LPCAT2 inhibits colorectal cancer progression via the PRMT1/SLC7A11 axis.

Colorectal cancer (CRC) has a high degree of heterogeneity and identifying the genetic information of individual tumor cells could help enhance our understanding of tumor biology and uncover potential therapeutic targets for CRC. In this study, we identified LPCAT2+ tumor cell populations with less malignancy than LPCAT2- tumor cells in human and mouse CRC tissues using scRNA-seq. Combining in vitro and in vivo experiments, we found that LPCAT2 could inhibit the proliferation of CRC cells by inducing ferroptosis. Mechanistically, LPCAT2 arrested PRMT1 in cytoplasm of CRC cells via regulating acetylation of PRMT1 at the K145 site. In turn, PRMT1 enhanced SLC7A11 promoter activity. Thus, LPCAT2 attenuated the positive regulatory effect of PRMT1 on SLC7A11 promoter. Notably, SLC7A11 acts as a ferroptosis regulator. Furthermore, in LPCAT2 knockout mice (LPCAT2-/-) colon cancer model, we found that LPCAT2-/- mice exhibited more severe lesions, while PRMT1 or SLC7A11 inhibitors delayed the progression. Altogether, we elucidated that LPCAT2 suppresses SLC7A11 expression by inhibiting PRMT1 nuclear translocation, thereby inducing ferroptosis in CRC cells. Moreover, inhibitors of the PRMT1/SLC7A11 axis could delay tumor progression in CRC with low LPCAT2 expression, making it a potentially effective treatment for CRC.

Leucine Aminopeptidase-Mediated Multifunctional Molecular Imaging Tool for Diagnosis, Drug Evaluation, and Surgical Guidance of Liver-Related Diseases.

Traditional molecular imaging tools used for detecting liver diseases own several drawbacks, such as poor optical performance and limited applicability. Monitoring the concentration of leucine aminopeptidase (LAP), which is closely related to liver diseases such as liver cancer and liver injury, and analyzing it in diagnosis, drug evaluation, and surgical treatment is still a challenging task. Herein, we construct an intramolecular charge-transfer mechanism-based, ultrasensitive, near-infrared fluorescent probe (LAN-lap) for dynamic monitoring of LAP fluctuations in living systems. LAN-lap, with high specificity, stability, sensitivity, and water solubility, can achieve in vitro monitoring of LAP through both fluorescence and colorimetric methods. Moreover, LAN-lap can successfully be used for the localization imaging of endogenous LAP, confirming the upregulation of LAP expression in liver cancer and liver injury cells. In addition, LAN-lap can realize the imaging of liver tumors in living organisms. Meanwhile, it can intuitively present the degree of drug-induced liver injury, achieving semi-quantitative imaging evaluation of the hepatotoxicity of two drugs. Furthermore, LAN-lap can track liver cancer tumors in mice with peritoneal metastasis and can assist in fluorescence-guided surgical resection of liver cancer tumors. This multifunctional LAN-lap probe could play an important role in facilitating simultaneous diagnoses, imaging, and synergistic surgical navigation to achieve better point-of-care therapeutic efficacy.

Temporal analysis of microRNAs associated with wing development in the English grain aphid, Sitobion avenae (F.) (Homoptera: Aphidiae).

Molecular mechanisms underlying wing evolution and development have been a point of scientific inquiry for decades. Phloem-feeding aphids are one of the most devastating global insect pests, where dispersal of winged morphs lead to annual movements, migrations, and range expansions. Aphids show a polyphenic wing dimorphism trait, and offer a model to study the role of environment in determining morphological plasticity of a single genotype. Despite recent progresses in the genetic understanding of wing polyphenism, the influence of environmental cues remains unclear. To investigate the involvement of miRNAs in wing development, we sequenced small RNA libraries of the English grain aphid, Sitobion avenae (F.) across six different developmental stages. As a result, we identified 113 conserved and 193 S. avenae-specific miRNAs. Gene Ontology and KEGG pathway analyses of putative target mRNAs for the six differentially expressed miRNAs are enriched for wing development processes. Dietary uptake of miR-263a, miR-316, and miR-184a agomirs and antagomirs led to significantly higher mortality (>70%) and a lower proportion of winged morphs (<5%). On the other hand, wing malformation was observed in miR-2 and miR-306 agomirs and miR-2 and miR-14 antagomirs, respectively, suggesting their involvement in S. avenae wing morphogenesis. These combined results not only shed light on the regulatory role of miRNAs in wing dimorphism, but also provide potential novel targets for the long-term sustainable management of S. avenae, a devastating global grain pest.

