Repression of the SUMO-conjugating enzyme UBC9 is associated with lowered double minutes and reduced tumor progression.

Double minutes (DMs), extrachromosomal gene fragments found within certain tumors, have been noted to carry onco- and drug resistance genes contributing to tumor pathogenesis and progression. After screening for SUMO-related molecule expression within various tumor sample and cell line databases, we found that SUMO-conjugating enzyme UBC9 has been associated with genome instability and tumor cell DM counts, which was confirmed both in vitro and in vivo. Karyotyping determined DM counts post-UBC9 knockdown or SUMOylation inhibitor 2-D08, while RT-qPCR and Western blot were used to measure DM-carried gene expression in vitro. In vivo, fluorescence in situ hybridization (FISH) identified micronucleus (MN) expulsion. Western blot and immunofluorescence staining were then used to determine DNA damage extent, and a reporter plasmid system was constructed to detect changes in homologous recombination (HR) and non-homologous end joining (NHEJ) pathways. Our research has shown that UBC9 inhibition is able to attenuate DM formation and lower DM-carried gene expression, in turn reducing tumor growth and malignant phenotype, via MN efflux of DMs and lowering NHEJ activity to increase DNA damage. These findings thus reveal a relationship between heightened UBC9 activity, increased DM counts, and tumor progression, providing a potential approach for targeted therapies, via UBC9 inhibition.

Multi-omic analyses of m5C readers reveal their characteristics and immunotherapeutic proficiency.

5-methylcytosine (m5C) is a post-transcriptional RNA modification identified, m5C readers can specifically identify and bind to m5C. ALYREF and YBX1 as members of m5C readers that have garnered increasing attention in cancer research. However, comprehensive analysis of their molecular functions across pancancer are lacking. Using the TCGA and GTEx databases, we investigated the expression levels and prognostic values of ALYREF and YBX1. Additionally, we assessed the tumor microenvironment, immune checkpoint-related genes, immunomodulators, Tumor Immune Dysfunction and Exclusion (TIDE) score and drug resistance of ALYREF and YBX1. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) analyses were performed to investigate the potential functions associated with m5C readers and coexpressed genes. Aberrant expression of ALYREF and YBX1 was observed and positively associated with prognosis in KIRP, LGG and LIHC. Furthermore, the expression levels of ALYREF and YBX1 were significantly correlated with immune infiltration of the tumor microenvironment and immune-related modulators. Last, our analysis revealed significant correlations between ALYREF, YBX1 and eIFs. Our study provides a substantial understanding of m5C readers and the intricate relationship between ALYREF, YBX1, eIFs, and mRNA dynamics. Through multidimensional analysis of immune infiltration and drug sensitivity/resistance in ALYREF and YBX1, we propose a possibility for combined modality therapy utilizing m5C readers.

KIAA1429 mediates epithelial mesenchymal transition in sorafenib-resistant hepatocellular carcinoma through m6A methylation modification.

BACKGROUND: Hepatocellular carcinoma (HCC) is a primary liver cancer with high mortality. The long-term use of sorafenib, a targeted drug for hepatocellular carcinoma, will lead to drug resistance, and patients are prone to cancer metastasis, the molecular mechanism of which is still unclear. METHODS: In our study, we constructed a sorafenib-resistant hepatocellular carcinoma cell line (HepG2/Sora) and validated the resistance in vivo and in vitro. Transwell assays confirmed the invasion and migration abilities of cells. Colorimetric assays confirmed that the level of m6A methylation modification in cells. RT-qPCR and Western blot assays confirmed that the expression levels of KIAA1429 in HepG2/Sora cells and tissues. The EMT related proteins were detected by Western blot assay. RESULTS: Transwell and Western blot assays confirmed that HepG2/Sora cells had higher invasion and migration abilities and showed EMT phenomena. Colorimetric assays confirmed that the level of m6A methylation modification was upregulated in HepG2/Sora cells. Transwell and Western blot assays confirmed that inhibiting m6A methylation in HepG2/Sora cells inhibited their invasion, migration ability and EMT phenomenon. RT-qPCR and Western blot assays confirmed that the expression levels of KIAA1429 in HepG2/Sora cells and tissues was increased. Silencing KIAA1429 in HepG2/Sora cells inhibited their invasion, migration ability and EMT phenomenon. Finally, we found that the medium supernatant of sorafenib-resistant HepG2/Sora cells induced vascular production of EA.hy926 cells, and silencing KIAA1429 inhibited this induction effect. CONCLUSION: We suggest that KIAA1429 promotes sorafenib-resistant hepatocellular carcinoma invasion, migration and EMT by mediating m6A methylation. KIAA1429 with its mediated m6A methylation may be a key factor for sorafenib-resistant patients prone to cancer cell metastasis.

