Sulfotransferase 1A1 (SULT1A1) is responsible for catalyzing various types of endogenous and exogenous compounds. Accumulating data indicates that the polymorphism rs9282861 (R213H) is responsible for inefficient enzymatic activity and associated with cancer progression. To characterize the detailed functional consequences of this mutation behind the loss-of-function of SULT1A1, the present study deployed molecular dynamics simulation to get insights into changes in the conformation and binding energy. The dynamics scenario of SULT1A1 in both wild and mutated types as well as with and without ligand showed that R213H induced local conformational changes, especially in the substrate-binding loop rather than impairing overall stability of the protein structure. The higher conformational changes were observed in the loop3 (residues, 235-263), turning loop conformation to A-helix and B-bridge, which ultimately disrupted the plasticity of the active site. This alteration reduced the binding site volume and hydrophobicity to decrease the binding affinity of the enzyme to substrates, which was highlighted by the MM-PBSA binding energy analysis. These findings highlight the key insights of structural consequences caused by R213H mutation, which would enrich the understanding regarding the role of SULT1A1 mutation in cancer development and also xenobiotics management to individuals in the different treatment stages. of sulfonate (SO 3 − ) group enhances the substrate hydrophilic potentiality or polarity and generates less toxic metabolites, and finally facilitates them for excretion [5,11]. In some cases, sulfonation of exogenous compounds turns them into active mutagens and carcinogens [12][13][14], although it sometimes acts as a chemical defense mechanism against xenobiotics [15].Recently, mutation at 213 positions of SULT1A1 exon 7 (rs9282861) [16,17] was reported by multiple studies to be involved in breast cancer progression [18], especially among the postmenopausal Asian women [19,20]. A meta-analysis showed that polymorphic rs9282861 has a significant association with bladder cancer [21], while a small scale case-control study found a significant association with the prevalence of intestinal cancer [22]. The significant association was also found for developing head and neck cancer [23], lung cancer [11,17,24], and also accountable for acute leukemia in infants and acute myeloid leukemia [25]. Patients having rs9282861 mutation, which caused the change of an amino acid from arginine to histidine at the 213th position (R213H), may have a higher susceptibility for developing esophageal cancer, due to the lower enzymatic activity and thermal stability that affect the procarcinogens metabolisms [4,8,26,27], including various steroid hormones, neurotransmitters, and non-opiateanalgesics [28,29]. Furthermore, the substitution occurred with amino acid having the same side chain polarity, although the mutation was reported to reduce the binding affinity of various substrates, as well as their pharmacokinetic properties [2...

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Hesperetin is potential natural compound for its attributes in various anticancer activities. Hesperetin can modulate diverse signaling pathways in cancer cells related to growth, metastasis, and apoptosis. Hesperetin also increases chemosensitivity in chemotherapy in a synergistic approach. Hesperetin processes less toxicity in human body but more bioavailability, conferring its application in clinical settings.

The ATP-binding cassette transporter A1 (ABCA1) is a membrane-bound exporter protein involved in regulating serum HDL level by exporting cholesterol and phospholipids to load up in lipid-poor ApoA-I and ApoE, which allows the formation of nascent HDL. Mutations in the ABCA1 gene, when presents in both alleles, disrupt the canonical function of ABCA1, which associates with many disorders related to lipid transport. Although many studies have reported the phenotypic effects of a large number of ABCA1 variants, the pathological effect of non-synonymous polymorphisms (nsSNPs) in ABCA1 remains elusive. Therefore, aiming at exploring the structural and functional consequences of nsSNPs in ABCA1, in this study, we employed an integrated computational approach consisting of nine well-known in silico tools to identify damaging SNPs and molecular dynamics (MD) simulation to get insights into the magnitudes of the damaging effects. In silico tools revealed four nsSNPs as being most deleterious, where the two SNPs (G1050V and S1067C) are identified as the highly conserved and functional disrupting mutations located in the NBD1 domain. MD simulation suggested that both SNPs, G1050V and S1067C, changed the overall structural flexibility and dynamics of NBD1, and induced substantial alteration in the structural organization of ATP binding site. Taken together, these findings direct future studies to get more insights into the role of these variants in the loss of the ABCA1 function.

: Plant-derived sterols, phytosterols, are well known for their cholesterol-lowering activity in serum and their anti-inflammatory activities. Recently, phytosterols have received considerable attention due to their beneficial effects on various non-communicable diseases, and recommended use as daily dietary components. The signaling pathways mediated in brain by phytosterols have been evaluated, but little is known of their effects on neuroinflammation, and no clinical studies have been undertaken phytosterols of interest. In this review, we discuss the beneficial roles of phytosterols, including their attenuating effects on inflammation, blood cholesterol levels, and hallmarks of disease, and their regulatory effects on neuroinflammatory disease pathways. Despite recent advancements made in phytosterol pharmacology, some critical questions remain unanswered. Therefore, we have tried to highlight the potentials of phytosterols as viable therapeutics against neuroinflammation and to direct future research with respect to clinical applications.