Functional Upgrading of an Organo-Ir(III) Complex to an Organo-Ir(III) Prodrug as a DNA Damage-Responsive Autophagic Inducer for Hypoxic Lung Cancer Therapy.

The efficiency of nitrogen mustards (NMs), among the first chemotherapeutic agents against cancer, is limited by their monotonous mechanism of action (MoA). And tumor hypoxia is a significant obstacle in the attenuation of the chemotherapeutic efficacy. To repurpose the drug and combat hypoxia, herein, we constructed an organo-Ir(III) prodrug, IrCpNM, with the composition of a reactive oxygen species (ROS)-inducing moiety (Ir-arene fragment)-a hypoxic responsive moiety (azo linker)-a DNA-alkylating moiety (nitrogen mustard), and realized DNA damage response (DDR)-mediated autophagy for hypoxic lung cancer therapy for the first time. Prodrug IrCpNM could upregulate the level of catalase (CAT) to catalyze the decomposition of excessive H2O2 to O2 and downregulate the expression of the hypoxia-inducible factor (HIF-1α) to relieve hypoxia. Subsequently, IrCpNM initiates the quadruple synergetic actions under hypoxia, as simultaneous ROS promotion and glutathione (GSH) depletion to enhance the redox disbalance and severe oxidative and cross-linking DNA damages to trigger the occurrence of DDR-mediated autophagy via the ATM/Chk2 cascade and the PIK3CA/PI3K-AKT1-mTOR-RPS6KB1 signaling pathway. In vitro and in vivo experiments have confirmed the greatly antiproliferative capacity of IrCpNM against the hypoxic solid tumor. This work demonstrated the effectiveness of the DNA damage-responsive organometallic prodrug strategy with the microenvironment targeting system and the rebirth of traditional chemotherapeutic agents with a new anticancer mechanism.

Consolidating Organometallic Complex Ir-CA Empowers Mitochondria-Directed Chemotherapy against Resistant Cancer via Stemness and Metastasis Inhibition.

Cancer treatment has faced severe obstacles due to the smart biological system of cancer cells. Herein, we report a three-in-one agent Ir-CA via attenuation of cancer cell stemness with the down-regulated biomarker CD133 expression from the mitochondria-directed chemotherapy. Over 80% of Ir-CA could accumulate in mitochondria, result in severe mitochondrial dysfunctions, and subsequently initiate mitophagy and cell cycle arrest to kill cisplatin-resistant A549R cells. In vitro and in vivo antimetastatic experiments demonstrated that Ir-CA can effectively inhibit metastasis with down-regulated MMP-2/MMP-9. RNA seq analysis and Western blotting indicated that Ir-CA also suppresses the GSTP1 expression to decrease the intracellular Pt-GS adducts, resulting in the detoxification and resensitization to cisplatin of A549R cells. In vivo evaluation indicated that Ir-CA restrains the tumor growth and has minimal side effects and superior biocompatibility. This work not only provides the first three-in-one agent to attenuate cancer cell stemness and simultaneously realize anticancer, antimetastasis, and conquer metallodrug resistance but also demonstrates the effectiveness of the mitochondria-directed strategy in cancer treatment.

Iridium(III)-Based PD-L1 Agonist Regulates p62 and ATF3 for Enhanced Cancer Immunotherapy.

Anti-PD-L1 immunotherapy, a new lung cancer treatment, is limited to a few patients due to low PD-L1 expression and tumor immunosuppression. To address these challenges, the upregulation of PD-L1 has the potential to elevate the response rate and efficiency of anti-PD-L1 and alleviate the immunosuppression of the tumor microenvironment. Herein, we developed a novel usnic acid-derived Iridium(III) complex, Ir-UA, that boosts PD-L1 expression and converts "cold tumors" to "hot". Subsequently, we administered Ir-UA combined with anti-PD-L1 in mice, which effectively inhibited tumor growth and promoted CD4+ and CD8+ T cell infiltration. To our knowledge, Ir-UA is the first iridium-based complex to stimulate the expression of PD-L1 by explicitly regulating its transcription factors, which not only provides a promising platform for immune checkpoint blockade but, more importantly, provides an effective treatment strategy for patients with low PD-L1 expression.

