Two azafulgides were synthesized and their crystal structures determined by a single crystal X‐ray diffraction analysis. The substances crystallized in the following symmetries and cell parameters. C23H19NO3(2): triclinic space group P&1bar; with a = 7.243(2). b = 10.981(6) and c = 12.672(8)Å, α = 80.40(5)°, β = 75.58(4)° and γ = 77.32(3)° Z = 2; C19H19NO3(1): orthogonal space group C2v9‐Pmc21 with a = 8.079(8), b = 12.752(9) and c = 15.752(13)Å, Z=4. The calculated densities are 1.26 and 1.27 g/cm3 respectively for 2 and 1. The crystal structures were determined by direct methods. The least‐squares refinement led to R values of 0.044 and 0.058 for 2 and 1 for 2738 and 952 reflections with I > 3σ‐(I) respectively.
Given their easy structural modification and good biocompatibility advantages, near-infrared (NIR) organic dyes with a large molar extinction coefficient, while a superlow fluorescence quantum yield shows considerable potential application in photothermal therapy (PTT). Herein, a new NIR-absorbing asymmetric cyanine dye, namely, RC, is designed and synthesized via the hybrid of rhodamine and hemicyanine derivatives. RC-BSA nanoparticles (NPs) are fabricated by using the bovine serum albumin (BSA) matrix. The NPs exhibit a strong NIR absorption peak at ∼868 nm and 28.7% photothermal conversion efficiency. Based on these features, RC-BSA NPs exhibit excellent performance in ablating tumor under a 915 nm laser radiation through a PTT mechanism. These NPs show no obvious toxicity to the treated mice. Thus, RC-BSA NPs can used as a new NIR laser-triggered PTT agent in cancer treatment.
Oncolytic viruses are an excellent platform for developing effective strategies in cancer immunotherapy. Several challenges remain in the use of viro-immunotherapy for cancer, such as the lack of costimulatory signals and negative regulation of immune checkpoints. In this study, we designed a novel adenovirus expressing a soluble fusion protein, programmed cell death protein 1 (PD-1)/CD137L, which contains the extracellular domains of PD-1 and CD137L at each terminus (Ad5-PC). Ad5-PC preserved the costimulatory activity of CD137L and facilitated the persistence of activated CD8 + T cells. Ad5-PC induced strikingly increased antitumor activity in both ascitic and subcutaneous hepatocellular carcinoma (HCC) tumor models, with 70% and 60% long-term cure rates, respectively. The improved antitumor effect of Ad5-PC was attributed to the sustained high-level lymphocyte activation and interferon (IFN)-g production in the tumor microenvironment, and was essentially dependent on CD8 + T cells rather than natural killer (NK) cells. Moreover, Ad5-huPC-expressing human soluble PD-1/CD137L fusion protein was effective in suppressing tumor growth and improving survival in a humanized mouse model. We confirmed that Ad5-PC induced tumor-specific and systematic protection against tumor rechallenges at both in situ and distant sites. Thus, Ad5-PC harnesses several distinct functions to efficiently overcome several major hurdles of viro-immunotherapy.
Hepatocellular carcinoma (HCC) is one of the primary liver malignancies with a poor prognosis. Glutamic-oxaloacetic transaminase 2 (GOT2) is a highly tissue-specific gene in the liver, but the roles GOT2 plays in the progression of HCC remain unclear. Here, we report that GOT2 is downregulated in HCC tumor tissues and that low expression of GOT2 is associated with advanced progression and poor prognosis. In HCC cells, knockdown of GOT2 promoted proliferation, migration, and invasion. In mouse models of HCC, loss of GOT2 promoted tumor growth as well as hematogenous and intrahepatic metastasis. Mechanistically, silencing of GOT2 enhanced glutaminolysis, nucleotide synthesis, and GSH synthesis by reprogramming glutamine metabolism to support the cellular antioxidant system, which activated the PI3K/AKT/mTOR pathway to contribute to HCC progression. Furthermore, HCC with low expression of GOT2 was highly dependent on glutamine metabolism and sensitive to the glutaminase inhibitor CB-839 in vitro and in vivo. Overall, GOT2 is involved in glutamine metabolic reprogramming to promote HCC progression and may serve as a therapeutic and diagnostic target for HCC.
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