Role of GADD45A in myocardial ischemia/reperfusion through mediation of the JNK/p38 MAPK and STAT3/VEGF pathways.

Rapid recovery of blocked coronary artery blood flow after myocardial infarction (MI) is the key to reducing the size of the infarcted area, improving clinical outcome and decreasing mortality. However, ischemia/reperfusion (I/R) injury has a complicated pathological mechanism and is an inevitable complication of coronary artery blood flow recovery. Growth arrest and DNA damage­inducible α (GADD45A) serves a vital role in myocardial injury induced by I/R. The present study aimed to explore the role and mechanisms of GADD45A in cardiac microvascular endothelial cells (CMEC)­I/R injury in vivo and in vitro. An I/R injury rat model and a hypoxia/reoxygenation (H/R) cellular model were established, and myocardial tissues were collected for GADD45A detection, 2,3,5­triphenyltetrazolium chloride staining, H&E staining, and dual staining of CD31 and TUNEL. Serum was also collected for the analysis of creatine kinase and lactate dehydrogenase in I/R rats following GADD45A silencing. Additionally, the protein expression levels of CD31, phosphorylated­endothelial nitric oxide synthase (p­eNOS), endothelin­1 (ET­1), JNK, p38 MAPK, STAT3 and VEGF were assessed by western blotting. The JNK and p38 MAPK activator, anisomycin, and the JAK2­STAT3 pathway inhibitor, AG490, were used to determine the involvement of JNK/p38 MAPK pathway and STAT3/VEGF pathway. GADD45A was highly expressed in I/R injury rat and cell models. GADD45A silencing reduced the ischemic area and improved myocardial pathological damage in vivo. Furthermore, the levels of CD31 and p­eNOS were increased, whereas ET­1 was decreased by GADD45A silencing in the I/R injury rats. Mechanistically, GADD45A silencing reduced JNK/p38 MAPK expression but activated STAT3/VEGF expression. GADD45A silencing inhibited H/R­induced viability reduction and apoptosis through MAPK signaling and suppressed angiogenesis via STAT3/VEGF in H/R­induced CMECs. Overall, GADD45A ameliorated apoptosis and functional injury of CMECs via the JNK/p38 MAPK and STAT3/VEGF pathways.

NADH dehydrogenase subunit 1/4/5 promotes survival of acute myeloid leukemia by mediating specific oxidative phosphorylation.

Acute myeloid leukemia (AML) is a type of hematological malignancy caused by uncontrolled clonal proliferation of hematopoietic stem cells. The special energy metabolism mode of AML relying on oxidative phosphorylation is different from the traditional 'Warburg effect'. However, its mechanism is not clear. In the present study, it was demonstrated that the mRNA expression levels of NADH dehydrogenase subunit 1, 4 and 5 (ND1, ND4 and ND5) were upregulated in AML samples from The Cancer Genome Atlas database using the limma package in the R programming language. Reverse transcription­quantitative PCR and ELISA were used to verify the upregulation of ND1, ND4 and ND5 in clinical samples. Pan­cancer analysis revealed that the expression of ND1 was upregulated only in AML, ND2 was upregulated only in AML and thymoma, and ND4 was upregulated only in AML and kidney chromophobe. In the present study, it was demonstrated that silencing of ND1/4/5 could inhibit the proliferation of AML cells in transplanted tumor of nude mice. Additionally, it was found that oxidative phosphorylation and energy metabolism of AML cells were decreased after silencing of ND1/4/5. In conclusion, the present study suggested that ND1/4/5 may be involved in the regulation of oxidative phosphorylation metabolism in AML as a potential cancer­promoting factor.