In situ oxygenating and 808 nm light-sensitized nanocomposite for multimodal imaging and mitochondria-assisted cancer therapy.

The efficiency of photodynamic therapy (PDT) is severely constrained due to the innate hypoxic environment, besides the elevated level of glutathione (GSH). To get rid of the hypoxic environment and higher concentrations of GSH in the solid tumors, we propose an approach of oxygen self-sufficient multimodal imaging-guided nanocomposite CaO2-MnO2-UCNPs-Ce6/DOX (abbreviated as CaMn-NUC), in which CaO2 nanoparticles in the hydrophobic layer were seated on the hydrophilic MnO2 sheet and conjugated with chlorin e6 (Ce6) loaded upconversion nanoparticles (UCNPs-Ce6) via the click chemistry approach. CaMn-NUC was presented to overcome hypoxia and GSH-associated photodynamic resistance due to in situ oxygen generation and GSH reduction of MnO2 upon endocytosis, and a bulk amount of Mn2+ ions generated in the process under acidic tumor environment acts as the MRI contrast agent. Moreover, the MnO2 sheet protects Ce6 from self-degradation under irradiation; thus, it can be used to switch control of cellular imaging. Afterwards, in a regulated and targeted manner, the chemotherapeutic drug (doxorubicin hydrochloride, DOX) can be released with the degradation of CaMn-NUC in the acidic tumor microenvironment (TME). Thus, we testify a competent nanoplatform employing 808 nm-excited UCNPs-Ce6 for concurrent imaging and PDT in consideration of the large anti-Stokes shifts, deep penetration into biological tissues, narrow emission bands, and high spatial-temporal resolution of the UCNPs. Thus, our proposed nanoplatform postulates a strategy to efficiently kill cancer cells in a concentration- and time-dependent manner via the in situ oxygenation of solid tumor hypoxia to enhance the efficiency of multimodal imaging-guided chemo-photodynamic therapy.

An all-in-one theranostic nanoplatform based on upconversion dendritic mesoporous silica nanocomposites for synergistic chemodynamic/photodynamic/gas therapy.

Gasotransmitters with high therapeutic efficacy and biosafety have been drawing the attention of researchers. Nevertheless, how to effectively deliver gases to and precisely control their generation at the lesion as well as integrate them with other therapies to realize precision therapy have remained elusive. Herein, we report a versatile Cu2+-initiated nitric oxide (NO) nanocomposite for multimodal imaging-guided synergistic chemodynamic/photodynamic/gas therapy. After the nanomedicine was ingested by tumor cells, the acidic tumor microenvironment accelerated the decomposition of CuO2 and simultaneously triggered the Fenton-like catalytic reaction of Cu2+ and H2O2 to produce highly toxic ˙OH. By virtue of the NO generation and glutathione depletion, UMNOCC-PEG can relieve the antioxidant capacity and hypoxia of the tumor to improve the efficiency of chemodynamic therapy (CDT) and photodynamic therapy (PDT). Importantly, NO and reactive oxygen species (ROS) can generate reactive nitrogen species (RNS), which can result in DNA damage, further improving the therapeutic effect (cell apoptosis rate up to 93.4%). Moreover, the inherent properties of lanthanide ions endow UMNOCC-PEG with upconversion luminescence (UCL), CT and MRI trimodal imaging capability, achieving precise cancer treatment. By taking advantage of these features, the strategy developed here may provide a promising application foreground to conquer malignant tumors.

