Light-Activated Reactive Oxygen Species-Responsive Nanocarriers for Enhanced Photodynamic Immunotherapy of Cancer.

Exploring polymeric nanoplatforms combined with reactive oxygen species (ROS) responsiveness with mitochondria targeting has emerged as an effective strategy for enhanced photodynamic therapy (PDT). Amphiphilic copolymers were synthesized by reacting acrylamide thioketal (TK) linkers with amino-terminated triphenylphosphonium-polyethylene glycol and dodecylamine for encapsulating chlorin e6 (Ce6) via self-assembly. Then, anionic cladding with tumor targeting deshelled in tumor acidic microenvironments was surface-anchored by electrostatic forces (BioPEGDMA@RM). After sequential targeting to the mitochondria of cancerous cells, BioPEGDMA@RM could be light-activated with Ce6 released upon ROS cleavage of TK linkages. It was found that Ce6-loaded BioPEGDMA@RM exhibited higher cytotoxicity on CT26 cells and performed stronger ability on the production of ROS than that without TK linkers. Moreover, a minimum illumination of 3 and 5 min could be required for achieving the maximum release of Ce6 and high in vitro cytotoxicity for Ce6-loaded BioPEGDMA@RM, respectively. Furthermore, Ce6-loaded BioPEGDMA@RM showed 1.29-fold and 1.21-fold higher tumor inhibition on BALB/c nude mice and Kunming mice and stimulated immunologic reactions with more generation of IFN-γ and TNF-α and activation of CD3+, CD4+, and CD8+ T-lymphocytes and DCs than that of Ce6-loaded nanoparticles without TK bonds. This work provided an academic reference for the development of ROS-responsive drug delivery systems for advanced PDT efficiency.

Sphingosine Kinase 1 and Sphingosine-1-Phosphate Signaling in Colorectal Cancer.

Sphingosine kinase 1 (Sphk1) is a highly conserved lipid kinase that phosphorylates sphingosine to form sphingosine-1-phosphate (S1P). Growing studies have demonstrated that Sphk1 is overexpressed in various types of solid cancers and can be induced by growth factors, cytokines, and carcinogens, leading to the increase of S1P production. Subsequently, the increased Sphk1/S1P facilitates cancer cell proliferation, mobility, angiogenesis, invasion, and metastasis. Therefore, Sphk1/S1P signaling plays oncogenic roles. This review summarizes the features of Sphk1/S1P signaling and their functions in colorectal cancer cell growth, tumorigenesis, and metastasis, as well as the possible underlying mechanisms.

Role of N in Transition-Metal-Nitrides for Anchoring Platinum-Group Metal Atoms toward Single-Atom Catalysis.

Single-atom catalysts (SACs) with a maximum atom utilization efficiency have received growing attention in heterogeneous catalysis. The supporting substrate that provides atomic-dispersed anchoring sites and the local electronic environment in these catalysts is crucial to their activity and stability. Here, inspired by N-doped graphene substrate, the role of N is explored in transition metal nitrides for anchoring single metal atoms toward single-atom catalysis. A pore-rich metallic vanadium nitride (VN) nanosheet is fabricated as one supporting-substrate example, whose surface features abundant unsaturated N sites with lower binding energy than that of widely used N-doped graphene. Impressively, it is found that this support can anchor nearly all platinum-group single atoms (e.g., platinum, palladium, iridium, and ruthenium), and even be extendable to multiple SACs, i.e., binary (Pt/Pd) and ternary (Pt/Pd/Ir). As a proof-of-concept application for hydrogen production, Pt-based SAC (Pt1 -VN) performs excellently, exhibiting a mass activity up to 22.55 A mg-1 Pt at 0.05 V and a high turnover frequency value close to 0.350 H2 s-1 , superior to commercial platinum/carbon catalyst. The catalyst's durability can be further improved by using binary (Pt1 Pd1 -VN) SAC. This work provides inexpensive and durable nitride-based support, giving a possible pathway for universally constructing platinum-group SACs.

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Clarifying the pattern of nitrogen absorption and utilization of rice under the treatments of Astragalus sinicus combined with chemical fertilizer application and the pattern of absorption, utilization, distribution and residue of A. sinicus nitrogen in rice-soil system could provide basis to rational fertilization for rice planting area in southern Henan. In this study, undisturbed soil column simulation and isotope tracer technology of 15N were used to examine the differences of nitrogen uptake and utilization of rice, nitrogen nutrient balance of rice-soil system and nitrogen uptake, utilization, distribution and residue of A. sinicus nitrogen after mineralization and decomposition among seven treatments. The treatments involved 1) no fertilization (CK); 2) chemical fertilizer+22500 kg·hm-2 A. sinicus (FM1); 3) chemical fertilizer+30000 kg·hm-2 A. sinicus (FM2); 4) chemical fertilizer+37500 kg·hm-2 A. sinicus (FM3); 5) chemical fertilizer+22500 kg·hm-2 A. sinicus +lime (FM1+CaO); 6) chemical fertilizer+30000 kg·hm-2 A. sinicus lime (FM2+CaO); 7) chemical fertilizer+37500 kg·hm-2 A. sinicus +lime (FM3+CaO). Results showed that compared with CK, fertilization significantly increased nitrogen uptake of grain and rice stalks, apparent nitrogen loss, and nitrogen surplus. The grain nitrogen uptake, rice straw nitrogen uptake and nitrogen use efficiency of rice increased firstly and then decreased with the increasing A. sinicus application rates, while the apparent nitrogen loss and nitrogen surplus showed the opposite trend. The best performance was presented under the treatment of chemical fertilizer combined with 30000 kg·hm-2 of A. sinicus. Lime addition could increase grain nitrogen uptake, rice straw nitrogen uptake, and nitrogen use efficiency of rice, while reducing apparent nitrogen loss and nitrogen surplus, with the best performance of FM2+CaO. For all the treatments, the proportion of nitrogen absorbed by rice from A. sinicus was 6.3%-13.2%, while that from soil and chemical fertilizer was 86.8%-93.7%. The utilization ratio of A. sinicus nitrogen by rice was 23.8%-33.6%. The utilization ratio of A. sinicus nitrogen in different parts of rice was grain > stem and leaf > root. The residue rate of A. sinicus nitrogen in soil was 37.6%-62.4%. The loss rate of A. sinicus nitrogen was 7.8%-38.6%. Comprehensively considering nitrogen absorption and utilization of rice, nitrogen nutrient balance of rice-soil system, and the distribution situation of nitrogen from A. sinicus in rice, FM2+CaO was the optimum fertilization pattern in the study area.