Delayed Implantation Induced by Letrozole in Mice.

Implantation timing is critical for a successful pregnancy. A short delay in embryo implantation caused by targeted gene ablation produced a cascading problem in the later stages of the pregnancy. Although several delayed implantation models have been established in wild mice, almost none of them is suitable for investigating the early delay's effects on the late events of pregnancy. Here, we report a new delayed implantation model established by the intraperitoneal administration of letrozole at 5 mg/kg body weight on day 3 of pregnancy. In these mice, initiation of implantation was induced at will by the injection of estradiol (E2). When the estradiol (3 ng) was injected on day 4 of pregnancy (i.e., without delay), the embryo implantation restarted, and the pregnancy continued normally. However, 25 ng estrogen caused compromised implantation. We also found that 67% of the female mice could be pregnant normally and finally gave birth when the estradiol injection (3 ng) was on day 5 of pregnancy (i.e., 1-day delay). Most failed pregnancies had impaired decidualization, decreased serum progesterone levels, and compromised angiogenesis. Progesterone supplementation could rescue decidualization failure in the mice. Collectively, we established a new model of delayed implantation by letrozole, which can be easily applied to study the effect and mechanisms of delay of embryo implantation on the progression of late pregnancy events.

New prognostic factors and scoring system for patients with acute myeloid leukemia.

Acute myeloid leukemia (AML) is a malignant disease originating from myeloid hematopoietic stem or progenitor cells. It is important to identify molecules associated with the prognosis of AML and conduct an individual risk assessment for different patients. In the present study, the RNA expression profile of 132 patients with AML and 337 healthy individuals were downloaded from the University of California Santa Cruz Xena and the Genotype-Tissue Expression project databases. Differentially expressed mRNA (DEmRNA) transcripts between normal blood and AML blood were identified. Among these, prognosis-associated signature mRNA molecules were screened using univariate Cox and least absolute shrinkage and selection operator regression. A total of four genes, namely, family with sequence similarity 124 member B (FAM124B), 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL), myeloperoxidase (MPO) and purinergic receptor P2Y1 (P2RY1), were identified using multivariate Cox regression analysis and were used to construct a prognostic scoring system. Moreover, the expression levels of HPDL and MPO were higher in the samples with high immunity scores and estimate scores (sum of stromal score and immune score), compared with those with low scores. Reverse transcription-quantitative PCR and western blot analysis were used to confirm the upregulation of the four candidate genes in AML cell lines as well as in clinical AML samples. In summary, the present study identified a novel mRNA-based prognostic risk scoring system for patients with AML. The four genes used in this scoring system may also play an important role in AML.

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.

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.

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.

Synergistic regulation of longitudinal and transverse relaxivity of extremely small iron oxide nanoparticles (ESIONPs) using pH-responsive nanoassemblies.

