RUNX3 Mediates Suppression of Tumor Growth and Metastasis of Human CCRCC by Regulating Cyclin Related Proteins and TIMP-1

Here we presented that the expression of RUNX3 was significantly decreased in 75 cases of clear cell renal cell carcinoma (CCRCC) tissues (p<0.05). Enforced RUNX3 expression mediated 786-O cells to exhibit inhibition of growth, G1 cell-cycle arrest and metastasis in vitro, and to lost tumorigenicity in nude mouse model in vivo. RUNX3-induced growth suppression was found partially to regulate various proteins, including inhibition of cyclinD1, cyclinE, cdk2, cdk4 and p-Rb, but increase of p27Kip1, Rb and TIMP-1. Therefore, RUNX3 had the function of inhibiting the proliferative and metastatic abilities of CCRCC cells by regulating cyclins and TIMP1

Copper phosphide decorated g-C₃N₄ catalysts for highly efficient photocatalytic H₂ evolution

Designing functional heterojunctions to enhance photocatalytic hydrogen evolution is still a key challenge in the field of efficient solar energy utilization. Copper phosphides become an ideal material to serve as the cocatalysts during photocatalytic hydrogen evolution by virtue of the lower prices. In this study, we synthesized graphitic carbon nitride (g-C3N4) based catalysts loaded with copper phosphide (Cu3P, Cu97P3), which exhibit superior performance in photocatalytic H2 evolution. Ultraviolet (UV)-visible spectroscopy illustrated that the absorption of light strengthened after the loading of copper phosphide, and the time-resolved transient photoluminescence (PL) spectra showed that the separation and transfer of the photoexcited carriers greatly improved. Moreover, both copper phosphide/g-C3N4 photocatalysts exhibited a relatively high H2 evolution rate: Cu3P/g-C3N4 (maximum 343 μmol h-1 g-1), Cu97P3/g-C3N4 (162.9 μmol h-1 g-1) while copper phosphide themself exhibit no photocatalytic activity. Thus, the copper phosphides (Cu3P, Cu97P3) work as a cocatalyst during photocatalytic H2 evolution. The cycling experiments illustrated that both copper phosphide/g-C3N4 photocatalysts perform excellent stability in the photocatalytic H2 evolution. It is worth noting that while the NaH2PO2 was heated in the tube furnace for phosphorization to obtain Cu3P, the excessive PH3 could pass through the solution of CuSO4 to obtain Cu97P3 at the same time, which significantly improved the utilization of PH3 and reduced the risk of toxicity. This work could provide new strategies to design photocatalysts decorated with copper phosphide for highly efficient visible-light-driven hydrogen evolution.This work was financially supported by the National Natural Science Foundation of China (Grant No. 52103339), Natural Science Foundation of Hubei Province (Grant No. 2018CFB282) and Science Foundation of Hubei University of Technology (Grant No. BSQD2017065)

B7H3-targeting chimeric antigen receptor modification enhances antitumor effect of Vγ9Vδ2 T cells in glioblastoma

