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Biomedical subjects

Yonghui Zhang

Publications and source records attributed to Yonghui Zhang.

At least 19 recordsLinked to original sources
PubMed2026

Mov10 mitigates hematopoietic stem cell exhaustion under stress by modulating the Camp-mediated inflammatory pathway.

The integrity of hematopoietic stem cell (HSC) function is crucial for robust hematopoietic regeneration following stress. Inflammatory responses are pivotal drivers of HSC stress response, yet the precise modulation of inflammatory pathways remains incompletely defined. In this study, we identify the RNA helicase Mov10 as a negative regulator of stress-induced inflammatory pathways in HSC. Our study indicates that Mov10, which is critically required for HSC maintenance, is highly expressed in HSC, and its loss adversely affects HSC fitness and survival during hematopoietic stress induced by bone marrow transplantation and irradiation (IR). Mechanistically, Mov10 mitigates excessive inflammatory activation to sustain HSC functional integrity during hematopoietic stress, primarily by enhancing the translation of CAMP, which inhibits the interaction between TNF-α and its receptor TNFR1 and suppresses NF-κB activation. Overall, our results imply that Mov10 plays a critical role in averting functional failure of hematopoiesis under stress, presenting viable paths for the therapeutic intervention of relevant diseases.

Camp↗
PubMed2006

Solid-state NMR, crystallographic, and computational investigation of bisphosphonates and farnesyl diphosphate synthase-bisphosphonate complexes.

Bisphosphonates are a class of molecules in widespread use in treating bone resorption diseases and are also of interest as immunomodulators and anti-infectives. They function by inhibiting the enzyme farnesyl diphosphate synthase (FPPS), but the details of how these molecules bind are not fully understood. Here, we report the results of a solid-state (13)C, (15)N, and (31)P magic-angle sample spinning (MAS) NMR and quantum chemical investigation of several bisphosphonates, both as pure compounds and when bound to FPPS, to provide information about side-chain and phosphonate backbone protonation states when bound to the enzyme. We then used computational docking methods (with the charges assigned by NMR) to predict how several bisphosphonates bind to FPPS. Finally, we used X-ray crystallography to determine the structures of two potent bisphosphonate inhibitors, finding good agreement with the computational results, opening up the possibility of using the combination of NMR, quantum chemistry and molecular docking to facilitate the design of other, novel prenytransferase inhibitors.

Crystallography, X-Ray↗
PubMed2006

Activity of nitrogen-containing and non-nitrogen-containing bisphosphonates on tumor cell lines.

We synthesized and tested three series of bisphosphonates for their activity in inhibiting the growth of three human tumor cell lines: MCF-7 (breast), NCI-H460 (lung), and SF-268 (CNS). The first series of compounds consisted of 49 nitrogen-containing bisphosphonates, the most active species being a tetrakispivaloyloxymethyl (POM) ester, having an (average) IC(50) of 6.8 microM. The second series of compounds consisted of nine terphenylbisphosphonates, the most active species also being a POM ester, having an IC(50) of 2.2 microM. The third series of compounds consisted of seven halogen or cyanophenylbisphosphonates, the most active species again being a POM ester, having an IC(50) of 500 nM. Taken together, these results are of interest because they show that bisphosphonate esters can have potent activity against a variety of tumor cell lines, with the most active terphenyl- and halophenyl-containing species having IC(50) values approximately 10-40x lower than the most potent commercially available bisphosphonates.

Antineoplastic Agents↗
PubMed2006

Immunomodulatory activity of the rhizomes of Impatiens pritzellii var. hupehensis on collagen-induced arthritis mice.

Impatiens pritzellii Hook. f. var. hupehensis Hook. f. (Balsaminaceae) has been well-known and widely used in China as an anti-rheumatoid arthritis (anti-RA) herb. In this present study, mice with collagen-induced arthritis (CIA) have been treated with the methanol (MeOH) extract (0.56, 1.12, 1.68 and 2.24 g/kg body weight) and the n-butanol (BuOH) fraction (0.13, 0.27, 0.40 and 0.53 g/kg body weight) of the rhizomes of Impatiens pritzellii orally for 3 weeks. The progression of CIA was evaluated by macroscopic scoring. Administration of the MeOH extract at dose of 1.12 g/kg and the BuOH fraction at 0.53 g/kg suppressed the development of CIA in mice significantly. The spleen and thymus indexes were measured and the levels of IgG, IL-10, INF-gamma and IL-18 in the serum of CIA mice were examined after the treatment of the MeOH extract (1.12 and 1.68 g/kg body weight) and the BuOH fraction (0.40 and 0.53 g/kg body weight). Administration of the MeOH extract and the BuOH fraction of Impatiens pritzellii decreased the spleen and thymus indexes, down-regulated the levels of IgG, INF-gamma, IL-18, and up-regulated the concentration of IL-10 in the serum of mice with CIA. From the results, it was concluded that administration of Impatiens pritzellii had obviously therapeutic effects on RA including immunomodulatory activity. Moreover, the BuOH fraction exerted the activity of anti-RA of Impatiens pritzellii.

