Reactive oxygen species (ROS) play a significant role in the survival and decline of various biological systems. In liver-related metabolic disorders such as steatohepatitis, ROS can act as both a cause and a consequence. Alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH) are two distinct types of steatohepatitis. Recently, there has been growing interest in using medications that target ROS formation and reduce ROS levels as a therapeutic approach for oxidative stress-related liver disorders. Mammalian systems have developed various antioxidant defenses to protect against excessive ROS generation. These defenses modulate ROS through a series of reactions, limiting their potential impact. However, as the condition worsens, exogenous antioxidants become necessary to control ROS levels. Nanotechnology has emerged as a promising avenue, utilizing nanocomplex systems as efficient nano-antioxidants. These systems demonstrate enhanced delivery of antioxidants to the target site, minimizing leakage and improving targeting accuracy. Therefore, it is essential to explore the evolving field of nanotechnology as an effective means to lower ROS levels and establish efficient therapeutic interventions for oxidative stress-related liver disorders.

Today's era and lifestyle have led to a quick rise in cases of diabetes. Diabetes mellitus (DM) has risen to the top of the list of serious diseases and stems from different health disorders. Human pancreatic alpha-amylase (HPA) enzyme plays a critical role in the digestion of carbohydrates, and inhibitors of alpha-amylase have been investigated as a way to slow the absorption of carbohydrates and reduce postprandial (after meal) hyperglycemia in patients with diabetes. Recently algal derivatives have been studied for their potential as a new drug against diabetes and other diseases. The study is aimed to find active biochemical compounds from the methanolic extract of Chlorella vulgaris. The in vitro studies were carried out and the results revealed that methanolic extract from C. vulgaris showed abundant inhibition efficacy of the α-amylase (IC₅₀ of about 2.66 µg/mL) compared to acarbose (IC₅₀ of about 2.85 µg/mL), a standard, commercial inhibitor. All the bioactive compounds from the methanolic extract were identified from the GCMS study and considered for in silico evaluation. Out of 14 bioactive compounds from GCMS, compound C3 showed higher docking energy (-8.3 kcal/mol) compared to other compounds. Subsequently, the comparative molecular dynamic simulation of apo and ligand-bound (compound C3 and acarbose) α-amylase complexes showed overall structural stability for compound C3 at the active site of α-amylase from various MD analyses. Hence, we believe, the bioactive compounds identified from GCMS may assist in diabetic therapeutics. Moreover, the compound C3 identified in this study could be a potential antidiabetic therapeutic inhibitor.Communicated by Ramaswamy H. Sarma.

Melanoma differentiation-associated protein 5 (MDA5) is a crucial RIG-I-like receptor RNA helicase enzyme encoded by IFIH1 in humans. Single nucleotide polymorphisms in the IFIH1 results in fatal genetic disorders such as Aicardi–Goutières syndrome and Singleton–Merten syndrome, and in increased risk of type I diabetes in humans. In this study, we chose four different amino acid substitutions of the MDA5 protein responsible for genetic disorders: MDA5^L372F, MDA5^A452T, MDA5^R779H, and MDA5^R822Q and analyzed their structural and functional relationships using molecular dynamic simulations. Our results suggest that the mutated complexes are relatively more stable than the wild-type MDA5. The radius of gyration, interaction energies, and intra-hydrogen bond analysis indicated the stability of mutated complexes over the wild type, especially MDA5^L372F and MDA5^R822Q. The dominant motions exhibited by the wild-type and mutant complexes varied significantly. Moreover, the betweenness centrality of the wild-type and mutant complexes showed shared residues for intra-signal propagation. The observed results indicate that the mutations lead to a gain of function, as reported in previous studies, due to increased interaction energies and stability between RNA and MDA5 in mutated complexes. These findings are expected to deepen our understanding of MDA5 variants and may assist in the development of relevant therapeutics against the disorders.

Estrogen-related receptor gamma (ERRγ), the latest member of the ERR family, does not have any known reported natural ligands. Although the crystal structures of the apo, agonist-bound, and inverse agonist-bound ligand-binding domain (LBD) of ERRγ have been solved previously, their dynamic behavior has not been studied. Hence, to explore the intrinsic dynamics of the apo and ligand-bound forms of ERRγ, we applied long-range molecular dynamics (MD) simulations to the crystal structures of the apo and ligand-bound forms of the LBD of ERRγ. Using the MD trajectories, we performed hydrogen bond and binding free energy analysis, which suggested that the agonist displayed more hydrogen bonds with ERRγ than the inverse agonist 4-OHT. However, the binding energy of 4-OHT was higher than that of the agonist GSK4716, indicating that hydrophobic interactions are crucial for the binding of the inverse agonist. From principal component analysis, we observed that the AF-2 helix conformation at the C-terminal domain was similar to the initial structures during simulations, indicating that the AF-2 helix conformation is crucial with respect to the agonist or inverse agonist for further functional activity of ERRγ. In addition, we performed residue network analysis to understand intramolecular signal transduction within the protein. The betweenness centrality suggested that few of the amino acids are important for residue signal transduction in apo and ligand-bound forms. The results from this study may assist in designing better therapeutic compounds against ERRγ associated diseases.

AIM2 and IFI16 are the most studied members of AIM2-like receptors (ALRs) in humans and share a common N-Terminal PYD domain and C-terminal HIN domain. The HIN domain binds to dsDNA in response to the invasion of bacterial and viral DNA, and the PYD domain directs apoptosis-associated speck-like protein via protein–protein interactions. Hence, activation of AIM2 and IFI16 is crucial for protection against pathogenic assaults, and any genetic variation in these inflammasomes can dysregulate the human immune system. In this study, different computational tools were used to identify the most deleterious and disease-causing non-synonymous single nucleotide polymorphisms (nsSNPs) in AIM2 and IFI16 proteins. Molecular dynamic simulation was performed for the top damaging nsSNPs to study single amino acid substitution-induced structural alterations in AIM2 and IFI16. The observed results suggest that the variants G13V, C304R, G266R, and G266D for AIM2, and G13E and C356F are deleterious and affect structural integrity. We hope that the suggested deleterious nsSNPs and structural dynamics of AIM2 and IFI16 variants will guide future research to better understand the function of these variants with large-scale studies and may assist in fresher therapeutics focusing on these polymorphisms. Communicated by Ramaswamy H. Sarma