Intelligent Fe-Mn Layered Double Hydroxides Nanosheets Anchored with Upconversion Nanoparticles for Oxygen-Elevated Synergetic Therapy and Bioimaging.

Multimodal synergistic therapy based on photodynamic therapy (PDT), photothermal therapy (PTT), and chemodynamic therapy (CDT) has attracted increasing attention in cancer therapy. However, the scant therapeutic efficiency is always a barrier for further application. Herein, a smart tumor microenvironment (TME) responsive nanocatalysts are developed by adopting Fe-Mn layered double hydroxides (FeMn-LDH) as an effective photothermal nanocarrier to load mesoporous silica and chlorin e6 (Ce6)-covalently coated upconversion nanoparticles (UCSP) for multimodal imaging for directed therapy. Under acidic TME, FeMn-LDH degrades into Fe3+ and Mn2+ ions to initiate a Fenton-like reaction inducing CDT and enhancing magnetic resonance imaging. Additionally, Fe3+ can decompose H2 O2 to oxygen (O2 ), enhancing PDT guided by UCSP. As a representative noninvasive imaging probe, the upconversion luminescence will recover after decomposition of FeMn-LDH, and provide high-resolution upconversion luminescent imaging guidance for pinpointed PDT. Moreover, the photothermal properties of FeMn-LDH can further enhance CDT effects. The synergistic therapy and multifunctional imaging can realize the integration of diagnosis and treatment.

A porous material excited by near-infrared light for photo/chemodynamic and photothermal dual-mode combination therapy.

Photodynamic therapy (PDT) and photothermal therapy (PTT) are well-developed light therapy methods for cancer; however, both have a few areas that need improvement. A sustained PDT effect depends on the sustained generation of reactive oxygen species (ROS); therefore, adjusting the type of photosensitizer or the reaction mechanism to prolong the duration of the oxidation-reduction reaction is a possible solution for the continuation of the PDT effect. Further, if PTT could be combined with other treatments, it would bring about a more satisfactory therapeutic effect. To increase the treatment effect of the above two therapeutic methods, a collaborative treatment model of photo/chemodynamic therapy (PCDT) and PTT is needed and is the focus of this study. On the one hand, PCDT is a therapy that integrates PDT with Fenton-like reactions, and Fenton-like reactions can help PDT to produce more ROS by making better use of H2O2 in the tumor microenvironment. On the other hand, the PTT effect can also promote PCDT effects to some extent because rising temperature can elevate the redox reaction rate. Therefore, a copper oxide semiconductor photosensitizer was selected in this research to realize the abovementioned therapeutic purposes and experimental concepts. A porous silica carrier can facilitate the uniform attachment of the copper oxide photosensitizer to the SiO2 surface to form a relatively uniform nanostructure, and the nanoporous structure can increase the performance of the whole material to a certain extent. Based on these perspectives, SiO2@CuO nanotube (NT), an agent of both Fenton-like photosensitization and photothermal reagent, is synthesized by the hydrothermal co-precipitation template approach to shrink the tumor through the combined effect of PCDT and PTT. In this system, copper ions can participate in the Fenton-like reactions and make better use of H2O2 to generate more ROS. Herein, 808 nm light was chosen for irradiation because of its suitable excitation ability, applicable penetration and low intrinsic damage. The experimental results show that SiO2@CuO NT is a promising agent that combines PCDT and PTT for cancer treatment. This work provides guidance for the synthesis of Fenton-like photosensitizers for the PCDT effect.

X-ray-triggered NO-released Bi-SNO nanoparticles: all-in-one nano-radiosensitizer with photothermal/gas therapy for enhanced radiotherapy.