1-Butanol↗
PubMed2006

Enthalpy versus entropy-driven binding of bisphosphonates to farnesyl diphosphate synthase.

We report the results of an ITC (isothermal titration calorimetry) investigation of the binding of six bisphosphonates to the enzyme farnesyl diphosphate synthase (FPPS; EC 2.5.1.10) from Trypanosoma brucei. The bisphosphonates investigated were zoledronate, risedronate, ibandronate, pamidronate, 2-phenyl-1-hydroxyethane-1,1-bisphosphonate, and 1-(2,2-bisphosphonoethyl)-3-iodo pyridinium. At pH = 7.4, both risedronate and the phenylethane bisphosphonate bind in an enthalpy-driven manner (DeltaH approximately -9 to 10 kcal mol-1), but the other four bisphosphonates bind in an entropy-driven manner (DeltaS varying from 31.2 to 55.1 cal K-1 mol-1). However, at pH = 8.5, zoledronate binding switches from entropy to enthalpy-driven. The DeltaG results are highly correlated with FPPS inhibition results obtained using a radiochemical assay (R2 = 0.85, N = 11, P < 0.001). The DeltaH and DeltaS results are interpreted in terms of a model in which bisphosphonates with charged side chains have positive DeltaH values, due to the enthalpic cost of desolvation (due to strong ion-dipole interactions) and, likewise, a positive DeltaS, due to an increase in water entropy (both ligand and protein associated) on ligand binding to FPPS: the hydrophobic effect. For the neutral side chains (risedronate at pH 7.4, 8.5 and zoledronate at pH 8.5, as well as the phenylethane bisphosphonate), binding is overwhelmingly enthalpy-driven, with the enhanced activity of the basic side chain containing species being attributable to their becoming protonated in the active site. Given the large size of the bisphosphonate market and the potential importance of the development of these compounds for cancer immunotherapy and anti-parasitic chemotherapy, these results are of broad general interest in the context of the development of new, potent, and selective FPPS inhibitors.

Animals↗
PubMed2006

Inhibition of Trypanosoma cruzi hexokinase by bisphosphonates.

Hexokinase is the first enzyme involved in glycolysis in most organisms, including the etiological agents of Chagas disease (Trypanosoma cruzi) and African sleeping sickness (Trypanosoma brucei). The T. cruzi enzyme is unusual since, unlike the human enzyme, it is inhibited by inorganic diphosphate (PPi). Here, we show that non-hydrolyzable analogues of PPi, bisphosphonates, are potent inhibitors of T. cruzi hexokinase (TcHK). We determined the activity of 42 bisphosphonates against TcHK, and the IC(50) values were used to construct pharmacophore and comparative molecular similarity indices analysis (CoMSIA) models for enzyme inhibition. Both models revealed the importance of electrostatic, hydrophobic, and steric interactions, and the IC(50) values for 17 active compounds were predicted with an average error of 2.4x by using the CoMSIA models. The compound most active against T. cruzi hexokinase was found to have a 2.2 microM IC(50) versus the clinically relevant intracellular amastigote form of T. cruzi, but only a approximately 1-2 mM IC(50) versus Dictyostelium discoideum and a human cell line, indicating selective activity versus T. cruzi.

Animals↗
PubMed2006

Structural studies of Vgamma2Vdelta2 T cell phosphoantigens.

Human gammadelta T cells containing the Vgamma2Vdelta2 (Vgamma9Vdelta2) T cell receptor are stimulated by a broad variety of small, phosphorus-containing antigenic molecules called phosphoantigens. The structures of several species present in both Mycobacteria (TUBags1-4) and in Escherichia coli have been reported to contain a formyl-alkyl diphosphate core. Here we report the synthesis of the lead member of the series, 3-formyl-1-butyl diphosphate. This compound has low activity for gammadelta T cell stimulation, unlike its highly active isomer (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate, necessitating a revision of the structure of TUBag1. Likewise, the structure of the species identified as the pentyl analog (TUBag 2) is revised to 6-phosphogluconate. These results indicate that neither TUBag1 nor the m/e 275 species proposed for TUBag2 are 3-formyl-1-alkyl diphosphates, leading to the conclusion that none of the natural phosphoantigens (TUBags1-4) possess the structures reported previously.

