Achyranthes bidentata Polysaccharide Activates Nuclear Factor-Kappa B and Promotes Cytokine Production in J774A.1 Cells Through TLR4/MyD88 Signaling Pathway.

Achyranthes bidentata Blume, a traditional Chinese medicine, is widely acknowledged for its function of invigorating the liver and kidneys and as a stranguria-relieving diuretic and used in the treatment of edema, gonorrhea, and other diseases. Polysaccharide (ABPS), isolated from Achyranthes bidentata Blume, has been demonstrated to have multiple biological activities including immunomodulatory effects. However, the mechanisms underlying the effects of ABPS have not been fully investigated. The present study is conducted to explore the underlying mechanism of immunomodulatory activities of ABPS. Results showed that ABPS significantly increased the secretion of IL-1ß and TNF-α in J744 A.1 cells. Nitric oxide (NO) also significantly increased after ABPS treatment. The special antibodies (Toll-like receptor 4 (TLR4) antibody and CD14/TLR4 antibody) significantly decreased the activation, while the Toll-like receptor 2 (TLR2) antibody could not abolish this activation. Meanwhile, pyrrolidine dithiocarbamate (PDTC), a specific inhibitor of NF-κB, remarkably inhibited the secretion of IL-1ß and TNF-α induced by ABPS in J744 A.1 cells. Western blotting (WB) and confocal laser scanning microscopy (CLSM) showed that ABPS promoted NF-κB translocation into the nucleus. Furthermore, the mRNA and protein expression of TLR4 and MyD88 were significantly increased after ABPS treatment. Taken together, these findings suggested that the immunomodulatory mechanism of ABPS was associated with the secretion of cytokines by stimulating the NF-κB pathway through TLR4/MyD88 signaling.

Lanthanide-Based Nanocomposites for Photothermal Therapy under Near-Infrared Laser: Relationship between Light and Heat, Biostability, and Reaction Temperature.

In this research, typical organic/inorganic photothermal therapy (PTT) agents were designed with a combination of upconversion luminescent (UCL) or near-infrared (NIR) II imaging rare-earth nanomaterials for photo-acoustic (PA)/UCL/NIR II imaging-guided PTT under NIR laser irradiation. The results show the following: (1) The PTT effect mainly comes from NIR absorption and partly from UCL light conversion. (2) Visible UCL emission is mainly quenched by NIR absorption of the coated PTT agent and partly quenched by visible absorption, indicating that excitation may play a more important role than in the UCL emission process. (3) The biostability of the composite might be decided by the synthesis reaction temperature. Among the five inorganic/organic nanocomposites, UCNP@MnO2 is the most suitable candidate for cancer diagnosis and treatment because of its stimuli-response ability to the micro-acid environment of tumor cells and highest biostability. The composites generate heat for PTT after entering the tumor cells, and then, the visible light emission gradually regains as MnO2 is reduced to colorless Mn2+ ions, thereby illuminating the cancer cells after the therapy.

Black Phosphorus Nanosheet with High Thermal Conversion Efficiency for Photodynamic/Photothermal/Immunotherapy.

The synergistic treatment through multiple treatment methods can effectively improve the effect of tumor treatment. Phototherapy and immunotherapy are two innovative and promising cancer diagnosis and treatment methods, so they are good candidates for collaborative diagnosis and treatment. Here we report a new inorganic nanosystem, which uses ultrathin black phosphorus (BP) nanosheets (minimum: 13 nm) as carriers and equips with up-conversion luminescence (UCL) nanoparticles as imaging probes, so that the system can generate photothermal and photodynamic effects to treat tumors together with immunotherapy. Especially, the photothermal conversion efficiency can reach 30.84% under the 980 nm laser, which is significantly higher than the conventional Au nanoparticles including nanostars (22.63%) and Au nanorods (23.33%). When the system works in conjunction with immunotherapy, it not only shows a good ability to treat tumors but also can inhibit tumors for a long time and prevent recurrence. Different from the past, in this work, we not only use this strategy to evaluate the performance during the treatment cycle but also observe the mice after the treatment to verify the long-term effect of suppressing tumors. Overall, this study reveals a new inorganic nanosystem and proposes a new strategy for treating tumors in combination with immunotherapy. The present work illustrates the new opportunities for the treatment of primary tumors.

