Pancreatic cancer is a prevalent lethal gastrointestinal cancer that generally does not show any symptoms until it reaches advanced stages, resulting in a high mortality rate. People at high risk, such as those with a family history or chronic pancreatitis, do not have a universally accepted screening protocol. Chemotherapy and radiotherapy demonstrate limited effectiveness in the management of pancreatic cancer, emphasizing the urgent need for innovative therapeutic strategies. Recent studies indicated that the complex interaction among pancreatic cancer cells within the dynamic microenvironment, comprising the extracellular matrix, cancer-associated cells, and diverse immune cells, intricately regulates the biological characteristics of the disease. Additionally, mounting evidence suggests that EVs play a crucial role as mediators in intercellular communication by the transportation of different biomolecules, such as miRNA, proteins, DNA, mRNA, and lipids, between heterogeneous cell subpopulations. This communication mediated by EVs significantly impacts multiple aspects of pancreatic cancer pathogenesis, including proliferation, angiogenesis, metastasis, and resistance to therapy. In this review, we delve into the pivotal role of EV-associated miRNAs in the progression, metastasis, and development of drug resistance in pancreatic cancer as well as their therapeutic potential as biomarkers and drug-delivery mechanisms for the management of pancreatic cancer.

The majority of the world population (around 25%) has latent Mycobacterium tuberculosis (Mtb) infection, among which only 5–10% of individuals develop active tuberculosis (TB), and 90–95% continue to have latent tuberculosis infection. This makes it the biggest global health concern. It has been reported that the resuscitation-promoting factor B (RpfB) is an exciting potential target for tuberculosis drug discovery due to its significant role in the reactivation of latent TB infection to an active infection. Several attempts have been made to investigate potential inhibitors against RpfB utilizing in-silico approaches. The present study also utilized a computational approach to investigate microbially derived natural compounds against the Mtb RpfB protein which is a very cost-effective This evaluation used structure-based virtual screening (SBVS), drug-likeness profiling, molecular docking, molecular dynamics simulation, and free-binding energy calculations. Six potential natural compounds, viz. Cyclizidine I, Boremexin C, Xenocoumacin 2, PM-94128, Cutinostatin B, and (+)1-O-demethylvariecolorquinone A were selected, which displayed a potential binding affinity between −52.39 and −60.87 Kcal/mol MMGBSA score and docking energy between −7.307 Kcal/mol to −6.972 Kcal/mol. All the complexes showed acceptable stability (<2.7 Å RMSD) during 100 ns MD simulation time except the RpfB protein-xenocoumacin 2 complex. This result exhibited that the selected compounds have high efficiency in inhibiting the Mtb RpfB and can be taken into account for additional in vitro and in vivo experimental validation. Communicated by Ramaswamy H. Sarma

Dormancy occurs when Mycobacterium tuberculosis (Mtb) enters a non-replicating and metabolically inactive state in response to hostile environment. During this state, it is highly resistant to conventional antibiotics, which increase the urgency to develop new potential drugs against dormant bacilli. In view of this, the dormancy survival regulator (DosR) protein is thought to be an essential component that plays a key role in bacterial adaptation to dormancy during hypoxic conditions. Herein, the NP-lib database containing natural product compounds was screened virtually against the binding site of the DosR protein using the MTiopen screen web server. A series of computational analyses were performed, including redocking, intermolecular interaction analysis, and MDS, followed by binding free energy analysis. Through screening, 1000 natural product compounds were obtained with docking energy ranging from −8.5 to −4.1 kcal/mol. The top four lead compounds were then selected for further investigation. On comparative analysis of intermolecular interaction, dynamics simulation and MM/GBSA calculation revealed that M3 docked with the DosR protein (docking score = −8.1 kcal/mol, RMSD = ~7 Å and ΔG Bind = −53.51 kcal/mol) exhibited stronger stability than reference compound Ursolic acid (docking score = −6.2 kcal/mol, RMSD = ~13.5 Å and ΔG Bind = −44.51 kcal/mol). Hence, M3 is recommended for further validation through in vitro and in vivo studies against latent tuberculosis infection.

Acute myeloid leukemia is one of the most prominent forms of acute leukemia in adults, which account for 32% of the overall incidents of adult leukemia, AML is a leukemia of bone marrow and blood characterized by uncontrolled proliferation of myeloid cells. CDK6 protein plays a crucial role in the regulation of cell cycle by forming complexes with cyclin D1, D2, D3 ensuring transition of cell cycle from D1 to S phase, this study focuses on identify the potential inhibitors of CDK6 protein for the management of AML. In silico approach was employed to identify the potential CDK6 protein inhibitors from natural compounds for the management of AML. 6,996 natural phytochemical compounds were screened, the top five compounds, were selected with the docking score ranging from −11.8 to −10.2 kcal/mol, which is better than the reference compound (−9.6 kcal/mol). Molecular dynamic simulations were performed for the top five chosen natural phytochemical compounds, i,e., Serpentinine, Strychnochrysine, Licoagrone, Tovophyllin B, and Isopsoralidin to further assess their stability and intermolecular interaction and they all displayed a good interaction with target protein. MM/GBSA was utilized to calculate free binding energy, in which all compounds showed reasonable stability (−80.06 to −41.52). Furthermore, ADME analysis demonstrated drug-likeness and pharmacokinetics properties of the chosen compounds. Hence these natural phytochemical compounds as potential inhibitors of CDK6 protein could be used for the management of AML.

Introduction: The global burden of tuberculosis (TB) remains a major concern for society that is worsening day by day with the emergence of drug-resistant TB as well as risks associated with latent TB. Isocitrate lyase (ICL) has been shown as a potential target that plays a role in the la-tent/dormant stage of M. tuberculosis. Several inhibitors against ICL have been designed and tested, which have various side effects. Methodology: This study focuses on the phytochemicals from plant extracts, which have anti-tuber-cular properties. A total of 1413 phytochemicals were virtually screened against ICL to identify the promising therapeutic compounds. The top four lead phytochemicals were selected based on their binding energy and subjected to redocking and intermolecular interaction analysis. These results were further validated through 100 ns MD simulation to check the stability of these complexes. The find-ings of these complexes were compared to the reference compound VGX. Results: The top selected compound viz., Allantoin, Gallic acid, Citric acid, and 3,5-Dihydroxyben-zoic acid from virtual screening result displayed better docking score ranging from -8 kcal/mol to -7.2 kcal/mol than the reference compound VGX (-7.5 kcal/mol). Moreover, during the MD simula-tion analysis, gallic acid exhibited greater stability compared to all other compounds, including the reference compound. Conclusion: Among selected phytochemicals, gallic acid exhibited highest stability and binding af-finity within the active site of ICL as compared to previously identified compounds, which suggests that it is as potential candidate against ICL. That can be used for further in vitro and in vivo studies to evaluate its effectiveness against TB.