Antigens, Bacterial↗
PubMed2006

[Analysis of volatile constituents in leaves of three cypress species by gas chromatography/mass spectrometry].

Volatile oils in leaves of three cypress species were extracted by hydrodistillation method and analyzed by gas chromatography/mass spectrometry. Sixty-four constituents were separated and identified. The majority of the components were found to be monoterpenes and sesquiterpenes. There were 33, 37, 37 compounds in the oils of leaves of Sabina chinensis (L.) Ant, Cupressus lusitanica 'zhongshan' Mill and Sabina chinensis (L.) Ant. Cv. Kaizuca, respectively. Fourteen compounds were common to them, which were thujene, alpha-pinene, camphene, sabinene, beta-myrcene, alpha-terpinene, gamma-terpinene, alpha-terpinolene, bornyl acetate, beta-elemene, alpha-amorphene, germacrene D, delta-cadinene and elemol. In addition, each species had particular compounds. The main components were found to be: sabinene (20.99%), limonene (19.78%) and bornyl acetate (11.68%) for Sabina chinensis (L.) Ant; alpha-pinene (10.39%), sabinene (11.19%) and delta-3-carene (8.88%) for Cupressus lusitanica 'zhongshan' Mill; limonene (24.56%), beta-myrcene (8.04%) for Sabina chinensis (L.) Ant. Cv. Kaizuca.

Acyclic Monoterpenes↗
PubMed2006

[Electroantennogram and behavioral responses of Monochamus alternatus to the volatiles from Pinus thunbergii with different physiological status].

The volatiles from healthy and pinewood nematode-infested branches of Pinus thunbergii were collected by distillation, and analyzed by using HPLC and GC-MS. Electroantennogram (EAG) and behavioral responses of Monochamus alternatus with different physiological status to the volatiles were investigated respectively. The results showed that unmated beetle had a greater EAG response potential to the volatiles from healthy branch than to those from infested branch, while it was reverse for mated beetle. The EAG response of unmated beetle under 15 days-old to the volatiles from healthy branch increased with its age. "Y" tube olfactory test showed unmated beetle had positive response to the volatiles from healthy branch and negative response to those from infested branch, while mated beetle showed positive response to the volatiles from infested branch and negative response to those from healthy branch. Female beetle with its age from 1 day to 15 days-old and male beetle from 1 day to 9 days-old had an increasing positive response to the volatiles from healthy branch, but the male after 9 days-old showed a negative response. It could be concluded that M. alternatus with different physiological status all had special sensitivity and selectivity to host tree.

Animals↗
PubMed2005

Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption.

We report the design, synthesis and testing of a series of novel bisphosphonates, pyridinium-1-yl-hydroxy-bisphosphonates, based on the results of comparative molecular similarity indices analysis and pharmacophore modeling studies of farnesyl diphosphate synthase (FPPS) inhibition, human Vgamma2Vdelta2 T cell activation and bone resorption inhibition. The most potent molecules have high activity against an expressed FPPS from Leishmania major, in Dictyostelium discoideum growth inhibition, in gammadelta T cell activation and in an in vitro bone resorption assay. As such, they represent useful new leads for the discovery of new bone resorption, antiinfective and anticancer drugs.

Alkyl and Aryl Transferases↗
PubMed2005

A crystallographic investigation of phosphoantigen binding to isopentenyl pyrophosphate/dimethylallyl pyrophosphate isomerase.

We report the crystallographic structures of the potent phosphoantigens Phosphostim (the bromohydrin of isopentenyl pyrophosphate) and E-4-hydroxy-3-methyl-but-2-enyl pyrophosphate bound to the mevalonate pathway enzyme isopentenyl pyrophosphate/dimethylallyl pyrophosphate isomerase (IPPI). Racemic Phosphostim forms covalent complexes with IPPI: a 4-thioether with C67 and a 4-ester with E116. Only the E116 ester forms with the chiral species, S-Phosphostim, with the w.t. enzyme, while the C67 thioether forms with a mutant Y104F IPPI. The potent phosphoantigen HMBPP also binds to IPPI, but is only a weak ( approximately 50 muM) inhibitor. These results strongly support an SN2 reaction for inhibition of IPPI by Phosphostim, in contrast to the SN1 or concerted type of reaction found with epoxide inhibitors, which react at C-3, and are of general interest in the context of the development of novel mevalonate pathway inhibitors. They also provide clues as to the nature of the binding site of synthetic phosphoantigens in gammadelta T cell activation. In particular, both bromohydrin and epoxy phosphoantigens are potent, irreversible inhibitors of IPPI while HMBPP is only a weak inhibitor, ruling out an IPPI or IPPI-like target for HMBPP in gammadelta T cell activation.