Extremely small iron oxide nanoparticles (ESIONPs), as a kind of the special T1 magnetic resonance imaging (MRI) contrast agent that can provide T1 contrasting enhancement since their magnetically disordered shells are dominant compared to their magnetic cores and have powerful potential for constructing stimuli-responsive contrast agents (CAs) to realize precise the tumor diagnosis with high specificity and sensitivity. The stimuli-responsive function of ESIONPs-based CAs can be directly endowed through the synergistic regulation of the longitudinal and transverse relaxivity (r1 and r2) of ESIONPs. However, the systematical investigation for the synergistic regulation of r1 and r2 of ESIONPs is quite lacking. Herein, based on the relaxivity theories, three kinds of ESIONPs-based nanoassemblies with pH-responsiveness were designed and constructed to explore the possibility of various synergistic regulations on r1 and r2. When three kinds of ESIONPs-based nanoassemblies were converted to dissociated ones under a weak acid environment, ESIONPs micelle could realize a synergistic regulation of the single r2 decrease along with the stable r1, while gold nanoparticles-ESIONPs (AuNPs-ESIONPs) vesicle could provide a synergistic regulation comprising the single r1 increase along with the stable r2, and ESIONPs vesicle could offer a synergistic regulation involving the r2 decrease together with the r1 increase. Moreover, all the synergistic regulations on r1 and r2 were efficient strategies to fabricate ESIONPs-based CAs with the stimuli-responsive function. These systematic and feasible synergistic regulations of r1 and r2 may guide and promote the development of ESIONPs-based stimuli-responsive CAs for the highly sensitive and specific tumor diagnosis.

Dual-Stimuli-Responsive Multifunctional Gd2Hf2O7 Nanoparticles for MRI-Guided Combined Chemo-/Photothermal-/Radiotherapy of Resistant Tumors.

The design and synthesis of a novel generation of a nanoscaled platform with imaging-guided therapy remain a real challenge. It can not only improve the imaging sensitivity of tumor tissues for guiding all kinds of treatments but also reduce the harm for healthy tissues. Here, polydopamine (PDA), polyethylene glycol (PEG), and c(RGDyK) peptide (RGD)-modified and cisplatin-loaded Gd2Hf2O7 nanoparticles (Gd2Hf2O7@PDA@PEG-Pt-RGD NPs) are designed for magnetic resonance imaging (MRI)-guided combined chemo-/photothermal-/radiotherapy of resistant tumors. The as-prepared NPs display high relaxivity (r1 = 38.28 mM-1 s-1) as an MRI contrast agent because of their ultrasmall size and surface modification with polyacrylic acid and PDA. Gd2Hf2O7@PDA@PEG-Pt-RGD NPs exhibit pH and NIR dual-stimuli responsiveness for cisplatin release. Based on competent NIR absorption and high X-ray attenuation efficiency, Gd2Hf2O7@PDA@PEG-Pt-RGD NPs show potential photothermal effect by exposing to an 808 nm NIR laser and significantly improve the generation of reactive oxygen species after X-ray radiation. Combined chemo-/photothermal-/radiotherapy can effectively treat the resistant A549R cells, providing the enhanced therapeutic efficiency to cancer tissues and the reduced side effect to healthy tissues. Furthermore, Gd2Hf2O7@PDA@PEG-Pt-RGD NPs present no obvious toxicity during the treatment, which demonstrates the potential as an efficient MRI-guided combined chemo-/photothermal-/radiotherapy nanoplatform for drug-resistant tumors.

Extremely Small Iron Oxide Nanoparticle-Encapsulated Nanogels as a Glutathione-Responsive T1 Contrast Agent for Tumor-Targeted Magnetic Resonance Imaging.

Activatable magnetic resonance imaging (MRI) contrast agents that can be selectively stimulated at a tumor region are urgently demanded to realize the efficient and accurate diagnosis of cancers. Here, extremely small iron oxide nanoparticles (ESIONPs) modified with citric acid (ESIONPs-CA) are encapsulated in disulfide-cross-linked poly(carboxybetaine methacrylate) (poly(CBMA)) nanogels, and a cyclo[Arg-Gly-Asp-d-Tyr-Lys] (c(RGD)) ligand is further introduced to obtain ESIONP-packaged poly(CBMA) nanogels equipped with tumor-targeted c(RGD) (ICNs-RGD). On the basis of the transformation of the clustered ESIONPs into dispersed ones induced by the reducing glutathione (GSH), ICNs-RGD can complete the conversion from a T2 contrast agent to a T1 one, realizing the selective activation of the T1 contrasting effect. The GSH-dependent MRI signal conversion of ICNs-RGD is feasible in the tumor cell and tissue. Moreover, ICNs-RGD exhibits obvious targeting specificity and favorable biocompatibility. In the MRI experiments of tumor-bearing mice, benefiting from the stimuli-responsiveness toward GSH and targeting specificity, the T1 contrasting effect of tumor tissues can be selectively enhanced after the intravenous injection of ICNs-RGD. Therefore, tumor-targeted ICNs-RGD with a switchable MRI signal derived from the activation of GSH is a potential contrast agent for the efficient and precise tumor diagnosis in the clinic.

