Corosolic acid and its structural analogs: A systematic review of their biological activities and underlying mechanism of action.

BACKGROUND: The corosolic acid (CA), also known as plant insulin, is a pentacyclic triterpenoid extracted from plants such as Lagerstroemia speciosa. It has been shown to have anti-diabetic, anti-inflammatory and anti-tumor effects. Its structural analogs ursolic acid (UA), oleanolic acid (OA), maslinic acid (MA), asiatic acid (AA) and betulinic acid (BA) display similar individual pharmacological activities to those of CA. However, there is no systematic review documenting pharmacological activities of CA and its structural analogues. This study aims to fill this gap in literature. PURPOSE: This systematic review aims to summarize the medical applications of CA and its analogues. METHODS: A systematic review summarizes and compares the extraction techniques, pharmacokinetic parameters, and pharmacological effects of CA and its structural analogs. Hypoglycemic effect is one of the key inclusion criteria for searching Web of Science, PubMed, Embase and Cochrane databases up to October 2020 without language restrictions. 'corosolic acid', 'ursolic acid', 'oleanolic acid', 'maslinic acid', 'asiatic acid', 'betulinic acid', 'extraction', 'pharmacokinetic', 'pharmacological' were used to extract relevant literature. The PRISMA guidelines were followed. RESULTS: At the end of the searching process, 140 articles were selected for the systematic review. Information of CA and five of its structural analogs including UA, OA, MA, AA and BA were included in this review. CA and its structural analogs are pentacyclic triterpenes extracted from plants and they have low solubilities in water due to their rigid scaffold and hydrophobic properties. The introduction of water-soluble groups such as sugar or amino groups could increase the solubility of CA and its structural analogs. Their biological activities and underlying mechanism of action are reviewed and compared. CONCLUSION: CA and its structural analogs UA, OA, MA, AA and BA are demonstrated to show activities in lowering blood sugar, anti-inflammation and anti-tumor. Their oral absorption and bioavailability can be improved through structural modification and formulation design. CA and its structural analogs are promising natural product-based lead compounds for further development and mechanistic studies.

Glucosylpolyphenols as Inhibitors of Aß-Induced Fyn Kinase Activation and Tau Phosphorylation: Synthesis, Membrane Permeability, and Exploratory Target Assessment within the Scope of Type 2 Diabetes and Alzheimer's Disease.

Despite the rapidly increasing number of patients suffering from type 2 diabetes, Alzheimer's disease, and diabetes-induced dementia, there are no disease-modifying therapies that are able to prevent or block disease progress. In this work, we investigate the potential of nature-inspired glucosylpolyphenols against relevant targets, including islet amyloid polypeptide, glucosidases, and cholinesterases. Moreover, with the premise of Fyn kinase as a paradigm-shifting target in Alzheimer's drug discovery, we explore glucosylpolyphenols as blockers of Aß-induced Fyn kinase activation while looking into downstream effects leading to Tau hyperphosphorylation. Several compounds inhibit Aß-induced Fyn kinase activation and decrease pTau levels at 10 µM concentration, particularly the per-O-methylated glucosylacetophloroglucinol and the 4-glucosylcatechol dibenzoate, the latter inhibiting also butyrylcholinesterase and ß-glucosidase. Both compounds are nontoxic with ideal pharmacokinetic properties for further development. This work ultimately highlights the multitarget nature, fine structural tuning capacity, and valuable therapeutic significance of glucosylpolyphenols in the context of these metabolic and neurodegenerative disorders.

Dissolved Black Carbon as an Efficient Sensitizer in the Photochemical Transformation of 17ß-Estradiol in Aqueous Solution.

Dissolved black carbon (DBC) is an important component of the dissolved organic matter (DOM) pool. Nonetheless, little is known about its role in the photochemical processes of organic contaminants. This study investigated the effect of DBC on the phototransformation of 17ß-estradiol in aqueous solutions under simulated sunlight. Four well-studied dissolved humic substances (DHS) were included as comparisons. DBC acted as a very effective sensitizer to facilitate the phototransformation of 17ß-estradiol. The apparent quantum yield for 17ß-estradiol phototransformation mediated by DBC was approximately six times higher than that by DHS at the same carbon concentration. Quenching experiments suggested that direct reaction with triplet-excited state DBC (3DBC*) was the predominant pathway of 17ß-estradiol phototransformation. The higher mediation efficiency of DBC than DHS is likely due to the higher contents of aromatic groups and smaller molecular sizes, which facilitated the generation of 3DBC*. The apparent quantum yield of triplet-excited states production for DBC was 4-8 times higher than that for DHS. The results suggest that 3DBC* may have a considerable contribution to the overall photoreactivity of triplet-excited state DOM in aquatic systems. Our findings also imply that DBC can play an important role in the phototransformation of organic contaminants in the environments.

A small molecule modulator of prion protein increases human mesenchymal stem cell lifespan, ex vivo expansion, and engraftment to bone marrow in NOD/SCID mice.

