Silver Nanoparticles Derived from Probiotic Lactobacillus casei-a Novel Approach for Combating Bacterial Infections and Cancer.

In the face of rising antibiotic resistance and the need for novel therapeutic approaches against cancer, the present study delves into the various facets of biosynthesized silver nanoparticles (AgNPs) derived from the probiotic strain Lactobacillus casei (AgNPs-LC), assessing their efficacy in combating bacterial infections, disrupting biofilm formation, interfering with quorum sensing mechanisms, and exhibiting anti-cancer properties. The results showed that the AgNPs-LC had a spherical shape with an average size of 15 nm. The biosynthesized AgNPs-LC showed a symmetrical absorption spectrum with a peak at 458 nm with a diameter of 5-20 nm. AgNPs-LC exhibited significant antibacterial activity against Gram-positive and Gram-negative bacteria and inhibited the biofilm formation (> 50% at sub-MIC) and quorum sensing-mediated virulence factors, such as the production of violacein in C. violaceum (> 80% at sub-MIC), pyocyanin in P. aeruginosa (> 70% at sub-MIC), and prodigiosin in S. marcescens (> 80% at sub-MIC). The exopolysaccharides (EPS) were also found to reduce in the presence of AgNPs-LC. Furthermore, the AgNPs-LC showed anti-cancer and anti-metastasis activity via inhibiting cell migration and invasion of human lung cancer (A-549) cells. Overall, the present study brings out the multifaceted therapeutic capabilities of AgNPs-LC which offer exciting prospects for the development of innovative biomedical and pharmaceutical interventions, making AgNPs-LC a versatile and promising candidate for a wide range of applications in healthcare and medicine. However, further research is essential to fully harness their therapeutic potential.

Therapeutic Role of ELOVL in Neurological Diseases.

Fatty acids play an important role in controlling the energy balance of mammals. De novo lipogenesis also generates a significant amount of lipids that are endogenously produced in addition to their ingestion. Fatty acid elongation beyond 16 carbons (palmitic acid), which can lead to the production of very long chain fatty acids (VLCFA), can be caused by the rate-limiting condensation process. Seven elongases, ELOVL1-7, have been identified in mammals and each has a unique substrate specificity. Researchers have recently developed a keen interest in the elongation of very long chain fatty acids protein 1 (ELOVL1) enzyme as a potential treatment for a variety of diseases. A number of neurological disorders directly or indirectly related to ELOVL1 involve the elongation of monounsaturated (C20:1 and C22:1) and saturated (C18:0-C26:0) acyl-CoAs. VLCFAs and ELOVL1 have a direct impact on the neurological disease. Other neurological symptoms such as ichthyotic keratoderma, spasticity, and hypomyelination have also been linked to the major enzyme (ELOVL1). Recently, ELOVL1 has also been heavily used to treat a number of diseases. The current review focuses on in-depth unique insights regarding the role of ELOVL1 as a therapeutic target and associated neurological disorders.

Computational insight into structural basis of human ELOVL1 inhibition.

Very long-chain fatty acids (VLCFAs) play a direct role in the development of a neurological disorder, X-linked adrenoleukodystrophy (X-ALD). Since ELOVL1 catalyzes the rate-limiting step of the synthesis of VLCFAs, it has emerged as an attractive target for the treatment of X-ALD. Recently two potent inhibitors, compound 22 (C22) and compound 27 (C27) have been reported to specifically inhibit human ELOVL1 but their structural basis of inhibition has not been explored. In the present study, we have used a homology model of human ELOVL1 to deduce the binding site and binding modes of C22 and C27. We have employed computational approaches to characterize the binding of C22 and C27. Initially, binding of hexacosanoyl-CoA (C26:0-CoA) to ELOVL1 was modelled and further validated by molecular dynamics (MD) simulation. We observed that the fatty acid tail of C26: CoA protrudes from a unique opening located at the occluded end of ELOVL1. Structural comparison of ELOVL1 with the crystal structure of ELOVL7 revealed that the unique opening was not present in human ELOVL7. Combined blind and focused molecular docking approaches revealed that C22 and C27 exhibit favourable binding in the same unique opening. Further, MD simulations and free binding energy calculations confirmed that C22 and C27 maintain the favourable binding in the unique opening of ELOVL1. Overall, our findings suggest that selective human ELOVL1 inhibitors block the binding of long tails of VLCFAs near the occluded end of ELOVL1. Present study will be helpful in the discovery and design of novel, selective and potent inhibitors of human ELOVL1.