Fusiform-Like Copper(II)-Based Metal-Organic Framework through Relief Hypoxia and GSH-Depletion Co-Enhanced Starvation and Chemodynamic Synergetic Cancer Therapy.

The therapeutic effect of traditional chemodynamic therapy (CDT) agents is severely restricted by their weakly acidic pH and glutathione (GSH) overexpression in the tumor microenvironment. Here, fusiform-like copper(II)-based tetrakis(4-carboxy phenyl)porphyrin (TCPP) nanoscale metal-organic frameworks (nMOFs) were designed and constructed for the first time (named PCN-224(Cu)-GOD@MnO2). The coated MnO2 layer can not only avoid conjugation of glucose oxidase (GOD) to damage normal cells but also catalyzes the generation of O2 from H2O2 to enhance the oxidation of glucose (Glu) by GOD, which also provides abundant H2O2 for the subsequent Cu+-based Fenton-like reaction. Meanwhile, the Cu2+ chelated to the TCPP ligand is converted to Cu+ by the excess GSH in the tumor, which reduces the tumor antioxidant activity to improve the CDT effect. Next, the Cu+ reacts with the plentiful H2O2 by enzyme catalysis to produce a toxic hydroxyl radical (•OH), and singlet oxygen (1O2) is synchronously generated from combination with Cu+, O2, and H2O via the Russell mechanism. Furthermore, the nanoplatform can be used for both TCPP-based in vivo fluorescence imaging and Mn2+-induced T1-weighted magnetic resonance imaging. In conclusion, fusiform-like PCN-224(Cu)-GOD@MnO2 nMOFs facilitate the therapeutic efficiency of chemodynamic and starvation therapy via combination with relief hypoxia and GSH depletion after acting as an accurate imaging guide.

Tumor Microenvironment-Responsive and Catalytic Cascade-Enhanced Nanocomposite for Tumor Thermal Ablation Synergizing with Chemodynamic and Chemotherapy.

Chemodynamic therapy (CDT) is considered as a promising nanocatalytic therapeutic strategy for cancer because of its specific response toward the tumor microenvironment (TME). Improving the efficiency of this kind of reactive oxygen species (ROS)-mediated therapy is still a formidable challenge. Herein, we integrate CDT with other therapeutic methods together to enhance anticancer effects via overcoming robust ROS defensive mechanisms and hypoxia in cancer cells. The biocompatible and biodegraded nanoplatform (HMnO2-DOX-GOD-HA) has been constructed on the basis of hollow MnO2 nanoparticles loaded with chemotherapeutics doxorubicin (DOX) and glucose oxide (GOD) and further decorated with hyaluronic acid (HA) for targeting tumor cells. We demonstrated that HMnO2-DOX-GOD-HA is not only able to deplete glutathione (GSH) to disturb the redox balance but also release Mn2+ to initiate the magnetic resonance imaging signal and induce Fenton reaction happening. Meanwhile, GOD-induced glucose oxidation and HMnO2-catalyzed O2 generation facilitate hypoxia relief and enhance toxic hydroxyl radical (•OH) production for CDT efficiency promotion. Upon 808 nm laser irradiation, cancer-killing efficiency can be notably increased by photothermally enhanced ion and drug release and thermal ablation. This work offers a paradigm to design a TME-responsive and imaging-guided synergistic strategy for hypoxia tumors based on GSH depletion and catalytic cascade-enhanced CDT, thermal ablation, and chemotherapy.

