(
) can become a long-term infection by evading the host immune response. Coevolution of
with humans has resulted in its ability to hijack the host's immune systems in a variety of ways. So far, ...every
defense strategy is essentially dependent on a subtle balance that, if shifted, can promote
proliferation in the host, resulting in disease progression. In this review, the authors summarize many important and previously unknown mechanisms by which
evades the host immune response. Besides recently found strategies by which
manipulates the host molecular regulatory machinery of innate and adaptive immunity, including the intranuclear regulatory machinery, costimulatory molecules, the ubiquitin system and cellular intrinsic immune components will be discussed. A holistic understanding of these immune-evasion mechanisms is of foremost importance for the prevention, diagnosis and treatment of tuberculosis and will lead to new insights into tuberculosis pathogenesis and the development of more effective vaccines and treatment regimens.
Fritillaria cirrhosa D. Don is a well-known medicinal plant of Kashmir Himalaya. Traditionally, it has been used to treat several diseases, including cancer. However, the molecular mechanism behind ...anticancer activity remains unclear. Therefore, in the present study, we have performed high performance-liquid chromatography-mass spectrometry (HR-LC/MS), network pharmacology, molecular docking and molecular dynamic (MD) simulation methods were used to explore the underlying molecular mechanism of F. cirrhosa for the treatment of breast cancer (BC). The targets of F. cirrhosa for treating BC were predicted using databases like SwissTargetPrediction, Gene Cards and OMIM. Protein-protein interaction analysis and network construction were performed using the Search Tool for the Retrieval of Interacting Genes/Proteins programme, and analysis of Gene Ontology term enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment was done using the Cytoscape programme. In addition, molecular docking was used to investigate intermolecular interactions between the compounds and the proteins using the Autodock tool. MD simulations studies were also used to explore the stability of the representative AKT1 gene peiminine and Imperialine-3-β-glucoside. In addition, experimental treatment of F. cirrhosa was also verified. HR-LC/MS detected the presence of several secondary metabolites. Afterward, molecular docking was used to verify the effective activity of the active ingredients against the prospective targets. Additionally, Peiminine and Imperialine-3-β-glucoside showed the highest binding energy score against AKT-1 (-12.99 kcal/mol and -12.08 kcal/mol). AKT1 with Peiminine and Imperialine-3-β-glucoside was further explored for MD simulations. During the MD simulation study at 100 nanoseconds, a stable complex formation of AKT1 + Peiminine and Imperialine-3-β-glucoside was observed. The binding free energy calculations using MM/GBSA showed significant binding of the ligand with protein (ΔG: -79.83 ± 3.0 kcal/mol) between AKT1 + Peiminine was observed. The principal component analysis exhibited a stable converged structure by achieving global motion. Lastly, F. cirrhosa extracts also exhibited momentous anticancer activity through in vitro studies. Therefore, present study revealed the molecular mechanism of F. cirrhosa constituents for the effective treatment of BC by deactivating various multiple gene targets, multiple pathways particularly the PI3K-Akt signaling pathway. These findings emphasized the momentous anti-BC activity of F. cirrhosa constituents.Communicated by Ramaswamy H. Sarma.
Enzymes, which are biological molecules, are constructed from polypeptide chains, and these molecules are activated through reaction mechanisms. It is the role of enzymes to speed up chemical ...reactions that are used to build or break down cell structures. Activation energy is reduced by the enzymes' selective binding of substrates in a protected environment. In enzyme tertiary structures, the active sites are commonly situated in a "cleft," which necessitates the diffusion of substrates and products. The amino acid residues of the active site may be far apart in the primary structure owing to the folding required for tertiary structure. Due to their critical role in substrate binding and attraction, changes in amino acid structure at or near the enzyme's active site usually alter enzyme activity. At the enzyme's active site, or where the chemical reactions occur, the substrate is bound. Enzyme substrates are the primary targets of the enzyme's active site, which is designed to assist in the chemical reaction. This chapter elucidates the summary of structure and chemistry of enzymes, their active site features, charges and role of water in the structures to clarify the biochemistry of the enzymes in the depth of atomic features.
The CDKs are known to play a critical role in cell cycle regulation process. Among the different groups of CDKs, CDK4 overexpression/hyperactivation is found to be present in many cancers and a ...specific CDK4 inhibitor, palbociclib has been recently approved by the FDA against breast cancer. However, the treatment with palbociclib has shown many associated toxicities such as—anemia, thrombocytopenia, neutropenia, and febrile neutropenia and more. Despite the fact being FDA approved for only breast cancer and no other cancers and CDK4 being overexpressed in multiple cancers. Therefore, we in our study intend to screen two novel CDK4 inhibitors that show considerably less associated toxicities and greater therapeutic implications than palbociclib. We screened the compounds using Lipinski’s rule, ADMET analysis and further analyzed the selected compounds using a virtual screening method called molecular docking and validated our results by MD simulation. We studied the expression patterns and prognostic significance of CDK4 across multiple carcinomas by using some database like UALCAN, cBioportal, and KM-Plotter.