Hypoxia in tumor cells is regarded as the most crucial cause of clinical drug resistance and radio-resistance; thus, relieving hypoxia of tumor cells is the key to enhancing the efficacy of anticancer therapy. As a gas signal molecule of vasodilatation factors, nitric oxide (NO) can relieve the hypoxia status of tumor cells, thereby, enhancing the sensitivity of tumor cells to radiotherapy. However, considering complications of vascular activity, the level of NO required for radiotherapy sensitization cannot be obtained in vivo. In view of this, we design and fabricate a multifunctional bismuth-based nanotheranostic agent, which is functionalized with S-nitrosothiol and termed Bi-SNO NPs. X-rays break down the S-N bond and simultaneously trigger large amount of NO-releasing (over 60 µM). Moreover, the as-prepared Bi-SNO NPs not only possess the capability of absorbing and converting 808 nm NIR photons into heat for photothermal therapy, but also have the ability to increase X-ray absorption and CT imaging sensitivity. In addition, the collaborative radio-, photothermal-, and gas-therapy of Bi-SNO in vivo was further investigated and remarkable synergistic tumor inhibition was realized. Finally, no obvious toxicity of Bi-SNO NPs was observed in the treated mice within 14 days. Therefore, the Bi-SNO developed in this work is an effective nano-agent for cancer theranostics with well-controlled morphology and uniform size (36 nm), which could serve as a versatile CT imaging-guided combined radio-, photothermal- and gas-therapy nanocomposite with negligible side effects.

SiO2@Cu7S4 nanotubes for photo/chemodynamic and photo-thermal dual-mode synergistic therapy under 808 nm laser irradiation.

Photodynamic therapy (PDT) is a light-based modality for tumor treatment that involves the generation of reactive oxygen species (ROS) by the combination of light, a photosensitizer, and molecular oxygen. Nevertheless, the therapeutic effects of PDT are limited by hypoxic conditions that worsen with oxygen consumption during the PDT process. Photo/chemodynamic therapy (PCDT) based on the Fenton reaction is one strategy to improve ROS generation, provided a highly effective Fenton reagent is developed. In this research, SiO2@Cu7S4 nanotubes (NTs) were synthesized as a PCDT agent. This double-valence metal-sulfide composite material can react with H2O2 at the tumor site. SiO2@Cu7S4 NTs can produce more ROS than the traditional PDT agents, and besides, they can also be used as a photothermal therapy (PTT) agent. SiO2@Cu7S4 NTs will trigger the PTT effect under 808 nm irradiation and generate a large amount of heat to eradicate cancer cells. This heat will also promote the PCDT effect by increasing the reaction rate. Thus, the SiO2@Cu7S4 NT is a suitable material for PCDT and PTT synergistic oncotherapy. The 808 nm laser is selected as the appropriate excitation source, providing adequate penetration and minimal harm to normal cells. The experimental data presented herein demonstrate the promising photosensitive, Fenton-like, and photothermal performance of SiO2@Cu7S4 NTs. Furthermore, the findings could promote the development of PCDT and PTT synergistic therapy. Thus, this research provides a feasible method to design a single, multifunctional material for cancer treatment.

An 808 nm Light-Sensitized Upconversion Nanoplatform for Multimodal Imaging and Efficient Cancer Therapy.

Photodynamic therapy (PDT) is commonly employed in clinics to treat the cancer, but because of the hypoxic tumor microenvironment prevalent inside tumors, PDT therapeutic efficiency is not adequate hence limiting the effectiveness of PDT. Therefore, we designed a nanocomposite consisting of reduced nanographene oxide (rGO) modified with polyethylene glycol (PEG), manganese dioxide (MnO2), upconversion nanoparticles (UCNPs), and Chlorin e6 (Ce6) to spark oxygen production from H2O2 with the aim of relieving the tumor hypoxic microenvironments. For in vivo tumor PDT and photothermal therapy (PTT), UCNPs-Ce6-labeled rGO-MnO2-PEG nanocomposites were used as a therapeutic agent, augmenting the therapeutic efficiency of PDT via redox progression through the catalytic H2O2 decomposition pathway and further achieving excellent tumor inhibition. It is important to mention that degradation of MnO2 in an acidic cellular microenvironment leads to the creation of a massive volume of Mn2+ which was employed as a contrast mediator for magnetic resonance imaging (MRI). Our research postulates an approach to spark O2 formation through an internal stimulus to augment the efficiency of MRI- and computerized tomography (CT)-imaging-guided PDT and PTT.