Abstract Background Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. This study investigates the therapeutic potential of human Vγ9Vδ2 T cells in GBM treatment. The sensitivity of different glioma specimens to Vγ9Vδ2 T cell-mediated cytotoxicity is assessed using a patient-derived tumor cell clusters (PTCs) model. Methods The study evaluates the anti-tumor effect of Vγ9Vδ2 T cells in 26 glioma cases through the PTCs model. Protein expression of BTN2A1 and BTN3A1, along with gene expression related to lipid metabolism and glioma inflammatory response pathways, is analyzed in matched tumor tissue samples. Additionally, the study explores two strategies to re-sensitize tumors in the weak anti-tumor effect (WAT) group: utilizing a BTN3A1 agonistic antibody or employing bisphosphonates to inhibit farnesyl diphosphate synthase (FPPS). Furthermore, the study investigates the efficacy of genetically engineered Vγ9Vδ2 T cells expressing Car-B7H3 in targeting diverse GBM specimens. Results The results demonstrate that Vγ9Vδ2 T cells display a stronger anti-tumor effect (SAT) in six glioma cases, while showing a weaker effect (WAT) in twenty cases. The SAT group exhibits elevated protein expression of BTN2A1 and BTN3A1, accompanied by differential gene expression related to lipid metabolism and glioma inflammatory response pathways. Importantly, the study reveals that the WAT group GBM can enhance Vγ9Vδ2 T cell-mediated killing sensitivity by incorporating either a BTN3A1 agonistic antibody or bisphosphonates. Both approaches support TCR-BTN mediated tumor recognition, which is distinct from the conventional MHC-peptide recognition by αβ T cells. Furthermore, the study explores an alternative strategy by genetically engineering Vγ9Vδ2 T cells with Car-B7H3, and both non-engineered and Car-B7H3 Vγ9Vδ2 T cells demonstrate promising efficacy in vivo, underscoring the versatile potential of Vγ9Vδ2 T cells for GBM treatment. Conclusions Vγ9Vδ2 T cells demonstrate a robust anti-tumor effect in some glioma cases, while weaker in others. Elevated BTN2A1 and BTN3A1 expression correlates with improved response. WAT group tumors can be sensitized using a BTN3A1 agonistic antibody or bisphosphonates. Genetically engineered Vγ9Vδ2 T cells, i.e.,  Car-B7H3, show promising efficacy. These results together highlight the versatility of Vγ9Vδ2 T cells for GBM treatment

Identification of the metabolites of T-2 toxin after incubation with recombinant CYP3A29.

<p>(A) Accurate extracted ion chromatograms of the metabolites of T-2 toxin after incubation with CYP3A29. (B) Accurate MS spectrum of 3′-OH-T-2. (C) Accurate MS spectrum of NEO. (D) Structural illustration of the metabolites of T-2 toxin metabolized by CYP3A29.</p

The thermogram of CYP3A29 and its mutants metabolizing T-2 toxin.

<p>The thermogram of CYP3A29 and its mutants metabolizing T-2 toxin.</p

Enzyme kinetic parameters of recombinant CYP3A29 and its mutants oxidizing nifedipine.

<p>Note: The values are expressed as means ± standard deviations of the results of three independent experiments. <i>n</i> indicates the Hill coefficients.</p><p>**(<i>p</i><0.01) and *(<i>p</i><0.05) indicate statistically significant difference between the wild-type and the mutant.</p><p>Enzyme kinetic parameters of recombinant CYP3A29 and its mutants oxidizing nifedipine.</p

HPLC chromatograms of the metabolite of nifedipine (NIF) catalyzed by recombinant CYP3A29.

<p>(A) NIF standard. (B) Oxidized nifedipine (ONIF) standard. (C) NIF incubated with Sf9 microsomes containing the recombinant CYP3A29 at 37°C for 30 min in the presence of NADPH-generating system. (D) NIF incubated with Sf9 microsomes free of the recombinant CYP3A29 at 37°C for 30 min in the presence of NADPH-generating system. (E) NIF incubated with Sf9 microsomes containing the recombinant CYP3A29 at 37°C for 30 min in the absence of NADPH-generating system.</p

The peak area of the mass spectra of 3′-OH-T-2 generated by CYP3A29 metabolizing T-2 toxin.

<p>The data were expressed as means ± standard deviations (error bars) (n = 3). **(<i>p</i><0.01) and *(<i>p</i><0.05) indicate statistically significant difference between the wild-type CYP3A29 and each mutant.</p

The binding pocket of porcine CYP3A29 docked with T-2 toxin.

<p>CYP3A29 interaction residues, Arg105, Arg106, Phe108, Ser119, Lys212, Phe213, Phe215, Arg372 and Glu374, are in distances within 5Å to T-2 toxin molecule. The T-2 toxin is colored in orange. The heme is represented in violet color. The green lines and numbers denote hydrogen bonds and bond lengths.</p