A network-based pharmacological investigation to identify the mechanistic regulatory pathway of andrographolide against colorectal cancer.

Traditional cancer treatments have posed numerous obstacles, including toxicity, multiple drug resistance, and financial cost. On the contrary, bioactive phytochemicals used in complementary alternative medicine have recently increased attention due to their potential to modulate a wide range of molecular mechanisms with a less toxic effect. Therefore, we investigated the potential regulatory mechanisms of andrographolide to treat colorectal cancer (CRC) using a network pharmacology approach. Target genes of andrographolide were retrieved from public databases (PharmMapper, Swiss target prediction, Targetnet, STITCH, and SuperPred), while targets related to CRC were retrieved from disease databases (Genecards and DisGeNet) and expression datasets (GSE32323 and GSE8671) were retrieved from gene expression omnibus (GEO). Protein-protein interaction networks (PPI) were generated using STRING and Cytoscape, and hub genes were identified by topology analysis and MCODE. Annotation of target proteins was performed using Gene Ontology (GO) database DAVID and signaling pathway enrichment analysis using the Kyoto Encyclopedia and Genome Database (KEGG). Survival and molecular docking analysis for the hub genes revealed three genes (PDGFRA, PTGS2, and MMP9) were involved in the overall survival of CRC patients, and the top three genes with the lowest binding energy include PDGFRA, MET, and MAPK1. MET gene upregulation and PDGFRA and PTGS2 gene downregulation are associated with the survival of CRC patients, as revealed by box plots and correlation analysis. In conclusion, this study has provided the first scientific evidence to support the use of andrographolide to inhibit cellular proliferation, migration, and growth, and induce apoptosis by targeting the hub genes (PDGFRA, PTGS2, MMP9, MAPK1, and MET) involved in CRC migration and invasion.

EGFR-Based Targeted Therapy for Colorectal Cancer-Promises and Challenges.

Colorectal carcinoma (CRC) is the most lethal and common form of cancer in the world. It was responsible for almost 881,000 cancer deaths in 2018. Approximately 25% of cases are diagnosed at advanced stages with metastasis-this poses challenges for effective surgical control and future tumor-related mortality. There are numerous diagnostic methods that can be used to reduce the risk of colorectal carcinoma. Among these, targeted nanotherapy aims to eliminate the tumor and any metastasis. Active targeting can increase the effectiveness and quantity of drugs delivered to the target site. Antibodies that target overexpressed receptors on cell surfaces and indicators are coupled with drug-loaded carriers. The major target receptors of chemotherapeutic drugs delivery include VEGFR, EGFR, FGFR, HER2, and TGF. On account of its major and diverse roles in cancer, it is important to target EGFR in particular for better tumor selection, as EGFR is overexpressed in 25 to 82% of colorectal carcinoma cases. The EGFR monoclonal immunoglobulins cetuximab/panitumumab can thus be used to treat colorectal cancer. This review examines carriers that contain cetuximab-conjugated therapeutic drugs as well as their efficacy in anticancer activities.

In silico identification of potential inhibitors against main protease of SARS-CoV-2 6LU7 from Andrographis panniculata via molecular docking, binding energy calculations and molecular dynamics simulation studies.

BACKGROUND: The ongoing global outbreak of new corona virus (SARS-CoV-2) has been recognized as global public health concern since it causes high morbidity and mortality every day. Due to the rapid spreading and re-emerging, we need to find a potent drug against SARS-CoV-2. Synthetic drugs, such as hydroxychloroquine, remdisivir have paid more attention and the effects of these drugs are still under investigation, due to their severe side effects. Therefore, the aim of the present study was performed to identify the potential inhibitor against main protease SARS-CoV-2 6LU7. OBJECTIVE: In this study, RO5, ADME properties, molecular dynamic simulations and free binding energy prediction were mainly investigated. RESULTS: The molecular docking study findings revealed that andrographolide had higher binding affinity among the selected natural diterpenoids compared to co-crystal native ligand inhibitor N3. The persistent inhibition of Ki for diterpenoids was analogous. Furthermore, the simulations of molecular dynamics and free binding energy findings have shown that andrographolide possesses a large amount of dynamic properties such as stability, flexibility and binding energy. CONCLUSION: In conclusion, findings of the current study suggest that selected diterpenoids were predicted to be the significant phytonutrient-based inhibitor against SARS-CoV-2 6LU7 (Mpro). However, preclinical and clinical trials are needed for the further scientific validation before use.

Shrimp shells extracted chitin in silver nanoparticle synthesis: Expanding its prophecy towards anticancer activity in human hepatocellular carcinoma HepG2 cells.

In this study, a well-organized, simplistic, and biological route of AgNPs (AgNPs) was synthesized using shrimp shell extracted chitin as reducing, capping and stabilizing factor under the optimized conditions. Also, the anticancer potential of synthesized biogenic AgNPs was evaluated against human hepatocarcinoma (HepG2) cells. Ultraviolet visible spectroscopy (UV-Vis spec) study indicated that the development of AgNPs present in the colloidal solution was single peak at 446 nm. FTIR results showed a strong chemical interaction between the chitin and biogenic AgNPs; whereas, XRD studies confirmed AgNPs presence in the composites. The SEM TEM analytical studies confirmed the synthesized AgNPs had a spherical shape crystalline structure with size ranges from 17 to 49 nm; EDX study also confirmed the percentage of weight and atomic elements available in the colloidal mixture. Furthermore, the synthesized AgNPs showed significant cytotoxic effect on the HepG2 cells with an IC50 value shown at 57 ± 1.5 µg/ml. The apoptotic and necrotic cell death effects of AgNPs were also confirmed by flow cytometry. The upregulated apoptotic related proteins Bax, cytochrome-c, caspase-3, caspase-9, PARP and downregulated anti-apoptotic related proteins Bcl-2 and Bcl-xl in cancer cells, confirmed the anticancer potential of AgNPs. These findings suggest that the AgNPs possess significant anticancer activity against HepG2 cells which could play major role in the therapeutic drug development to treat cancer in future.

Chitosan-mediated synthesis of biogenic silver nanoparticles (AgNPs), nanoparticle characterisation and in vitro assessment of anticancer activity in human hepatocellular carcinoma HepG2 cells.

The biopolymer chitosan is currently in widespread use because of its nontoxicity, biocompatibility and biodegradability. Therefore, in this study, chitosan extracted from shrimp shells was used to synthesise biogenic silver nanoparticles (AgNPs). UV-visible spectrophotometry of reduced silver nanoparticles in the colloidal solution showed a single peak at 400 nm, confirming the formation of AgNPs. The presence of biomolecules responsible for reducing and capping the biogenic AgNPs was confirmed by FTIR. Surface morphology of the biosynthesised AgNPs was characterised using SEM, and TEM analysis showed the formation of spherical shapes 17-50 nm. The presence of elemental silver in the synthesised biogenic AgNPs was confirmed using EDX and the crystalline structure characterised by XRD. Cytotoxicity of biogenic AgNPs was determined using MTT and the trypan blue exclusion assay. Morphological changes in HepG2 cells were detected by analysis of the DNA ladder pattern via gel electrophoresis, and the IC50 of HepG2 cell inhibition by AgNPs was 48 µg/ml. The upregulated caspase 3 and 9 protein expression results confirmed cell death via apoptosis. In conclusion, chitosan has the ability to synthesise AgNPs with in vitro apoptotic activities.