Construction of Bi/phthalocyanine manganese nanocomposite for trimodal imaging directed photodynamic and photothermal therapy mediated by 808 nm light.

The current conventional photo-therapeutic agents often show low therapy efficacy because of their single treatment model, the limited penetration depth of excitation light and hypoxia in the tumor microenvironment (TME). Herein, a new type of phthalocyanine manganese (MnPcE4) photosensitizer with strong NIR absorption was designed and fabricated for the first time, and was used to modify pure Bi nanomaterials to obtain an intelligent multifunctional Bi/MnPcE4 nanocomposites. The Mn2+ in the Bi/MnPcE4 nanocomposite could catalyze H2O2 to generate O2, thus helping to overcome TME hypoxia and enhancing the photodynamic therapy (PDT) efficacy. Further, the nanocomposites showed excellent T1-weighted MRI performance. Our novel use of a pure metal Bi core, offers lower toxicity, higher CT imaging performance, and a photothermal therapy (PTT) effect triggered by 808 nm near infrared (NIR) laser. Moreover, in vivo fluorescence imaging (in vivo FL) vividly showed that the nanocomposite rapidly accumulates in tumor sites due to the enhanced permeability and retention (EPR) effect and metabolized in the organs. The presence of Bi enables the use of these nanocomposites as a CT contrast agent, and the Mn content enables them to be used in MRI. This triple imaging ability implies that our nanocomposites have a high potential for use in imaging directed tumor therapy.

The cisplatin-induced lncRNA PANDAR dictates the chemoresistance of ovarian cancer via regulating SFRS2-mediated p53 phosphorylation.

As a component of p53-dependent lncRNA (long non-coding RNA), PANDAR (the promoter of CDKN1A antisense DNA damage activated RNA) participates in the epigenetic regulation in human cancer. However, the involvement of PANDAR in cancer chemoresistance is unknown. In this study, we report that PANDAR serves as a negative regulator of cisplatin sensitivity in human ovarian cancer via PANDAR-SRFS2-p53 feedback regulation in nuclear. Our data showed that among the drugs commonly used in ovarian cancer therapy, cisplatin induces higher levels of PANDAR compared with doxorubicin and paclitaxel. We also proved that PANDAR exhibited higher expression in cisplatin-resistant ovarian cancer tissues and cells, compared with cisplatin-sensitive ones, and this expression pattern depends on wild-type p53 (wt-p53), not mutant-p53 (mt-p53). In vitro and in vivo, PANDAR overexpression improved cell survival rate and tumor growth in response to cisplatin, while depletion of PANDAR leads to a reduced tumor growth. Further investigation revealed that PANDAR-reduced cisplatin sensitivity was likely or partly due to the PANDAR-binding protein SFRS2 (arginine/serine-rich 2), a splicing factor with the ability to negative regulate p53 and its phosphorylation at Serine 15 (Ser15). This feedback regulation of PANDAR-SFRS2-p53 leads to a reduced transactivation of p53-related pro-apoptotic genes, such as PUMA (p53-upregulated modulator of apoptosis). In addition, in platinum-treated patients with relapsed ovarian cancer, resistant period was positively correlated with the expression of PANDAR and SFRS2, and inversely associated with expression of p53-Ser15 and PUMA in these clinical tissues. Last but not least, the role of PANDAR in chemoresistance was confirmed in patients with ovarian cancer. These findings reveal a novel regulatory maneuver of cancer cells in response to chemostress, and might shed light on overcoming cisplatin resistance in ovarian cancer.

Geometrical Confinement of Gadolinium Oxide Nanoparticles in Poly(ethylene glycol)/Arginylglycylaspartic Acid-Modified Mesoporous Carbon Nanospheres as an Enhanced T1 Magnetic Resonance Imaging Contrast Agent.