Discovery of novel glycogen synthase kinase-3α inhibitors: Structure-based virtual screening, preliminary SAR and biological evaluation for treatment of acute myeloid leukemia.

Glycogen synthase kinase 3α (GSK-3α) plays a constitutive role in various physiological processes and has been proved to be a therapeutic target for acute myeloid leukemia (AML). In this paper, by means of computer-aided drug design, we discovered a novel chemical series of GSK-3α inhibitors with an IC50 value of 0.033-2.804 µM. The preliminary structure-activity relationship was concluded and, notably, the most potent and isoform-selective compound G28_14 was identified with IC50 values of 33 nM and 218 nM against GSK-3α and -3ß, respectively, exhibiting a nearly ten-fold isoform-selectivity. Further cell viability assays and colony formation assays revealed that G28_14 suppressed cell survival by impairing cell proliferation by up to 90% in two AML cell lines. Moreover, surface marker expression analysis demonstrated that G28_14 induced terminal differentiation with a high level of CD11b, CD11c, and CD14. Western immunoblotting showed that G28_14 isoform-selectively inhibited the phosphorylation of GSK-3α in-cell without activating Wnt/ß-catenin signaling. In addition, to elucidate its structure-activity relationship, the binding mode of this chemical series was proposed using molecular docking and molecular dynamics simulations. Taken together, this chemical series is worth developing as differentiation therapies for the treatment of AML.

Discovery of new GSK-3ß inhibitors through structure-based virtual screening.

Glycogen synthase kinase-3ß (GSK-3ß) is an attractive therapeutic target for human diseases, such as diabetes, cancer, neurodegenerative diseases, and inflammation. Thus, structure-based virtual screening was performed to identify novel scaffolds of GSK-3ß inhibitors, and we observed that conserved water molecules of GSK-3ß were suitable for virtual screening. We found 14 hits and D1 (IC50 of 0.71 µM) were identified. Furthermore, the neuroprotection activity of D1-D3 was validated on a cellular level. 2D similarity searches were used to find derivatives of high inhibitory compounds and an enriched structure-activity relationship suggested that these skeletons were worthy of study as potent GSK-3ß inhibitors.

Discovery of acylphloroglucinol-based meroterpenoid enantiomers as KSHV inhibitors from Hypericum japonicum.

Kaposi's sarcoma associated herpesvirus (KSHV) has gained considerable attention as a type of carcinogenic pathogen. Recent research suggests that KSHV has participated in the pathogenesis of Kaposi's sarcoma-related malignant neoplastic diseases. Viral lytic infection might be pivotal for the etiopathogenesis of KSHV-induced diseases; however, most clinical KSHV lytic replication inhibitors like ganciclovir, nelfinavir, or cidofovir do not restrain virus replication effectively enough to achieve clinical efficacy. In our continued pharmaceutical studies on Chinese herbal medicines, new acylphloroglucinol-based meroterpenoid enantiomers have been discovered from Hypericum japonicum. Most of these metabolites have potential inhibitory activities that target KSHV lytic replication. Amongst these analogues, compounds 1a and 1b possess an unreported ring system cyclopenta[b]chromene. Compounds 1a with 4a exhibit stronger inhibitory activities towards the lytic replication of KSHV in Vero cells. In addition, 1a and 4a have IC50 values of 8.30 and 4.90 µM and selectivity indexes of 23.49 and 25.70, respectively. Qualitative and quantitative SAR and molecular docking studies for acylphloroglucinol-based meroterpenoids with regard to anti-KSHV activity were conducted. An explanation for the variation in the activity and selectivity indexes was proposed in accordance with the predicted binding pose found with molecular docking to a putative target, thymidylate synthase (kTS). Compounds 1a and 4a have potential for further development and optimization of their anti-KSHV activities which could lead to new candidate drugs.