One-step fabrication of boronic-acid-functionalized carbon dots for the detection of sialic acid.

Typically, sialic acids (SA) with a nine-carbon backbone are found at the glycan chain termini on the cell membranes, which play crucial roles in various physiological and pathological processes. The expression level of SA in the blood serum has been reported to correlate with various disease states among cancer. In this study, a novel approach for preparing fluorescent boronic-acid-modified carbon dots (C-dots) for the detection of SA was developed. The functionalized C-dots were synthesized by a facile, one-step hydrothermal method using 3-pyridineboronic acid as the sole carbon source. The added SA selectively recognized the C-dots, leading to the fluorescence quenching of the C-dots in a linear range of 80-4000 µM with a detection limit of 54 µM. The as-developed boronic-acid nanoprobe was successfully applied for the detection of SA in human serum samples with satisfactory results. In addition, this method afforded results within 4 min. Compared to other methods, this new proposed approach was simpler and exhibited excellent sensitivity and selectivity, demonstrating immense potential as an alternative for SA detection.

Rapid aqueous synthesis of CuInS/ZnS quantum dots as sensor probe for alkaline phosphatase detection and targeted imaging in cancer cells.

Early diagnosis of chronic, critical diseases improves clinical outcomes, and biomarkers play an important role as an indicator of severity or presence of a disease. Alkaline phosphatase (ALP) is one such vital biomarker in the diagnosis of several diseases. Herein we introduce a facile, sensitive fluorescent assay, based on the inner filter effect (IFE), for ALP activity determination in serum and in living cells. It is well known that the key to maximize the sensitivity of an IFE-based fluorescence assays is to broaden the overlap between the absorption of an absorber and the excitation/emission of a fluorophore. We employed CuInS/ZnS quantum dots (CIS/ZnS QDs) and p-nitrophenylphosphate (PNPP) as the fluorescent indicator and the substrate, respectively, for ALP activity assessment. Due to the CIS/ZnS QDs have an efficient excitation at 405 nm, meanwhile with a large Stokes shift emission at 588 nm, p-nitrophenol (PNP) with absorption peak at 405 nm, the hydrolyzed produce of PNPP and ALP, can act as a competitive absorber to absorb the excitation light of CIS/ZnS QDs, resulting in noticeable quenching of CIS/ZnS QDs. The proposed sensor detects ALP activity in human serum samples (sample consumption: 20 µL) with detection limit of 0.01 U L-1. Excellent biocompatibility of CIS/ZnS QDs enables the sensor to monitor endogenous ALP in living cells. Furthermore, because the surface modification or the linking between the receptor and the fluorophore is no longer required, this fluorescent sensing system has the potential to simplify ALP clinical measurement, thereby improving diagnostics of relevant diseases.

Comparative profiling of microRNAs in the winged and wingless English grain aphid, Sitobion avenae (F.) (Homoptera: Aphididae).

MicroRNAs (miRNAs) are short single-stranded non-coding RNAs that regulate gene expression, particularly during development. In this study, 345 miRNAs were identified from the English green aphid, Sitobion avenae (F.), of which 168 were conserved and 177 were S. avenae-specific. Quantitative comparison of miRNA expression levels indicated that 16 and 12 miRNAs were significantly up-regulated in winged and wingless S. avenae small RNA libraries, respectively. Differential expression of these miRNAs was confirmed by real-time quantitative RT-PCR validation. The putative transcript targets for these candidate miRNAs were predicted based on sequences from a model species Drosophila melanogaster and four aphid species Acyrthosiphon pisum, Myzus persicae, Toxoptera citricida, and Aphis gosspii. Gene Ontology and KEGG pathway analyses shed light on the potential functions of these miRNAs in the regulation of genes involved in the metabolism, development and wing polyphenism of S. avenae.