Idiopathic pulmonary fibrosis (IPF) is a chronic fatal disease with limited therapeutic options. The infiltration of monocytes and fibroblasts into the injured lungs is implicated in IPF. Enolase-1 ...(ENO1) is a cytosolic glycolytic enzyme which could translocate onto the cell surface and act as a plasminogen receptor to facilitate cell migration via plasmin activation. Our proprietary ENO1 antibody, HL217, was screened for its specific binding to ENO1 and significant inhibition of cell migration and plasmin activation (patent: US9382331B2).
In this study, effects of HL217 were evaluated in vivo and in vitro for treating lung fibrosis.
Elevated ENO1 expression was found in fibrotic lungs in human and in bleomycin-treated mice. In the mouse model, HL217 reduced bleomycin-induced lung fibrosis, inflammation, body weight loss, lung weight gain, TGF-β upregulation in bronchial alveolar lavage fluid (BALF), and collagen deposition in lung. Moreover, HL217 reduced the migration of peripheral blood mononuclear cells (PBMC) and the recruitment of myeloid cells into the lungs. In vitro, HL217 significantly reduced cell-associated plasmin activation and cytokines secretion from primary human PBMC and endothelial cells. In primary human lung fibroblasts, HL217 also reduced cell migration and collagen secretion.
These findings suggest multi-faceted roles of cell surface ENO1 and a potential therapeutic approach for pulmonary fibrosis.
Prostate cancer is one of the most common causes of cancer death in men worldwide, and the treatment options are limited for patients with advanced stages of prostate cancer. Upon oncogenic or ...inflammatory stimulation, tumor cells or immune cells express cell surface enolase-1 (ENO1) as plasminogen receptor to facilitate their migration via plasmin activation. Little is known about the roles of ENO1 in prostate cancer, especially in the tumor microenvironment (TME). We hypothesized that targeting surface ENO1 with specific mAbs would exert multifactorial therapeutic potentials against prostate cancer. In vivo, we showed ENO1 mAb (HuL227) reduced the growth of subcutaneous PC-3 xenograft, monocytes recruitment, and intratumoral angiogenesis. In a PC-3 intratibial implantation model, HuL227 reduced tumor growth and osteoclast activation in the bone. To investigate the antitumor mechanism of ENO1 mAb, we found that blocking surface ENO1 significantly reduced VEGF-A-induced tube formation of endothelial cells in vitro. Furthermore, HuL227 inhibited inflammation-enhanced osteoclasts activity and the secretion of invasion-related cytokines CCL2 and TGFβ from osteoclasts. In addition, inflammation-induced migration and chemotaxis of androgen-independent prostate cancer cells were dose-dependently inhibited by HuL227. In summary, we showed that, ENO1 mAb targets multiple TME niches involved in prostate cancer progression and bone metastasis via a plasmin-related mechanism, which may provide a novel immunotherapy approach for men with advanced prostate cancer.
The 5th Asia Partnership Conference of Regenerative Medicine (APACRM) was held online on April 7, 2022 to promote regulatory harmonization of regenerative medicine products throughout Asia. The ...recognition of domestic regulatory guidelines within each country and region and the underpinning rationales are important initial steps toward the harmonization of regulations. The 5th APACRM featured open dialog regarding non-clinical, quality and environmental impact assessment settings for cell and gene therapy products through presentations from the industry and panel discussions with regulatory agencies. The latest updates on regenerative medicine fields in each country and region were also introduced. This paper summarizes the proceedings of the 5th APACRM for public dissemination to foster future discussion.