Engineered Cell-Assisted Photoactive Nanoparticle Delivery for Image-Guided Synergistic Photodynamic/Photothermal Therapy of Cancer.

Photoactivated therapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is a spatiotemporally precise, controllable, and noninvasive method for tumor therapy and has therefore attracted increasing attention in recent years. However, it is still a challenge to obtain highly efficient therapeutic photoactive agents (PAAs) and deliver them into tumor, especially the core of solid tumors. Here, we have developed a newly engineered monocyte (MNC)-based PAA system that realizes precise and highly efficient tumor diagnosis and therapy. First, a near-infrared emissive PAA molecule with both strong singlet oxygen (1O2) production and high photothermal conversion efficiency was precisely designed for realizing simultaneous PDT and PTT of tumor and was further fabricated to form PAA nanoparticles (NPs). After loading the PAA NPs into MNCs, the MNCs were then decorated with cyclic Arg-Gly-Asp (cRGD) groups through a metabolic labeling method to further improve their ability of targeting and homing into the deep regions of tumors. Using this strategy, we have achieved highly efficient solid tumor ablation results both in vitro and in vivo, indicating that our strategy has a promising prospect for solid tumor therapy.

E6-induced selective translation of WNT4 and JIP2 promotes the progression of cervical cancer via a noncanonical WNT signaling pathway.

mRNA translation reprogramming occurs frequently in many pathologies, including cancer and viral infection. It remains largely unknown whether viral-induced alterations in mRNA translation contribute to carcinogenesis. Most cervical cancer is caused by high-risk human papillomavirus infection, resulting in the malignant transformation of normal epithelial cells mainly via viral E6 and E7 oncoproteins. Here, we utilized polysome profiling and deep RNA sequencing to systematically evaluate E6-regulated mRNA translation in HPV18-infected cervical cancer cells. We found that silencing E6 can cause over a two-fold change in the translation efficiency of ~653 mRNAs, most likely in an eIF4E- and eIF2α-independent manner. In addition, we identified that E6 can selectively upregulate the translation of WNT4, JIP1, and JIP2, resulting in the activation of the noncanonical WNT/PCP/JNK pathway to promote cell proliferation in vitro and tumor growth in vivo. Ectopic expression of WNT4/JIP2 can effectively rescue the decreased cell proliferation caused by E6 silencing, strongly suggesting that the WNT4/JIP2 pathway mediates the role of E6 in promoting cell proliferation. Thus, our results revealed a novel oncogenic mechanism of E6 via regulating the translation of mRNAs.

Novel hybrid molecule overcomes the limited response of solid tumours to HDAC inhibitors via suppressing JAK1-STAT3-BCL2 signalling.

Despite initial progress in preclinical models, most known histone deacetylase inhibitors (HDACis) used as a single agent have failed to show clinical benefits in nearly all types of solid tumours. Hence, the efficacy of HDACis in solid tumours remains uncertain. Herein, we developed a hybrid HDAC inhibitor that sensitized solid tumours to HDAC-targeted treatment. Methods: A hybrid molecule, Roxyl-zhc-84 was designed and synthesized with novel architecture. The pharmacokinetics and toxicity of Roxyl-zhc-84 were analysed. The antitumour effects of Roxyl-zhc-84 on solid tumours were investigated by assessing cell growth, apoptosis and cell cycle in vitro and in three in vivo mouse models and compared to those of corresponding control inhibitors alone or in combination. Gene set enrichment analysis was performed, and relevant JAK1-STAT3-BCL2 signalling was identified in vitro and in vivo in mechanistic studies. Results: Roxyl-zhc-84 showed excellent pharmacokinetics and low toxicity. The novel hybrid inhibitor Roxyl-zhc-84 induced cell apoptosis and G1-phase arrest in breast cancer and ovarian cancer cell lines. In three mouse models, oral administration of Roxyl-zhc-84 led to significant tumour regression without obvious toxicity. Moreover, Roxyl-zhc-84 dramatically improved the limited response of traditional HDAC inhibitors in solid tumours via overcoming JAK1-STAT3-BCL2-mediated drug resistance. Roxyl-zhc-84 treatment exhibited vastly superior efficacy than the combination of HDAC and JAK1 inhibitors both in vitro and in vivo. Conclusion: Concurrent inhibition of HDAC and CDK using Roxyl-zhc-84 with additional JAK1 targeting resolved the limited response of traditional HDAC inhibitors in solid tumours via overcoming JAK1-STAT3-BCL2-mediated drug resistance, providing a rational multi-target treatment to sensitize solid tumours to HDACi therapy.