Stretchable Tb-Tb Distance Regulates the Piezofluorochromic Behavior of Chiral Tb(III)-MOF upon Compression.

Luminescent chiral Tb-MOF microcrystals with the Tb2(COO)4 subunit indicated strong green mechano-luminescence under compression. Furthermore, piezofluorochromic behavior in the diamond anvil cell was observed, with the intensity tendency of decreasing-increasing-decreasing and a shortened lifetime upon compression, due to the reversible stretchable Tb-Tb interactions. The Tb-Tb distance upon compression was refined through in situ high-pressure X-ray absorption spectra, which was consistent with the tendency of the piezofluorochromic intensity. In situ high-pressure UV-vis absorption spectra, Fourier transform infrared spectra, and powder X-ray diffraction demonstrated the full recovery of Tb-MOF after over 10 GPa compressions due to the semiflexible ligand. This work not only provided an ultrastable Tb-MOF but also illustrated the relationship of the piezofluorochromic behavior with the detailed structural transformation for the first time.

Advantages of contrast-enhanced CT combined with DCE-MRI in identifying malignant parotid tumor.

OBJECTIVE: To study the value of single and combined application of contrast-enhanced computerized tomography (CT) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in diagnosing parotid tumors. METHODS: In this retrospective study, 82 patients with parotid gland mass who received contrast-enhanced CT and DCE-MRI detection in The First People's Hospital of Huzhou from March 2018 to March 2022 were selected as study subjects. The nature of the parotid tumor was pathologically examined following the surgery. According to the pathological diagnosis results, these patients were divided into a benign group (n=59) and a malignant group (n=23). All patients underwent contrast-enhanced CT and DCE-MRI examinations. The diagnostic accuracy rates of contrast-enhanced CT, DCE-MRI and the joint application were compared. The CT or MRI images of benign and malignant parotid tumors were compared. The correlation of parotid cancer with the imaging features was analyzed. Diagnostic efficiency of contrast-enhanced CT, DCE-MRI and joint application for parotid cancer was assessed by receiver operating characteristic curve. RESULTS: In terms of diagnostic accuracy, there was a significant difference between contrast-enhanced CT combined with DCE-MRI and contrast-enhanced CT alone (95.12% vs. 81.71%, P<0.001), and between the joint application and DCE-MRI alone (95.12% vs. 86.58%, P=0.004). Results of contrast-enhanced CT revealed statistical differences in tumor boundary, tumor size, calcification and cystic degeneration between benign and malignant tumors (P<0.05), but no obvious difference in lymph node enlargement between the two groups. MRI results showed that there were differences in the DCE-MRI time-signal intensity curve and ADC value between benign and malignant tumors (P<0.05). Correlation analysis results showed that the malignant tumor was negatively correlated with tumor boundary, calcification, cystic degeneration and ADC values, and it was positively correlated with DCE-MRI time-signal intensity curve and tumor size (P<0.05). Analysis of diagnostic efficacy showed that contrast-enhanced CT combined with DCE-MRI were significantly better than contrast-enhanced CT alone in terms of sensitivity and specificity (P<0.05). Moreover, the sensitivity of the joint application was also higher than that of MRI alone, while no obvious difference was found for specificity between joint application and MRI alone. The areas under the curve of contrast-enhanced CT combined with DCE-MRI in diagnosing malignant parotid tumor was remarkably greater than that of CT or MRI alone (P<0.05). CONCLUSION: Contrast-enhanced CT combined with DCE-MRI can significantly improve the diagnostic accuracy, sensitivity and specificity for malignant parotid tumor, and the joint application was able to point out the direction of targeted surgical treatment plans.