A new strategy for designing contrast agents (CAs) based on geometrical confinement will become a competent way to improve the relaxivity of CAs. Herein, a magnetic resonance imaging (MRI) nanoconstruct is fabricated through loading Gd2O3 nanoparticles into mesoporous carbon nanospheres, followed by conjugation of poly(ethylene glycol) (PEG) and the c(RGDyK) peptide (Gd2O3@OMCN-PEG-RGD), which could prolong the blood circulation half-life as well as improve the tumor-targeting ability. As a result, the Gd2O3@OMCN-PEG-RGD exhibits an outstandingly high relaxivity ( r1 = 68.02 mM-1 s-1), which is ∼5.3 times higher than that of Gd2O3 nanoparticles ( r1 = 12.74 mM-1 s-1). Afterward, both the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test and H&E staining show that the Gd2O3@OMCN-PEG-RGD has wonderful biocompatibility in vitro and in vivo. Moreover, the in vivo MR images indicate that the Gd2O3@OMCN-PEG-RGD could accumulate in the tumor region more rapidly than Gd2O3@OMCN-PEG. This study presents a facile method to fabricate an MRI CA with excellent T1 contrast ability based on geometrical confinement and excellent biocompatibility, which could act as an optimal contender for sensitive in vivo tumor imaging with outstanding targeting ability.

Biodegradable Nanoglobular Magnetic Resonance Imaging Contrast Agent Constructed with Host-Guest Self-Assembly for Tumor-Targeted Imaging.

Gadolinium-based macromolecular magnetic resonance imaging (MRI) contrast agents (CAs) have attracted increasing interest in tumor diagnosis. However, their practical application is potentially limited because the long-term retention of gadolinium ion in vivo will induce toxicity. Here, a nanoglobular MRI contrast agent (CA) PAMAM-PG- g-s-s-DOTA(Gd) + FA was designed and synthesized on the basis of the facile host-guest interaction between ß-cyclodextrin and adamantane, which initiated the self-assembly of poly(glycerol) (PG) separately conjugated with gadolinium chelates by disulfide bonds and folic acid (FA) molecule onto the surface of poly(amidoamine) (PAMAM) dendrimer, finally realizing the biodegradability and targeting specificity. The nanoglobular CA has a higher longitudinal relaxivity ( r1) than commercial gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA), showing a value of 8.39 mM-1 s-1 at 0.5 T, and presents favorable biocompatibility on the observations of cytotoxicity and tissue toxicity. Furthermore, MRI on cells and tumor-bearing mice both demonstrate the obvious targeting specificity, on the basis of which the effective contrast enhancement at tumor location was obtained. In addition, this CA exhibits the ability of cleavage to form free small-molecule gadolinium chelates and can realize minimal gadolinium retention in main organs and tissues after tumor detection. These results suggest that the biodegradable nanoglobular PAMAM-PG- g-s-s-DOTA(Gd) + FA can be a safe and efficient MRI CA for tumor diagnosis.

Oxaloacetate Ameliorates Chemical Liver Injury via Oxidative Stress Reduction and Enhancement of Bioenergetic Fluxes.

Chemical injury is partly due to free radical lipid peroxidation, which can induce oxidative stress and produce a large number of reactive oxygen species (ROS). Oxaloacetic acid is an important intermediary in the tricarboxylic acid cycle (TCA cycle) and participates in metabolism and energy production. In our study, we found that oxaloacetate (OA) effectively alleviated liver injury which was induced by hydrogen peroxide (H2O2) in vitro and carbon tetrachloride (CCl4) in vivo. OA scavenged ROS, prevented oxidative damage and maintained the normal structure of mitochondria. We further confirmed that OA increased adenosine triphosphate (ATP) by promoting the TCA production cycle and oxidative phosphorylation (OXPHOS). Finally, OA inhibited the mitogen-activated protein kinase (MAPK) and apoptotic pathways by suppressing tumor necrosis factor-α (TNF-α). Our findings reveal a mechanism for OA ameliorating chemical liver injury and suggest a possible implementation for preventing the chemical liver injury.