In natural infection, hepatitis B virus (HBV) core protein (HBc) accumulates frequent mutations. The most frequent HBc variant in chronic hepatitis B patients is mutant 97L, changing from an ...isoleucine or phenylalanine to a leucine (L) at HBc amino acid 97. One dogma in the HBV research field is that wild type HBV secretes predominantly virions containing mature double-stranded DNA genomes. Immature genomes, containing single-stranded RNA or DNA, do not get efficiently secreted until reaching genome maturity. Interestingly, HBc variant 97L does not follow this dogma in virion secretion. Instead, it exhibits an immature secretion phenotype, which preferentially secretes virions containing immature genomes. Other aberrant behaviors in virion secretion were also observed in different naturally occurring HBc variants. A hydrophobic pocket around amino acid 97 was identified by bioinformatics, genetic analysis, and cryo-EM. We postulated that this hydrophobic pocket could mediate the transduction of the genome maturation signal for envelopment from the capsid interior to its surface. Virion morphogenesis must involve interactions between HBc, envelope proteins (HBsAg) and host factors, such as components of ESCRT (endosomal sorting complex required for transport). Immature secretion can be offset by compensatory mutations, occurring at other positions in HBc or HBsAg. Recently, we demonstrated in mice that the persistence of intrahepatic HBV DNA is related to virion secretion regulated by HBV genome maturity. HBV virion secretion could be an antiviral drug target.
In this paper, we present a copper(I)-catalyzed nitrile-addition/
-arylation ring-closure cascade for the synthesis of 5,11-dihydro-6
-indolo3,2-
quinolin-6-ones from 2-(2-bromophenyl)-
...-(2-cyanophenyl)acetamides. Using CuBr and
-BuONa in dimethylformamide (DMF) as the optimal reaction conditions, the cascade reaction gave the target products, in high yields, with a good substrate scope. Application of the cascade reaction was demonstrated on the concise total syntheses of alkaloid isocryptolepine. Further optimization of the products from the cascade reaction led to 3-chloro-5,12-bis2-(dimethylamino)ethyl-5,12-dihydro-6
-1,3dioxolo4',5':5,6indolo3,2-
quinolin-6-one (
), which exhibited the characteristic DNA topoisomerase-I inhibitory mechanism of action with potent in vitro anticancer activity. Compound
actively inhibited ARC-111- and SN-38-resistant HCT-116 cells and showed in vivo activity in mice bearing human HCT-116 and SJCRH30 xenografts. The interaction of
with the Top-DNA cleavable complex was revealed by docking simulations to guide the future optimization of 5,11-dihydro-6
-indolo3,2-
quinolin-6-ones as topoisomerase-I inhibitors.
IC
50 14
nM for in vitro EGFR kinase inhibition.
A series of C-6 or C-3′ alkynyl-substituted 4-anilinoquinazoline derivatives was prepared straightforwardly by a Sonogashira reaction of the ...corresponding bromo-substituted 4-anilinoquinazolines. Bioactive assay of these compounds for in vitro EGFR kinase inhibition demonstrated that the novel 6-hydroxypropynyl-4-anilinoquinazoline
5e was a very potent EGFR kinase inhibitor with an IC
50 of 14
nM.
A series of pyrrole−indolin-2-ones were synthesized, and their inhibition profile for Aurora kinases was studied. The potent compound 33 with phenylsulfonamido at the C-5 position and a carboxyethyl ...group at the C-3′ position selectively inhibited Aurora A over Aurora B with IC50 values of 12 and 156 nM, respectively. Replacement of the carboxyl group with an amino group led to compound 47, which retained the activity for Aurora B and lost activity for Aurora A (IC50 = 2.19 μM). Computation modeling was used to address the different inhibition profiles of 33 and 47. Compounds 47 and 36 (the ethyl ester analogue of 33) inhibited the proliferation of HCT-116 and HT-29 cells and suppressed levels of the phosphorylated substrates of Aurora A and Aurora B in the Western blots.
In this study, the correlation or comparability was assessed in the values of virus titers measured by either infectivity assay reported as 50% tissue culture infectious doses (TCID(50)/ml) or by ...immunofluorescence assay reported as 50% fluorescent antibody infectious dose (FAID(50)/ml). The results demonstrate that bovine virus titers measured in infected bovine turbinate cells by these two methods are comparable. Clear demonstration of the comparability of these two methods provides a choice of a method for measuring the titer of bovine viruses.
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