Pollution Characteristics and Spatial Distribution of Heavy Metals in Coal-Bearing Sandstone Soil: A Case Study of Coal Mine Area in Southwest China.

Soil pollution in coal mining areas is a serious environmental problem in China and elsewhere. In this study, surface and vertical profile soil samples were collected from a coal mine area in Dazhu, Southwestern China. Microscopic observation, concentrations, chemical speciation, statistical analysis, spatial distribution, and risk assessment were used to assess heavy metal pollution. The results show that the weathering of coal-bearing sandstone and mining activities substantially contributed to soil pollution. The concentrations of Fe, Ni, Cu, Zn, Mn, Cd, Hg, and Pb exceeded their background values. Cd caused the most intense pollution and was associated with heavily-extremely contaminated soils. The residual fraction was dominant for most metals, except Cd and Mn, for which the reducible fraction was dominant (Cd: 55.17%; Mn: 81.16%). Zn, Ni, Cd, and Cu presented similar distribution patterns, and Hg and As also shared similar distribution characteristics. Factor 1 represented anthropogenic and lithologic sources, which were affected by mining activities; Factor 2 represented anthropogenic sources, e.g., fertilizers and traffic pollution; and Factor 3 represented the contribution of metals from soil-forming parent material. More than half of the study area had high pollution risk and was not suitable for vegetable cultivation.

Performance of Ir(III)-Based Anticancer Agents in the Treatment of Cisplatin-Resistant Cancer Cells.

The resistance of cancer cells to cisplatin has dramatically blocked the further application of this drug in practical treatment settings. The generation of cisplatin resistance is a complex physiological process, and several mechanisms have been reported for this. New metal-based agents with distinct anticancer mechanisms are still highly desired. In this concept article, we describe Ir(III)-based anticancer agents and their underlying anticancer mechanisms, which could inhibit the proliferation of cisplatin-resistant tumors. This work could be beneficial in developing more effective Ir(III)-based agents to combat cisplatin resistance.

An Event-Related Potentials Study on the Syntactic Transfer Effect of Late Language Learners.

This study explored the syntactic transfer effect of the non-local subject-verb agreement structure with plural head noun after two intensive phases of input training with event-related potentials (ERP). The non-local subject-verb agreement stimuli with the plural head nouns, which never appeared in training phases, were used for the stimuli. A total of 26 late L1-Chinese L2-English learners, who began to learn English after a critical period and participated in our previous experiments, were asked back to take part in this syntactic transfer experiment. Results indicated that a significant ERP component P600 occurred in the key region (the verb) of the sentences with syntactic violations in the experimental group, but none occurred in the control group. This demonstrated that there was a significant transfer effect of the input training. The possible theoretical explanation was provided and also the malleability of the late L2 learners was discussed.

Effect of multiple factors on the adsorption of Cd in an alluvial soil from Xiba, China.

The effects of organic matter, free Fe oxides and Mn oxides in an alluvial soil on adsorption of Cd were studied through selective chemical extraction and adsorption experiments. Compared to untreated soil, after H2O2 treatment for removal of organic matter and NH2OH·HCl treatment for removal Mn oxides, the distribution coefficient (Kd) decreased by a maximum of 25.2% and 64.1%, respectively. After dithionite-citrate-bicarbonate treatment for removal of free Fe oxides, Kd increased by 1670.2%. After increasing the solution pH from 2 to 3, Kd increased by 2842.1%, whereas after increasing the solution pH from 3 to 7, the adsorption tended stabilize. As the ionic strength increased from 0.001 M to 0.1 M NaNO3, Kd gradually decreased, whereas at the same ionic strength, Kd decreased as the initial concentration of Cd increased. The effects of different background electrolytes on Cd adsorption was as follows: Ca2+ > Mg2+ > K+ > Na+ for cations and Cl- ≈ SO42- > NO3- for anions. The adsorption capacity of Cd increased as the increased of temperature, and it's a spontaneous endothermic process. The pseudo second-order rate model described the process of Cd adsorption well.