Antigens↗
PubMed2004

Synthesis of chiral phosphoantigens and their activity in gamma delta T cell stimulation.

Gammadelta T cells expressing Vgamma2Vdelta2 T cell receptors are activated by a broad range of phosphorus-containing small molecules, termed phosphoantigens, and are of interest in the context of the chemotherapy of B cell malignancies. Here, we report the synthesis of four pairs of chiral phosphoantigens: the bromohydrins of isopentenyl diphosphate (Phosphostim), the epoxides of isopentenyl diphosphate (EIPP); and the corresponding bromohydrin and epoxide analogs of but-3-enyl diphosphate. The ability of each compound to stimulate human Vgamma2Vdelta2 T cells was determined by TNF-alpha release and cell proliferation. In these assays, the (R)-bromohydrin diphosphates were, on average, about twice as active as the (S)-bromohydrin diphosphates. In contrast, the (S)-form of EIPP was about twice as active as (R)-EIPP. The activities of the epoxy but-3-enyl diphosphates were both very low. These results suggest that chiral phosphoantigens, as opposed to racemic mixtures, may have utility in immunotherapy.

Alcohols↗
PubMed2004

Stereospecific living Ziegler-Natta polymerization via rapid and reversible chloride degenerative transfer between active and dormant sites.

The successful realization of a stereospecific chloride degenerative transfer living Ziegler-Natta polymerization process that provides isotactic polyolefins of narrow polydispersity (Mw/Mn </= 1.05) is documented. Variable-temperature NMR studies confirm the configurational stability of all species with respect to metal-centered epimerization and large magnitudes for both kbeta and k-beta. Additional kinetic analyses with an increasing concentration of the dormant state establish that kbeta is larger than k-beta. Finally, [Et3Si][B(C6F5)4] has been shown to be an effective substoichiometric halide abstractor for chloride degenerative transfer Ziegler-Natta polymerization.

Journal Article↗
PubMed2003

Enzymatic synthesis of phosphocarnitine, phosphogabob and fosfomycin.

Phosphocarnitine was conveniently obtained from easily available diethyl 3-chloro-2-oxopropanephosphonates, followed by subsequent reduction, Mucor miehei lipase (IM) mediated resolution, amination and dealkylation. Candida antarctica lipase B (CALB) served as an effective biocatalyst in the resolution of several 1- or 2-hydroxyalkanephosphonates. The chlorine atom in different positions on the molecules greatly affected their enantioselectivity. CALB also showed satisfactory enantioselectivity toward those molecules bearing an azido moiety. Both enantiomers of phosphogabob and fosfomycin were also prepared via CALB-mediated resolution as the key step.

Alkanes↗
PubMed2003

Degenerative transfer living Ziegler-Natta polymerization: application to the synthesis of monomodal stereoblock polyolefins of narrow polydispersity and tunable block length.

The neutral dimethyl pentamethylcyclopentadienylzirconium acetamidinate, (eta(5)-C(5)Me(5))ZrMe(2)[N(t-Bu)C(Me)N(Et)], can serve as a highly active initiator for the living Ziegler-Natta polymerization of alpha-olefins to produce polyolefins of narrow polydispersity (D < or = 1.05) when "activated" through mono demethylation by a substoichiometric amount of the borate, [PhNMe(2)H][B(C(6)F(5))(4)]. The mechanism by which this living polymerization proceeds is through a process of degenerative transfer involving rapid and reversible methyl group exchange between cationic (active) zirconium propagating centers and neutral (dormant) methyl, polymeryl zirconium end groups. Facile metal-centered epimerization of the dormant species is responsible for a loss of stereocontrol during propagation that produces iso-rich material in contrast to the pure isotactic polymer microstructure obtained when degenerative transfer is not present. By turning degenerative transfer "on" and "off" between successive monomer polymerizations, a successful strategy for the production of monomodal stereoblock polyolefins of narrow polydispersity and tunable block length has been demonstrated.

Journal Article↗