), and MCL1 (-8.6 kcal/mol), which were strongly implicated in CRC management than other the five hub proteins. Moreover, the pharmacokinetic features of enzastaurin revealed that it is an effective therapeutic agent with minimal adverse effects. Enzastaurin may inhibit the potential biological targets that are thought to be responsible for the advancement of CRC and this study suggests a potential novel therapeutic target for CRC.

Bioinformatics and In silico approaches to identify novel biomarkers and key pathways for cancers that are linked to the progression of female infertility: A comprehensive approach for drug discovery.

Despite modern treatment, infertility remains one of the most common gynecologic diseases causing severe health effects worldwide. The clinical and epidemiological data have shown that several cancerous risk factors are strongly linked to Female Infertility (FI) development, but the exact causes remain unknown. Understanding how these risk factors affect FI-affected cell pathways might pave the door for the discovery of critical signaling pathways and hub proteins that may be targeted for therapeutic intervention. To deal with this, we have used a bioinformatics pipeline to build a transcriptome study of FI with four carcinogenic risk factors: Endometrial Cancer (EC), Ovarian Cancer (OC), Cervical Cancer (CC), and Thyroid Cancer (TC). We identified FI sharing 97, 211, 87 and 33 differentially expressed genes (DEGs) with EC, OC, CC, and TC, respectively. We have built gene-disease association networks from the identified genes based on the multilayer network and neighbour-based benchmarking. Identified TNF signalling pathways, ovarian infertility genes, cholesterol metabolic process, and cellular response to cytokine stimulus were significant molecular and GO pathways, both of which improved our understanding the fundamental molecular mechanisms of cancers associated with FI progression. For therapeutic intervention, we have targeted the two most significant hub proteins VEGFA and PIK3R1, out of ten proteins based on Maximal Clique Centrality (MCC) value of cytoscape and literature analysis for molecular docking with 27 phytoestrogenic compounds. Among them, sesamin, galangin and coumestrol showed the highest binding affinity for VEGFA and PIK3R1 proteins together with favourable ADMET properties. We recommended that our identified pathway, hub proteins and phytocompounds may be served as new targets and therapeutic interventions for accurate diagnosis and treatment of multiple diseases.

Identification of Leading Compounds from Euphorbia neriifolia (Dudsor) Extracts as a Potential Inhibitor of SARS-CoV-2 ACE2-RBDS1 Receptor Complex: An Insight from Molecular Docking ADMET Profiling and MD-simulation Studies.

Coronavirus disease-19 (COVID-19) are deadly and infectious disease that impacts individuals in a variety of ways. Scientists have stepped up their attempts to find an antiviral drug that targets the spike protein (S) of Angiotensin converting enzyme 2 (ACE2) (receptor protein) as a viable therapeutic target for coronavirus. The most recent study examines the potential antagonistic effects of 17 phytochemicals present in the plant extraction of Euphorbia neriifolia on the anti-SARS-CoV-2 ACE2 protein. Computational techniques like molecular docking, absorption, distribution, metabolism, excretion, and toxicity (ADMET) investigations, and molecular dynamics (MD) simulation analysis were used to investigate the actions of these phytochemicals. The results of molecular docking studies showed that the control ligand (2-acetamido-2-deoxy-ß-D-glucopyranose) had a binding potential of -6.2 kcal/mol, but the binding potentials of delphin, ß-amyrin, and tulipanin are greater at -10.4, 10.0, and -9.6 kcal/mol. To verify their drug-likeness, the discovered hits were put via Lipinski filters and ADMET analysis. According to MD simulations of the complex run for 100 numbers, delphin binds to the SARS-CoV-2 ACE2 receptor's active region with good stability. In root-mean-square deviation (RMSD) and root mean square fluctuation (RMSF) calculations, delphinan, ß-amyrin, and tulipanin showed reduced variance with the receptor binding domain subunit 1(RBD S1) ACE2 protein complex. The solvent accessible surface area (SASA), radius of gyration (Rg), molecular surface area (MolSA), and polar surface area (PSA) validation results for these three compounds were likewise encouraging. The convenient binding energies across the 100 numbers binding period were discovered by using molecular mechanics of generalized born and surface (MM/GBSA) to estimate the ligand-binding free energies to the protein receptor. All things considered, the information points to a greater likelihood of chemicals found in Euphorbia neriifolia binding to the SARS-CoV-2 ACE2 active site. To determine these lead compounds' anti-SARS-CoV-2 potential, in vitro and in vivo studies should be conducted. How to cite this article: Islam MN, Pramanik MEA, Hossain MA, et al. Identification of Leading Compounds from Euphorbia Neriifolia (Dudsor) Extracts as a Potential Inhibitor of SARS-CoV-2 ACE2-RBDS1 Receptor Complex: An Insight from Molecular Docking ADMET Profiling and MD-simulation Studies. Euroasian J Hepato-Gastroenterol 2023;13(2):89-107.