Human mesenchymal stem cells (hMSCs) have been shown to have potential in regenerative approaches in bone and blood. Most protocols rely on their in vitro expansion prior to clinical use. However, several groups including our own have shown that hMSCs lose proliferation and differentiation ability with serial passage in culture, limiting their clinical applications. Cellular prion protein (PrP) has been shown to enhance proliferation and promote self-renewal of hematopoietic, mammary gland, and neural stem cells. Here we show, for the first time, that expression of PrP decreased in hMSC following ex vivo expansion. When PrP expression was knocked down, hMSC showed significant reduction in proliferation and differentiation. In contrast, hMSC expanded in the presence of small molecule 3/689, a modulator of PrP expression, showed retention of PrP expression with ex vivo expansion and extended lifespan up to 10 population doublings. Moreover, cultures produced a 300-fold increase in the number of cells generated. These cells showed a 10-fold increase in engraftment levels in bone marrow 5 weeks post-transplant. hMSC treated with 3/689 showed enhanced protection from DNA damage and enhanced cell cycle progression, in line with data obtained by gene expression profiling. Moreover, upregulation of superoxide dismutase-2 (SOD2) was also observed in hMSC expanded in the presence of 3/689. The increase in SOD2 was dependent on PrP expression and suggests increased scavenging of reactive oxygen species as mechanism of action. These data point to PrP as a good target for chemical intervention in stem cell regenerative medicine.

Knowledge-based interaction fingerprint scoring: a simple method for improving the effectiveness of fast scoring functions.

A new method for the postprocessing of docking outputs has been developed, based on encoding putative 3D binding modes (docking solutions) as ligand-protein interactions into simple bit strings, a method analogous to the structural interaction fingerprint. Instead of employing traditional scoring functions, the method uses a series of new, knowledge-based scores derived from the similarity of the bit strings for each docking solution to that of a known reference binding mode. A GOLD docking study was carried out using the Bissantz estrogen receptor antagonist set along with the new scoring method. Superior recovery rates, with up to 2-fold enrichments, were observed when the new knowledge-based scoring was compared to the GOLD fitness score. In addition, top ranking sets of molecules (actives and potential actives or decoys) were structurally diverse with low molecular weights and structural complexities. Principal component analysis and clustering of the fingerprints permits the easy separation of active from inactive binding modes and the visualization of diverse binding modes.

Predicted consequences of site-directed mutagenesis and the impact of species variation on prion protein misfolding through the N-terminal domain.

Variant Creutzfeldt-Jacob disease (vCJD) is considered to afflict humans through the acquisition of variant isomers and misfolding of the normal cellular prion polypeptide, PrP(C). Although the exact mechanism of the misfolding is not been yet clearly understood, this paper provides four additional pieces of evidence in support of the hypothesis that misfolding within PrP(C) involves N-terminal residues, up to and including Asn178. Structural predictions for N-terminal residues between Leu4 and Gly124 revealed that Leu4-Leu19 might adopt a helical conformation. Furthermore, measurement of C(alpha) distance variations, as determined from available NMR solution structures of wild type, as well as the biologically significant Val166, Asn170 and Lys220 variants of PrP(C), revealed previously unreported global and local conformational differences may occur in PrP(C) as a result of these amino-acid substitutions. Notably, three regions, His140-Tyr150 and Met166-Phe175 showed deviations greater than 3 A in their C(alpha)-coordinates (cf wild type) indicating that the majority of the N-terminal domain is likely to contribute to the misfolding of PrP(C). Minor variations in the orientation of amino acids Thr193-Glu200, located towards the C terminus of the protein, were also noted. This most likely indicates the presence of a hinge mechanism, inherent to a Helix-Loop-helix (HLH) motif formed by amino acids within alpha2, LIII and alpha3, in order to accommodate reorientation of the motif in response to misalignment of the N-terminal domain. An unexpected 3 angstroms deviation from the coordinates of the wild type polypeptide, absent from either Val166, Asn170 variants was observed over the region Arg154-Tyr155 within the Val166 form of PrP(C). This may contribute to the explanation as to why patients carrying the Val166 isoform of PrP(C) may be more susceptible to vCJD.

Prostate-specific antigen (PSA)-mediated proliferation, androgenic regulation and inhibitory effects of LY312340 in HOS-TE85 (TE85) human osteosarcoma cells.

BACKGROUND: PSA mediates growth factor responses that stimulate proliferation of prostatic and other cellular types. Androgen-sensitive TE85 human osteosarcoma cells were used to study PSA as a potential mediator of prostatic cancer growth and osseous metastasis. MATERIALS AND METHODS: TE85 cells were probed for PSA mRNA and protein levels under testosterone (T)-replete and--depleted conditions. TE85 proliferative responses to PSA were evaluated in the absence and presence of LY312340, a monocyclic beta-lactam inhibitor of PSA enzymatic activity. RESULTS: A 3.1-fold increase in PSA mRNA was observed following T stimulation. Low levels of immunoreactive PSA (iPSA) were detected in media of androgen-stimulated TE85 cells while iPSA was not found in control media. Conversely, iPSA was detected in TE85 cell pellets from control but not in androgen-stimulated cell cultures. Exogenously added enzymatically active PSA stimulated TE85 proliferation in a bi-phasic manner. LY312340 inhibited PSA-induced increases in TE85 cell numbers but had no effect on basal or T- stimulated cellular proliferation. CONCLUSION: While the PSA levels produced by TE-85 cells in response to androgen stimulation are too low to be biologically active, PSA produced by metastatic PCa cells may mediate paracrine stimulation of osteogenic PCa metastasis. Inhibitors of PSA enzymatic activity could be useful therapeutic agents.