Breast cancer represents the leading cause of mortality among women worldwide. Since the complexity of breast cancer as a disease resides in its heterogeneity as it consists of several subtypes such ...as hormone receptor-positive subtypes: Luminal A, Luminal B, Her2- overexpressed, basal-like and hormone receptor-negative subtype: TNBC. Among all the subtypes, triple negative breast cancer (TNBC) is the most lethal and complex subtype. Moreover, the available treatment options like surgery, radiation therapy, and chemotherapy are not sufficient because of the associated side effects and drug resistance development. Therefore, discovery of new effective natural compounds with anti-tumor activity is required. In this pursuit, marine organisms provide a plentiful supply of such chemicals compounds. A marine compound Brugine found in the bark and stem of mangrove species
Bruguiera sexangula
is a potential anti-cancer compound. It has shown its cytotoxic activity against sarcoma 180 and lewis lung cancer. The molecular processes, however, are currently unknown. So, in order to research the molecular pathways this compound utilizes, we sought to apply a network pharmacology approach. The network pharmacology strategy we used in this investigation to identify and evaluate possible molecular pathways involved in the treatment of breast cancer with brugine was supported by simulation and molecular docking experiments. The study was conducted using various databases such as the cancer genome atlas (TCGA) for the genetic profile study of breast cancer, Swiss ADME for studying the pharmacodynamic study of brugine, Gene cards for collection of information of genes, STRING was used to study the interaction among proteins, AutoDock vina was to study the binding efficacy of brugine with the best fit protein. The results showed that the compound and breast cancer target network shared 90 common targets. According to the functional enrichment analysis brugine exhibited its effects in breast cancer via modulating certain pathways such as cAMP signaling pathway, JAK/STAT pathway, HIF-1 signaling pathway PI3K-Akt pathway, calcium signaling pathway, and Necroptosis. Molecular docking investigations demonstrated that the investigated marine compound has a high affinity for the key target, protein kinase A (PKA). A stable protein–ligand combination was created by the best hit molecule, according to molecular dynamics modeling. The purpose of this research was to examine the importance of brugine as a potentially effective treatment for breast cancer and to obtain knowledge of the molecular mechanism used by this substance in breast cancer.
Graphical abstract
Capsicum is a common spice used in food flavouring. However, they are prone to mycotoxin contamination. Mycotoxins are natural toxins produced by filamentous fungi and can pose serious risks to human ...health. Fungal contamination was assessed in 130 randomly collected samples following ISO 21527–2:2008 standards. Results revealed that 84.6% of the samples exceeded the acceptable fungal count limit (102 CFU/g) according to Gulf Cooperation Council (GCC) standards (GSO1016:2015). The predominant fungal isolates were Aspergillus (51.1%), notably Aspergillus flavus (38.8%) and Aspergillus niger (37.7%). Molecular characterization focused on crucial genes associated with aflatoxin (AF) and ochratoxin (OT) biosynthesis, 14.4% of the isolates exhibited all targeted AF genes. The mycotoxin analysis, conducted on 34.6% of samples via liquid chromatography-mass spectrometry (LC-MS), detected AFB1 in 28.8% (0.2–13.8 μg/kg) and OTA in 35.5% (6.87–59.00 μg/kg) of the tested samples. This study demonstrates the need of implementing rules governing the methods of storing, shipping, and packing spices in Saudi Arabia, which may help to minimizes the prevalence of toxigenic fungus and mycotoxins. This was the first study in KSA that focused on Aspergillus in Capsicum products.
•Fungus contaminations were revealed in 84.6 % of the tested powder capsicum samples.•Aspergillus spp. is the most prevalent genus in the tested samples.•Mycotoxin biosynthesis genes were detected in several Aspergillus isolates.•Sample packaging has no effect on fungal contamination in this study.•AFB1 and OTA were found in 28.8 and 35.5% of the samples analyzed, respectively.
The SARS-CoV-2 spike (S) glycoprotein with its mobile receptor-binding domain (RBD), binds to the human ACE2 receptor and thus facilitates virus entry through low-pH-endosomal pathways. The high ...degree of SARS-CoV-2 mutability has raised concern among scientists and medical professionals because it created doubt about the effectiveness of drugs and vaccinations designed specifically for COVID-19. In this study, we used computational saturation mutagenesis approach, including structure-based free energy calculations to analyse the effects of the missense mutations on the SARS-CoV-2 S-RBD stability and the S-RBD binding affinity with ACE2 at three different pH (pH 4.5, pH 6.5, and pH 7.4). A total of 3705 mutations in the S-RBD protein were analyzed, and we discovered that most of these mutations destabilize the RBD protein. Specifically, residues G404, G431, G447, A475, and G526 were important for RBD protein stability. In addition, RBD residues Y449, Y489, Y495, Q498, and N487 were critical for the RBD-ACE2 interaction. Next, we found that the distribution of the mean stability changes and mean binding energy changes of RBD due to mutations at both serological and endosomal pH correlated well, indicating the similar effects of mutations. Overall, this computational analysis is useful for understanding the effects of missense mutations in SARS-CoV-2 pathogenesis at different pH.
Communicated by Ramaswamy H. Sarma