Chemotherapeutic Activities of Dietary Phytoestrogens against Prostate Cancer: From Observational to Clinical Studies.

Prostate cancer remains one of the most frequent and deadliest malignancies in males, where the rate of disease progression is closely associated with the type of dietary intake, specifically a Western-style diet. Indeed intake of the Asian diet, which contains abundant phytoestrogens, is inversely correlated with a higher risk of prostate cancer, suggesting a chemoprotective effect of phytoestrogen against cancer progression. Although the role of phytoestrogens in cancer treatment has been well documented, their impact on prostate cancer is not well understood. Therefore, the present review discusses the possible chemopreventive effect of phytoestrogens, emphasizing their efficacy at the different stages of carcinogenesis. Furthermore, phytoestrogens provide a cytoprotective effect in conventional chemotherapy and enhance chemosensitivity to tumor cells, which have also been discussed. This compilation provides a solid basis for future research on phytoestrogens as a promising avenue for anticancer drug development and also recommends these beneficiary compounds in the daily diet to manage and prevent prostate cancer.

Pharmacological Properties to Pharmacological Insight of Sesamin in Breast Cancer Treatment: A Literature-Based Review Study.

The use of dietary phytochemical rather than conventional therapies to treat numerous cancers is now a well-known approach in medical science. Easily available and less toxic dietary phytochemicals present in plants should be introduced in the list of phytochemical-based treatment areas. Sesamin, a natural phytochemical, may be a promising chemopreventive agent aiming to manage breast cancer. In this study, we discussed the pharmacological properties of sesamin that determine its therapeutics opportunity to be used in breast cancer treatment and other diseases. Sesamin is available in medicinal plants, especially in Sesamum indicum, and is easily metabolized by the liver. To better understand the antibreast cancer consequence of sesamin, we postulate some putative pathways related to the antibreast cancer mechanism: (1) regulation of estrogen receptor (ER-α and ER-ß) activities, (2) suppressing programmed death-ligand 1 (PD-L1) overexpression, (3) growth factor receptor inhibition, and (4) some tyrosine kinase pathways. Targeting these pathways, sesamin can modulate cell proliferation, cell cycle arrest, cell growth and viability, metastasis, angiogenesis, apoptosis, and oncogene inactivation in various in vitro and animal models. Although the actual tumor intrinsic signaling mechanism targeted by sesamin in cancer treatment is still unknown, this review summarized that this phytoestrogen suppressed NF-κB, STAT, MAPK, and PIK/AKT signaling pathways and activated some tumor suppressor protein in numerous breast cancer models. Cotreatment with γ-tocotrienol, conventional drugs, and several drug carriers systems increased the anticancer potentiality of sesamin. Furthermore, sesamin exhibited promising pharmacokinetics properties with less toxicity in the bodies. Overall, the shreds of evidence highlight that sesamin can be a potent candidate to design drugs against breast cancer. So, like other phytochemicals, sesamin can be consumed for better therapeutic advantages due to having the ability to target a plethora of molecular pathways until clinically trialed standard drugs are not available in pharma markets.

Chemotherapeutic potential of hesperetin for cancer treatment, with mechanistic insights: A comprehensive review.

BACKGROUND: Cancer has become a significant concern in the medical sector with increasing disease complexity. Although some available conventional treatments are still a blessing for cancer patients, short-and long-term adverse effects and poor efficiency make it more difficult to treat cancer patients, demonstrating the need for new potent and selective anticancer drugs. In search of potent anticancer agents, naturally occurring compounds have always been admired due to their structural diversity, where Hesperetin (HSP) may be one of the potent candidates. PURPOSE: We aimed to summarize all sources, pharmacological properties, anticancer activities of HSP against numerous cancers types through targeting multiple pathological processes, mechanism of HSP on sensitizing the current anti-cancer agents and other phytochemicals, overcoming resistance pattern and determining absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox). METHODS: Information was retrieved from PubMed, Science Direct, and Google Scholar based on some key points like Hesperetin, cancer name, anticancer resistance, nanoformulation, and ADME/Tox was determined by in silico approaches. RESULT: HSP is a phytoestrogen present in citrus fruits in a high concentration (several hundred mg/kg) and exhibited anti-cancer activities through interfering at several pathways. HSP can suppress tumor formation by targeting several cellular proteins such as cell cycle regulatory, apoptosis, metastatic, tyrosine kinase, growth factor receptor, estrogen metabolism, and antioxidant-related protein.HSP has shown remarkable synergistic properties in combination therapy and has been reported to overcome multidrug cancer resistance drugs, leading to an improved defensive mechanism. These anticancer activities of HSP may be due to proper structural chemistry. CONCLUSION: Overall, HSP showed potential anticancer activities against all cancer and possess better pharmacokinetic properties. So this phytochemical alone or combination with other agents can be an effective alternative drug for cancer treatment.