Bacteriocin-Nanoconjugates (Bac10307-AgNPs) Biosynthesized from Lactobacillus acidophilus-Derived Bacteriocins Exhibit Enhanced and Promising Biological Activities.

The proteinaceous compounds produced by lactic acid bacteria are called bacteriocins and have a wide variety of bioactive properties. However, bacteriocin's commercial availability is limited due to short stability periods and low yields. Therefore, the objective of this study was to synthesize bacteriocin-derived silver nanoparticles (Bac10307-AgNPs) extracted from Lactobacillus acidophilus (L. acidophilus), which may have the potential to increase the bioactivity of bacteriocins and overcome the hurdles. It was found that extracted and purified Bac10307 had a broad range of stability for both temperature (20-100 °C) and pH (3-12). Further, based on Sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis, its molecular weight was estimated to be 4.2 kDa. The synthesized Bac10307-AgNPs showed a peak of surface plasmon resonance at 430 nm λmax. Fourier transform infrared (FTIR) confirmed the presence of biological moieties, and transmission electron microscopy (TEM) coupled with Energy dispersive X-Ray (EDX) confirmed that AgNPs were spherical and irregularly shaped, with a size range of 9-20 nm. As a result, the Bac10307-AgNPs displayed very strong antibacterial activity with MIC values as low as 8 µg/mL for Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa), when compared to Bac10307 alone. In addition, Bac10307-AgNPs demonstrated promising in vitro antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) (IC50 = 116.04 µg/mL) and in vitro cytotoxicity against human liver cancer cells (HepG2) (IC50 = 135.63 µg/mL), more than Bac10307 alone (IC50 = 139.82 µg/mL against DPPH and 158.20 µg/mL against HepG2). Furthermore, a protein-protein molecular docking simulation study of bacteriocins with target proteins of different biological functions was also carried out in order to ascertain the interactions between bacteriocins and target proteins.

Identifying novel and potent inhibitors of EGFR protein for the drug development against the breast cancer.

The epidermal growth factor receptor (EGFR) has been shown to be extremely important in numerous signaling pathways, particularly those involved in cancer progression. Many therapeutic inhibitors, consisting of both small molecules and monoclonal antibodies, have been developed to target inflammatory, triple-negative and metastatic breast cancer. With the emergence of resistance in breast cancer treatment strategies, there is a need to develop novel drug targets that not only overcome resistance, but also exhibit low toxicity and high specificity. The work presented here focuses on the identification of new inhibitors against the EGFR protein using combined computational approaches. Using a comprehensive machine learning-based virtual screening approach complemented by other computational approaches, we identified six new molecules from the ZINC database. The gold docking score of these six novel molecules is 125.95, 125.38, 123.13, 119.71, 115.64 and 113.73, respectively, while the gold score of the control group is 120.74. In addition, we also analyzed the FEC value of these compounds and found that the values of compounds 1, 2, 3 and 4 (-61.82, -63.98, -67.98 and -63.32, respectively) were higher are than those of the control group (-61.05). Furthermore, these molecules showed highly stable RMSD plots and good interaction of hydrogen bonds. The identified inhibitors provided interesting insights for understanding the electronic, hydrophobic, steric and structural requirements for EGFR inhibitory activity. Distinguishing these novel molecules could lead to the development of new drugs useful in treating breast cancer.Communicated by Ramaswamy H. Sarma.